Histotripsy Method and System

Abstract

Described herein are methods, systems, and computer storage media for improved treatment of biological tissue, such as skin, muscle, fat, nerves, or glands, or components thereof. In some embodiments, a method of treating biological tissue in a patient includes disposing ultrasonic pressure waves within a target volume of a region of the biological tissue, using the pressure waves to form a cavitation bubble cloud within the target volume, and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate within the target volume. In some embodiments, the homogenate is fractionated into non-homogenized or healthy biological tissue within the region of the biological tissue.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority pursuant to 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 443,209, filed February 3, 2023, which is incorporated herein by reference in its entirety. [Technical Field]

[0002] The techniques described herein relate generally to the treatment of living tissue (eg, skin, muscle, fat, nerves, and / or glands), and more particularly to the treatment of tissue using ultrasound. [Background technology]

[0003] Histotripsy refers to the application of acoustic energy (e.g., provided by a focused ultrasound beam) to a target volume within a patient's body. Histotripsy can be used, among other things, to ablate biological tissue by initiating, maintaining, and controlling acoustic cavitation within a desired location within the body. Such histotripsy ablation of tissue generally occurs through "homogenization" or "fractionation" of the tissue, which means that the tissue is broken down into a suspension of cellular fragments and components using acoustic energy.

[0004] Current systems and methods for histotripsy may have one or more drawbacks, including in clinical applications. For example, some systems and methods for histotripsy may present safety concerns or be less efficient. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a therapeutic need for improved systems and methods of treatment using histotripsy that can provide both efficacy and reduced risk of adverse events, such as over- or under-treatment of target tissues and / or damage to healthy tissues. [Means for solving the problem]

[0006] This Summary is provided to introduce selected concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used solely as an aid in determining the scope of the claimed subject matter.

[0007] Embodiments of the technology described herein are directed to treating biological tissues, for example, in patients, which achieve improved safety and clinical outcomes. The disclosed technology can be used to treat various types of biological tissues in patients (such as human or animal patients) in need of treatment, including, for example, skin tissue, muscle tissue, fat tissue, nerve tissue, cartilage, other connective tissues (e.g., fibrous septa), and / or glands, and / or components of skin, muscle, fat, nerves, glands, and / or other tissues on or within the patient's body. In some non-limiting cases, for example, the disclosed technology can be used to treat individual nerves or skin glands, such as sweat glands, sebaceous glands, and / or hair follicles.

[0008] Generally, methods, systems, and computer storage media are described herein for improved treatment of biological tissue (e.g., skin, muscle, fat, nerves, cartilage, connective tissue, and / or glands, or components thereof). In some embodiments, a method of treating a patient's biological tissue (e.g., skin, muscle, fat, nerves, cartilage, connective tissue, and / or glands) and / or components thereof includes placing ultrasonic pressure waves within a target volume of a region of the biological tissue to form a cavitation bubble cloud within the target volume using the pressure waves, and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate or homogenize the tissue or to generate homogenized tissue within the target volume, e.g., through repeated expansion and contraction of the bubbles.

[0009] Furthermore, the aforementioned process can be repeated multiple times to treat a region of biological tissue. That is, multiple distinct target volumes can be treated sequentially or in parallel with the ultrasonic pressure waves. In some embodiments, for example, the methods described herein further include positioning the pressure waves within a second target volume of the region of biological tissue to form a second cavitation bubble cloud within the second target volume. The second cavitation bubble cloud can be maintained within the second target volume for a second period of time sufficient to generate a homogenate or homogenize the tissue or produce homogenized tissue. As described above, the second target volume can be different from the first target volume in such embodiments, and additional target volumes can also be treated. Thus, in some cases, the methods described herein further include disposing pressure waves within n additional target volumes in the region of biological tissue to form n additional cavitation bubble clouds within the n additional target volumes, and maintaining the n additional cavitation bubble clouds within the n additional target volumes for n additional time periods sufficient to generate a homogenate or homogenize the tissue or generate homogenized tissue within the n additional target volumes. The n additional target volumes are different from each other and from the first target volume and the second target volume, and n may be any integer consistent with the technical objectives of the present disclosure, e.g., an integer between 1 and 1,000,000. It should be further understood that each target volume can represent or correspond to a different treatment site, and in some cases, the ultrasound beam / pressure wave can be moved from one location to another as the method of treatment is performed, for example, by using mechanical translation, mechanical rotation, electronic steering and focusing, or any combination thereof, of the ultrasound beam / pressure wave or its source relative to the patient or treatment region.

[0010] The methods described herein may also, in some cases, include or be characterized by certain additional steps or features (or combinations of additional steps and features) that may provide one or more advantages over other methods. For example, in some embodiments, the homogenate or homogenized tissue (of the first, second, and / or nth target volumes) is fractionated within non-homogenized or healthy biological tissue. In still other embodiments, the pressure wave of the methods described herein is a complex pressure wave that includes high-frequency and low-frequency component waves.

[0011] In some embodiments, at least one cycle of the high frequency component wave is positioned in the trough of at least one cycle of the low frequency component wave, e.g., in some embodiments, such a positioning may increase the likelihood of reaching a target cavitation pressure without requiring significant thermal energy.

[0012] Also, a high-frequency component wave may be placed in the compression portion of a low-frequency component wave. For example, in some embodiments, this may be used when or after cavitation is generated. In some embodiments, placing a high-frequency component wave in the compression portion of a low frequency may reduce the amplitude required to maintain a bubble cloud. In some embodiments, placing a high-frequency component wave in the compression portion of a low frequency may increase the chance of impact scattering. In some embodiments, placing a high-frequency component wave in the compression portion of a low frequency may increase the tendency to generate harmonics, and therefore, may generate more nonlinear heating in the intended treatment area.

[0013] Furthermore, in some examples of the methods described herein, maintaining a cavitation bubble cloud within the target volume does not deliver a thermal dose to tissue within the target volume sufficient to cause degeneration, coagulation, or apoptosis, whereas in other embodiments, maintaining a cavitation bubble cloud within the target volume delivers a thermal dose to tissue within the target volume sufficient to produce degeneration, coagulation, or apoptosis.

[0014] Additionally, in some embodiments, disposing pressure waves within the target volume includes irradiating the target volume with an ultrasound beam, which may be a pulsed ultrasound beam. Additionally, a focal point of the ultrasound beam may be disposed within the target volume. Additionally, in some instances, the focal point of the ultrasound beam is a point focus. In other instances, the focal point of the ultrasound beam is a line focus. In still other embodiments, the focal point includes or consists of a combination of simultaneous line and point foci, or a combination of multiple simultaneous line or point foci.

[0015] Additionally, in some embodiments, the methods described herein further include detecting the onset of cavitation, which is time t=0 when a cavitation bubble cloud begins to form within the target volume. In some embodiments, the onset of cavitation may be detected based on acoustic cavitation emissions. In some embodiments, a transducer is used as the detection device. In some cases, the same transducer used to transmit the ultrasound pulse may be used as the detection device. In other embodiments, the transducer used as the detection device (e.g., to detect acoustic cavitation emissions) is different from the transducer used to apply the ultrasound pulse. In some cases, a transducer can be used to transmit another ultrasound pulse toward a region where cavitation may be occurring and detect backscatter from this region as a means of identifying the presence of cavitation. This transducer may also be the same or different from the treatment transducer.

[0016] Systems for treating a region of biological tissue (e.g., skin, muscle, fat, nerve, cartilage, connective tissue, and / or glands) are also described herein. In some embodiments, a system for treating a patient's biological tissue comprises one or more ultrasound transducers for providing ultrasonic pressure waves to a target volume within the region of biological tissue and forming a cavitation bubble cloud within the target volume. In some cases, the system may include a tissue acquisition system (e.g., vacuum), which may include one or more transducers that generate ultrasonic pressure waves within the acquired tissue volume and generate a cavitation bubble cloud as described herein. The system may also comprise a control device for maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate within the target volume. Furthermore, in some cases, the systems described herein may comprise one or more electromagnetic radiation sources for providing one or more electromagnetic radiation beams to the region of biological tissue for imaging, thermal ablation, and / or delivery of non-ablative energy to the region of biological tissue. Furthermore, systems according to the present disclosure may also comprise one or more microneedles for providing treatment to the skin in some embodiments. In some embodiments, a system according to the present invention may be a "hybrid" system that includes multiple features as described above (e.g., one or more microneedles, a detection transducer, a treatment transducer, additional ultrasound components such as additional transducers, a tissue acquisition system, a control device, a radiation source such as electromagnetic radiation, and / or a broadband light therapy system).

[0017] In yet another aspect, improved computer devices and storage media are also described herein. For example, computer storage media storing computer-usable instructions are described herein. Such computer storage media can be used to perform the methods and / or use the systems described herein. For example, in some cases, a computer storage medium stores computer-usable instructions that, when used by one or more computing devices, cause the one or more computing devices to treat a region of biological tissue of a patient, the operations including: disposing ultrasonic pressure waves within a target volume of the region of biological tissue to form a cavitation bubble cloud within the target volume; and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate within the target volume, the homogenate being fractionated within non-homogenized biological tissue within the region of biological tissue. In some examples, the operations further include forming a thermal coagulation zone around the target volume. In still other cases, the operations include placing pressure waves within n additional target volumes in the region of biological tissue to form n additional cavitation bubble clouds within the n additional target volumes, and maintaining the n additional cavitation bubble clouds within the n additional target volumes for n additional time periods sufficient to produce homogenates within the n additional target volumes, wherein the n additional target volumes are different from each other and from the first target volume, and n is an integer between 1 and 1,000,000.

[0018] Additional objects, advantages, and novel features of the present invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention.

[0019] Aspects of the technology presented herein are described in detail below with reference to the accompanying drawings, which are not necessarily drawn to scale. [Brief explanation of the drawings]

[0020] [Figure 1A] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 1B] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 2A] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 2B] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 3A] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 3B] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 4A] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 4B] FIG. 1 illustrates a pattern of homogenized regions produced by one embodiment of the method described herein. [Figure 5A] 1 illustrates a composite pressure wave according to one embodiment described herein. [Figure 5B] FIG. 5B shows an enlarged portion of FIG. 5A. [Figure 6A] 1 illustrates a composite pressure wave according to one embodiment described herein. [Figure 6B] FIG. 6B shows an enlarged portion of FIG. 6A. [Figure 7] 1 is a plan view of a composite ultrasound transducer or array according to one embodiment described herein; [Figure 8] 1 is a plan view of a first target volume and a second target volume to be treated according to an embodiment described herein; [Figure 9A] FIG. 1 illustrates a system according to one embodiment described herein. [Figure 9B] FIG. 1 illustrates a system according to another embodiment described herein. [Figure 10] 1 illustrates steps of a method according to one embodiment described herein. [Figure 11]A block diagram of an exemplary computing environment and / or device architecture in which some implementations of the present technology may be employed. [Figure 12] Cross section of a bowl-shaped ultrasonic transducer [Figure 13A] 1 is a perspective view of an ultrasound transducer according to one embodiment described herein; [Figure 13B] 1 is a cross-sectional view of an ultrasound transducer according to one embodiment described herein; [Figure 14A] 1 illustrates a cylinder corresponding to an ultrasonic transducer according to one embodiment described herein. [Figure 14B] 1 illustrates a cylinder corresponding to an ultrasonic transducer according to one embodiment described herein. [Figure 14C] 1 is a perspective view of an ultrasound transducer according to one embodiment described herein; [Figure 14D] 1 is a cross-sectional view of an ultrasound transducer according to one embodiment described herein; [Figure 14E] 1 is a perspective view of an ultrasound transducer according to one embodiment described herein; [Figure 15] 1 is a cross-sectional view of an ultrasound transducer according to one embodiment described herein; [Figure 16] 1 is a cross-sectional view of an ultrasound transducer according to one embodiment described herein; [Figure 17] 1 is a perspective view of an ultrasound transducer according to one embodiment described herein; [Figure 18] 1 is a perspective view of a reflector of an apparatus according to one embodiment described herein; [Figure 19] 1 is a perspective view of an apparatus according to one embodiment described herein; [Figure 20] 1 is a perspective view of an apparatus according to one embodiment described herein; [Figure 21] 1 is a perspective view of an apparatus according to one embodiment described herein; [Figure 22] 1 is a perspective view of an apparatus according to one embodiment described herein; [Figure 23] 1 is a perspective view of an apparatus according to one embodiment described herein; [Figure 24] 1A-1C illustrate various transducer designs according to embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0021] The subject matter of the embodiments of the present disclosure is specifically described herein to satisfy statutory requirements. However, the description itself is not intended to limit the scope of the patent. Rather, the inventors contemplate that the claimed subject matter may also be embodied in other ways, including different steps or combinations of steps similar to those described herein, in conjunction with other current or future technologies. Furthermore, although the terms "step" and / or "block" may be used herein to refer to different elements of the method employed, these terms should not be construed to imply a particular order between or among the various steps disclosed herein, unless the order of individual steps is explicitly described.

