Ultrasonic array for improved acoustic dynamics therapy to treat cancer

Abstract

An ultrasound transducer element array uses an acoustic radiation drive pattern via a patient interface for activation of an ultrasound sensitizer in sonodynamic therapy. The generation of an incoherent acoustic field is achieved through the controlled delivery of low-intensity plane acoustic waves with varying phase, frequency, and / or amplitude. The method includes generating first and second signals to generate respective acoustic radiation drive patterns having phase, frequency, and amplitude, and generating at least one relative phase, frequency, or amplitude difference to generate a third incoherent acoustic radiation pattern to activate the ultrasound sensitizer. Calibration and complementary therapy procedures for improving cellular sensitivity to sonodynamic therapy are disclosed.

Description

[Technical Field]

[0001] This paper relates to a method and apparatus for generating irradiation-driven patterns using an ultrasonic transducer array to initiate and enhance cancer treatment with acoustic dynamics therapy. [Background technology]

[0002] <Incorporation by reference of any priority application> This application relates to U.S. Provisional Patent Application No. 63 / 062,879, filed on August 7, 2020, entitled "Ensonization Drive Patterns For Sonodynamic Therapy"; Provisional Patent Application No. 63 / 062,895, filed on August 7, 2020, entitled "Sonodynamic Therapy Methods and Systems For Treating Cancer"; Provisional Patent Application No. 63 / 062,915, filed on August 7, 2020, entitled "Sonodynamic Therapy Methods and Systems For Treating Cancer"; Provisional Patent Application No. 63 / 062,926, filed on August 7, 2020, entitled "Sonodynamic Therapy System for Treating Brain Cancer"; and the Enhanced Sonodynamic Therapy Application, filed on August 7, 2020. Priority is claimed to be claimed by U.S. Provisional Patent Application No. 63 / 062,937, entitled Therapy, each of which is incorporated herein by reference in whole.

[0003] Acoustic therapy is a proposed form of cancer treatment that uses ultrasonic energy to activate drugs, prodrugs, and / or ultrasound sensitizers that selectively accumulate in cancer cells. In one embodiment, the ultrasound sensitizer (e.g., drug, prodrug, ultrasound sensitizer) preferentially accumulates in the cells of the lesion. In one embodiment, the ultrasound sensitizer increases the amount, accumulation, or concentration of the ultrasound sensitizer in cancer cells. When exposed to ultrasonic energy, the ultrasound sensitizer initiates a cytotoxic response in the target tissue. When activated by ultrasonic energy, the acoustic therapy drug or "ultrasound sensitizer" generates reactive oxygen species (ROS) that produce a cytotoxic effect. They can be used alone or in combination with other ultrasound sensitizers, many of which are approved by the U.S. Food and Drug Administration (FDA) for use in neurosurgical diagnostic imaging or treatment of systemic tumors.

[0004] Many types of ultrasound devices (e.g., transducer arrays) and therapies have been developed over the years. However, none of these devices (e.g., arrays) and their respective irradiation patterns have been developed specifically for the purpose of activating ultrasound sensitizers. For example, research into acoustic dynamics therapy to date has largely repurposed ultrasound machines designed for high-intensity focused ultrasound (HIFU). These machines adjust the irradiation pattern to coherently focus energy onto one or more specific areas. The basic principle is similar to using a magnifying glass to focus a beam of sunlight to a single point and burn the pores of a leaf. In focused ultrasound, acoustic lenses or electron focusing are used to focus multiple intersecting beams of ultrasound onto a single deep target in the body with extreme precision and accuracy. If each individual beam passes through the tissue, there is no effect. However, at the focal point, the convergence of multiple beams of focused ultrasound energy results in indiscriminate tissue death in the area of ​​interest via thermal ablation. [Overview of the project]

[0005] The following summary is provided to facilitate understanding of some of the innovative features specific to the embodiments disclosed herein and is not intended to be a complete description. A complete understanding of the various embodiments can be obtained by interpreting the specification, claims, and abstract as a whole.

[0006] As described herein, in some embodiments, tumors are treated using an ultrasound sensitizer and ultrasound, which generates reactive oxygen species that intentionally damage cancer cells by activating the ultrasound sensitizer by cavitation, thermal energy, and stressing and / or inhibiting the repair mechanisms of cancer cells through oxidation and associated thermal, chemical, and / or luminescence phenomena to interact with other molecules and enhance the cytotoxic effect (e.g., by affecting heme production in cancer cells, removing iron ions, and / or inhibiting the action of ferrochelatase). Advantageously, in one embodiment, the acoustic dynamics therapy system delivers attenuated and amplified signals to reduce the amount of energy required to destroy cancer cells, and the treatment limits damage to surrounding healthy cells. In various embodiments, the acoustic dynamics therapy system generates electrically driven signals to form incoherent acoustic wave parameters modulated at relatively low energy intensity and frequency. In one embodiment, the ultrasound energy is not focused, thus simplifying the efficient treatment of larger areas of target tissue. In one embodiment, complementary therapy further enhances the effectiveness of acoustic dynamics cancer treatment. Low-intensity, dispersed, non-focused acoustic dynamics therapy, delivered through a comfortable and flexible patient interface that conforms to the patient's body, allows for targeted treatment of unwanted tissue while preserving healthy tissue.

[0007] In one embodiment, the target tissue for treatment is treated at a single site. In various embodiments, the target tissue is treated at one or more sites, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 50, 100, 200, 500, 1000 or more sites, within the ranges of 1-1000, 1-500, 1-100, 1-50, 1-25, 1-10, and 1-5 sites (within any value and range thereof). In one embodiment, sequential acoustic dynamics therapy affects a first portion of the target tissue, a second portion of the target tissue, and any subsequent portions of the target tissue. In one embodiment, the target tissue is partially treated or extracted, and then subsequent treatment treats the remaining target tissue at one or more sites. In one embodiment, the target tissue is partially treated or extracted in a core or central portion, and then subsequent treatment treats the remaining target tissue at one or more sites along the periphery of the target tissue. In one embodiment, a portion of the target tissue is treated, and the treated portion of the target tissue is 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, and any value and range within these (e.g., 1-100%, 1-50%, 1-75%, 1-25%, 1- These percentages include 10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 80-100%, 90-100%, 90-95%, 90-96%, 90-97%, 90-98%, 90-99%, 25-50%, 50-75%, 25-75%, 25-100%, 50-100%, 75-100%, etc.

[0008] In one embodiment, a targeting template is placed on the patient to facilitate the alignment of the transducer to various treatment sites. In various embodiments, the targeting template is a wearable elastic template with markers to facilitate treatment, such as by isolating skin markings based on a grid, anatomical structure, or indicators. In one embodiment, the targeting template is a cap. In one embodiment, the targeting template is a band configured to wrap around the head, neck, chest, torso, back, waist, legs, buttocks, genital area, or other body parts. In one embodiment, the targeting template is drawn on the body (e.g., ink, wax, cosmetics, pencil, charcoal, tattoos (e.g., permanent and / or permanent), stickers, tabs, or other markings). In one embodiment, the targeting template includes a measuring gradient that allows the user to customize the treatment location to the patient's specific anatomical size. In some embodiments, the targeting template remains in place during ultrasound treatment. In some embodiments, the targeting template is made removable before ultrasound treatment.

[0009] In addition to the treatment of brain cancer, cancerous tissues of the lungs, breasts, colorectal region, prostate, bladder, and pancreas can be treated using, for example, one or more ultrasound sensitizers with the ultrasound parameters described herein, using several embodiments described herein. In some embodiments, ovarian cancer is treated. Tumors that are difficult to access, including those surrounded by bone structures, are treated in various embodiments, but are not limited to brain tumors or spinal tumors. Treatment of unwanted tissues in joints and other orthopedic applications are also provided herein. In some embodiments, acoustic dynamics therapy is used to improve the efficiency of chemotherapy molecules, sonoporation, and / or gene delivery.

[0010] In some embodiments, a system for acoustic dynamics therapy includes at least one ultrasonic transducer array housed with a patient interface to acoustically couple transducers to a patient. A controller coupled to the transducers generates an electrically driven signal from a set of modulated acoustic wave parameters, calibrates and / or modulates the driven signal for each element in the ultrasonic array, drives the transducers at a frequency that generates a modulated acoustic wave to produce sufficient acoustic intensity to activate an ultrasonic sensitizer within the therapeutic area, and / or is configured to operate by a complementary therapy system. Some embodiments of irradiation driving patterns using an incoherent acoustic field do not require beam focusing and thus reduce the need for precision and cost associated with small-area focused ultrasound techniques and / or high-resolution imaging or diagnosis. Accordingly, in some embodiments, one or more ultrasonic sensitizers are administered to a patient without imaging the location of one or more ultrasonic sensitizers or their products, by-products, and / or metabolites (for purposes such as tumor localization). According to one embodiment, low-intensity dispersed non-focused acoustic dynamics therapy delivered via a comfortable interface, such as a flexible patient interface that conforms to the patient's body, allows for lower doses over longer periods of time. The patient interface may include orientation mechanisms and anatomical landmarks to simplify cancer treatment in a hospital or office setting.

[0011] In various embodiments, cancer tissue is treated with 8, 10, 15, and 20 W / cm² of fluid. 2 (For example, 0.1~8W / cm²) 2 , 0.1~4W / cm 2 , 0.5~5W / cm 2Acoustic therapy using an ultrasound array that delivers time-averaged intensity output (values ​​and ranges) below such values ​​can be used to induce and activate ultrasound sensitizers at relatively deep depths within the patient's body, with or without cavitation and / or thermal effects and / or sonoluminescence, thereby generating reactive oxygen species, intracellular singlet oxygen and / or free radicals in a cascade of events that activate the ultrasound sensitizers and consequently damage cancer cells. In various embodiments, acoustic therapy can be used in conjunction with or without other therapies, such as photodynamic therapy. In some embodiments, ultrasound is 8, 10, 15, and 20 W / cm². 2 (For example, 0.1~8W / cm²) 2 , 0.1~4W / cm 2 , 0.5~5W / cm 2 At time-averaged intensity outputs below (including values ​​and ranges within these limits), cavitation and sonoluminescence are used to deliver to target tissue and damage the target tissue (e.g., cancer cells).

[0012] Some embodiments described herein are used synergistically with other cancer therapies, including, for example, radiation, chemotherapy, and cell therapy. In one embodiment, the combination of ultrasound and ultrasound sensitizer described herein reduces or eliminates the need for one or more additional complementary therapies. For example, when treating cancerous tissue with the combination of ultrasound and ultrasound sensitizer described herein, lower doses or fewer additional therapies such as chemotherapy, radiation, and cell therapy may be required, thus enhancing patient care and reducing side effects.

[0013] Several embodiments described herein administer irradiation patterns to establish and / or deliver array technologies that can appropriately optimize ultrasound sensitizer activation and provide appropriate accompanying broad ultrasound sensitizer activation for treatment. Some embodiments treat types of cancer that are difficult to remove surgically, as well as types of cancer that suffer from high recurrence. For example, glioblastoma (GBM), which is a grade IV (i.e., highly aggressive) diffuse astroglioma, is the most common and deadly type of brain cancer. Despite aggressive multimodal treatment at diagnosis, the median overall survival for glioblastoma is about one year, and the five-year survival rate is only 10%. The pattern of recurrence in glioblastoma highlights the limitations of current treatments in targeting and removing all cancer cells. Cancers such as glioblastoma have no clear margins, and therefore finger-like tentacles extend undetectably into surrounding healthy tissue, making surgical removal of cancer cells virtually impossible. In some embodiments, the compositions, apparatuses, and systems described herein are used to treat glioblastoma as well as other tumors (both brain tumors and extrabrain tumors). In various embodiments, cancers and tumors for acoustic dynamics therapy include, for example, hepatocellular carcinoma, mouse sarcoma, leukemia, myeloid leukemia, cholangiocarcinoma, melanoma, squamous cell carcinoma, osteosarcoma, gliosarcoma, astrocytoma, hepatocellular carcinoma, prostate cancer, nephroblastoma, adenocarcinoma, and other cancers. In some embodiments, glioma, glial cell carcinoma and / or astrocytoma are treated (e.g., selectively or preferentially).