[0022] Accordingly, the embodiments described herein can be more readily understood by reference to the following detailed description, examples, and drawings. However, the elements, features, devices, and methods described herein are not limited to the specific embodiments presented in the detailed description, examples, and drawings. It should be recognized that the exemplary embodiments herein are merely illustrative of the principles of the present invention. Numerous modifications and adaptations will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0023] Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a range stated as "1.0 to 10.0" should be considered to include any and all subranges beginning with a minimum value of 1.0 or greater and ending with a maximum value of 10.0 or less, such as, for example, 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9. All ranges disclosed herein should also be considered to include the endpoints of the range unless expressly stated otherwise. For example, a range "between 5 and 10" or "from 5 to 10" or "5 to 10" should generally be considered to include the endpoints 5 and 10, as well as any and all subranges subsumed within these values.

[0024] Additionally, the term "up to" is used in reference to an amount or quantity; it is understood that the amount is at least a detectable amount or quantity. For example, a substance present in an amount "up to" a particular amount can be present in an amount from a detectable amount up to and including the particular amount.

[0025] Additionally, in any disclosed embodiment, the terms "substantially," "approximately," and "about" can be substituted with "within [a percentage] of" what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.

[0026] Unless the context of a particular use clearly requires otherwise, the article "a" or "an" should also be understood to refer to "at least one."

[0027] In one aspect, methods of treating a human or animal patient or biological tissue of a human or animal patient are described herein. In some embodiments, such methods include disposing ultrasonic pressure waves within a target volume of a region of biological tissue, using the pressure waves to form a cavitation bubble cloud within the target volume, and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate or homogenize the tissue, or to generate homogenized tissue within the target volume. Furthermore, the foregoing process can be repeated as many times as desired to treat the region of biological tissue. That is, multiple mutually distinct target volumes can be treated with ultrasonic pressure waves as described herein. In some embodiments, for example, the methods described herein further include disposing pressure waves within a second target volume of the region of biological tissue and forming a second cavitation bubble cloud within the second target volume. The second cavitation bubble cloud can be maintained within the second target volume for a second period of time sufficient to generate a homogenate or homogenize the tissue, or to generate homogenized tissue within the second target volume. As explained above, in such embodiments, the second target volume may be different from the first target volume, and the additional target volumes may also be treated. Thus, in some cases, the methods described herein further include disposing pressure waves within n additional target volumes in the region of biological tissue to form n additional cavitation bubble clouds within the n additional target volumes, and maintaining the n additional cavitation bubble clouds within the n additional target volumes for n additional time periods sufficient to produce a homogenate or homogenize the tissue, or to produce homogenized tissue within the n additional target volumes. The n additional target volumes are different from each other and from the first and second target volumes, where n is any integer not inconsistent with the technical objectives of the present disclosure, e.g., an integer between 1 and 1,000,000.It should further be understood that each target volume may indicate or correspond to a different treatment site, and in some cases the ultrasound beam / pressure waves may be moved from one location to another as the method of treatment is performed.

[0028] For clarity and convenience, when a target volume (or tissue thereof) or multiple target volumes (or tissues thereof) are described in this disclosure, it should be understood that the target volume may be a first, second, or nth target volume, unless the context requires otherwise. Furthermore, as described later herein, one or more target volumes treated by the methods described herein may collectively define a treatment pattern or collectively provide a single treatment of a related region of biological tissue.

[0029] The pressure waves can be disposed within the target volume (or a plurality of or a series of target volumes) in any manner consistent with the technical objectives of the present disclosure. For example, in some implementations, disposing the pressure waves within the target volume includes irradiating the target volume with an ultrasound beam. The ultrasound beam can have any characteristics and can be provided in any manner consistent with the technical objectives of the present disclosure. In some cases, for example, the ultrasound beam is a pulsed ultrasound beam. Such a beam can be provided by one or more ultrasound transducers, for example, one or more high-intensity focused ultrasound (HIFU) transducers, in some examples. Furthermore, in some embodiments described herein, the focus of one or more ultrasound beams is disposed within the target volume (or a plurality of or a series of target volumes). Furthermore, the focus of the ultrasound beam described herein can have any size and shape consistent with the technical objectives of the present disclosure. In some cases, for example, the focus of the ultrasound beam is a point focus (i.e., a three-dimensional focus, such as x, y, and z). The point focus can be symmetric or asymmetric in x, y, and / or z. In other words, the size of the region within the "focus" where the pressure exceeds the required cavitation threshold can vary in x, y, and z.

[0030] In other examples, as further described below in the examples, the focus of the ultrasound beam is a line focus or a two-dimensional (e.g., x, z, or y, z) focus. In this case, the ultrasound beam can have at least one dimension that is not mechanically or electronically focused. The ultrasound beam focus described herein can also be a compound focus, e.g., a focus in both x, z and y, z, and the focal depth (z) of the two foci can vary. Such a configuration allows for the creation of a line focus with slightly higher focal gain than designs with only x, z or y, z foci, allowing the cavitation threshold to be exceeded. Furthermore, it should be understood that the focus described herein can be described in one or more dimensions using Cartesian coordinates (x, y, z) or other coordinate systems, such as spherical coordinates (rho, theta, phi) or cylindrical coordinates (rho, theta, z), and the coordinate system is not particularly limited.

[0031] In some embodiments, the methods described herein can include detecting the onset of cavitation, as described in more detail below. Detecting the onset of cavitation allows a user to select or optimize one or more system parameters. The onset of cavitation is defined as time t=0, at which a cavitation bubble cloud begins to form in the target volume. The point at which bubbles begin to form (e.g., time t=0) can be detected in any manner consistent with the technical objectives of the present disclosure. For example, in some cases, the onset of cavitation is detected based on acoustic cavitation emissions (similar to "listening" for bubbles). Any detection device consistent with the objectives of the present invention can be used to detect acoustic cavitation emissions and / or the onset of cavitation. In some embodiments, a transducer can be used as a detection device for detecting the onset of cavitation and / or for detecting acoustic cavitation emissions. In some embodiments, the same transducer used to apply ultrasound pulses to the target volume is also used to detect acoustic cavitation emissions and / or for detecting the onset of cavitation. In other embodiments, the transducer used as the detection device (e.g., to detect acoustic cavitation emissions) is different from the transducer used to apply the ultrasound pulse. In some cases, a transducer can be used to transmit another ultrasound pulse toward an area where cavitation may be occurring and detect backscatter from this area as a means of identifying the presence of cavitation. This transducer may be the same or different from the treatment transducer. In some embodiments, the onset of cavitation can be detected simultaneously with the emission of the interrogation pulse. In some embodiments, the detection device can also be used at other points in the process to determine the progression of cavitation.That is, in some embodiments, the methods described herein involve applying ultrasound or interrogation pulses to a target volume while simultaneously detecting acoustic cavitation emissions at the onset of cavitation and / or throughout treatment.

[0032] It is also possible for the methods or systems described herein to use multiple ultrasound beams and / or multiple ultrasound transducers or other ultrasound sources. For example, in some embodiments, multiple ultrasound beams are used to provide a single focal point or overlapping focal regions. In some such cases, for example, the multiple ultrasound beams are arranged so that the respective foci of the ultrasound beams overlap and / or have an interference pattern that provides a "compound" focal point that differs in size, shape, and / or peak negative pressure compared to the foci of any individual ultrasound beams used to form the "compound" focal point. In some cases, these techniques can further increase the achievable pressure at the intended focal point and / or change the shape of the pressure field, exceeding the associated cavitation threshold.

[0033] Additionally, in some cases, the pressure waves (or "compound" foci of combinations of pressure waves) of the methods described herein have peak negative pressures of 10 MPa to 100 MPa, 10 MPa to 80 MPa, 10 MPa to 75 MPa, 10 MPa to 50 MPa, 20 MPa to 100 MPa, 20 MPa to 80 MPa, 20 MPa to 50 MPa, or 20 MPa to 40 MPa. It should be further appreciated that the aforementioned peak negative pressures can be achieved through coherent summation of pressure waves, or reflections from bubble clouds, reflections from bone, and / or reflections from coagulation regions, as further described herein. Furthermore, in some embodiments, the peak negative pressures of the pressure waves used in the methods described herein are selected based on the target tissue type. For example, in some instances, the peak negative pressure can be selected according to the data in Table 1 below, taken from Vlaisavljevich et al., “Histotripsy-Induced Cavitation Cloud Initiation Thresholds in Tissues of Different Mechanical Properties,” IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol. 61, No. 2, February 2014 (hereinafter “Vlaisavljevich”). [Table 1]

[0034] Furthermore, the methods described herein can be used to treat any type of biological tissue consistent with the objectives of the present disclosure. Treatment can be for aesthetic, medical, or other purposes. For example, in some cases, the biological tissue includes skin tissue, adipose tissue, connective tissue, muscle tissue, nerve tissue, cartilage, and / or glandular tissue. Furthermore, in some embodiments, the methods described herein are used to target adipocytes and / or other causes of cellulite. In other cases, the methods described herein are used to target tissue components that cause skin laxity. In some embodiments, the methods described herein are used to target: lentigines or "port wine stain" tissue; tissue components that cause wrinkles or creases; tissue containing ink from tattoos for tattoo removal purposes; glands or other tissues that cause hyperhidrosis; tissues that cause incontinence; glands or other tissues that cause excessive salivation; scar tissue; and / or seborrheic keratosis. In some embodiments, the methods described herein provide a cosmetic effect, a medical or therapeutic effect, or a combination of the foregoing. In some instances, the methods described herein provide aesthetic benefits but do not provide medical or therapeutic benefits. As will be understood by those skilled in the art, aesthetic benefits are benefits that are primarily related to the patient's appearance, with no or minimal benefit to the patient's physical health, or without treating the patient's disease or disorder. In contrast, medical or therapeutic benefits are benefits that are primarily related to the treatment of a patient's disease, illness, or other condition, not necessarily related to the patient's appearance, but instead primarily related to physical health.

[0035] The methods described herein may also include or be characterized by certain additional steps or features (or combinations of additional steps and features) that may, in some cases, provide one or more advantages over other methods. For example, in some embodiments, a homogenate or homogenized tissue (of the first, second, and / or nth target volumes) is fractionated within non-homogenized or healthy tissue within a region of biological tissue. As will be understood by those skilled in the art, a homogenate may refer to a suspension of cell fragments and cellular components obtained when tissue is homogenized, such as occurs in histotripsy. In some embodiments of the methods described herein, the ratio (by mass or volume) of homogenate (or homogenized or damaged tissue) to non-homogenized (or healthy) tissue within a region of biological tissue is 10:1 to 1:10, 5:1 to 1:5, 2:1 to 1:2, 1:1 to 1:10, or 1:2 to 1:5. That is, the damage or tissue injury produced by the methods described herein corresponds to mechanical injury points (MIPs) embedded within healthy viable tissue. Thus, a 1:1 ratio indicates that 50% of the total area, volume, or mass within a tissue space (or region of living tissue) is damaged or homogenized; similarly, a 1:2 ratio indicates that 33% of the total area, volume, or mass within a tissue space is damaged or homogenized. In some cases, the percentage of non-homogenized (or healthy) tissue within a treatment area of ​​biological tissue is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, 30%-99%, 30%-90%, 40%-99%, 40%-90%, 50%-99%, 50%-90%, 60%-99%, 60%-90%, 70%-99%, or 70%-90% based on the total mass or volume of tissue within the treatment area. It should be further understood that the aforementioned ratios or percentages can be achieved through a single treatment (or single "session" or treatment / provider visit) or multiple separate, consecutive treatments (or "sessions" or treatments / provider visits). For example, in some cases, up to "n" separate, consecutive treatments, sessions, or visits are used, where "n" can be an integer ranging from 2 to 1000.Furthermore, when the above overall ratios or percentages are achieved through multiple treatments (or sessions or visits), successive treatments (or sessions or visits) may be separated by a particular or average period, such as one day, one week, or one month. That is, in some cases, the methods described herein are carried out over or by the course of regular treatments (or sessions or visits) that may occur daily, weekly, monthly, or some other frequency.

[0036] MIPs embedded within healthy viable tissue can also be described in terms of a "composite" structure based on the connectivity between individual or distinct MIPs and / or distinct regions of healthy tissue. For example, the compartmentalized tissue patterns described herein may be referred to as "AB" complexes, where "A" refers to the number of different spatial directions (e.g., represented by the x-, y-, and z-axes) along which it is possible to "travel" from one MIP to another without "crossing the boundary" of, encountering, or crossing into healthy tissue. Thus, a three-dimensional "column" of MIPs in a three-dimensional "sea" of healthy tissue has an "A" value or connectivity score of 1 (movement greater than 2 mm is only possible along the height or long axis of the column without encountering healthy tissue). Similarly, "B" refers to the number of different spatial directions (e.g., represented by the x-, y-, and z-axes) in which it is possible to "travel" from one region of healthy tissue to another distinct region of healthy tissue without having to "cross the boundary" of the MIP, encounter a MIP, or traverse within a MIP. Thus, using the same example of a "column" of MIPs arranged in a "sea" of healthy tissue, a movement of more than 2 mm is possible in three directions (x, y, and z), so the "B" value or "B" connectivity score is 3. Figures 1-4, further described below, illustrate various "AB" composite patterns. In composite structures, such as those illustrated in Figures 1-4 or other patterns of MIPs, the average distance (center-to-center or edge-to-edge) between individual regions of non-homogenized or healthy tissue can, in some embodiments, be 5 mm or less in at least one dimension, e.g., 0.2-5 mm. In some cases, the average distance between regions of non-homogenized or healthy tissue is 5 mm or less in two or all three dimensions.

[0037] Therefore, it should be clearly understood that a "fractionated" homogenate or homogenized tissue within a non-homogenized or healthy tissue corresponds to the result of modifying or treating only a portion of the overall tissue space (or region of biological tissue). It should be noted that in this context, "fractionated" does not mean "homogenized." In some literature related to histotripsy, the verb "to fractionate" a tissue is used to mean "homogenizing" the tissue. This use of "fraction" should be distinguished from the use of "fractionated" in this application.

[0038] The treated area of ​​biological tissue generally does not refer to the entire treated organism (e.g., the entire human patient or the entire body of the human patient), but instead refers to a specific treated area of ​​the organism, e.g., about 1000 cm 2 or 1000cm 3 It should be further understood to refer to the area or volume of a patient's skin, muscle, fat, nerves, or glands having the following areas or volumes:

[0039] Furthermore, in some embodiments, the methods described herein do not mechanically disrupt large tissue regions (e.g., tumors), such as tissue regions having a size in at least one dimension (e.g., in the x, y, or z directions) of 10 mm or greater. In some cases, the methods described herein do not mechanically disrupt or homogenize regions of tissue having a size in one, two, or three dimensions greater than 10 mm. That is, the methods described herein do not necessarily mechanically disrupt or homogenize all tissue within a relatively large volume, e.g., a volume having a size in one, two, or three dimensions of 10 mm or greater.

[0040] The methods described herein may, in some cases, produce localized lesions (or homogenized regions), allowing healthy tissue to grow into the space created by the lesions (homogenization) produced by the methods. For example, in some instances, the homogenized or homogenized tissue region or area (or lesion) has a size in one, two, or three dimensions that is less than 5 mm, less than 3 mm, less than 2 mm, or less than 1 mm. However, it should be understood that the methods described herein may produce lesions (or homogenized regions) that individually have small sizes (as described above), but that, when combined, have a total or combined size that exceeds the specific size limits listed in this paragraph. That is, multiple lesions (or homogenized regions) may be formed by the methods described herein in a single treatment session, and these multiple lesions (or homogenized regions) may be generated at spatial locations relative to each other that provide a coherent overall treatment of a tissue region, while none of the lesions (or homogenized regions) has a size greater than the maximum size listed in this paragraph.

[0041] Furthermore, the target volume of the methods described herein can be located at any desired location within an organism or human patient, for example, the target volume can have an average or median depth below the skin or outer surface of the organism or human patient. In some cases, a target volume described herein has an average or median depth of 0.1 to 20 mm, 0.1 to 15 mm, 0.1 to 10 mm, 0.1 to 5 mm, 0.1 to 3 mm, 0.1 to 2 mm, 0.2 to 20 mm, 0.2 to 15 mm, 0.2 to 10 mm, 0.2 to 5 mm, 0.2 to 3 mm, 0.2 to 2 mm, 0.5 to 20 mm, 0.5 to 15 mm, 0.5 to 10 mm, 0.5 to 5 mm, 0.5 to 3 mm, 0.5 to 2 mm, 0.7 to 20 mm, 0.7 to 15 mm, 0.7 to 10 mm, 0.7 to 5 mm, 0.7 to 3 mm, 0.7 to 2 mm, 1 to 20 mm, 1 to 15 mm, 1 to 10 mm, 1 to 5 mm, 1 to 3 mm, or 1 to 2 mm below the skin or outer surface of an organism. Additionally, in some implementations, it is also possible to vary the depth or position of the target volume (or, as further described herein, a series of n target volumes) during the course of performing the methods described herein.

[0042] Additionally, in some cases, the type and / or density of the lesion (or homogenized region) produced by the methods described herein may be selected based on one or more clinically relevant factors, such as one of the following factors, one or more of the following factors, or all of the following factors: location of the target volume (e.g., depth), tissue type, subject / patient demographics (e.g., age, skin type), and clinical end goal (e.g., wrinkle reduction, skin tightening, body contouring).

[0043] 1-4 show some non-limiting examples of lesion (or homogenization region) patterns or characteristics that may be provided according to the methods described herein. While the lesions shown in Figures 1-4 appear to have repeating patterns, this is not a requirement, as the treatment may have different periodicities in the x, y, and z directions (or two of these dimensions), or may be aperiodic in one, two, or all three dimensions.

[0044] Referring to the drawings, FIG. 1 illustrates a pattern of MIPs or homogenization regions 101 produced by the methods described herein, according to one embodiment of the present disclosure. More specifically, FIG. 1A shows the pattern of MIPs or homogenization regions 101 in a coronal plane (e.g., the xy plane). FIG. 1B shows the same pattern of MIPs or homogenization regions 101 in a cross-sectional plane (e.g., the xz plane). The pattern of MIPs or homogenization regions 101 shown in FIG. 1 corresponds to one to three complex fractionation regions of biological tissue. In the embodiment of FIG. 1, the MIPs or homogenization regions 101 define an array of cylindrical MIPs or homogenization regions. The MIPs or homogenization regions 101 are surrounded by or embedded within an "ocean" of healthy tissue 102.

[0045] Similarly, FIG. 2 illustrates a pattern of MIPs or homogenization regions 201 generated by the method described herein according to one embodiment of the present disclosure. Specifically, FIG. 2A illustrates a pattern of MIPs or homogenization regions 201 in a coronal plane (e.g., the xy plane). FIG. 2B illustrates the same pattern of MIPs or homogenization regions 201 in a cross-sectional plane (e.g., the xz plane). The pattern of MIPs or homogenization regions 201 illustrated in FIG. 2 corresponds to a 2-2 complex fractionation region of biological tissue. In the embodiment of FIG. 2, the MIPs or homogenization regions 201 define an array of rectangular columnar MIPs or homogenization regions. The MIPs or homogenization regions 201 are surrounded by or embedded within healthy tissue 202.

[0046] FIG. 3 illustrates a pattern of MIP or homogenization regions 301 generated by the methods described herein, according to one embodiment of the present disclosure. More specifically, FIG. 3A illustrates the pattern of MIP or homogenization regions 301 in a coronal plane (e.g., the xy plane). FIG. 3B illustrates the same pattern of MIP or homogenization regions 301 in a cross-sectional plane (e.g., the xz plane), with the cross-section taken along the xz line shown in FIG. 3A. The pattern of MIP or homogenization regions 301 illustrated in FIG. 3 corresponds to a 3-1 complex fractionation region of biological tissue. In the embodiment of FIG. 3, the MIP or homogenization regions 301 define a periodic grid of MIP or homogenization regions. The MIP or homogenization regions 301 are surrounded by or embedded within healthy tissue 302.

[0047] FIG. 4 illustrates a pattern of MIP or homogenization regions 401 generated by the method described herein, according to one embodiment of the present disclosure. More specifically, FIG. 4A illustrates the pattern of MIP or homogenization regions 401 in a coronal plane (e.g., the xy plane). FIG. 4B illustrates the same pattern of MIP or homogenization regions 401 in a cross-sectional plane (e.g., the xz plane), with the cross-section taken along the xz line shown in FIG. 4A. The pattern of MIP or homogenization regions 401 illustrated in FIG. 4 corresponds to a 3-1 complex fractionation region of biological tissue. In the embodiment of FIG. 4, the MIP or homogenization regions 401 define a periodic grid of MIP or homogenization regions. The MIP or homogenization regions 401 are surrounded by or embedded within healthy tissue 402.

[0048] Furthermore, in some embodiments, the ultrasonic pressure waves used in the methods described herein are modified after the initial formation of the cavitation bubble cloud. For example, in some cases, cavitation or the cavitation bubble cloud is generated or initiated using relatively high-amplitude ultrasound waves or pulses, and then maintained with lower-amplitude ultrasound waves or pulses. Thus, in some implementations, the methods described herein include reducing the amplitude or power of the ultrasonic pressure waves after the cavitation bubble cloud is formed, while still maintaining the cavitation bubble cloud. The maintained cavitation bubble cloud may, in some cases, be referred to as a "reduced-amplitude" cavitation bubble cloud. In this aspect (using a reduced-amplitude cavitation bubble cloud), the methods described herein may be more efficient and may generate less heating or thermal energy in a biological environment. A reduced-amplitude cavitation bubble cloud may also provide better safety performance and a reduced likelihood of pre- and / or post-focal tissue heating. Furthermore, in some cases, the reduced-amplitude bubble cloud may be maintained at the same spatial location after the initial formation of the bubble cloud, or the bubble cloud may be subsequently moved to another location either through mechanical or electronic steering or focusing of pressure waves at a lower amplitude. In such cases where the focal point of the reduced-amplitude bubble cloud is moved after formation, the movement speed is sufficiently slow to maintain the bubble cloud at the reduced amplitude. In some embodiments, the target or allowable movement speed may be related to the size of the bubble cloud (including the direction of movement), the intensity distribution within the ultrasound beam, the pulse repetition frequency (PRF), and / or the time required to homogenize the tissue. Without being bound by theory, in some embodiments, the reduced-amplitude bubble cloud appears to generate a pressure field that creates a low-pressure zone throughout the treated area.Tracking of the bubble cloud can be achieved, for example, by moving the bubble cloud in the direction of transducer movement, for example, by using a low pressure gradient to cause the bubble cloud to move as the ultrasound beam is moved from one spatial location to another. In some embodiments, the amplitude, PRF, and / or other conditions or variables can be manipulated or varied until a bubble is detected. In some embodiments, the bubble cloud may be moved spatially at a rate that promotes cloud maintenance.

[0049] In some embodiments of the methods described herein, pressure waves can be placed in n target volumes of n regions of biological tissue to form n cavitation bubble clouds within the n target volumes. The n cavitation bubble clouds can be maintained for a predetermined or desired period of time while the transducer is moved (i.e., translated or rotated). The transducer can be moved manually, mechanically, electronically, or by any other available means. In some embodiments, the transducer is moved (i.e., rotated or translated) sufficiently to generate a homogenate or homogenized tissue while maintaining a bubble cloud that tracks the transducer's movement. As a result, it is also possible to generate homogenized or homogenized tissue within another of the n target volumes. In such embodiments, the bubble cloud can be "dragged" through the tissue, generating homogenized or homogenized tissue in multiple target volumes and / or multiple regions of the biological tissue along the path of the bubble cloud.