[0014] In some embodiments, one or more of the following features are provided: an irradiation pattern that optimizes the activation of the ultrasound sensitizer; an irradiation pattern that fully saturates a large treatment volume so that exogenous cancer cells in the surrounding tissue are also treated; and, according to one embodiment, an irradiation pattern and transducer array technique that reduces or avoids the risk of coherently adjusting and guiding energy in methods requiring MRI or other imaging-guided, diagnostic, and / or monitoring, as these systems are not available to provide office-based treatment such as acoustic dynamics therapy. However, in some embodiments, MRI or other imaging-guided, diagnostic, and / or monitoring is used in conjunction with the apparatus described herein. In some embodiments, acoustic dynamics therapy is performed as a non-invasive, clinic-based treatment of cancer (e.g., an oncology clinic). In one embodiment, the treatment plan for acoustic dynamics therapy includes multiple iterative treatments of acoustic dynamics therapy over a period of several weeks (very similar to chemotherapy). The benefits of acoustic dynamics therapy over other cancer treatments include one or more of the following: minimal or no side effects; the ultrasound sensitizer class of drugs being affordable natural compounds; efficient outpatient treatment regimens; and complementarity with other treatment options. In one embodiment, one or more ultrasound sensitizers (e.g., 5-aminolevulinic acid (5-ALA)) are administered to a patient (e.g., orally) without imaging the location of the ultrasound sensitizer or its metabolites and / or products (e.g., protoporphyrin IX (PpIX)), for purposes such as tumor localization. In another embodiment, one or more ultrasound sensitizers (e.g., 5-ALA) are administered to a patient (e.g., orally) without using the ultrasound sensitizer or its metabolites and / or products (e.g., PpIX) for diagnostic purposes (e.g., administration of 5-ALA is therapeutic only).

[0015] In one embodiment, the present disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with the provision of sonodynamic therapy. The ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent acoustic pressure field having an energy profile for activating an ultrasonic sensitizer disposed within a patient's tissue.

[0016] In one embodiment, the present disclosure provides at least one ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with the provision of sonodynamic therapy. In one embodiment, the ultrasonic transducer is (e.g., 5 mm 3 , 10 mm 3 , 20 mm 3 , 50 mm 3 , 100 mm 3 , 200 mm 3 , 500 mm 3 , 1 cm 3 , 5 cm 3 , 10 cm 3 , 25 cm 3 , 50 cm 3 , 75 cm 3 , 100 cm 3 , 200 cm 3 , 500 cm 3(In various embodiments having the incoherent sound pressure described above) the system includes a plurality of ultrasonic transducer elements (e.g., 64, 128, 256, 512 elements, etc.) arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer placed in the patient's tissue, wherein the incoherent sound pressure field includes one or more of the modulation phase across the plurality of ultrasonic transducer elements, the modulation frequency across the plurality of ultrasonic transducer elements, and the modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers includes a planar radiating surface configured to emit planar acoustic waves. In one embodiment, the modulation phase includes a randomized phase difference. Optionally, the modulation frequency modulates the frequency in a single burst and / or between bursts. Optionally, the modulation amplitude modulates the amplitude in a single burst and / or between bursts. The cooling system described herein may optionally be included. The ultrasonic sensitizer is optionally 5-aminolevulinic acid (5-ALA) and / or protoporphyrin IX (PpIX) or other related compounds. In one embodiment, the energy profile is driven by ultrasonic frequencies (and values ​​and ranges) in the range of 250 kHz to 3 MHz. In one embodiment, the incoherent sound pressure field is 1 to 20 W / cm². 2 Includes time-averaged intensity output (and the values ​​and ranges within it). Focused ultrasound featuring high-intensity focused ultrasound (HIFU), 50mm 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3 The following acoustic waves can be focused to a point within tissue (for example, in tissue, tumor, bone, etc., at 50 mm). 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3 It is not used in some embodiments (which are focused on the following points).

[0017] In one embodiment, the ultrasonic transducer includes a cooling system configured to remove excess heat from the patient, the cooling system including a conduit or cavity (e.g., a flexible cavity for circulating a cooling fluid).

[0018] In some embodiments, an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy includes a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer placed in the patient's tissue.

[0019] In one embodiment, the Disclosure provides, in conjunction with the provision of acoustic dynamics therapy, one or more ultrasonic transducers for activating an ultrasonic sensitizer (e.g., 5-aminolevulinic acid (5-ALA) and / or protoporphyrin IX (PpIX) or metabolites thereof, which can be administered orally or by other means), wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements (e.g., 64, 128, 256, 512 elements, and values ​​and ranges thereof) arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the patient's tissue, wherein the incoherent sound pressure field comprises one or more of the randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers comprises a planar radiating surface configured to emit planar acoustic waves. Optionally, the ultrasonic transducer includes a cooling system configured to remove excess heat from the patient, and the cooling system includes a flexible cavity for circulating a cooling fluid. The energy profile can be driven by ultrasonic frequencies (and values ​​and ranges within them) in the range of 250 kHz to 3 MHz. The incoherent sound pressure field is optionally 1 to 20 W / cm². 2This includes a time-averaged intensity output. Each ultrasonic transducer element may include an opening of a size and configuration that contours with and / or closely conforms to the patient's body, and optionally, the size of the opening is selected such that the embodiment ratio of the opening to the size of the lesion is the same size as or larger than the lesion being treated, allowing for the initiation of a wide incoherent sound pressure field to treat the lesion and surrounding tissue. The ultrasonic transducer elements may be arranged in one of a group consisting of a helical configuration, a rectangular array, a concentric array, and a randomly and irregularly arranged heterogeneous distribution. The ultrasonic transducers can define a concentric circular or rounded array shape. Multiple ultrasonic transducer elements may be arranged in an array placed on a helmet configured to be coupled to the patient's head. The diameter of the array may be in the range of 100 mm to 200 mm (and values ​​and ranges within that range), and / or the diameter of the ultrasonic transducer elements may be in the range of 2 mm to 10 mm (and values ​​and ranges within that range). Ultrasound may be used optionally, solely for therapeutic purposes (it does not have to be used for imaging or diagnostic purposes). Focused ultrasound featuring high-intensity focused ultrasound (HIFU), 50mm 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3 The following acoustic waves can be focused to a point within tissue (for example, in tissue, tumor, bone, etc., at 50 mm). 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3 Ultrasound may be used for therapeutic purposes (not for imaging or diagnostic purposes), as it is focused on the following points (and is not used in some embodiments).

[0020] In one embodiment, each ultrasonic transducer element includes an opening of a size and configuration that outlines the patient's body and / or closely conforms to the patient's body. In one embodiment, the size of the opening is selected such that the embodiment ratio of the opening to the size of the lesion is the same size as or larger than the lesion being treated, allowing for the initiation of a wide incoherent sound pressure field to treat the lesion and surrounding tissue.

[0021] In one embodiment, the ultrasonic transducer elements are arranged in one of the following configurations: a helical configuration, a rectangular array, a concentric array, or a randomly and irregularly arranged heterogeneous distribution. In one embodiment, the ultrasonic transducer elements are arranged in a helical configuration. In one embodiment, the ultrasonic transducer elements are arranged in an Archimedean spiral.

[0022] In one embodiment, the ultrasonic transducer elements are arranged in a sunflower spiral. In one embodiment, additional ultrasonic transducer elements are arranged on a specific ring of the sunflower spiral. In one embodiment, the ultrasonic transducer includes a pair of ultrasonic transducer elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 128 elements. In one embodiment, the ultrasonic transducer array comprises 256 elements. In one embodiment, the ultrasonic transducer comprises a sparse spiral array of 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 256 elements skipping every two elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 384 elements skipping every three elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 512 elements, skipping every 4 elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 640 elements, skipping every 5 elements to yield 128 actual ultrasonic transducer elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 768 elements, skipping every 6 elements. In one embodiment, the ultrasonic transducer comprises 128 active ultrasonic transducer elements arranged on a sunflower spiral grid of 896 elements, skipping every 7 elements. In one embodiment, the ultrasonic transducer elements are arranged according to a predetermined element packing technique. In one embodiment, the ultrasonic transducer elements are arranged randomly and irregularly in a non-uniform distribution.

[0023] In one embodiment, the ultrasonic transducer element defines a circular shape. In one embodiment, the ultrasonic transducer defines a concentric circular array shape. In one embodiment, the ultrasonic transducer defines a linear array shape. In one embodiment, the ultrasonic transducer defines a rectangular array shape. In one embodiment, the rectangle defines a square.

[0024] In one embodiment, the ultrasonic transducer includes a plurality of ultrasonic lens elements positioned on the plurality of ultrasonic transducer elements to geometrically focus each of the plurality of ultrasonic transducer elements. In one embodiment, at least one of the plurality of ultrasonic lenses is repositionable. In one embodiment, at least one of the plurality of ultrasonic lenses provides a different degree of focus. In one embodiment, at least one of the plurality of ultrasonic lenses changes the direction of the ultrasonic transducer, at least one of the fergents, or a combination thereof. In one embodiment, at least one of the plurality of ultrasonic lenses is rotatable with three degrees of freedom.

[0025] In one embodiment, the ultrasonic transducer elements are arranged in an array positioned on a helmet configured to bond to the patient's head (e.g., scalp, forehead, skull, face, cheeks, jaw, neck). In another embodiment, the ultrasonic transducer elements are arranged in an array positioned on a dome helmet configured to bond to the patient's head. In yet another embodiment, the ultrasonic transducer elements are arranged in an array individually positioned on the patient's head. In yet another embodiment, the ultrasonic transducer elements are arranged in a flat array. In yet another embodiment, the ultrasonic transducer elements are arranged in a hemispherical array. In yet another embodiment, the ultrasonic transducer elements are arranged in a curved linear array.

[0026] In one embodiment, multiple ultrasonic transducer elements are arranged in a 2D matrix array. In one embodiment, the diameter of the array is in the range of 100mm to 200mm, 100 to 150mm, and / or 120 to 165mm. In one embodiment, the diameter of the ultrasonic transducer elements is in the range of 0.5mm to 20mm, and / or 2mm to 10mm. In one embodiment, the ultrasonic transducer is configured to activate an ultrasonic sensitizer without focusing the ultrasound. In one embodiment, the ultrasonic transducer is configured to treat cancerous tissue of the brain, spine, mouth, lungs, breast, colorectal region, prostate, or pancreas. In one embodiment, the ultrasonic transducer is configured for acoustic dynamics therapy with at least one of the group consisting of radiotherapy, chemotherapy, and cell therapy. In one embodiment, the ultrasonic sensitizer is configured for oral administration to the patient. In one embodiment, the ultrasonic sensitizer is selected from the group consisting of 5-aminolevulinic acid (5-ALA), protoporphyrin IX (PpIX), hematoporphyrin, rose bengal, curcumin, titanium nanoparticles, chlorin e6, pheobromide-a, ATX-S10 (4-formyloxymethylidene-3-hydroxy-2-vinyl-duterioporfinyl(IX)-6,7-diaspartic acid), photophyllin, DCPH-P-Na(I), NPe6 (mono-l-aspartylchlorin e6), polyhydroxyfullerene, hypocrelin-B, ZnPcS2P2, methylene blue, and sinoporphyrin sodium.

[0027] In one embodiment, the ultrasonic transducer is minimally invasive. In one embodiment, the ultrasonic transducer is configured to be inserted into a natural orifice. In one embodiment, multiple ultrasonic transducer elements are acoustically coupled to the patient via a fluid-filled cavity. In one embodiment, the ultrasonic transducer includes a membrane-free patient interface.

[0028] In various embodiments, systems for applying acoustic mechanical therapy to anatomical structures are disclosed. The system includes an ultrasonic transducer array, each piezoelectric transducer in the array comprising a planar radiating surface configured to emit planar acoustic waves, a patient interface for coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The patient interface is configured to acoustically couple to at least two alignment mechanisms configured to accept predetermined anatomical landmarks of the anatomical structure. The controller is configured to activate an ultrasonic sensitizer in the ultrasonic transducer array within a therapeutic area of ​​the anatomical structure. In one embodiment, the anatomical structure is the patient's head, and the at least two alignment mechanisms are configured to accept predetermined anatomical landmarks of the patient's head. In one embodiment, the predetermined anatomical landmarks include the zygomatic arch, the tip of the mastoid process, the midline of the eyebrow, or a combination thereof. In one embodiment, the patient interface comprises a receptacle that can be releasably coupled to the ultrasonic transducer array. In one embodiment, the receptacle is movable relative to the patient interface between a plurality of predetermined therapeutic positions. In one embodiment, the patient interface comprises spaced receptacles, and the ultrasound transducer array is selectively and releasably coupled to the receptacles to achieve the optimal therapeutic position of the ultrasound transducer array.

[0029] In various embodiments, systems for applying acoustic mechanical therapy to anatomical structures are disclosed. The system includes an ultrasonic transducer array, where each piezoelectric transducer in the piezoelectric transducer array comprises a planar radiating surface configured to emit planar acoustic waves, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The patient interface includes an acoustic coupling membrane configured to conform to the anatomical structure. The controller is configured to activate an ultrasonic sensitizer in the ultrasonic transducer array within a therapeutic area in the anatomical structure.

[0030] In one embodiment, the acoustic coupling membrane is positioned on the exit surface of the ultrasonic transducer array. In one embodiment, the acoustic coupling membrane is an acoustically neutral elastic membrane. In one embodiment, the acoustic coupling membrane defines a portion of the fluid-filled cavity. In one embodiment, the ultrasonic transducer array protrudes from the patient interface toward the cavity. In one embodiment, the cavity can be filled with fluid to a predetermined volume. In one embodiment, the fluid is degassed water. In one embodiment, the fluid is circulated through the cavity. In one embodiment, the fluid is cooled to remove residual heat during treatment.

[0031] In one embodiment, a system is disclosed for applying acoustic mechanical therapy to an anatomical structure, comprising: a planar radiating surface configured to emit planar acoustic waves, each piezoelectric transducer in an array of piezoelectric transducers; a patient interface for acoustically coupling the ultrasonic transducer array to a patient; and a controller coupled to the ultrasonic transducer array. The patient interface is configured to acoustically couple to, for example, at least two alignment mechanisms configured to accept predetermined anatomical landmarks of the anatomical structure. The controller may be configured to activate an ultrasonic sensitizer in the ultrasonic transducer array in a therapeutic area within the anatomical structure. The anatomical structure may be the patient's head (e.g., skull) or other body part, and the at least two alignment mechanisms may be configured to accept predetermined anatomical landmarks of the patient's head. Optionally, the predetermined anatomical landmarks include the zygomatic arch, the tip of the mastoid process, the midline of the eyebrow, or a combination thereof. The patient interface may include a receptacle that can be releasably coupled to the ultrasonic transducer array, and the receptacle may be movable relative to the patient interface between a plurality of predetermined therapeutic positions. The patient interface may also comprise spaced receptacles, and the ultrasonic transducer array may be selectively and releasably coupled to the receptacles to achieve optimal therapeutic positioning for the ultrasonic transducer array. The patient interface optionally includes one or more acoustic coupling membranes configured to conform to anatomical structures. For example, the acoustic coupling membrane may be located on the exit surface of the ultrasonic transducer array and may be an acoustically neutral elastic membrane. In one embodiment, each piezoelectric element has its own coupling membrane. The acoustic coupling membrane may define a conduit or cavity having the patient interface, and the ultrasonic transducer array protrudes from the patient interface toward the conduit or cavity.The acoustic coupling membrane is open and may seal to another patient interface or the patient's skin to form a conduit or cavity, and the ultrasound transducer array protrudes from the patient interface toward the conduit or cavity. The cavity may be fillable with fluid (e.g., up to a predetermined volume). The fluid may include degassed water or other fluids which are circulated through the conduit or cavity and cooled to remove residual heat during processing. Other types of heat sinks or heat shunts may be provided. In some embodiments, ultrasound, when used, activates ultrasound sensitizers (e.g., 5-aminolevulinic acid (5-ALA) and / or protoporphyrin IX (PpIX) or their metabolites, which can be administered orally or by other means) that kill or otherwise damage undesirable tissues, including but not limited to tumor cells that may be cancerous. Ultrasound can be used for such therapeutic purposes (not for imaging or diagnostic purposes). In some embodiments, high-intensity focused ultrasound (HIFU), 2 mm. 3 Acoustic wave focusing to the following areas, focusing to a point within tissue (e.g., 2 mm in tissue, tumor, bone, etc.) 3 Focused ultrasound characterized by being focused to the following points will not be used.

[0032] In various embodiments, an ultrasonic transducer system for applying acoustic dynamics therapy to anatomical structures is disclosed. The system includes an ultrasonic transducer array, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The patient interface includes an array holder that can be coupled to the ultrasonic transducer array. The array holder is adjustable to move the ultrasonic transducer array relative to the patient interface between multiple treatment positions. The controller is configured to activate an ultrasonic sensitizer in the ultrasonic transducer array within a treatment area in the anatomical structure.

[0033] In one embodiment, the controller is configured to receive imaging data and select one of a plurality of treatment locations based on the imaging data. In one embodiment, the ultrasonic transducer system includes a user interface, and the controller is configured to recommend one of a plurality of selected treatment locations via the user interface. In one embodiment, the patient interface includes an acoustic coupling membrane. In one embodiment, the acoustic coupling membrane is located on the exit surface of the ultrasonic transducer array. In one embodiment, the acoustic coupling membrane is an acoustically neutral elastic membrane. In one embodiment, the acoustic coupling membrane forms a seal with the patient. In one embodiment, the acoustic coupling membrane defines a cavity having the patient interface. In one embodiment, the ultrasonic transducer array protrudes from the patient interface toward the cavity. In one embodiment, the cavity can be filled with fluid to a predetermined volume. In one embodiment, the fluid is degassed water. In one embodiment, the volume of fluid in the cavity is selectively adjustable in coordination with the movement of at least one of the array holders to control the position and distance of the ultrasonic transducer array relative to an anatomical structure.

[0034] In various embodiments, systems for applying acoustic mechanical therapy to anatomical structures are disclosed. The system includes an ultrasonic transducer array, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The controller is configured to activate an ultrasonic sensitizer within a therapeutic area within the anatomical structure for each ultrasonic irradiation parameter established by calibrating the ultrasonic transducer array to patient-specific attributes. In one embodiment, the patient-specific attributes are anatomical. In another embodiment, the patient-specific attributes are non-anatomical, such as specific mechanical, acoustic, thermal, and / or properties.

[0035] In various embodiments, the controller is configured to receive image data of anatomical structures and perform calibration of the ultrasonic transducer array based on the image data. In various embodiments, the image data shows thickness measurements of the patient's skull, and the controller is configured to determine whether the thickness measurements are within a predetermined thickness measurement range. In various embodiments, the system further includes a user interface, and the controller is configured to issue a warning via the user interface if one or more determined thickness measurements are outside the predetermined thickness measurement range. In various embodiments, the controller is configured to adjust the input signals of the elements of the ultrasonic transducer array based on the image data. In various embodiments, the controller is configured to adjust the input signals of the elements of the ultrasonic transducer array based on the thickness measurements of the skull portion closest to the element.

[0036] In various embodiments, a system for applying acoustic dynamics therapy to a patient's brain is disclosed. The system includes an ultrasonic transducer array comprising multiple elements, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The controller is configured to select one of the multiple elements of the ultrasonic transducer array for a calibration procedure, generate an ultrasonic pulse using one of the multiple elements, detect the reflection of the ultrasonic pulse on the multiple elements of the ultrasonic transducer array, set the amplitude and frequency of one of the multiple elements based on the reflection to optimize, maximize, and / or modulate the ultrasonic transmission through the patient's skull, and select another of the multiple elements of the ultrasonic transducer array for a calibration procedure.

[0037] In one embodiment, the controller is configured to calculate the minimum distance from one of a plurality of elements to the patient's skull based on the reflection of an ultrasonic pulse. In one embodiment, the minimum distance is the distance from one of the plurality of elements to a portion of the skull adjacent to one of the plurality of elements, and the controller is further configured to calculate the skull thickness in the skull portion based on the reflection of an ultrasonic pulse. In one embodiment, the controller is configured to compare the skull thickness calculated by the controller with a corresponding skull thickness confirmed from skull imaging data. In one embodiment, the amplitude and frequency settings by the controller are based on at least one of the minimum distance and skull thickness. In one embodiment, an appropriate maximum value of ultrasonic transmission through the skull is confirmed based on a predetermined threshold. In one embodiment, the controller is configured to further set the amplitude and frequency of one of the plurality of elements based on reflection to minimize skull heating of the patient's skull during acoustic dynamics therapy. In one embodiment, an appropriate minimum value of skull heating is confirmed based on a predetermined threshold. In one embodiment, the ultrasound is configured to pass through the skull wall perpendicular to the skull surface. In one embodiment, the ultrasound is configured to be focused on the skull wall.

[0038] In one embodiment, an ultrasonic transducer system for applying acoustic dynamics therapy to a patient's brain includes: an ultrasonic transducer array comprising a plurality of elements, each piezoelectric transducer in the piezoelectric transducer array including a planar radiating surface configured to emit planar acoustic waves; a patient interface for acoustically coupling the ultrasonic transducer array to a patient; and a controller coupled to the ultrasonic transducer array, further configured to select at least one of the plurality of elements of the ultrasonic transducer array for a calibration procedure, set at least one of the intensity, amplitude, and frequency of at least one of the plurality of elements based on digital imaging and communication images of the patient's skull, and generate an ultrasonic pulse having at least one of the plurality of elements having at least one of the intensity, amplitude, and frequency. The controller may be configured to calculate skull thickness or skull density based on digital imaging and communication images, and the setting of intensity, amplitude, and / or frequency by the controller is based on skull thickness based on digital imaging and communication images. The controller may be configured to calculate the minimum distance from one of the plurality of elements to the patient's skull based on digital imaging and communication images of the patient's skull. For example, the minimum distance is the distance from one of the elements to the skull portion adjacent to one of the elements, and the controller is further configured to calculate the skull thickness in the skull portion based on digital imaging and communication images. The intensity setting by the controller may be based on at least one of the minimum distance and skull thickness. For example, the appropriate maximum value of ultrasound transmission through the skull may be determined based on a predetermined threshold. At least one of the intensity, amplitude, and frequency is optionally set to minimize heating of the patient's skull during acoustic therapy.In use, according to some such embodiments, the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to activate an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, and to generate an incoherent sound pressure field having an energy profile for activating the ultrasonic sensitizer located within the patient's tissue, wherein the incoherent sound pressure field comprises one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers includes a planar radiating surface configured to emit planar acoustic waves; a patient interface for acoustically coupling the ultrasonic transducer array to the patient; and a controller coupled to the ultrasonic transducer array. Optionally, the patient interfaces with conduits and / or cavities for containing or circulating fluid to remove residual heat during treatment. Other types of heat sinks or heat shunts may be provided. For example, a heat sink can be used to remove residual heat. In another example, a thermoelectric cooler can be used to remove residual heat. Focused ultrasound, featuring high-intensity focused ultrasound (HIFU), 50mm. 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3 The following acoustic waves can be focused to a point within tissue (for example, in tissue, tumor, bone, etc., at 50 mm). 3 , 20mm 3 , 10mm 3 , 5mm 3 , or 2mm 3Ultrasound may be used for therapeutic purposes (not for imaging or diagnostic purposes), as it is focused on the following points. In some embodiments, ultrasound activates ultrasound sensitizers (such as 5-aminolevulinic acid (5-ALA) and / or protoporphyrin IX (PpIX) or their metabolites) that, when used, kill or otherwise damage undesirable tissues, including but not limited to tumor cells that may be cancerous. Ultrasound may be used for therapeutic purposes (not for imaging 5-aminolevulinic acid (5-ALA) and / or protoporphyrin IX (PpIX) or their metabolites, which may be administered orally or by other means).

[0039] The system includes an ultrasonic transducer array containing multiple elements, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The controller is configured to select one of the multiple elements of the ultrasonic transducer array for a calibration procedure, generate a frequency sweep with one of the multiple elements, detect the amplitude of reflected energy at each frequency of the frequency sweep, calculate an optimal frequency for one of the multiple elements which is the frequency that minimizes the reflected energy, set one of the multiple elements to the optimal frequency, and select another of the multiple elements of the ultrasonic transducer array for a calibration procedure.

[0040] In one embodiment, the appropriate minimum value of reflected energy is below a predetermined threshold.

[0041] In one embodiment, the system includes an ultrasonic transducer array comprising a plurality of elements, a patient interface for acoustically coupling the ultrasonic transducer array to a patient, and a controller coupled to the ultrasonic transducer array. The controller is configured to select one of the plurality of elements of the ultrasonic transducer array for a calibration procedure, generate a question signal using one of the plurality of elements, detect a reflected signal in response to the question signal, the reflected signal being reflected by the patient's skull, calculate in-situ variables based on the reflected signal, adjust the irradiation pattern of the ultrasonic transducer array to the patient interface, or both, based on the in-situ variables, and select another of the plurality of elements of the ultrasonic transducer array for a calibration procedure.

[0042] In one embodiment, the controller is further configured to compare in-situ variables calculated by the controller with external data. In one embodiment, the controller is configured to further adjust the irradiation pattern or array arrangement of the ultrasound transducer array to the patient interface, or both, based on the results of the comparison.

[0043] In various embodiments, methods for enhancing the effectiveness of acoustic dynamics therapy are disclosed herein. Acoustic dynamics therapy is configured to treat cells within an anatomical object, the cells having baseline sensitivity to acoustic dynamics therapy, and the method includes: performing complementary therapy on the anatomical object via a complementary therapy system; inducing a preacoustic state within the cells via the complementary therapy system; determining that the preacoustic state exceeds a predetermined threshold, the predetermined threshold being related to improved sensitivity of the cells to acoustic dynamics therapy; administering an ultrasonic sensitizer to the cells within the anatomical object; generating acoustic waves using a transducer via the acoustic dynamics therapy system; and activating the intracellular ultrasonic sensitizer via the acoustic waves.

[0044] In one embodiment, evaluating the preacoustic state includes determining that the preacoustic state exceeds a predetermined threshold, the predetermined threshold being related to the improved sensitivity of cells to acoustic therapy. In one embodiment, the complementary therapy includes immunotherapy. In one embodiment, the complementary therapy includes anti-inflammatory therapy. In one embodiment, the method includes administering microbubbles configured to enhance cavitation. In one embodiment, the method includes administering nanoparticles configured to enhance cavitation.