[0050] Additionally, in some embodiments of the methods described herein, a reduced amplitude cavitation bubble cloud can be used throughout the majority of the duration of the methods described herein (e.g., throughout the majority of the total treatment time). For example, in some cases, a reduced amplitude bubble cloud can be used for at least 80%, at least 70%, or at least 60% of the total time of performing a method or treatment described herein (or applying ultrasound). In some examples, a reduced amplitude bubble cloud can be used for 10-99%, 10-90%, 10-80%, 10-70%, 20-99%, 20-90%, 20-85%, 20-80%, 20-70%, 20-60%, 20-50%, 30-99%, 30-90%, 30-85%, or 30-95% of the total time of performing a method or treatment described herein (or applying ultrasound). %, 23-80%, 30-70%, 30-60%, 30-50%, 40-99%, 40-90%, 40-85%, 40-80%, 40-70%, 40-60%, 50-99%, 50-90%, 50-85%, 50-80%, 50-70%, 60-99%, 60-90%, 60-85%, 60-80%, or 60-70%.

[0051] Furthermore, in some embodiments, the pressure waves used in the methods described herein are composite pressure waves including a high-frequency component wave (or waveform) and a low-frequency component wave (or waveform). The high-frequency and low-frequency waves may have the same or different functions, including imaging, detection, and / or treatment. For example, in some embodiments, the high-frequency component wave may be used for imaging and / or detection, and the low-frequency component wave may be used for treatment. In other embodiments, the high-frequency component wave may be used for treatment, and the low-frequency component wave may be used for imaging and / or detection. In still other embodiments, both frequencies may be used for treatment. Any combination of functions for the high-frequency and low-frequency waves that is not inconsistent with the technical objectives of the present disclosure may be employed without departing from the scope of the present invention.

[0052] FIG. 5A illustrates such a composite pressure wave. Referring to FIG. 5A, composite pressure wave 500 includes a high-frequency component wave 501 and a low-frequency component wave 502, and it is understood that the terms "high" and "low" are relative to one another (i.e., a "high" frequency has a higher frequency than a "low" frequency). FIG. 5B illustrates an enlarged portion of FIG. 5A. As shown in FIG. 5A, five cycles of a 10 MHz wave (high-frequency component wave 501) are superimposed on five cycles of a 250 kHz wave (low-frequency component wave 502). Other combinations of high-frequency and low-frequency component waves are possible. Specifically, while FIGS. 5A and 5B illustrate the low frequency being longer in time than the high frequency, other combinations are possible without departing from the scope of the present disclosure. For example, in some embodiments, the high frequency may be longer than the low frequency.

[0053] As noted above, in some embodiments, high and low frequencies may serve multiple purposes. In some embodiments, high frequencies may be used to maintain a bubble cloud, detect Doppler shifts from movement, and / or detect bubble vibrations through scattering. Any combination of therapeutic, imaging, and / or detection operations may be employed without departing from the basic spirit and scope of the present invention.

[0054] In some embodiments, the low frequency may be 1 / 50, 1 / 40, 1 / 30, 1 / 20, 1 / 10, 1 / 5, 1 / 2, and / or any value or ratio between these values. These ratios represent the ratio of two frequencies, with the first number being the low frequency and the second number being the high frequency. For example, comparing a low frequency of 500 kHz to a high frequency of 10 MHz, the ratio is 1 / 20 (500 kHz / 10,000 kHz). The larger this ratio, the easier it is for the high frequency to fit within the trough or peak of the low frequency. In some embodiments, the peak amplitude of the low frequency may be 1 / 50, 1 / 40, 1 / 30, 1 / 20, 1 / 10, 1 / 5, 1 / 2, or 0.99 of the required cavitation threshold. Cavitation thresholds are tissue-dependent. Cavitation thresholds for various tissues are disclosed in Tables 1 and 4 herein.

[0055] In some embodiments, the low frequency wave may be generated from the same transducer as the high frequency wave, while in other embodiments, the low frequency wave may be generated from a different transducer than the high frequency wave. In some embodiments, the decision regarding which transducer to use to generate the low frequency wave is based on the target timing of the waveform. If the target timing of the waveform is met, the high frequency wave can be placed at the desired or target location on the low frequency wave.

[0056] 5A, the high frequency component wave "rides" the trough of the low frequency component wave. That is, the high frequency component wave is disposed or positioned within the trough of the low frequency component wave, and in some embodiments, all of the cycles of the high frequency component wave "fit within" the trough of the low frequency component wave. In other embodiments, one or more, but not all, cycles of the high frequency wave are located within the trough of at least one cycle of the low frequency wave.

[0057] With respect to the placement of high and low frequencies, in some embodiments, the high frequency component may be placed or positioned within the peak of the low frequency component wave. In some embodiments, by placing the high frequency component within the peak of the low frequency component wave, all cycles of the high frequency component wave "fit" within the peak of the low frequency component wave. Thus, in some embodiments, the high frequency component wave "rides" on the peak of the low frequency component. Furthermore, in some embodiments, such "riding" can result in enhanced support and / or enhanced nonlinear heating of the bubble cloud, especially when bubbles are already at the focus.

[0058] Furthermore, in some implementations, the cycles of the high frequency component waves may be spaced apart from one another such that at least one cycle of the high frequency component wave is located within a trough (or multiple troughs) of at least one cycle of the low frequency component wave. In some embodiments, one or more cycles of the high frequency component wave are located in a trough of one or more cycles of the low frequency component wave. In some embodiments, the high frequency component wave is located in a trough of the low frequency component wave.

[0059] For example, as shown in FIG. 6A, one cycle of a high-frequency component wave can be placed within each trough of a low-frequency component wave. In some embodiments, this allows the lower frequency to achieve a higher frequency. Furthermore, in some such embodiments, cycles of the high-frequency component wave are separated by one or more "wait" cycles. In some embodiments, the wait time can promote greater growth and / or shrinkage of cavitation bubbles, leading to more efficient and / or safer treatment.

[0060] Referring to FIG. 6A, a composite pressure wave 600 includes multiple cycles of a high-frequency component wave 601 and multiple cycles of a low-frequency component wave 602. FIG. 6B shows an enlarged portion of FIG. 6A. As shown in FIG. 6A, five cycles of a 2 MHz wave (low-frequency component wave 602) are superimposed with five cycles of a 10 MHz wave (high-frequency component wave 601). Specifically, one cycle of the high-frequency component wave 601 is placed in each trough of the illustrated low-frequency component wave 602, and the high-frequency cycles 601 are separated by a time equivalent to a 2 MHz cycle (i.e., adjacent cycles of the high-frequency component wave are separated by the frequency of the low-frequency component wave, which in this example is 2 MHz). A component pressure wave such as that shown in FIG. 6A allows the multiple troughs of the low-frequency component wave to include one or more high-frequency component waves that each "ride" on the low-frequency component wave. FIG. 6B shows an enlarged portion of FIG. 6A.

[0061] In some embodiments of the methods described herein, a high-frequency component wave or waveform can also be placed in a compression portion of a lower-frequency component wave or waveform of a composite wave, and it should be understood that the compression portion of a wave or waveform is generally the portion of the wave or waveform where the transformation of energy at the fundamental frequency is converted into harmonics. Providing such a composite wave as described herein can, in some implementations, provide one or more advantages. For example, in some such cases, the probability of generating mechanical bubbles, maintaining a bubble cloud, and / or generating more bubbles is reduced, and the probability of generating nonlinear harmonics that increase heating near the intended treatment site is increased. Thus, in some embodiments described herein, absorption increases with frequency, and a majority of the harmonics are generated near the ultrasound focus, allowing additional heat to be generated at the focus. Furthermore, once a threshold for bubble cloud generation is reached as described herein, other advantages can be obtained by placing a high-frequency component wave in a compression portion of a lower frequency. For example, without intending to be bound by theory, pulse reversal may result from reflections from existing bubbles of the formed bubble cloud, which may help maintain the bubble cloud at a reduced intensity. It may also be possible to encourage more nonlinear heating around the bubble cloud.

[0062] In general, the high-frequency component wave and the low-frequency component wave can each have any frequency consistent with the technical objectives of the present disclosure. In some embodiments, for example, the high-frequency component wave and the low-frequency component wave have frequencies according to Equation 1:

number

[0063] Equation 1 above is based in part on the relationship or ratio between the minimum negative pressure within the burst and the maximum negative pressure within the burst. In some embodiments, since the likelihood of cavitation may depend on the negative pressure (and consequently on the effectiveness), Equation 1 can be used to determine whether a threshold pressure has been exceeded throughout the burst.

[0064] Furthermore, in some cases, f high is a preselected treatment frequency, and for reference purposes herein, a "therapeutic" frequency is a frequency selected for its therapeutic or clinical effect. A treatment frequency may also be selected for its performance attributes, such as penetration depth, beam width, etc. For example, in some embodiments, f high is between 1 MHz and 15 MHz, for example, 5 MHz. high Other values ​​of f are also possible. lOW is between 0.1 and 5 MHz, between 0.1 and 3 MHz, less than 5 MHz, less than 3 MHz, or less than 2 MHz. lOW Other values ​​of are possible.

[0065] Additionally, in some embodiments, the frequency of the high frequency component wave ("high frequency") and the frequency of the low frequency component wave ("low frequency") may be selected based on one or more of the following: a desired or preselected number of cycles of the high frequency component wave per trough of the low frequency component wave; a desired, preselected, or allowable fluctuation (said "fluctuation" being defined as the ratio of the final negative pressure in the burst to the maximum pressure); and a desired or preselected treatment frequency. Table 2 below shows some non-limiting examples of possible low frequency values ​​based on a 5 MHz high frequency (treatment frequency) for different numbers of cycles in the trough and different selections of allowable signal fluctuation. Table 2

[0066] The composite pressure wave described above can be provided in any manner consistent with the technical objectives of the present disclosure. In some cases, the composite pressure wave is provided or formed by a hybrid ultrasonic transducer or transducer array, for example, a hybrid ultrasonic transducer or array including a low-frequency transducer component and a high-frequency transducer component. In some examples, the high-frequency transducer component is positioned around or surrounds the low-frequency transducer component. One such arrangement is shown in FIG. 7, which shows a plan view of a hybrid ultrasonic transducer or array according to one embodiment described herein. Referring to FIG. 7, the hybrid ultrasonic transducer or array 700 includes a high-frequency transducer component 701 surrounding a low-frequency transducer component 702. Other structures or arrangements are possible. Specifically, the outer transducer can be a low-frequency or high-frequency transducer, and the inner transducer can be the opposite. The arrangement of the embodiment of FIG. 7 can be particularly advantageous for inflicting mechanical damage with a narrow effective width. Furthermore, while Figure 7 shows the high-frequency and low-frequency transducers co-located within the same region, in other embodiments, they may be located one or more higher above the intended target tissue so that the acoustic energy from each transducer can reach the intended target tissue coherently. For example, the high-frequency transducer may be located orthogonal to or spaced apart from the low-frequency transducer, as opposed to being physically overlapping in at least one dimension. Depending on the bandwidth and resonant behavior of the transducer, it may also be possible to use a transducer that can be excited simultaneously by both low- and high-frequency components. For example, as will be understood by those skilled in the art, broadband or dual-frequency transducers (e.g., bilayer transducers) can be designed, constructed, and used in the methods described herein.

[0067] It should be further noted that the methods described herein can provide varying levels of heating to regions of biological tissue. Controlling the thermal effects of ultrasound-based methods can provide advantages over other methods. In some cases, the methods described herein provide relatively small amounts of thermal energy. For example, in some embodiments, maintaining a cavitation bubble cloud within a target volume (or multiple or series of target volumes) does not deliver a thermal dose to the tissue within the target volume (or multiple or series of target volumes) sufficient to cause coagulation, denaturation, apoptosis, or any other type of cell death. It should be understood that denaturation refers to a permanent change in the structure of a protein, while coagulation refers to the process of converting liquid molecules to a solid or semi-solid state. Denaturation is the first step in coagulation. Coagulation is more visible than denaturation but less reversible. Apoptosis, on the other hand, refers to the process of programmed cell death and can be used to remove irreparably damaged cells from the body.

[0068] It will be understood that a thermal dose can include a total amount of heat or thermal energy (or acoustic energy converted to heat by absorption) delivered to or experienced by tissue sufficient to provide a given tissue response, such as coagulation, degeneration, or apoptosis, or a given probability of tissue death (e.g., 60% or greater). Furthermore, the thermal dose can be determined according to a bioheat function or other heating parameters. For example, in some instances, the thermal dose is based on the Arrhenius equation. Furthermore, in some embodiments, the thermal dose described herein corresponds to a total equivalent number of minutes greater than 240 at 43°C, as described in Dewhirst et al., "Thermal Dose Requirement for Tissue Effect: Experimental and Clinical Findings," Proc SPIE Int Soc Opt Eng. 2003 June 2;4954:37-. doi:10.1117 / 12.476637. Avoiding the delivery of thermal doses as described herein can, in some cases, provide safer and more effective treatments, particularly for promoting the survival and growth of healthy tissue.

[0069] In some embodiments, to limit or avoid delivery of thermal effects or thermal dose, the methods described herein use an intentionally limited duty cycle of the ultrasound pulses. For example, in some cases, the pulse duty cycle is less than 10%, less than 5%, less than 2%, or less than 1%.

[0070] Alternatively, if desired, the methods described herein can deliver a thermal dose sufficient to cause coagulation, denaturation, or apoptosis. Thus, in some cases, maintaining a cavitation bubble cloud within a target volume (or a plurality or series of target volumes) delivers a thermal dose to tissue within the target volume (or a plurality or series of target volumes) sufficient to produce coagulation, denaturation, or apoptosis. Furthermore, in some such cases, the thermal dose is sufficient to thermally ablate all or substantially all (e.g., at least 90%, at least 95%, at least 98%, or at least 99%) of the tissue within the target volume (or a plurality or series of target volumes). Furthermore, in some cases, the thermal dose is delivered before mechanical damage (or homogenization zone) is generated by the bubble cloud. In such cases, in some embodiments, delivering the thermal dose and increasing the temperature within the target volume can reduce the cavitation threshold of the target volume, allowing for the use of lower peak negative pressures. In other cases, the thermal dose is delivered after mechanical damage (or homogenization zone) is generated by the bubble cloud. In some such embodiments, delivery of a thermal dose after creation of the mechanical lesion can promote coagulation within the mechanical lesion. In yet other implementations, the methods described herein deliver a thermal dose and simultaneously create the mechanical lesion. In some such cases, without intending to be bound by theory, it is believed that the cavitation cloud locally enhances ultrasound energy absorption.

[0071] The thermal dose may be administered or delivered before, during, or after homogenization of healthy tissue. Additionally, in some cases, the methods described herein further include forming a thermal coagulation zone around the target volume, which, in some embodiments, may include homogenized tissue or a homogenate. In some embodiments, tissue denaturation, tissue coagulation, and / or apoptosis may increase acoustic attenuation of the tissue. In some embodiments, cavitation may be enhanced by thermally coagulating or denaturing the target volume in the region immediately below the treatment region. Without being bound by theory, in some embodiments, it appears that when denatured or coagulated tissue is directly below the target treatment region (i.e., directly below the region where the intended treatment, such as histotripsy, will occur), reflections may occur from such denatured or coagulated tissue, thus improving cavitation. Increasing acoustic attenuation may also be used in some embodiments to prevent propagation of acoustic energy into deeper tissue regions.

[0072] In yet other embodiments, precise delivery of thermal energy, including in combination with cavitation, can be used to generate more complex structures within a region of biological tissue. For example, in some cases, the methods described herein further include forming a thermal coagulation zone (or multiple or series of thermal coagulation zones) around a target volume (or multiple or series of target volumes) described herein. Such a thermal coagulation zone can surround or at least partially encapsulate the homogenized tissue within the target volume. In some cases, the combination of mechanical cavitation and peripheral thermal coagulation is provided using the same or different pressure waves, or using compound pressure waves, or using a series of target volumes. In some embodiments, for example, a first target volume described herein is homogenized without the delivery of a thermal dose, and a second target volume is thermally coagulated by the delivery of a thermal dose.

[0073] Furthermore, in such cases, the second target volume can surround or enclose the first target volume, as illustrated in FIG. 8 , which shows a plan view of the first and second target volumes to be treated according to one embodiment of the methods described herein. Referring to FIG. 8 , the first target volume 801 has a circular cross-section when viewed from the top (e.g., along a line perpendicular to the patient's outer surface or skin) and is generally cylindrical in shape. However, other shapes are possible. The first target volume 801 contains uncoagulated homogenate. The second target volume 802 concentrically surrounds the first target volume 801, such that the first and second target volumes 801 and 802 form concentric cylinders within the region of biological tissue. The second target volume 802 includes coagulated tissue, which may be achieved, for example, when a method described herein is performed to deliver a thermal dose to the second target volume 802, the thermal dose being sufficient to coagulate the tissue within the second target volume 802. In some embodiments, the thermal denaturation or coagulation may be limited to a surface area surrounding the bubble cloud. In some embodiments, the thermal denaturation or coagulation may occur within the treatment volume. In some embodiments, the thermal denaturation or coagulation may occur both surface area surrounding the bubble cloud and within the treatment volume.

[0074] Furthermore, in some embodiments, the methods described herein can be performed in combination with, in conjunction with, sequentially with, or in parallel with one or more other methods for treating a patient. For example, in some cases, the ultrasound-based treatment methods described herein can be used in combination with light-based treatments, such as laser-based or broadband light (BBL)-based treatments, or microneedle-based treatments. In some cases, the ultrasound-based treatment methods described herein can be used in combination with one or more of the methods and systems described in U.S. Patent Application Publication Nos. 2001 / 016732; 2019 / 125445; 2021 / 282855; U.S. Patent Nos. 6,575,964; 6,770,069; 11,071,588; 11,213,350; or 11,219,485, the contents of each of which are incorporated herein by reference in their entirety.

[0075] Referring again to the drawings, it should be understood that the steps of the methods according to the present disclosure may be performed in any manner using any system, equipment, hardware, and / or software not inconsistent with the technical objectives of the present disclosure. For example, referring to FIG. 9A, this figure illustrates aspects of a treatment system 900 according to various embodiments of the present disclosure. The treatment system 900 may include multiple devices, components, engines, and / or modules. For example, the treatment system 900 may include an “aesthetic” component, system, or subsystem 910. The treatment system 900 may also include an “ultrasound” component, system, or subsystem 920 and a “patient application” component, system, or subsystem 930. Furthermore, the system 900 may further include one or more connector components, components, systems, or subsystems 940.

[0076] It should be understood that the "aesthetic" system 910 can provide aesthetic treatments to a patient in addition to or in combination with the ultrasound treatments provided by the overall system 900. For example, in some cases, the aesthetic system 910 can provide wrinkle removal, skin tightening, body contouring, and / or other treatments separate from the histotripsy provided by the overall system 900. Thus, in some embodiments, the aesthetic system 910 comprises devices or components such as radiofrequency needle or microneedle components, laser or broadband light (BBL) components, ultrasound components distinct from the ultrasound system providing histotripsy, and / or one or more controllers or user interfaces. More specifically, in some cases, the aesthetic system 910 may include devices that irradiate biological tissue with electromagnetic radiation (e.g., a laser beam or BBL beam) for ablative, non-ablative, or other therapeutic purposes, or devices that provide chemical, electrical, mechanical, or electromechanical treatments to biological tissue, for example, using microneedles. In some embodiments, system 900 may be a "hybrid" system and include multiple features, such as one or more microneedles, a detection transducer, a treatment transducer, additional ultrasound components, e.g., additional transducers, a tissue acquisition system, a control device, a radiation source, e.g., an electromagnetic radiation source, and / or a broadband light therapy system.

[0077] The "ultrasound" system 920 of the overall system 900 can provide ultrasound for histotripsy as described herein. Accordingly, the "ultrasound" system 920 can include, among other components, one or more ultrasound transducers or other ultrasound sources for providing one or more ultrasound beams / pressure waves and one or more display devices, such as a monitor, for displaying ultrasound image results in real time. The "ultrasound" system 920 can also include one or more imaging or cavitation detection devices or subsystems, which may be a spectrophotometer or visible light (e.g., RGB) camera, a thermal or infrared (IR) camera, an optical coherence tomography (OCT) device or system, a multiphoton imaging device or system, a reflectance confocal microscopy (RCM) device or system, a wideband piezoelectric receiver, or any other imaging system consistent with the technical objectives of the present disclosure. In some embodiments, an ultrasound transducer can be used as a cavitation detection device. In some embodiments, the same transducer or transducers used to provide the ultrasound beam can also be used to detect the onset of cavitation. When the same transducer is used to provide the ultrasound beam and detect the onset of cavitation, the transducer may be configured with both a "transmit" mode (to provide and transmit the ultrasound beam) and a "receive" mode (to receive or detect acoustic cavitation emissions).

[0078] Additionally, the ultrasound system 920 may further comprise a control device (e.g., a real-time controller) capable of maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to generate a homogenate (or homogenize tissue or generate homogenized tissue) within the target volume. The control device may also control and / or regulate other components of the overall system 900, the ultrasound system 920, or another subsystem in addition to the ultrasound transducer. For example, the control device may also control the display device, imaging device, and / or additional treatment devices of the “aesthetic” system 910. Additionally, the ultrasound system 920 may further include a mapping component, which may include a content repository, which may be multiple repositories, capable of operatively communicating with the treatment device, the control device, and any associated engines or modules.

[0079] The overall system 900 may also include a "patient application" system 930, which contacts or is otherwise disposed on or near a patient to be treated by the overall system 900. For example, the "patient application" system 930 may include one or more ultrasound transducers (which may serve to perform ultrasound / histotripsy treatments by the overall system 900 or by the ultrasound system 920), one or more tissue acquisition systems (e.g., vacuum), and any disposable components. The overall system 900 may further include one or more connector components (940), e.g., one or more electrical and / or mechanical cables for connecting various components of the various systems / subsystems.

[0080] The overall system 900 can also include a mechanism for transmitting test pulses or test pulse amplitude gradients so that the overall system 900 detects the onset of bubble formation as bubbles first form. It should be understood that test pulses are sequences of pulses of increasing amplitude, or potential for such. These test pulses also have significantly less “burst” so as not to produce a therapeutic effect in the tissue. In other words, test pulses are pulses of varying amplitude, duration, and / or PRF used to determine the required cavitation amplitude without producing a therapeutic effect in the target tissue (so that the change is reversible). In some embodiments, detection of bubble formation signals the system that it needs to determine how to treat the tissue of interest. Thus, in some embodiments, detection of a bubble allows the overall system 900 to manipulate system parameters to treat a specific target volume within a specific region of tissue in a specific manner without affecting other target volumes and / or other regions of the tissue.

[0081] FIG. 9B shows a system according to another embodiment of the present disclosure. Specifically, FIG. 9B illustrates the interaction between the histotripsy system, imaging / detection system, real-time controller, transducer, and CPU according to one embodiment of the present disclosure. As shown in FIG. 9B, the therapy transducer can be connected to a movement mechanism. The movement mechanism is designed to move the transducer across the target treatment area. In some embodiments, the transducer moves "back and forth" along a straight line. In other embodiments, the transducer can move in a circle, a serpentine, or any other nonlinear manner consistent with the technical objectives of the present disclosure.

[0082] In some embodiments, the detection transducer can be used as a passive listening device or in pulse-echo mode to "interrogate" the treated region or volume. Specifically, a high frequency pulse can "ride" on a low frequency pulse, as described elsewhere in this disclosure, which acts as an "interrogation" pulse, allowing the low frequency to be distinguished from the high frequency by "listening" for bubbles, if any, and using the backscatter as a guide.

[0083] In the embodiment of FIG. 9B, a high-power pulser is connected to the treatment transducer. In some embodiments, ultrasound backscatter on the treatment transducer and / or the detection transducer may be used to guide the treatment. In some embodiments, a multiplexer may be used to switch between the detection and treatment transducers. In some embodiments, for example, when both the detection and treatment transducers are used simultaneously, the system has two paths for receiving the backscatter signal and therefore does not need to use a multiplexer.

[0084] In some embodiments, the backscattered signal will follow a path similar to other ultrasound imaging systems. For example, a time gain control (TCG) increases the signal amplitude based on delay time and / or signal depth. The backscattered signal may be further conditioned through an analog pass filter, anti-aliasing filter, or similar filter and then digitized in some embodiments.