[0045] In one embodiment, evaluating the preacoustic state includes determining that the preacoustic state exceeds a predetermined threshold, the predetermined threshold being related to the improved sensitivity of cells to acoustic therapy. In one embodiment, complementary therapy includes oxygenation therapy configured to provide supplemental oxygen to cells. In one embodiment, oxygen is delivered to cells via the patient's respiratory system. In one embodiment, oxygen is delivered to cells intravenously into the patient's bloodstream. In one embodiment, oxygenation therapy includes microparticles containing supplemental oxygen, configured to deliver the supplemental oxygen to cells. In one embodiment, the microparticles are specifically configured to target specific locations of cells within anatomical structures. In one embodiment, oxygenation therapy includes extracorporeal membrane oxygenation. In one embodiment, extracorporeal membrane oxygenation includes removing a portion of the patient's blood, oxygenating the removed portion of the blood with supplemental oxygen, and returning the oxygenated portion of the blood to the patient. In one embodiment, oxygenation therapy includes directly injecting supplemental oxygen into target tissue. In one embodiment, oxygenation therapy includes hyperbaric oxygenation. In one embodiment, hyperbaric oxygenation involves delivering oxygen to cells at a pressure exceeding atmospheric pressure. In one embodiment, supplemental oxygenation therapy includes delivering a drug to increase the intracellular oxygen concentration. In one embodiment, the drug includes an antihypoxia drug configured to increase intracellular oxygen levels. In one embodiment, supplemental oxygenation therapy includes reducing cellular metabolism, thereby reducing the rate at which oxygen is used by the cell and increasing intracellular oxygen levels. In one embodiment, the intracellular preacoustic state includes intracellular oxygen levels. In one embodiment, the method includes monitoring the intracellular preacoustic state using a brain oxygen meter. In one embodiment, the brain oxygen meter includes near-infrared spectroscopy. In one embodiment, the method includes monitoring the intracellular preacoustic state using a magnetic resonance imaging device. In one embodiment, the method includes modifying the acoustic therapy at least in part based on the determination that the preacoustic state exceeds a predetermined threshold. In one embodiment, the method includes notifying the clinician that the preacoustic state exceeds a predetermined threshold.In one embodiment, acoustic waves are generated autonomously, at least in part, based on the determination that the pre-acoustic state exceeds a predetermined threshold. In one embodiment, the method includes destroying cells via the activation of an ultrasonic sensitizer. In one embodiment, the method includes destroying cells via the activation of an ultrasonic sensitizer.

[0046] This method includes administering an ultrasound sensitizer to cells within an anatomical target; generating acoustic waves using a transducer via an acoustic dynamics therapy system; activating the ultrasound sensitizer within the cells via the acoustic waves; destroying cells within an anatomical structure via the activation of the ultrasound sensitizer; and inducing an immunotherapeutic effect within the anatomical structure via the activation of the ultrasound sensitizer.

[0047] In one embodiment, the immunotherapeutic effect includes resistance to recurrence of cells within an anatomical structure. The method includes administering an ultrasound sensitizer to cells within an anatomical object, generating acoustic waves using a transducer via an acoustic dynamics therapy system, activating the ultrasound sensitizer within the cells via the acoustic waves, and destroying the cells within the anatomical structure via the activation of the ultrasound sensitizer. In one embodiment, destroying the cells initiates a biological signal. In one embodiment, the biological signal is a damage-associated molecular pattern. In one embodiment, destroying the cells activates an immune response.

[0048] In one embodiment, the ultrasound sensitizer comprises at least one of type-specific ultrasound sensitizers, site-specific ultrasound sensitizers, or wavelength-specific ultrasound sensitizers, or any combination thereof. In one embodiment, the ultrasound sensitizer is specifically configured to target a specific type of cell at a specific location on an anatomical object. In one embodiment, the specific type of cell is at least one of wounds, ulcers, abscesses, or tumors, or any combination thereof. In one embodiment, the acoustic wave comprises a specific wavelength, and the ultrasound sensitizer is specifically configured to respond to the specific wavelength. In one embodiment, the ultrasound sensitizer comprises nanoparticle ultrasound sensitizers configured to produce a desired cytotoxic effect. In one embodiment, the desired cytotoxic effect comprises at least one of reduced toxicity, increased biodegradability, or improved ability to target cells, or any combination thereof. In one embodiment, the ultrasound sensitizer comprises 5-aminolevulinic acid, for example as protoporphyrin IX (PpIX), which accumulates in tumor cells, and ultrasound therapy is applied after accumulation.

[0049] In various embodiments, enhanced acoustic systems configured to treat cells within an anatomical object, wherein the cells include baseline sensitivity to acoustic therapy, are disclosed herein. The system includes: a complementary therapy system configured to induce a preacoustic state within cells; an ultrasonic sensitizer configured to target cells within an anatomical object; an acoustic therapy system configured to generate acoustic waves using a transducer, wherein the acoustic waves are configured to activate the ultrasonic sensitizer within cells; a memory configured to store a predetermined threshold, wherein the predetermined threshold is related to the improved sensitivity of cells to acoustic therapy; and a control circuit coupled to the complementary therapy system and the acoustic therapy system, wherein the control circuit is configured to receive a signal from the complementary therapy system, determine based on the signal whether the preacoustic state exceeds a predetermined threshold, and control the acoustic therapy system to generate acoustic waves at least in part based on the determination that the preacoustic state exceeds the predetermined threshold.

[0050] In another embodiment, the disclosure provides an acoustic irradiation drive pattern for activating an ultrasound sensitizer in conjunction with providing acoustic dynamics therapy. The acoustic irradiation drive pattern generates an incoherent acoustic field for distributing low-intensity energy. The acoustic irradiation drive pattern includes a first acoustic irradiation drive pattern having a first phase, a first frequency, and a first amplitude, and a second acoustic irradiation drive pattern having a second phase, a second frequency, and a second amplitude. At least one of the relative phase difference, frequency, and amplitude of the first and second acoustic irradiation drive patterns is selected to generate a third incoherent acoustic irradiation pattern to activate an ultrasound sensitizer placed in the patient's tissue.

[0051] In one embodiment, the acoustic irradiation drive pattern further includes a fourth acoustic irradiation drive pattern having a fourth phase and a fifth acoustic irradiation drive pattern having a fifth phase, wherein the relative phase difference between the fourth and fifth acoustic irradiation drive patterns is selected to generate a sixth incoherent acoustic irradiation pattern to activate an ultrasonic sensitizer placed in patient tissue, the sixth incoherent acoustic irradiation pattern being different from a third incoherent acoustic irradiation pattern.

[0052] In one embodiment, the acoustic irradiation drive pattern further includes a fourth acoustic irradiation drive pattern having a fourth frequency and a fifth acoustic irradiation drive pattern having a fifth frequency, wherein the relative frequency difference between the fourth and fifth acoustic irradiation drive patterns is selected to generate a sixth incoherent acoustic irradiation pattern to activate an ultrasonic sensitizer placed in patient tissue, the sixth incoherent acoustic irradiation pattern being different from a third incoherent acoustic irradiation pattern.

[0053] In one embodiment, the acoustic irradiation drive pattern further includes a fourth acoustic irradiation drive pattern having a fourth amplitude and a fifth acoustic irradiation drive pattern having a fifth amplitude, wherein the relative amplitude difference between the fourth and fifth acoustic irradiation drive patterns is selected to generate a sixth incoherent acoustic irradiation pattern to activate an ultrasonic sensitizer placed in patient tissue, the sixth incoherent acoustic irradiation pattern being different from a third incoherent acoustic irradiation pattern.

[0054] In one embodiment, the first and second phases are different. In one embodiment, the first and second frequencies are different. In one embodiment, the first and second amplitudes are different. In one embodiment, the first or second acoustic irradiation drive pattern is pulsed. In one embodiment, each of the pulsed first or second acoustic irradiation drive patterns includes a pulse defined by an amplitude having a pulse width shorter than that period and a predetermined number of cycles, pulsed at a certain period. In one embodiment, the pulse includes 10 to 1000 cycles. In one embodiment, the time between pulses is defined as the time to allow for the restoration of local oxygen supply and to regulate the temperature of patient tissue. In one embodiment, the acoustic irradiation drive pattern includes modulating the pulses. In one embodiment, modulating the pulses includes modulating the phase, frequency, or amplitude of the first pulse, or any combination thereof.

[0055] In one embodiment, the phase difference between the first and second acoustic irradiation drive patterns is randomized.

[0056] In one embodiment, the first and second acoustic irradiation drive patterns are frequency modulated. In one embodiment, the first and second acoustic irradiation drive patterns are amplitude modulated. In one embodiment, the first and second acoustic irradiation drive patterns are phase modulated. In one embodiment, the amplitude of the first acoustic irradiation drive pattern is greater than the amplitude of the second acoustic irradiation drive pattern.

[0057] In one embodiment, the disclosure provides a method for generating an acoustic irradiation drive pattern for activating an ultrasonic sensitizer, in conjunction with providing acoustic dynamics therapy. The acoustic irradiation drive pattern generates an incoherent acoustic field for distributing low-intensity energy. The method includes generating a first signal for driving a first ultrasonic transducer element to generate a first acoustic irradiation drive pattern having a first phase, a first frequency, and a first amplitude, and generating a second signal for driving a second ultrasonic transducer element to generate a second acoustic irradiation drive pattern having a second phase, a second frequency, and a second amplitude. At least one of the relative phase difference, frequency, and amplitude of the first and second signals is selected to generate a third incoherent acoustic irradiation pattern for activating an ultrasonic sensitizer located in patient tissue.

[0058] In one embodiment, the first and second phases of the first and second signals are different. In one embodiment, the first and second frequencies of the first and second signals are different. In one embodiment, the first and second amplitudes of the first and second signals are different.

[0059] In one embodiment, the method includes pulsing a first signal, a second signal, or both the first and second signals to generate a pulsed first or second acoustic irradiation drive pattern. In one embodiment, each of the pulsed first or second signals includes a pulse defined by an amplitude having a pulse width shorter than that period and a predetermined number of cycles, with the pulse being pulsed at a certain period. In one embodiment, the pulse includes 10 to 1000 cycles. In one embodiment, the time between pulses is defined as the time to allow for the restoration of local oxygen supply and to regulate the temperature of patient tissue. In one embodiment, the method includes modulating the pulse. In one embodiment, modulating the pulse includes modulating the phase, frequency, or amplitude of the first pulse, or any combination thereof.

[0060] In one embodiment, the method includes randomly selecting the phases of first and second signals, driving first and second ultrasonic transducer elements with the first and second signals, and generating first and second acoustic irradiation patterns having randomized phase differences.

[0061] In one embodiment, the method includes selecting the phase of each element across the array in a randomized manner among the phases and values ​​and ranges within the 0-220 degree range (e.g., 0-45, 0-90, 1-135, 0-180, 0-200, 45-90, 45-135, 45-180, 45-220, 90-135, 90-180, 90-220, 120-220, 120-180, 120-150, 180-220, and / or 200-220 degrees), and then including a variance adjustment to select groups of elements for the remaining 140-360 degree phases (e.g., 140-300, 140-270, 140-225, 140-180, 140-150 degrees and values ​​and ranges within that range).

[0062] In one embodiment, the method includes modulating the frequencies of first and second signals, driving first and second ultrasonic transducer elements with the respective frequency-modulated first and second signals, and generating first and second frequency-modulated acoustic irradiation patterns.

[0063] In one embodiment, the method includes modulating the amplitudes of first and second signals, driving first and second ultrasonic transducer elements with the amplitude-modulated first and second signals, respectively, and generating first and second amplitude-modulated acoustic irradiation patterns.

[0064] In one embodiment, the method includes modulating the phases of first and second signals, driving first and second ultrasonic transducer elements with the respective phase-modulated first and second signals, and generating first and second phase-modulated acoustic irradiation patterns.

[0065] In one embodiment, the method includes varying the amplitudes of a second signal and driving first and second ultrasonic transducer elements by the respective amplitudes of the first and second signals. In one embodiment, the amplitude of the first signal is greater than the amplitude of the second signal.

[0066] In another embodiment, the present disclosure provides a method for enhancing the effectiveness of acoustic dynamics therapy configured to treat cells within an anatomical object, comprising: administering an ultrasonic sensitizer to cells within an anatomical object; generating a plurality of plane acoustic waves using a transducer array via an acoustic dynamics therapy system; activating the intracellular ultrasonic sensitizer via the plurality of plane acoustic waves; destroying cells within an anatomical structure via the activation of the ultrasonic sensitizer; and inducing an immunotherapeutic effect within the anatomical structure via the activation of the ultrasonic sensitizer.