[0085] In some embodiments, the digitized signal can be used to generate a spectral Doppler signal and / or detect an increase in the noise floor from bubbles. In some embodiments, the signal (i.e., the Doppler signal) can be sent to the input of an artificial neural network, which can be "trained" to detect bubbles based on the input. In such cases, the computation and / or implementation of the neural network can be performed in a CPU (Central Processing Unit). In some embodiments, the computation and / or implementation of the neural network can be performed in an FPGA (Field Programmable Gate Array), for example, if faster speed is required. In some embodiments, computation can be used to determine whether bubbles are present and / or whether process parameters should be adjusted to obtain and / or maintain a cloud of bubbles. Non-limiting examples of system parameters that can be monitored and / or manipulated include transducer position, focal position, pulser amplitude, PRF, burst, treatment focus, and combinations thereof.

[0086] Referring now to FIG. 10 , a flowchart illustrating one exemplary method 1000 for treating a patient or a region or component of biological tissue is provided. Method 1000 and other methods described herein are not limited to those illustrated, and it is contemplated that other blocks or steps may be incorporated at any point in a method according to the present disclosure. In step 1010, ultrasonic pressure waves are placed within a target volume to form a cavitation bubble cloud within the target volume. The target volume may be based on or defined by a point focus of the pressure waves or a line focus of the pressure waves. Furthermore, the ultrasonic pressure waves may have any other characteristics of the pressure waves described herein or may be any type of pressure wave. For example, the pressure waves may be compound pressure waves. In step 1020, the cavitation bubble cloud is maintained within the target volume for a time sufficient to generate a homogenate as described herein. Optionally, for example, in step 1020, ultrasound intensity is reduced. Optionally, in step 1030, a thermal dose may be intentionally delivered to or intentionally avoided from the target volume or the biological tissue within its environment. When a thermal dose is delivered, it is also possible to form a coagulation zone (if desired) or to coagulate tissue within the target volume (step 1040). Then, in step 1050, ultrasonic pressure waves can be placed into one or more additional target volumes, either in series or parallel, or in any other manner desired to provide a particular treatment. For example, in some cases, periodic or aperiodic MIPs are generated by method 1000.

[0087] 11 provides an exemplary operating environment for implementing embodiments of the present disclosure, shown and designated generally as computing device 1100. Computing device 1100 is only one example of a suitable computing environment and is not intended to suggest any limitation as to the scope of use or functionality of the invention. Computing device 1100 should not be interpreted as having any dependency or requirement relating to any one or combination of components illustrated.

[0088] Embodiments of the invention may be described in the general context of computer code or machine-usable instructions, including computer-executable instructions, such as program modules, executed by a computer, FPGA, or other machine (virtual or otherwise), such as a smartphone or other handheld device. Generally, a program module or engine, including routines, programs, objects, components, data structures, etc., refers to code that performs particular tasks or implements particular abstract data types. Embodiments of the invention may be practiced in a variety of system configurations, including handheld devices, consumer electronics, general-purpose computers, more specialized computing devices, etc. Embodiments of the invention may also be practiced in distributed computing environments where tasks are performed by remote processing devices that are linked through a communications network.

[0089] FIG. 11 illustrates an exemplary embodiment of a “user interface and CPU” block within an aesthetic system (such as aesthetic system 910 of FIG. 9 ). Referring to FIG. 11 , computing device 1100 includes a bus 1110 that directly or indirectly couples the following devices: memory 1112, one or more processors 1114, one or more presentation components 1116, input / output ports 1118, input / output components 1120, and an exemplary power source 1122. In some embodiments, the devices described herein utilize wired and rechargeable batteries and power sources. Bus 1110 represents what may be one or more buses (e.g., an address bus, a data bus, or a combination thereof). While the various blocks in FIG. 11 are clearly delineated for clarity, in practice, such delineations are not always so clear and these lines may overlap. For example, presentation components such as display devices can also be considered I / O components. Processors also generally have memory in the form of a cache. It is recognized that such is the nature of the art, and it is reiterated that the diagram of Figure 11 is merely illustrative of an exemplary computing device that may be used in connection with one or more embodiments of the present disclosure. Categories such as "workstation," "server," "laptop," "handheld device," etc. are not distinguished, as all are within the scope of Figure 11 and are considered to refer to a "computing device."

[0090] Computing device 1100 typically includes a variety of computer-readable media. Computer-readable media can be any available media that can be accessed by computing device 1100, including both volatile and nonvolatile media, removable and non-removable media. By way of example, and not limitation, computer-readable media can include computer storage media and communication media.

[0091] Computer storage media include volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information, such as computer-readable instructions, data structures, program modules, or other data. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVDs) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by the computing device 1100. Computer storage media excludes the signals themselves.

[0092] Communication media typically embodies computer-readable instructions, data structures, program modules, or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term "modulated data signal" means a signal that has one or more characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, infrared, NFC, Bluetooth, and other wireless media. Combinations of any of the above should also be included within the scope of computer-readable media.

[0093] The memory 1112 includes computer storage media in the form of volatile and / or nonvolatile memory. As shown, the memory 1112 includes instructions 1124 that, when executed by the processor 1114, are configured to cause the computing device to perform any of the operations described herein with reference to the above-mentioned figures or to implement any program modules described herein. The memory may be removable, non-removable, or a combination thereof. Exemplary hardware devices include solid-state memory, hard drives, optical disk drives, etc. The computing device 1100 includes one or more processors that read data from various entities, such as the memory 1112 or the I / O components 1120. The presentation component 1116 presents data indications to a user or other device. Exemplary presentation components include a display device, a speaker, a printing component, a vibrating component, etc.

[0094] I / O ports 1118 allow computing device 1100 to be logically coupled to other devices, including I / O components 1120, some of which may be built-in. Example components include a microphone, joystick, directional pad, monitor, scanner, printer, wireless device, battery, etc.

[0095] The embodiments described herein can be more readily understood by reference to the following examples. However, the elements, devices, and methods described herein are not limited to any particular embodiments presented in the examples. It should be recognized that these are merely illustrative of some principles of the present disclosure, and are non-limiting. Numerous modifications and adaptations will be readily apparent without departing from the spirit and scope of the present disclosure. [Example]

[0096] Ultrasound with a Line Focus Ultrasound therapy applications, including those described herein, can use a point focus to heat and / or mechanically disrupt tissue. Tissue heating is achieved by generating high intensity at the focus with sufficient absorption and for a sufficient time to raise the tissue temperature. Mechanical tissue disruption is achieved by generating a peak negative pressure of sufficient magnitude within the intended target tissue. In some applications, heating is limited or avoided by keeping the ultrasound pulses short and / or with a low duty cycle. Additionally, many applications can use a focusing bowl, since all points on the resonating surface are aimed at the same location. This results in significant focal gain, which is related to the bowl area, focal length, and frequency. The formula for focal gain "FG" is given by Equation (2):

number

number

[0097] Furthermore, it should be understood that other shapes can also be used to generate the necessary pressure in tissue to exceed the required cavitation pressure, and the shape is not particularly limited. For example, cylindrical, spherical, parabolic, or paraboloidal shapes can also be used. However, point focusing is not effective for treating large volumes at high speeds. This has been circumvented (including in the present disclosure) by adding a motion or translation mechanism to increase the speed of delivery, by using multiple transducers simultaneously, or by electronically focusing the transducer.

[0098] Figure 24 shows an embodiment using multiple transducers simultaneously. In the embodiment of Figure 24, movement of transducer 2402 is effected by a motion mechanism 2401. In some embodiments, motion mechanism 2401 may be a lead screw, a crankshaft, a cylindrical cam, a cam and follower, a quick return mechanism, a scotch yoke, and / or a rack and pinion.

[0099] In row A of Figure 24, a transducer 2402 is connected to a motion mechanism 2401 such that only one area of ​​tissue is treated at a time.

[0100] Row B of Figure 24 shows the transducer 2402 as an annular array, which, in some embodiments, can enable bubble generation at multiple depths. The annular array allows treatment of various target regions or volumes at different depths in a single pass, rather than multiple passes. Furthermore, because the duty cycle of histotripsy can, in some cases, be less than 1%, it is possible to interleave or raster different depths and / or different treatment points in a single treatment, further reducing treatment time. In some embodiments, the annular array can have enough channels to move the beam a significant distance, such as ±3 mm (for the same amount of travel for the same bowl size as a conventional design). In some cases, time reduction can be enhanced by reducing treatment time per site. In some embodiments, reductions of up to -75%, -70%, -65%, -60%, -50%, or -45% can be achieved, with percentages expressed as negative values ​​indicating a reduction (as opposed to an increase) in time. In some embodiments, a reduction of at least -10%, at least -15%, at least -20%, or at least -25% is obtained. In some embodiments, a reduction of -41% is obtained at 50 milliseconds per mechanical damage point or MIP. In some embodiments, the beam may be rastered in depth to interleave pulse delivery while maintaining the same PRF, which in some embodiments provides even improved time reduction, which is constant for the same treatment time per MIP. In some cases, embodiments with rastering can obtain time reductions of at least -67%.

[0101] Row C of Figure 24 shows an embodiment in which two transducers 2402 are placed together. This embodiment also allows for a reduction in treatment time, as twice the distance is covered in half the time for each line feed. Thus, the row C embodiment can achieve a -50% reduction in treatment time.

[0102] Row D of Figure 24 shows an embodiment in which the techniques shown in rows B and C are combined. Specifically, in row D, two therapeutic annular array transducers are placed together, resulting in twice the distance being covered in half the time for each line feed. This embodiment can result in further reductions in treatment time. For example, if each depth is treated sequentially, a time savings of -71% can be obtained. As another example, if the device uses a rastering approach, a time savings of -83% can be obtained because the duty cycle is only 1%.

[0103] Row E of Figure 24 illustrates an embodiment in which four treatment annular array transducers are placed together. In such an embodiment, four times the distance is covered in one-quarter of the time for each line feed, thereby further reducing treatment time. For example, if each depth is treated sequentially, a time savings or reduction of -85% can be obtained. As another example, if the device uses a rastering approach, a time reduction of -92% can be achieved.

[0104] In other embodiments, it is also possible to improve the delivery rate using a line focus rather than applying a motion or translation mechanism. Three different exemplary designs for generating the line focus are further described below: (i) a cylinder segment, (ii) a flat plate with a lens, and (iii) a flat plate with a reflector. A line focus at a depth of at least 1.5 mm can be obtained, including using the transducer specifications in Table 3 below. In some embodiments, the focal gain may be further increased by focusing along the linear dimension, which may further increase the likelihood of achieving the target pressure for cavitation. [Table 3]

[0105] 13A and 13B illustrate an exemplary cylinder segment 1300 operating at 10 MHz. FIG. 13A shows a 3D perspective view, and FIG. 13B shows a cross-section of the cylinder segment 1300. The cylinder segment 1300, in some embodiments, may be a piezoelectric cylinder, such as a cylinder made from a piezoelectric ceramic material (e.g., lead zirconate titanate, or "PZT"). The cylinder has a length 1302, a height 1303, and a radius 1304. The patient-facing surface A (concave surface) can be electrically attached to an electrical connection 1301. In some embodiments, the electrical connection 1301 can be a ground electrode. Multiple electrical connections 1301 can be used to reduce return resistance. The convex surface B of the cylinder segment 1300, shown in FIG. 13B, can be electrically attached to a wire 1310. The wire 1310 can be a coaxial cable, a twisted pair, or the like. The concave surface B can have a low-impedance backing 1311. As shown in FIG. 13B, wires 1310 can be attached to the high side H and low side L of the excitation form (not shown).

[0106] FIG. 14A shows a schematic diagram of a cylinder shell 1400. The cylinder shell has a base 1401a, a base 1401b, and a height H. The thickness of the cylinder is selected based on the frequency of operation. FIG. 14B shows chords 1402 on the top and bottom bases 1401a and 1401b (respectively) of the cylinder, which define the cutting plane that forms the cylinder shell segment 1403 (shown in FIGS. 14C and 14D). The two chords 1402 are at the same point on the top and bottom bases 1401a and 1401b of the cylinder, respectively. As shown in FIGS. 14C and 14D, the cylinder shell segment 1403 has a uniform radius of curvature ROC that focuses in only one dimension, thus forming a line focus 1404 (see FIG. 14E). If the focal gain is sufficient from the cylinder surface to the focal point, the surface intensity of the segment is sufficiently high, and the dose duration is sufficiently long, tissue heating can be localized along the line. Furthermore, sufficient focal gain and intensity may enable cavitation along the line. Specifically, increased focal gain may be achieved in some embodiments through focusing along the line dimension. In some cases, such an approach may reduce the line length for a given transducer size, but this can be addressed by increasing the overall size of the transducer along the line dimension.