[0067] In one embodiment, the immunotherapeutic effect includes resistance to cell recurrence within anatomical structures.

[0068] In another embodiment, the present disclosure provides a method for enhancing the effectiveness of acoustic dynamics therapy configured to treat cells within an anatomical object, comprising: administering an ultrasonic sensitizer to cells within an anatomical object; generating a plurality of plane acoustic waves using a transducer array via an acoustic dynamics therapy system; activating the intracellular ultrasonic sensitizer via the plurality of plane acoustic waves; and destroying the cells within an anatomical structure via the activation of the ultrasonic sensitizer.

[0069] In one embodiment, the ultrasonic sensitizer comprises at least one of a type-specific ultrasonic sensitizer, a site-specific ultrasonic sensitizer, or a wavelength-specific ultrasonic sensitizer, or any combination thereof. In one embodiment, the ultrasonic sensitizer is particularly configured to target a specific type of cell at a specific location of an anatomical object. In one embodiment, the specific type of cell is at least one of a wound, ulcer, abscess, or tumor, or any combination thereof. In one embodiment, the acoustic wave comprises a specific wavelength, and the ultrasonic sensitizer is particularly configured to respond to the specific wavelength. In one embodiment, the ultrasonic sensitizer comprises a nanoparticle ultrasonic sensitizer configured to produce a desired cytotoxic effect. In one embodiment, the desired cytotoxic effect comprises at least one of reduced toxicity, increased biodegradability, or improved cell targeting ability, or any combination thereof. In one embodiment, the ultrasonic sensitizer comprises 5-ALA, and the ultrasonic sensitizer comprises protoporphyrin IX (PpIX).

[0070] In another embodiment, the Disclosure relates to an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the tissue of a patient, the incoherent sound pressure field comprising one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers comprises a planar radiating surface configured to emit planar acoustic waves, and the ultrasonic transducer The present invention provides an ultrasonic transducer comprising: a patient interface for acoustically coupling an ultrasonic transducer array to a patient, the patient interface comprising at least one of (i) at least two alignment mechanisms configured to accept predetermined anatomical landmarks of an anatomical structure, (ii) an acoustic coupling membrane configured to conform to the anatomical structure, and (iii) an array holder capable of being coupled to an ultrasonic transducer array, wherein the array holder is adjustable to move the ultrasonic transducer array relative to the patient interface between a plurality of therapeutic positions; and an ultrasonic transducer coupled to the ultrasonic transducer array, the controller configured to activate an ultrasonic sensitizer in the ultrasonic transducer array within a therapeutic area in an anatomical structure.

[0071] In another embodiment, the Disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, comprising: a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located within the tissue of a patient; a patient interface for acoustically coupling the ultrasonic transducer array to a patient, comprising at least one of (i) an alignment mechanism configured to accept a predetermined anatomical landmark of an anatomical structure; (ii) an acoustic coupling membrane configured to conform to the anatomical structure; and (iii) an array holder capable of being coupled to the ultrasonic transducer array, wherein the array holder is adjustable to move the ultrasonic transducer array relative to the patient interface between a plurality of treatment locations; and a controller coupled to the ultrasonic transducer array, configured to cause the ultrasonic transducer array to activate an ultrasonic sensitizer within a treatment area in an anatomical structure.

[0072] In another embodiment, the Disclosure relates to an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the tissue of a patient, the incoherent sound pressure field comprising one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers comprises a planar radiating surface configured to emit a planar acoustic wave. The present invention provides an ultrasonic transducer comprising: a plurality of ultrasonic transducer elements; a patient interface for acoustically coupling the ultrasonic transducer array to a patient; and a controller coupled to the ultrasonic transducer array, the controller being configured to select one of the plurality of elements of the ultrasonic transducer array for a calibration procedure, generate an ultrasonic pulse using one of the plurality of elements, detect the reflection of the ultrasonic pulse on the plurality of elements of the ultrasonic transducer array, set the amplitude and frequency of one of the plurality of elements based on the reflection to maximize the ultrasonic transmission through the patient's skull, and select another of the plurality of elements of the ultrasonic transducer array for a calibration procedure.

[0073] In another embodiment, the Disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, the ultrasonic transducer comprising: a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the patient's tissue; a patient interface for acoustically coupling the ultrasonic transducer array to the patient; and a controller coupled to the ultrasonic transducer array, the controller configured to select one of the plurality of elements of the ultrasonic transducer array for a calibration procedure, generate an ultrasonic pulse using one of the plurality of elements, detect reflections of the ultrasonic pulses on the plurality of elements of the ultrasonic transducer array, set the amplitude and frequency of one of the plurality of elements based on the reflections to maximize ultrasonic transmission through the patient's skull, and select another of the plurality of elements of the ultrasonic transducer array for a calibration procedure.

[0074] In another embodiment, the Disclosure relates to an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the tissue of a patient, the incoherent sound pressure field comprising one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers is configured to emit a plane acoustic wave. The present invention provides an ultrasonic transducer comprising a plurality of ultrasonic transducer elements including a surface radiating surface, and an acoustic irradiation driving pattern for activating an ultrasonic sensitizer in connection with providing acoustic dynamics therapy, the acoustic irradiation driving pattern comprising a first acoustic irradiation driving pattern having a first phase, a first frequency, and a first amplitude, and a second acoustic irradiation driving pattern having a second phase, a second frequency, and a second amplitude, wherein at least one of the relative phase difference, frequency, and amplitude of the first and second acoustic irradiation driving patterns is selected to generate a third incoherent acoustic irradiation pattern for activating an ultrasonic sensitizer placed in patient tissue.

[0075] In another embodiment, the Disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located within the patient's tissue, and an acoustic irradiation drive pattern for activating the ultrasonic sensitizer in connection with providing acoustic dynamics therapy, comprising an acoustic irradiation drive pattern that generates an incoherent acoustic field for distributing low-intensity energy and includes a first acoustic irradiation drive pattern having a first phase, a first frequency, and a first amplitude, and a second acoustic irradiation drive pattern having a second phase, a second frequency, and a second amplitude, wherein at least one of the relative phase difference, frequency, and amplitude of the first and second acoustic irradiation drive patterns is selected to generate a third incoherent acoustic irradiation pattern for activating an ultrasonic sensitizer located within the patient's tissue.

[0076] In another embodiment, the Disclosure relates to an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the tissue of a patient, the incoherent sound pressure field comprising one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transformer in the array of piezoelectric transducers The present invention provides an ultrasonic transducer comprising: a plurality of ultrasonic transducer elements including a planar radiating surface configured to emit planar acoustic waves; and a complementary therapy system configured to perform complementary therapy on an anatomical object by administering an ultrasonic sensitizer to cells in an anatomical object via an acoustic therapy system, by generating acoustic waves using the transducer, and by activating the intracellular ultrasonic sensitizer via acoustic waves, by administering an ultrasonic sensitizer to cells in an anatomical object via an acoustic therapy system, by inducing an intracellular preacoustic state, and by evaluating whether the preacoustic state corresponds to improved sensitivity of cells to acoustic therapy.

[0077] In another embodiment, the present disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, comprising: a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located within the tissue of a patient; and a complementary therapy system configured to perform complementary therapy on an anatomical object by administering an ultrasonic sensitizer to cells within an anatomical object by inducing a preacoustic state within cells via the acoustic therapy system, by activating the intracellular ultrasonic sensitizer via acoustic waves by generating acoustic waves using the transducer via the acoustic therapy system, and by evaluating whether the preacoustic state corresponds to improved sensitivity of cells to acoustic dynamics therapy.

[0078] In another embodiment, the Disclosure relates to an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, wherein the ultrasonic transducer comprises a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located in the tissue of a patient, the incoherent sound pressure field comprising one or more of the following: a randomized phase difference across the plurality of ultrasonic transducer elements, a modulation frequency across the plurality of ultrasonic transducer elements, and a modulation amplitude across the plurality of ultrasonic transducer elements, and each piezoelectric transducer in the array of piezoelectric transducers emits a plane acoustic wave. The present invention provides an ultrasonic transducer comprising: a plurality of ultrasonic transducer elements including a planar radiating surface configured to induce a preacoustic state within a cell; a complementary therapy system configured to induce a preacoustic state within a cell; an ultrasonic sensitizer configured to target cells within an anatomical object; an acoustic dynamics therapy system configured to generate sound waves using the transducer, wherein the sound waves are configured to activate the ultrasonic sensitizer within the cell; a memory configured to store a predetermined threshold, wherein the predetermined threshold is associated with an improved sensitivity of cells to acoustic dynamics therapy; and a control circuit coupled to the complementary therapy system and the acoustic dynamics therapy system. In one embodiment, the control circuit is configured to determine whether the preacoustic state exceeds a predetermined threshold. In one embodiment, the control circuit is configured to receive a signal from the complementary therapy system and, based on the signal, determine whether the preacoustic state exceeds a predetermined threshold. In one embodiment, the control circuit is configured to control the acoustic dynamics therapy system to generate sound waves, at least in part, based on the determination that the preacoustic state exceeds a predetermined threshold.

[0079] In another embodiment, the Disclosure provides an ultrasonic transducer for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, comprising: a plurality of ultrasonic transducer elements arranged in an array configured to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer located within the tissue of a patient; a complementary therapy system configured to induce a preacoustic state within a cell; an ultrasonic sensitizer configured to target cells within an anatomical object; an acoustic dynamics therapy system configured to generate sound waves using the transducer, wherein the sound waves are configured to activate an ultrasonic sensitizer within a cell; a memory configured to store a predetermined threshold, wherein the predetermined threshold is associated with an improved sensitivity of cells to acoustic dynamics therapy; and a control circuit coupled to the complementary therapy system and the acoustic dynamics therapy system, wherein the control circuit is configured to receive a signal from the complementary therapy system, determine based on the signal whether the preacoustic state exceeds a predetermined threshold, and control the acoustic dynamics therapy system to generate sound waves at least in part based on the determination that the preacoustic state exceeds a predetermined threshold.

[0080] In another embodiment, the present disclosure relates to a compound of formula (I) to increase the production of protoporphyrin IX, so that the protoporphyrin IX is preferentially accumulated in cancer, and so that the protoporphyrin IX is activated to produce reactive oxygen species (ROS), thereby inducing apoptosis in multiple cancer cells: JPEG0007884503000001.jpg1321(I) The use of a cooling fluid further includes providing a cooling fluid for the patient by circulating it through a membrane configured to conform to the patient's skin surface.

[0081] In another embodiment, the present disclosure relates to a compound of formula (I) to a patient with cancer: JPEG0007884503000002.jpg1321(I), To instruct the oral administration of a prodrug containing, wherein the prodrug results in increased production of the compound of formula (II), JPEG0007884503000003.jpg2323(II), The present invention provides the use of a compound of formula (I), comprising: directing the compound of formula (ii) to preferentially accumulate in the cancer; activating the compound of formula (ii) to produce reactive oxygen species (ROS), thereby inducing apoptosis in multiple cancer cells; and cooling the patient by circulating a cooling fluid through a membrane configured to conform to the patient's skin surface.

[0082] In another embodiment, the present disclosure relates to a compound of formula (I) to a patient with cancer: JPEG0007884503000004.jpg1321(I), The present invention provides a method for treating cancer with a compound of formula (I), comprising: directing the oral administration of a prodrug comprising 5-aminolevulinic acid (5-ALA), wherein the 5-ALA results in increased production of protoporphyrin IX, which is preferentially accumulated in the cancer; activating the protoporphyrin IX to produce reactive oxygen species (ROS), thereby inducing apoptosis in multiple cancer cells; and cooling the patient by circulating a cooling fluid through a membrane configured to conform to the patient's skin surface.

[0083] In one embodiment, the skin surface to be cooled is the head, and activation of protoporphyrin IX maintains the temperature of multiple cancer cells below 45°C, causing necrotic cell death of multiple cancer cells while preserving healthy tissue. In one embodiment, administration of 5-ALA increases the heme biosynthesis pathway stepwise. In one embodiment, protoporphyrin IX accumulates in multiple cancer cells and converts dissolved molecular oxygen into reactive oxygen species. In one embodiment, protoporphyrin IX becomes cytotoxic when producing the reactive oxygen species. In one embodiment, activation of protoporphyrin IX includes sonoluminescence. In one embodiment, activation of protoporphyrin IX includes pyrolysis. In one embodiment, the method further includes oxygenating multiple cancer cells. In one embodiment, the method further includes treating the area surrounding multiple cancer cells to reduce the recurrence of malignant tumors. In one embodiment, protoporphyrin IX accumulates in glioblastoma multiforme (GBM) in the brain. In one embodiment, protoporphyrin IX accumulates in multiple cancer cells of a cancer selected from the group consisting of cancers of the brain, lung, breast, stomach, liver, pancreas, intestine, rectum, vagina, testis, prostate, or cervix. In one embodiment, activating protoporphyrin IX maintains the temperature of the multiple cancer cells below 43°C, causing thermal damage to the multiple cancer cells. In one embodiment, activating protoporphyrin IX results in a non-thermal excision treatment with time-averaged intensity without raising the temperature of healthy tissue in a treatment area above 43°C. In one embodiment, the method includes measuring the temperature of a cooling fluid. In one embodiment, the method includes measuring the temperature of the skin surface. In one embodiment, the method includes measuring the temperature of multiple cancer cells. In one embodiment, the method includes cooling the patient before activating protoporphyrin IX. In one embodiment, the method includes cooling the patient before treating the cancer. In one embodiment, cooling the patient prevents the temperature of the cooling fluid from rising. In some embodiments, one or more sensors are used to measure temperature and / or other parameters.Automatic shutoff and / or notification are provided, in one embodiment, based on sensor information (for example, when the temperature exceeds a certain point). [Brief explanation of the drawing]

[0084] The following drawings illustrate specific aspects (e.g., embodiments) of the present disclosure and are not intended to limit the scope of the appended claims. The drawings are intended to be used in conjunction with the descriptions herein. The disclosed aspects are described below in conjunction with the appended drawings, and similar reference numerals indicate similar elements.