[0107] An exemplary slab with a lens is shown in FIG. 15. Specifically, FIG. 15 shows a cross section of a slab 1501 formed from a piezoelectric ceramic material operating at approximately 10 MHz bonded to a lens 1503 via a joint 1502. In the embodiment of FIG. 15, the piezoelectric ceramic material is PZT. However, it should be understood that any material that exhibits piezoelectric behavior can be used, including, for example, PZT, piezoelectric micromachined ultrasonic transducers (PMUTs), and capacitive micromachined ultrasonic transducers (CMUTs). One way to create a line focus is to use a composite PZT with an aluminum lens that matches the composite acoustic impedance. In the non-limiting design of this example, the slab is 10 mm by 4.5 mm (45 mm 2The lens has a radius of curvature (1504) to the focal point of 3.6 mm relative to the concave surface of the lens. The focal gain is slightly less than that of a cylinder segment because of the reduced area and the aluminum lens (if used) creating standing waves that result in uneven intensity on the lens surface. A ground electrode (not shown) is attached to the patient-facing face of the transducer, and the excitation electrode is soldered to the opposite side. The excitation is bundled together with the ground return in a coaxial cable. A housing is again used to seal the back of the transducer and prevent water ingress. In some preferred embodiments, the lens has a surface roughness (Ra, roughness average) of 0.2 μm or less. The maximum acoustic power of an exemplary plate is 90 W.

[0108] Another approach to achieving a line focus is to use a flat (uncurved or substantially uncurved) plate and a reflector such as a parabolic mirror. In this design, a flat piezoelectric ceramic plate (e.g., a PZT plate) is sandwiched between two reflectors. Although ultrasonic waves are diffracted, this design assumes that the PZT plate and reflector are close enough together to eliminate diffraction concerns. Figure 16 shows a side or cross-sectional view of a PZT plate sandwiched or placed between two acoustic reflectors.

[0109] 16, the reflective surface f(z) (reference numeral 1601) is provided by a reflector 1602. The reflective surface 1601 can have a geometric shape defined as described below. In some embodiments, the curvature of the top and bottom reflectors is prescribed or defined by Equation 4:

number

[0110] In the specific embodiment shown in FIG. 16, the PZT plate 1603 is 10 mm wide by 3 mm long and has a thickness that produces a 10 MHz resonance. In the embodiment of FIG. 16, the PZT plate 1603 is surrounded on both sides by water or a material with a similar acoustic impedance to water. An incident wave 1604 is reflected by the reflector 1602, and the reflected wave (1605) generates a line focus 1606. Electrodes (not shown) are used on both the bottom and top of the PZT plate 1603, and the design is independent of the location of the excitation and ground electrodes. One possible connection scheme is to have a portion of the PZT plate 1603 outside the water environment (e.g., where the reflectors intersect) as a location for attaching electrical leads. This eliminates or minimizes the possibility of solder interfering with plate vibration. If the reflector 1602 is metal, portions of the PZT plate 1603 can be coated with parylene (or another electrically insulating material) to reduce the chance of shorting the electrodes. , a housing may also be used to isolate the electrical connections. In some preferred embodiments, the reflector 1602 has a surface roughness (Ra, roughness average) of 0.2 μm or less. Furthermore, in some preferred embodiments, the maximum translation or tilt of the transducer plate 1603 with respect to its ideal position relative to the reflector 1602 is 10 μm or 0.2 degrees, respectively. Maintaining such a small range can be useful to avoid amplifying misalignment on acoustic performance. Because of the top and bottom reflectors 1602, misalignment affects the constructive interference pattern at the focal point 1606. Because of the top and bottom surfaces, the total effective surface area of ​​the particular embodiment of FIG. 16 is 60 mm 2 The maximum power from this exemplary device is 120 W. Figure 17 shows a three-dimensional or 3D perspective view of the device of Figure 16. Figure 17 shows the curvature (1607) of the reflector 1602.

[0111] Furthermore, although not specifically shown in the drawings, it should be noted that the plate (e.g., PZT plate) may be patterned, such as by etching, to provide individual elements or apodization. For example, in some cases, the plate (e.g., PZT plate) may include an electrode pattern that shields material closer to the ultrasound focus of the entire device. Similarly, it is also possible to pattern a reflector, for example, to generate apodization correction. Furthermore, in some embodiments of the devices described herein, the plate (e.g., PZT plate) is separated into multiple individually controlled elements. Such a structure allows elements closer to the focus to be driven with less power, or elements closer to the origin to be driven with more power. This can result in a line focus with a more uniform intensity.

[0112] Simulations were performed using a "flat plate plus reflector" structure, specifically using the following parameters: 1. Flat plate, width 3mm (z axis, depth), length 10mm (x axis, azimuth) 2. Ideal reflectivity (Zr>>Zi), therefore reflection coefficient = 1 (even at different angles)

number

[0113] The results of the simulation were as follows: 1.Maximum focus gain=10.42 2.Focal gain@(0,0,5)=9.32 3. Total area (piezoelectric ceramic) = 30 mm 2 (double-sided, 60mm 2 ) 4. Line @5mm depth 5. Beam width z, -3dB = 0.377mm 6.Beam width x, -3dB=9.3mm 7.Beam width y, -3dB<0.100mm 8. Parabolic reflector area = 46.39 mm 2 (double-sided, 92.77mm 2 ) 9. For seven cylinders, the total length is approximately 31.85mm, plus the length for the thickness of the reflector. The height of one is 4.55mm. The number of cylinders and the height of the reflector can be adjusted to fit any footprint. 10.Line length can be adjusted based on footprint. 11. Cavitation [Table 4]

[0114] Focal gain of 9 and maximum surface intensity of 250W / cm 2 Assuming that, the maximum intensity is about 20 kW / cm 2 This corresponds to a negative pressure of 24.5 MPa, above the threshold pressure for multiple tissues. In some embodiments, higher negative pressures can be achieved by focusing in a linear dimension and / or by using multiple transducers in the tissue acquisition system to the same tissue depth.

[0115] 250W / cm2 This corresponds to an acoustic power output of 150 W per plate or 75 W per side. If a 60% electrical to acoustic efficiency is assumed, this is 250 W of electricity per plate or 150 W per side. With seven plates, this is a total instantaneous power of 1,750 W. With a duty cycle of 0.5%, the average power is 8.75 W. Note further that in some embodiments, cooling of the plates may be used.

[0116] Furthermore, this analysis demonstrates the possibility of exceeding the cavitation threshold using a line focus where the focus exists only in two dimensions (e.g., xz or yz). Because calculations indicate this is correct at the threshold for most tissues, another method for further improving the focus gain and maintaining the line length is to use a compound focus. Figure 17 shows that energy is focused only in elevation. If a reflector or aluminum lens provides slight focusing in the azimuthal dimension, the focus gain can be further increased to exceed the cavitation threshold. This can be achieved by placing the focus at a depth slightly greater than the intended line focus in the azimuthal dimension. The line length may be slightly reduced, but this can be avoided by increasing the plate length.

[0117] Specific devices for providing a line focus (and, in some cases, a point focus) are described and illustrated in more detail in Figures 18-23, which are not necessarily drawn to scale.

[0118] FIG. 18 shows a three-dimensional (3D) perspective view of an acoustic reflector 1802 according to one embodiment described herein. The reflector 1802 is one component of a device; other possible components are described further below. The reflector may focus only in the yz plane, or in some cases, it may be desirable or beneficial to have a slight focus in the xz plane, which may improve the focusing gain. In the embodiment of FIG. 18, the two reflective surfaces 18A and 18B are mirror images of each other (mirrored about the z-axis). Furthermore, as illustrated in FIG. 18, the reflector comprises a top reflective surface or component 18A and a bottom reflective surface or component 18B. The top and bottom surfaces are opposite each other. The top and bottom surfaces connect, touch, or have a relatively small separation distance at a first end (left side of FIG. 18) of the reflector 1802. At the second end (right side of FIG. 18), the top and bottom surfaces do not connect or touch, but have a relatively large separation distance. As shown in FIG. 18, the top and bottom surfaces 18A and 18B define a parabolic or parabolic-like reflector, with an interior volume in the "center" of the parabolic or parabolic-like shaped "V" or "U." This volume can be accommodation space for additional components, as further described below. Furthermore, in some preferred embodiments, the top and bottom surfaces are symmetrical or substantially symmetrical and have complementary or similar shapes and sizes in one, two, or three dimensions.

[0119] As shown in FIG. 19 , a piezoelectric plate 1803 is added to the center of the acoustic reflector 1802 shown in FIG. 18 . Furthermore, in the embodiment of FIG. 19 , the distance between the plate 1803 and the top and bottom portions / surfaces of the reflector (18A and 18B shown in FIG. 18 ) is the same (e.g., if a line perpendicular to the top surface of the plate is drawn toward the top reflector component, and if a line perpendicular to the bottom surface of the plate is drawn toward the bottom reflector component). The piezoelectric plate 1903 can be formed from a piezoelectric material, including those described herein. Furthermore, in some embodiments, the reflector 1802 can include slots, grooves, or other fasteners or retention means on its two ends in the y-z plane to aid in aligning the piezoelectric plate 1803. In some preferred embodiments, the reflector surface is slightly larger (e.g., up to 10% or up to 20% larger) than the piezoelectric plate 1803 in the x and z directions.

[0120] FIG. 20 illustrates a treatment line 1805 focused in the y and z directions using the system or device illustrated in FIGS. 18 and 19. The effective length of the treatment line 1805 is approximately equal to the width of the plate 1803 in the x direction. As previously mentioned, slight focal spots in the x and z directions may be added to help improve the overall focal gain. In this case, the treatment line length 1804 is slightly reduced for the same plate width and potentially moved to a shallower depth. While not intending to be bound by theory, it is believed that this design can utilize or use all or substantially all of the acoustic energy generated by the top and bottom surfaces of the plate 1803. Furthermore, in this embodiment, there is no backing, meaning that no heating of the backing occurs and more energy is transmitted to the patient. Furthermore, if the piezoelectric plate 1803 and reflector 1802 are submerged or water-cooled, the configuration of the device in FIGS. 19-20 allows for better removal of thermal energy in the piezoelectric plate 1803 compared to other configurations. Heat may be removed from both sides instead of just one side.

[0121] FIG. 21 shows a perspective view (not necessarily to scale) of a more specific device according to one embodiment described herein. The device of FIG. 21 comprises a curved, symmetric reflector structure 2102 similar to that described above and illustrated in FIGS. 18-20. In FIG. 21, a piezoelectric plate 2103 (which, similar to FIGS. 19 and 20, is positioned in the center of the reflector 2102's containment volume) is divided into multiple independently controlled elements (El 1, El 2, El 3, ...El N) in the x-direction. These elements can be formed from the same or different piezoelectric materials. This structure can be described as a linear array. However, in this embodiment, both the front and rear of the piezoelectric plate 2103 transmit acoustic energy into the field. Electrical connections to the array can also be simplified because portions of plate 2103 (e.g., the 2-2 complex) can "hang" outside the reflector (e.g., in region 2106, exiting the "back" or left side of the reflector in FIG. 21, with top and bottom components, portions, or surfaces of reflector 2102 "clamping down" on plate 2103 at the back, or plate 2103 being positioned between top and bottom components, portions, or surfaces that are normally touching, contacting, or near each other). In some embodiments, one side of the plate (e.g., in the x-direction) receives a signal connection and the other side of the plate receives a ground connection. By having separate control of the delay in the x-direction via independently controlled element 2107, a point focus 2108 or a point focus 2109 can be created. Furthermore, the point focus may be electronically swept back and forth or restored, as indicated by the "spot" and double-headed arrow in FIG. 21.

[0122] Another embodiment is shown in FIG. 22. The device of FIG. 22 includes a curved, symmetric reflector structure 2202 similar to that described above and illustrated in FIGS. 18-20. However, in the device of FIG. 22, the piezoelectric plate 2203 is split into multiple independently controlled elements 2209 in the z-direction. Because there is no or little focusing remaining in the x-direction, the treatment line 2205 can be moved or split in the z-direction. Again, the front and rear of the piezoelectric plate 2203 transmit acoustic energy to the field. As discussed above with respect to FIG. 21, electrical connections to the array can also be simplified because a portion of the plate 2203 (which in some embodiments may be a 2-2 composite) can hang outside the reflector 2202. In some cases, one side of the plate 2203 (e.g., in the z-direction) is signal connected and the other side of the plate is ground connected. By separately controlling the delay in the z direction, the effect of the reflector 2202 can be modified to move the line focus inward or outward. This can be advantageous to allow treatment at multiple depths depending on the location of the patient and the affected tissue type. It is also possible to use time delays to split the focus so that the focus is not at y=0. If the top and bottom of the plate 2203 are treated separately (independent time delays for the top and bottom), the beam can be focused along the y axis.

[0123] FIG. 23 illustrates yet another exemplary embodiment of a device for providing a line focus 2309 or a point focus 2308. In the embodiment of FIG. 23, a piezoelectric plate 2303 in the form of a row-column transducer is added to a reflector 2302. In some cases, the row-column transducer 2303 includes or is constructed from a 1-3 composite material with edge connections. Such a structure allows acoustic energy to be focused at different depths, not just in the x-direction. The focus may be constructed from a line focus 2309 or a point focus 2308, which can be electronically restored or swept back and forth, as further described herein.

[0124] Some additional exemplary, non-limiting embodiments of methods, systems, and computer storage media are provided below.

[0125] Embodiment 1. A method of treating a region of biological tissue of a patient in need of treatment, comprising: disposing ultrasonic pressure waves within a target volume of the region of biological tissue to form a cavitation bubble cloud within the target volume; and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume, wherein the homogenate is fractionated within non-homogenized biological tissue within the region of biological tissue. A method comprising:

[0126] Embodiment 2. The method of embodiment 1, wherein the pressure wave is a complex pressure wave comprising a high frequency component wave and a low frequency component wave.

[0127] Embodiment 3. The high frequency component wave and the low frequency component wave are expressed by Equation 1:

number

[0128] Embodiment 4. The method of embodiment 2 or 3, wherein at least one cycle of the high frequency component wave is located at a trough of at least one cycle of the low frequency component wave.

[0129] Embodiment 5. The method of any of embodiments 2-4, wherein one cycle of the high frequency component wave is disposed within each trough of the low frequency component wave.

[0130] Embodiment 6. The method of any one of embodiments 2-5, wherein the high frequency component wave is disposed in a compression portion of the low frequency component wave.

[0131] Embodiment 7. The method of any one of embodiments 1-6, wherein maintaining the cavitation bubble cloud within the target volume delivers a thermal dose to tissue within the target volume that does not cause denaturation or coagulation.

[0132] Embodiment 8. The method of any one of embodiments 1-7, wherein maintaining the cavitation bubble cloud within the target volume delivers a thermal dose to tissue within the target volume that causes denaturation or coagulation.

[0133] Embodiment 9. The method of embodiment 8, wherein the thermal dose is sufficient to thermally ablate all or substantially all of the tissue within the target volume.

[0134] Embodiment 10. The method of any one of embodiments 1-9, further comprising forming a thermal coagulation zone around the target volume.

[0135] Embodiment 11. The method of any one of embodiments 1-10, wherein disposing pressure waves in the target volume comprises applying an ultrasound beam to the target volume.

[0136] Embodiment 12. The method of embodiment 11, wherein the ultrasound beam is a pulsed ultrasound beam.

[0137] Embodiment 13. The method of embodiment 11 or 12, wherein the focal point of the ultrasound beam is located within the target volume.

[0138] Embodiment 14. The method of any one of embodiments 11-13, wherein the focus of the ultrasound beam is a point focus.

[0139] Embodiment 15. The method of any one of embodiments 11-13, wherein the focus of the ultrasound beam is a line focus.

[0140] Embodiment 16. The method of any one of embodiments 1-15, further comprising detecting the onset of cavitation, the onset of cavitation being defined as the time t=0 when a cavitation bubble cloud within the target volume begins to form.

[0141] Embodiment 17. The method of embodiment 16, wherein detecting the onset of cavitation is based on acoustic cavitation emissions.

[0142] Embodiment 18. The method of embodiment 17, wherein the acoustic cavitation emissions are detected using a detection device.

[0143] Embodiment 19. The method of embodiment 18, wherein the detection device is a transducer.

[0144] Embodiment 20. The method of embodiment 19, wherein the transducer also applies an ultrasound beam to the target volume.

[0145] Embodiment 21. The method of any of embodiments 17-20, wherein the onset of cavitation is detected simultaneously with imaging.

[0146] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the pressure wave has a peak negative pressure of 10 to 100 MPa.

[0147] Embodiment 23. Disposing a pressure wave in a second target volume of the region of biological tissue to form a second cavitation bubble cloud in the second target volume; and maintaining the second cavitation bubble cloud in the second target volume for a second period of time sufficient to produce a homogenate in the second target volume, wherein the second target volume is different from the first target volume. 23. The method of any one of embodiments 1 to 22, further comprising:

[0148] Embodiment 24. Disposing pressure waves in n additional target volumes of the region of biological tissue to form additional cavitation bubble clouds in the n additional target volumes; and maintaining the n additional cavitation bubble clouds in the n additional target volumes for n additional periods sufficient to produce homogenates in the n additional target volumes, wherein the n additional target volumes are different from each other and from the first target volume and the second target volume, and n is an integer between 1 and 1,000,000. 24. The method of any one of embodiments 1 to 23, further comprising:

[0149] Embodiment 25. The method of any one of embodiments 1-24, wherein the biological tissue comprises skin tissue, adipose tissue, connective tissue, or muscle tissue.

[0150] Embodiment 26. The method of any one of embodiments 1-25, wherein the method provides an aesthetic effect.

[0151] Embodiment 27. The method of any of the preceding embodiments, wherein the method does not provide a medical or therapeutic benefit other than a cosmetic benefit.

[0152] Embodiment 28. A system for treating a region of biological tissue of a patient in need of treatment, comprising: one or more ultrasonic transducers for providing ultrasonic pressure waves to a target volume within the region of biological tissue to form a cavitation bubble cloud within the target volume; and a control device for maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume. A system comprising:

[0153] Embodiment 29. The system of embodiment 28, further comprising one or more electromagnetic radiation sources for providing one or more electromagnetic radiation beams to the region of biological tissue for imaging, thermal ablation, and / or delivery of non-ablative energy to the region of biological tissue.

[0154] Embodiment 30. The system of embodiment 28 or 29, further comprising one or more microneedles for providing treatment to the skin.

[0155] Embodiment 31. A computer storage medium storing computer usable instructions that, when used by one or more computing devices, cause the one or more computing devices to treat biological tissue of a patient, the operations comprising: disposing ultrasonic pressure waves within a target volume in a region of biological tissue to form a cavitation bubble cloud within the target volume; and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume, wherein the homogenate is fractionated within non-homogenized biological tissue within the region of biological tissue. a computer storage medium,

Claims

1. 1. A method of treating a region of body tissue in a patient in need of treatment, comprising: disposing ultrasonic pressure waves within a target volume in the region of biological tissue to form a cavitation bubble cloud within the target volume; and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume. Including, The homogenate is fractionated within the non-homogenized tissue within the tissue region. A method characterized by:

2. The method of claim 1 , wherein the pressure wave is a complex pressure wave including a high frequency component wave and a low frequency component wave.

3. The high frequency component wave and the low frequency component wave are expressed by Equation 1: [Equation 1] and having a frequency according to where p is the maximum negative pressure (i.e., A Ｈｉｇｈ and A ＬＯＷ is the ratio of the magnitude of the final negative peak pressure (i.e., the negative peak pressure of the last cycle of the wave) to the sum of the final negative peak pressure (i.e., the negative peak pressure of the last cycle of the wave), n is the number of cycles of the high frequency component wave in one pulse of the ultrasonic pressure wave, and f ｌＯＷ is the frequency of the low-frequency component wave, and f ｈｉｇｈ is the frequency of the high frequency component wave, and A ＬＯＷ is the amplitude of the low-frequency excitation, and A Ｈｉｇｈ is the amplitude of the high frequency excitation 3. The method according to claim 2.

4. 3. The method of claim 2, wherein at least one cycle of the high frequency component wave is located at a trough of at least one cycle of the low frequency component wave.

5. 3. The method of claim 2, wherein one cycle of the high frequency component wave is disposed within each trough of the low frequency component wave.

6. 3. The method of claim 2, wherein the high frequency component wave is located in a compressional portion of the low frequency component wave.

7. 2. The method of claim 1, wherein the step of maintaining a cavitation bubble cloud within the target volume comprises delivering a thermal dose to tissue within the target volume that does not cause denaturation or coagulation.

8. 2. The method of claim 1, wherein the step of maintaining a cavitation bubble cloud within the target volume comprises delivering a thermal dose to tissue within the target volume that causes denaturation or coagulation.

9. 8. The method of claim 7, wherein the thermal dose is sufficient to thermally ablate all or substantially all of the tissue within the target volume.

10. 8. The method of claim 7, further comprising forming a thermal coagulation zone around the target volume.

11. The method of claim 1 , wherein placing the pressure waves in the target volume comprises applying the ultrasound beam to the target volume.

12. 12. The method of claim 11, wherein the ultrasound beam is a pulsed ultrasound beam.

13. 12. The method of claim 11, wherein the focal point of the ultrasound beam is located within a target volume.

14. 12. The method of claim 11, wherein the focus of the ultrasound beam is a point focus.

15. 12. The method of claim 11, wherein the focus of the ultrasound beam is a line focus.

16. 2. The method of claim 1, further comprising detecting the onset of cavitation, wherein the onset of cavitation is defined as time t=0 when a cavitation bubble cloud within the target volume begins to form.

17. 17. The method of claim 16, wherein detecting the onset of cavitation is based on detecting acoustic cavitation emissions.

18. 18. The method of claim 17, wherein the acoustic cavitation emissions are detected using a detection device.

19. 20. The method of claim 18, wherein the detection device is a transducer.

20. 20. The method of claim 19, wherein the transducer also applies the ultrasound beam to a target volume.

21. 21. The method of claim 20, wherein the onset of cavitation is detected simultaneously with imaging.

22. 2. The method of claim 1, wherein the pressure wave has a peak negative pressure of 10 to 100 MPa.

23. disposing the pressure wave within a second target volume of the region of biological tissue to form a second cavitation bubble cloud within the second target volume; and maintaining the second cavitation bubble cloud within the second target volume for a second period of time sufficient to produce a homogenate within the second target volume. further comprising The second target volume is different from the first target volume.

2. The method of claim 1.

24. disposing the pressure waves within n additional target volumes in the region of biological tissue to form additional cavitation bubble clouds within the n additional target volumes; and maintaining the n additional cavitation bubble clouds within the n additional target volumes for n additional periods of time sufficient to produce homogenates within the n additional target volumes; further comprising The n additional target volumes are different from each other and from the first target volume and the second target volume, and n is an integer between 1 and 1,000,000.

24. The method of claim 23.

25. The method of claim 1 , wherein the biological tissue comprises skin tissue, adipose tissue, connective tissue, or muscle tissue.

26. 10. The method of claim 1, wherein the method provides an aesthetic effect.

27. 27. The method of claim 26, wherein the method does not provide any medical or therapeutic benefit other than a cosmetic benefit.

28. 1. A system for treating a region of body tissue of a patient in need of treatment, comprising: one or more ultrasonic transducers for providing ultrasonic pressure waves to a target volume within the region of biological tissue to form a cavitation bubble cloud within the target volume; and a control device for maintaining a cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume. A system comprising:

29. 30. The system of claim 28, further comprising one or more electromagnetic radiation sources for providing one or more beams of electromagnetic radiation to the region of biological tissue for imaging, thermal ablation, and / or delivery of non-ablative energy to the region of biological tissue.

30. 30. The system of claim 28, further comprising one or more microneedles for providing treatment to the skin.

31. 1. A computer storage medium storing computer usable instructions that, when used by one or more computing devices, cause the one or more computing devices to treat biological tissue of a patient, the operations comprising: disposing ultrasonic pressure waves within a target volume in the region of biological tissue to form a cavitation bubble cloud within the target volume; and maintaining the cavitation bubble cloud within the target volume for a period of time sufficient to produce a homogenate within the target volume. Including, The homogenate is fractionated within the non-homogenized tissue within the tissue region. A computer storage medium comprising:

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