[0085] [Figure 1] This is a perspective view of a transcranial acoustics therapy device having a shell with a plurality of transducers and a cooling system positioned above the patient's head, according to at least one aspect of the present disclosure.

[0086] [Figure 2] This is a perspective view of a transcranial acoustics therapy device having a plurality of transducers and a cooling system positioned over a patient's head, according to at least one aspect of the present disclosure.

[0087] [Figure 3] A partial fractured view of a transcranial acoustics therapy device positioned over a patient's head, showing a partial view of a plurality of transducers according to at least one aspect of the present disclosure.

[0088] [Figure 4] This is a schematic diagram of a transducer having a lens defining a concave surface, according to at least one aspect of the present disclosure.

[0089] [Figure 5] This is a schematic diagram of a transducer having a lens defining a convex surface, according to at least one aspect of the present disclosure.

[0090] [Figure 6]This is a schematic diagram of a transducer having a plurality of elements that can be individually excited to generate various acoustic waves, such as convergent, divergent, and / or plane acoustic waves, according to at least one aspect of the present disclosure.

[0091] [Figure 7] This is a bottom view of a transducer having an inner element surrounded by a concentric ring, according to at least one aspect of the present disclosure.

[0092] [Figure 8] This is a bottom view of a transducer having inner elements arranged in a two-dimensional (2D) grid array, according to at least one aspect of the present disclosure.

[0093] [Figure 9] This is a diagram of two constructively interfering, delay-free acoustic ultrasonic pulses according to at least one aspect of the present disclosure.

[0094] [Figure 10] This is a diagram of a pulse packet consisting of a sinusoidal signal modulated by a Gaussian pulse signal, according to at least one aspect of the present disclosure.

[0095] [Figure 11] A partial fractured view of a transcranial acoustic therapy device positioned on the head of a patient, showing a partial view of the patient's skull and brain, and a plurality of transducers, each having one transducer that releases energy into the patient's brain, according to at least one aspect of the present disclosure.

[0096] [Figure 12] This is a chart showing intensity transmittance ratios across multiple frequencies, relating to at least one aspect of the present disclosure.

[0097] [Figure 13]This is a chart showing the transmittance and reflectance ratio in millimeters for a skull thickness at 1 MHz, according to at least one aspect of the present disclosure.

[0098] [Figure 14] This is a chart showing the transmittance and reflectance ratio at 1 MHz with respect to skull thickness at wavelength, according to at least one aspect of the present disclosure.

[0099] [Figure 15] This is a chart showing the intensity transmittance ratio as a function of frequency, relating to at least one aspect of the present disclosure.

[0100] [Figure 16] A chart showing the reflectance ratio as a function of frequency, relating to at least one aspect of the present disclosure.

[0101] [Figure 17] This is a chart showing the field intensity of a plane wave applied to a multi-tissue skull model, relating to at least one aspect of the present disclosure.

[0102] [Figure 18] This is a chart showing the energy absorption rates of a newly excised human skull at multiple frequencies, relating to at least one aspect of the present disclosure.

[0103] [Figure 19] A partial break diagram of a transcranial acoustics therapy device positioned over a patient's head, showing a partial diagram of a plurality of transducers and an overall diagram of a cooling system, relating to at least one aspect of the present disclosure.

[0104] [Figure 20] This is a perspective view of a patient interface relating to at least one aspect of the present disclosure.

[0105] [Figure 21]This is a schematic diagram of a patient interface having a fluid-filled bonding membrane according to at least one aspect of the present disclosure.

[0106] [Figure 22] This chart shows a relative sensitivity plot of an infrared (IR) temperature sensor according to at least one aspect of the present disclosure.

[0107] [Figure 23] This is a block diagram of a general non-invasive acoustic dynamics therapy system according to at least one aspect of the present disclosure.

[0108] [Figure 24] Figure 18 is an explanatory diagram of an acoustic dynamics therapy system according to at least one aspect of this disclosure.

[0109] [Figure 25] These are schematic diagrams of the acoustic dynamics therapy system shown in Figures 18 and 19, relating to at least one aspect of this disclosure.

[0110] [Figure 26] This is a schematic diagram of an acoustic dynamics therapy system having separate transmitting and receiving transducers, according to at least one aspect of the present disclosure.

[0111] [Figure 27] This is a schematic diagram of an acoustic dynamics therapy system having a single transmit and receive transducer, according to at least one aspect of the present disclosure.

[0112] [Figure 28] This is a diagram of a coherent driving field according to at least one aspect of the present disclosure.

[0113] [Figure 29] This is a diagram of an incoherent field relating to at least one aspect of the present disclosure.

[0114] [Figure 30] This is a diagram of pulse therapy according to at least one aspect of the present disclosure.

[0115] [Figure 31] This is a diagram of pulse therapy according to at least one aspect of the present disclosure.

[0116] [Figure 32] This is a logic flow diagram for generating a sound wave processing drive pattern for acoustic dynamics therapy, according to at least one aspect of the present disclosure.

[0117] [Figure 33] An array of ultrasonic transducer elements arranged in an Archimedean spiral (e.g., a linear spiral) according to at least one aspect of the present disclosure.

[0118] [Figure 34] A sunflower helical array of ultrasonic transducer elements according to at least one aspect of the present disclosure.

[0119] [Figure 35] A sunflower spiral array of ultrasonic transducer elements according to at least one aspect of the present disclosure, wherein additional ultrasonic transducer elements are added to the outer region of the sunflower spiral.

[0120] [Figure 36] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 256 elements skipped every two elements, according to at least one aspect of the present disclosure.

[0121] [Figure 37] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 384 elements skipped every three elements, according to at least one aspect of the present disclosure.

[0122] [Figure 38] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 512 elements, skipping every four elements, according to at least one aspect of the present disclosure.

[0123] [Figure 39] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 640 elements, skipping every five elements, according to at least one aspect of the present disclosure.

[0124] [Figure 40] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 768 elements, skipping every six elements, according to at least one aspect of the present disclosure.

[0125] [Figure 41] A sparse sunflower spiral array comprising 128 active ultrasonic transducer elements arranged on a grid of 896 elements skipped every seven elements, according to at least one aspect of the present disclosure.

[0126] [Figure 42] An array comprising 128 active ultrasonic transducer elements arranged randomly and irregularly in a non-uniform distribution, according to at least one aspect of the present disclosure.

[0127] [Figure 43] An array of concentrically arranged active ultrasonic transducer elements, having additional active ultrasonic transducer elements located on the outer portion of the outer ring, according to at least one aspect of the present disclosure.

[0128] [Figure 44] An array of concentrically arranged ultrasonic transducer elements according to at least one aspect of the present disclosure.

[0129] [Figure 45] This disclosure shows several uniform element packing techniques for arranging ultrasonic transducer elements according to at least one aspect of this disclosure.

[0130] [Figure 46] A 3 mm diameter transducer aperture replaced by four 1 mm diameter aperture elements according to at least one aspect of the present disclosure.

[0131] [Figure 47] This is a side view of a 2D matrix array of ultrasonic transducer elements configured to generate a steering beam, according to at least one aspect of the present disclosure.

[0132] [Figure 48] This is an end view of the 2D matrix array shown in Figure 42A, relating to at least one aspect of the present disclosure.

[0133] [Figure 49] This is a logic flow diagram for calibrating an ultrasonic transducer array in an acoustic dynamics therapy system, according to at least one aspect of the present disclosure.

[0134] [Figure 50] This is a logic flow diagram for calibrating an ultrasonic transducer array in an acoustic dynamics therapy system, according to at least one aspect of the present disclosure.

[0135] [Figure 51] This is a logic flow diagram for calibrating an ultrasonic transducer array in an acoustic dynamics therapy system, according to at least one aspect of the present disclosure.

[0136] [Figure 52] A graph showing a chirp signal according to at least one aspect of the present disclosure.

[0137] [Figure 53] A graph showing an enveloped chirp signal according to at least one aspect of the present disclosure.

[0138] [Figure 54] A graph showing a square ping signal according to at least one aspect of the present disclosure.

[0139] [Figure 55] A graph showing a smoothed ping signal according to at least one aspect of the present disclosure.

[0140] [Figure 56] A graph showing an impulse signal, relating to at least one aspect of this disclosure.

[0141] [Figure 57] A graph showing an impulse input signal and first and second echoes with time delays, relating to at least one aspect of the present disclosure.

[0142] [Figure 58] This is a flowchart of a method for using complementary and / or adjunctive therapies to enhance the effectiveness of acoustic dynamics therapy, according to at least one aspect of the present disclosure.

[0143] [Figure 59] This is a flowchart of a method for using supplemental oxygen therapy to enhance the effectiveness of acoustic dynamics therapy, according to at least one aspect of the present disclosure.

[0144] [Figure 60] This is a flowchart of a method for using immunotherapy to enhance the effectiveness of acoustic dynamics therapy, according to at least one aspect of the present disclosure.

[0145] [Figure 61]This is a block diagram of a block diagram showing various therapeutic ultrasound sensitizers configured to enhance the effectiveness of acoustic dynamics therapy, according to at least one aspect of the present disclosure.

[0146] [Figure 62] This is a schematic bottom view of an ultrasonic transducer system according to at least one aspect of the present disclosure.

[0147] [Figure 63] This is a schematic isometric view of an ultrasonic transducer system according to at least one aspect of the present disclosure.

[0148] [Figure 64] Figure 56 is a schematic side cross-sectional view of the ultrasonic transducer system.

[0149] [Figure 65] This is an enlarged view of section 58-58 shown in Figure 57.

[0150] [Figure 66] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 67] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 68] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 69] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 70]This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 71] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure.

[0151] [Figure 72] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 73] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 74] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 75] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 76] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 77] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 78] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 79]This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 80] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure. [Figure 81] This is a schematic image of the arrangement of an ultrasound transducer system at multiple locations around the head for the treatment of overlapping tissues within the head, according to at least one aspect of the present disclosure.

[0152] [Figure 82] This is a schematic image of a targeted template in which markers are placed on the patient to facilitate the alignment of the transducer to various treatment sites, according to various embodiments. [Figure 83] This is a schematic image of a targeted template in which markers are placed on the patient to facilitate the alignment of the transducer to various treatment sites, according to various embodiments.

[0153] [Figure 84] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 85] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 86] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 87] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 88]This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 89] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 90] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 91] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 92] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure. [Figure 93] This is a schematic image of the arrangement of an ultrasonic transducer system at multiple locations around the head using a targeted template according to at least one aspect of the present disclosure.

[0154] [Figure 94] This is a schematic image of an embodiment of an acoustic dynamics therapy system having a transducer array, support arms, cart, console / controller, ultrasound generator, user interface, and / or cooling fluid circulation unit. [Figure 95] This is a schematic image of an embodiment of an acoustic dynamics therapy system having a transducer array, support arms, cart, console / controller, ultrasound generator, user interface, and / or cooling fluid circulation unit. [Figure 96] This is a schematic image of an embodiment of an acoustic dynamics therapy system having a transducer array, support arms, cart, console / controller, ultrasound generator, user interface, and / or cooling fluid circulation unit.

[0155] Similar reference symbols represent corresponding parts throughout the whole. [Modes for carrying out the invention]

[0156] Before proceeding to describe the drawings, this disclosure will first move to a general description of various aspects of non-invasive acoustic dynamics therapy systems. In some embodiments, this disclosure relates to a system for acoustic dynamics therapy comprising, or essentially comprising, a transducer, a patient interface for acoustically coupling the transducer to a patient, and a controller coupled to the transducer. The controller is configured to generate an electrically driven signal from a set of modulated acoustic wave parameters, modulate the driven signal, and drive the transducer at a certain frequency by the modulated driven signal to generate a modulated acoustic wave, which generates an acoustic intensity sufficient to activate an ultrasonic sensitizer in the treatment area. In some embodiments, the non-invasive therapy system is not implanted in the patient. In other embodiments, a minimally invasive system is provided.

[0157] In another aspect, the disclosure relates to another system for acoustic dynamics therapy. The system comprises a first transducer, a second transducer, and a controller coupled to the first and second transducers. The controller is configured to generate a first electrically driven signal from a set of modulated acoustic wave parameters, a second electrically driven signal from a set of modulated acoustic wave parameters, to drive the first transducer with the first electrically driven signal to generate a first acoustic wave, and to drive the second transducer with the second electrically driven signal to generate a second acoustic wave. The first and second acoustic waves can be combined to produce an acoustic intensity sufficient to activate an ultrasonic sensitizer in a therapeutic area.

[0158] In yet another aspect, the disclosure relates to yet another system for acoustic dynamics therapy. The system comprises, or essentially consists of, a plurality of transducers and a controller coupled to the plurality of transducers. The controller is configured to generate a plurality of electrically driven signals from a set of modulated acoustic wave parameters and to drive the plurality of transducers with the plurality of electrically driven signals to generate a plurality of modulated acoustic waves. The plurality of modulated acoustic waves can be combined to produce an acoustic intensity sufficient to actuate an ultrasonic sensitizer in a therapeutic area.

[0159] The following description provides examples of the application of non-invasive acoustic dynamics therapy techniques for treating tissues such as tumors in the body, including, but not limited to, the brain, spine, lungs, breasts, mouth, tongue, stomach, liver, pancreas, intestines, rectum, colon, vagina, ovaries, testes, leukemia, and lymphoma, regardless of whether the tumors are malignant or non-malignant. However, it will be understood that such techniques can be applied to treat tumors or unwanted tissues / cells in other parts of the body. For example, cancerous tissues of the lungs, breasts, colorectal region, prostate, and pancreas can be treated using some of the embodiments described herein, for example, with one or more ultrasound sensitizers together with the ultrasound parameters described herein. Tumors that are difficult to access, including those surrounded by bone structures, can be treated in various embodiments, including, but not limited to, spinal tumors. Treatment of unwanted tissues in joints and other orthopedic applications are also provided herein.

[0160] In some embodiments, acoustic dynamics therapy is used herein to improve the efficiency of chemotherapy molecules, sonoporation, and / or gene delivery. In various embodiments, 8, 10, 15, and 20 W / cm² are applied to cancer tissue. 2 (For example, 0.1~8W / cm²) 2 , 0.1~4W / cm 2 , 0.5~5W / cm 2Acoustic therapy using an ultrasound array delivering a time-averaged intensity output of less than (etc.) can induce and activate ultrasound sensitizers at relatively deep depths within the patient's body, with or without cavitation and / or thermal effects and / or sonoluminescence, thereby generating reactive oxygen species, intracellular singlet oxygen and / or free radicals in a cascade of events that activate the ultrasound sensitizers and ultimately damage cancer cells. In various embodiments, acoustic therapy can be used with or without photodynamic therapy.

[0161] Some embodiments described herein are used synergistically with other cancer therapies, including, for example, radiation, chemotherapy, and cell therapy. In one embodiment, the combination of ultrasound and ultrasound sensitizer described herein reduces or eliminates the need for one or more additional complementary therapies. For example, when treating cancerous tissue with the combination of ultrasound and ultrasound sensitizer described herein, lower doses or fewer additional therapies such as chemotherapy, radiation, and cell therapy may be required, thus enhancing patient care and reducing side effects.

[0162] The applicant of this application owns the following PCT international patent applications, the disclosures of which are incorporated herein by reference in their entirety: (1) PCT international application PCT / US2015 / 010053, now U.S. Patent No. 10,675,482, filed on 2 January 2015, entitled Device and Method For Use Of Photodynamic Therapy; (2) PCT international application PCT / US2019 / 045802, entitled Tissue Treatment with Sensitizer and Light and / or Sound, filed on 8 August 2019; (3) PCT international application PCT / US2020 / 017983, entitled Non-Invasive Sonodynamic Therapy, filed on 12 February 2020.

[0163] Referring here to Figure 1, the human skull can vary depending on sex and anatomical location. One aspect of the present disclosure provides a non-invasive acoustic dynamics therapy device 100 as shown in Figure 1. The non-invasive acoustic dynamics therapy device 100 may comprise a shell 110 having transducers 150 that can provide predictable and consistent irradiation and / or irradiation despite these variations. The shell 110 may include a rigid material. The known relative positions of the transducers 150 can enable imaging of the head, even at low resolution using large transducers 150. In one embodiment, the illustrated embodiment may include a movable stand for holding the patient in a fixed position while the patient is waiting in a seated or supine position. In one embodiment, the rigid shell 110 may be a lightweight helmet that can be worn by the patient during treatment, enabling predictable placement of the transducers 150 with little infrastructure requirement. In one embodiment, the rigid shell 110 may be part of a positionable system attached to an arm and / or movable stand.

[0164] The non-invasive acoustic dynamics therapy device 100 may comprise a flexible shell 110 (e.g., a helmet) having transducers 150 positioned on a liquid-cooled cranial cap 160, as further described elsewhere in this specification, requiring little to no infrastructure to support the array of transducers 150. While the patient awaits the completion of treatment, it may be possible for the patient to wear the cranial cap 160 and shell 110 in any chair. The lightweight design minimizes neck pain caused by the patient holding their head up for extended periods due to the weight of the transducers 150 and cooling cap. The flexible shell 110 can conform to the shape of each skull. Such a device can accommodate subtle variations between treatments depending on the shape of each patient's head, which may further curve some of the transducers 150 inward or outward.

[0165] The non-invasive acoustic dynamics therapy device 100 may comprise a rigid or flexible patch having several transducers 150 that can be detachably applied to the head. Such embodiments may include the clinician applying each patch individually. Having separate patches allows for some degree of treatment flexibility without the need to individually plan and position each transducer 150. The exemplary non-invasive acoustic dynamics therapy device 100 can minimize the pain caused by repeatedly attaching the patches to the head, which may be of particular concern to older and sickly patients.

[0166] The non-invasive acoustic dynamics therapy device 100 may comprise a patch having a single transducer 150 that can be detachably applied to the head. Individual transducers 150 can offer the highest level of therapeutic flexibility. Such a device may include a detailed process for applying and planning the transducer 150. Considering the further flexibility, the exemplary non-invasive acoustic dynamics therapy device 100 can address greater efficacy risks.

[0167] As shown in Figure 2, the size and shape of the transducer 150 can vary across the various disclosed embodiments. For cost-effective and simple systems, larger transducers 150 that generate directional acoustic waves can be used. As further described elsewhere in this specification, the directivity of the large transducers 150 can be reduced by applying acoustic lenses that bend acoustic waves to each transducer 150. For systems that can be fitted to a head, smaller transducers 150 that can radiate more broadly than larger transducers 150 can be used. Such small transducers 150 can have a greater ability to image or beam steer as an array.

[0168] Figure 3 is a partial breakaway of a transcranial acoustics therapy device 100 positioned over a patient's head, showing a partial view of a plurality of transducers 150 according to at least one aspect of the present disclosure. Instead of focusing the acoustic waves 200 into a small point, the acoustic waves 200 can be defocused to minimize spatial fluctuations in acoustic wave intensity within the brain.

[0169] In various embodiments, the size and / or shape of the transducer 150 and / or one or more lenses can cause each transducer 150 to be non-focused or focused. In various embodiments, the size and shape of the transducer elements can cause each transducer element to be non-focused or focused. As used herein (unless otherwise stated), the term focused refers to an acoustic wavefront that converges more than the wavefront produced by the transducer 150 having a planar radiating surface, and the term non-focused refers to an acoustic wavefront that diverges more than the wavefront produced by the transducer 150 having a planar radiating surface. Whether the lens needs to be concave or convex to cause the wave to diverge more depends on whether the acoustic wave is transitioning from a low acoustic impedance region to a high acoustic impedance region, or from a high acoustic impedance region to a low acoustic impedance region. In this regard, if the lens is composed of a material with a higher acoustic impedance than the medium of interest (water / tissue), the acoustic wave originates from the high-impedance material and transitions to the low-impedance medium of interest. When a lens is concave, it "focuses" the sound waves, making them more concentrated. When a lens is convex, it "defocuses" the sound waves, causing them to diverge more.

[0170] Figure 4 is a schematic diagram of a transducer 150 having a lens 302 defining a concave surface 304, according to at least one aspect of the present disclosure. The lens 302 may be acoustically coupled to the transducer 150 or may be integrally formed with the transducer. In the illustrated example, the lens 302 is made of a material having a higher acoustic impedance than the target medium (water / tissue) so that acoustic waves 306 originate from a high-impedance material and transition to a low-acoustic-impedance target medium, "focusing" or converging the acoustic waves 306 onto the target tissue. In one embodiment of the illustrated example, the lens 302 is made of a material having a higher acoustic impedance than the target medium (water / tissue) so that acoustic waves 306 originate from a high-impedance material and transition to a low-acoustic-impedance target medium, "focusing" or converging the acoustic waves 306 onto the target tissue.

[0171] Figure 5 is a schematic diagram of a transducer 150 having a lens 308 defining a convex surface 310, according to at least one aspect of the present disclosure. The lens 308 may be acoustically coupled to the transducer 150 or may be integrally formed with the transducer. In the illustrated example, the lens 308 is made of a material with a higher acoustic impedance than the target medium (water / tissue). Thus, the acoustic wave 312 originates from the high-impedance material and transitions to the low-acoustic-impedance target medium, causing the acoustic wave 312 to be "unfocused" or diverged to the target tissue. In one embodiment of the illustrated example, the lens 308 is made of a material having a higher acoustic impedance than the target medium (water / tissue). Thus, the acoustic wave 312 originates from the high-impedance material and transitions to the low-acoustic-impedance target medium, causing the acoustic wave 312 to be "unfocused" or diverged to the target tissue.

[0172] The focus of transducer 150 also depends on the material and shape of the lens (not shown). The focus blur of transducer 150 also depends on the material and shape of the lens (not shown). Using lenses 302, 308 allows transducer 150 to be flattened, which can minimize manufacturing costs. Both lens 302 having a concave surface 304 and lens 310 having a convex surface 310 may be configured to produce a fixed focus. In one embodiment, both lens 302 having a concave surface 304 and lens 310 having a convex surface 310 may be configured to produce a fixed focus or a beam-expanding focus. In one embodiment, lens 302 having a concave surface 304 and lens 310 having a convex surface 310 may be configured to produce an unfocused beam.

[0173] It may be possible to manufacture lenses whose shape can be adjusted to produce different focal points. It may be possible to create elastic fluid-filled pockets that function as lenses. In one embodiment, the fluid-filled pocket is configured to focus acoustic waves. In one embodiment, the fluid-filled pocket is configured to diverge acoustic waves. In one embodiment, the fluid-filled pocket does not affect the focusing or divergence of acoustic waves. In one embodiment, the fluid-filled pocket does not affect plane acoustic waves. Fluid can be pumped into or out of the lens to adjust the shape of the pocket, and therefore the focus of the transducer.

[0174] Figure 6 is a schematic diagram of a transducer 150 having a plurality of elements 150a to 150h that can be individually excited to generate various sound waves, according to at least one aspect of the present disclosure. As shown in Figure 6, the plurality of transducer elements 150a to 150h are arranged in an array to generate convergent, divergent, or planar acoustic waves. In one embodiment, one or more of the individual elements 150a to 150h include a flat planar radiating surface that generates planar acoustic waves. In various embodiments, one or more elements in the array (e.g., 1, 5, 10, 20, 50, 100, 200, 250, 256, 300, 500, 1000, or more, and in some embodiments, all) include a flat planar radiating surface. In some embodiments, the array essentially consists of flat planar radiating surfaces ranging from, for example, 150 to 350 elements, 100 to 300 elements, 200 to 300 elements, and 800 to 1200 elements, as well as values ​​and ranges within them. In one embodiment, the array of flat planar radiating surfaces is arranged on a flat array. In one embodiment, the array of flat planar radiating surfaces is arranged with a curvature configured to direct each flat element in the array to radiate planar acoustic waves perpendicular to a body surface such as the skull or other bony structures. In some embodiments, the abdomen, back, waist, shoulders, or other body structures are treated. In various embodiments, for example, transducer elements 150a to 150h can be operated in a predetermined order to selectively generate convergent / divergent / planar acoustic waves, such as convergent acoustic waves 314 shown in Figure 4, or divergent acoustic waves 312 shown in Figure 5. To generate the converged acoustic wave 314, for example, the outer transducer elements 150a and 150h are excited first, and after a time delay, the adjacent inner transducer elements 150b and 150g are excited.In various embodiments, the time delay is in the range of 0.1 μs to 10 s, including 0.1 μs, 0.2 μs, 0.3 μs, 0.4 μs, 0.5 μs, 1 μs, 5 μs, 10 μs, 15 μs, 20 μs, 25 μs, 30 μs, 35 μs, 40 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 0.1 ms, 0.2 ms, 0.3 ms, 0.4 ms, 0.5 ms, 1 ms, 5 ms, 10 ms, 50 ms, 100 ms, 500 ms, 1 s, 2 s, 5 s, and 10 s, as well as any value and range within them. The next adjacent inner transducer elements 150c, 150f are excited after a second time delay. Finally, the inner transducer elements 150d, 150e are excited after a third time delay. This pattern can be repeated to generate a convergent acoustic wave 314. The first, second, and third time delays may be equal or different to generate more complex acoustic waves. Alternatively, transducer elements 150a to 150h may be excited in reverse order to generate divergent acoustic waves using equal or different time delays. Transducer elements 150a to 150h may be configured interchangeably to transmit or receive acoustic waves.

[0175] Figure 7 is a bottom view of a transducer 400 having an inner element 420 surrounded by a concentric ring 410, according to at least one aspect of the present disclosure. In one embodiment, the inner element 420 is surrounded by the concentric element 410. Each transducer 150 can be adapted and configured to generate acoustic waves with variable focus. One way to achieve this is that each transducer 400 may have a concentric ring 410 (e.g., an annular array), as shown in Figure 7. Each concentric ring 410 can be driven by a different signal. In one embodiment for focusing acoustic waves, the signal directed toward the inner element 420 may be gradually delayed compared to the signal outside the concentric ring 410. Acoustic waves from each concentric ring 410 may converge at a certain point. In one embodiment for defocusing acoustic waves arriving from an annular array, the acoustic waves outside the concentric ring 410 may be gradually delayed relative to the inner element 420. One way to fabricate an embodiment of an annular array is that it may have concentric rings 410 of equal area. In another embodiment, the annular array may include concentric rings 410 with unequal areas.

[0176] Figure 8 is a bottom view of a transducer comprising inner elements 452 arranged in a two-dimensional (2D) grid array 450, according to at least one aspect of the present disclosure. In one embodiment, one or more elements 452, 454 in the two-dimensional (2D) grid array 450 are flat planar radiating surfaces that generate planar acoustic waves. Each inner element 452 of the 2D grid transducer array 450 can be driven by a different signal. In one embodiment, to generate a converged acoustic wave (e.g., “focused”) from the two-dimensional (2D) grid array 450, the signal applied to the inner element 454 may be gradually delayed compared to the signal applied to the outer elements of the 2D grid transducer array 450. In one embodiment, to generate a divergent acoustic wave (e.g., “unfocused”) from the two-dimensional (2D) grid array 450, the acoustic wave generated by the outer element 452 may be gradually delayed relative to the inner element 454. In one embodiment for generating a steering beam, the elements are delayed in a standard delay pattern so that the acoustic beam converges at a desired position. In one embodiment, each of the inner elements 452 of the 2D grid transducer array 450 can define an equal area. In another embodiment, each of the inner elements 452 of the 2D grid transducer array 450 can define an uneven area.

[0177] In one embodiment, transducers 150, 400, and 450 may be implemented as a single transducer comprising multiple piezoelectric elements having acoustically / electrically independent portions arranged in an array. In other embodiments, transducers 150, 400, and 450 may be implemented as different transducers operating in coordination. In one embodiment, there is little or no physical distinction between a single transducer with multiple elements and different transducers operating in coordination. In one embodiment, there are some and / or significant physical differences between a single transducer with multiple elements and different transducers operating in coordination. The elements in the array can be on the order of wavelength. In various embodiments, the wavelengths are 0.1mm to 5mm, 0.1mm to 4mm, 0.1mm to 3mm, 0.1mm to 2mm, 0.1mm to 1.5mm, 0.1mm to 1mm, 0.5mm to 3mm, 0.5mm to 2mm, 0.5mm to 1.5mm, 0.5mm to 1mm, 1mm to 5mm, 1mm to 4mm, 1mm to 3mm, 1mm to 2mm, 1mm to 1.5mm, 1.5mm to 4mm, 1.5mm to 3mm, 1.5mm to 2mm, 2mm to 5mm, 2mm to 4mm, 2mm to 3mm, 3mm to 5mm, 3mm to 4mm, 0.1mm to 10mm, and values ​​within these ranges. In one embodiment, transducers 150, 400, and 450 may be implemented as a single transducer including multiple elements implemented as an annular array as shown in Figure 7, or as a grid array as shown in Figure 8. In another embodiment, transducers 150, 400, and 450 may be implemented as a plurality of individual transducers.

[0178] In one embodiment, each of the transducers 150, 400, 450 or their elements shown in Figures 4 to 8 is non-invasive and can be implemented in an appropriate size and shape to fit a part of the patient's body. The individual number and arrangement of transducer elements may also be selected to fit a part of the patient's body. In one embodiment, an array of flat planar radiating surfaces is arranged with a curvature configured to direct each flat element in the array to radiate planar acoustic waves perpendicular to a body surface, such as the skull. In one embodiment, the array of flat elements may be arranged along a surface specifically configured to position one or more individual flat elements perpendicular to orthogonal or perpendicular to a body surface in order to radiate individual planar acoustic waves perpendicular to the body surface. For example, this arrangement for aligning flat planar acoustic waves radiated from a flat element is 50mm~175mm, 50mm~150mm, 50mm~125mm, 50mm~100mm, 60mm~150mm, 60mm~140mm, 70mm~130mm, 70mm~110mm, 75mm~150mm, 75mm~125mm, 75mm~100mm, 80mm~120mm, 80mm~100mm, 90mm~130mm, 90 The arrangement may surround a body structure such as a skull, having a radius of curvature in the range of 50mm to 200mm, including 110mm, 100mm to 125mm, 100mm to 150mm, 100mm to 175mm, 125mm to 150mm, 125mm to 175mm, 125mm to 200mm, 150mm to 175mm, 150mm to 200mm, 125mm, 150mm, 165mm, 175mm, and 200mm. In various embodiments, the arrangement may have a single radius of curvature, such as part of a sphere. In various embodiments, the arrangement may have two or more radii of curvature, such as a primary curvature across the anterior / posterior axis of the skull and a secondary curvature across the transverse axis of the skull. In one embodiment, the transducers 150, 400, 450 or their elements may be made from piezoelectric or single-crystal materials that convert electrical energy into ultrasonic energy. Transducers 150, 400, and 450 can also receive ultrasonic energy again and convert it into electrical energy.Each of the transducers 150, 400, and 450, or any element thereof, may be adaptively focused to generate acoustic waves through coordinated transducer performance. For example, each of the transducers 150, 400, and 450, or any element thereof, can be selectively controlled by a controller to operate as either a transmitter or a receiver, as described below. Furthermore, as will be described in more detail herein, each of the transducers 150, 400, and 450, or any element thereof, can be selectively excited and actuated to generate focused, divergent, or plane acoustic waves.

[0179] Referring here to Figures 4 to 8, in one embodiment, the acoustic waves generated by transducers 150, 400, and 450 can be defined by the Fergenz—a measure of the curvature of the acoustic wavefront. A negative Fergenz is when the acoustic wavefront propagates away from a point (e.g., divergence). A positive Fergenz is when the acoustic wavefront propagates toward a point (e.g., convergence). A zero Fergenz is a plane acoustic wavefront that neither converges nor diverges. The Fergenz is a characteristic of a single acoustic wavefront. In one embodiment, a single convergent / divergent acoustic wavefront may be generated by multiple elements of transducers 150, 400, and 450 (e.g., transducers comprising annular arrays 400 or grid arrays 450). In one embodiment, the convergent / divergent acoustic wavefront may be generated by individual elements of transducers 150, 400, and 450 (e.g., transducers comprising annular arrays 400 or grid arrays 450).

[0180] In one embodiment, the acoustic waves generated by transducers 150, 400, and 450 can be characterized by phase and / or delay. Phase and / or delay can be used to measure the relative time shift between two acoustic waves. Phase is the amount of time shifted between two acoustic waves with respect to the period of the two acoustic waves (e.g., measured in degrees or radians). Delay is a measure of the amount of time shifted between two acoustic waves (e.g., measured in milliseconds). In various embodiments, the time delay is in the range of 0.1 μs to 10 s, including 0.1 μs, 0.2 μs, 0.3 μs, 0.4 μs, 0.5 μs, 1 μs, 5 μs, 10 μs, 15 μs, 20 μs, 25 μs, 30 μs, 35 μs, 45 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 0.1 ms to 10 s, including 0.1 ms, 0.2 ms, 0.3 ms, 0.4 ms, 0.5 ms, 1 ms, 5 ms, 10 ms, 50 ms, 100 ms, 500 ms, 1 s, 2 s, 5 s, and 10 s, as well as any value and range within them. Delay and phase are often used interchangeably. For example, “delay” can be described in units of degrees or radians, but in certain embodiments, it is often understood that “delay” is an abbreviation for “phase delay”. In various embodiments, the phase delay is 0.2, 0.4, 0.5, 0.6, 0.8, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.28 radians, and values ​​and ranges within these. In various embodiments, the phase delay is 10, 20, 40, 50, 60, 80, 100, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 250, 260, 280, 300, 310, 320, 340, 350, 360 degrees, and values ​​and ranges within these. For a single acoustic wave pulse, the phase shift requires a periodic signal, making it clearer to discuss the delay between the peaks of two acoustic wave pulses in terms of time. When the acoustic wave repeats, the relative delay is often measured with respect to phase.In the case of continuous periodic acoustic waves, by definition, a periodic signal should have no effect when delayed by an integer number of periods because it exhibits symmetry over a full period shift. In the case of a pulse of a repetitive acoustic wave (e.g., 1000 cycles of a sine wave), the acoustic wave can be delayed by an integer number of cycles. The start and end of a wave packet have some edge effect when one signal starts / ends before the other. At the center of two wave packets, there is no effect (if the signals are still overlapping).

[0181] In one aspect, transducers 150, 400, 450 may be adapted and configured to generate a "focused" acoustic wave by generating a converging acoustic wave that converges to a point. In another aspect, transducers 150, 400, 450 may be adapted and configured to generate a "non-focused" acoustic wave, such as a diverging acoustic wave. In other aspects, transducers 150, 400, 450 may be adapted and configured to generate a planar acoustic wave (e.g., zero felgens) where the acoustic wave is neither "focused" nor "non-focused".

[0182] In various aspects, the transducers 150, 400, 450 may be driven at ultrasonic frequencies in the range of approximately 20.00 kHz to approximately 12.00 MHz, including any value and range therein, such as, for example, 20 kHz, 50 kHz, 100 kHz, 250 kHz, 400 kHz, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, 850 kHz, 900 kHz, 950 kHz, 1 MHz, 1.1 MHz, 1.2 MHz, 1.3 MHz, 1.4 MHz, 1.5 MHz, 2 MHz, 3 MHz, 4 MHz, 5 MHz, 10 MHz, 12 MHz, 20 MHz, 25 MHz, 50 MHz, 75 MHz, 100 MHz, and 0.5 to 1.5 MHz, 0.6 to 1.4 MHz, 0.7 to 1.1 MHz, 0.8 to 1.2 MHz, 1 to 5 MHz. More specifically, the transducers 150, 400, 450 may be driven at ultrasonic frequencies in the range of approximately 650.00 kHz to approximately 2.00 MHz. In one preferred range, the transducers 150, 400, 450 may be driven at ultrasonic frequencies in the range of approximately 900.00 kHz to approximately 1.20 MHz, 975 kHz to 1.1 MHz, and, by way of example, in one embodiment, may be driven at approximately 1 MHz, 1.03 MHz, 1.06 MHz, 1.10 MHz, 1.20 MHz, etc.)

[0183] Figure 9 is Figure 470 of two constructively interfering, delay-free acoustic-ultrasonic pulses 472, 474 according to at least one aspect of the present disclosure. As previously stated, transducers 150, 400, 450 can be adapted and configured to produce “focused,” “defocused,” or plane acoustic waves by adjusting the timing between multiple acoustic wavefronts to produce constructively interfering wavefronts. The adjustment of acoustic wavefronts is independent of the fergenz of the acoustic wavefronts. The point at which the wavefronts converge can be adjusted by delaying one signal relative to another. Figure 470 shown in Figure 9 shows two pulses 472, 474 produced without relative delay. The two pulses 472, 474 can be said to constructively interfere when they reach the center and be focused or defocused at the center to produce a combined pulse 474. If the left acoustic pulse 472 is delayed relative to the right acoustic pulse 474, the two pulses 472 and 474 intersect at a point to the left of the center, thus shifting the point of constructive interference to the left of the center. Similarly, if the right acoustic pulse 474 is delayed relative to the right acoustic pulse 474, the two pulses 472 and 474 intersect at a point to the right of the center, thus shifting the point of constructive interference to the right of the center.

[0184] In another embodiment, a mixture of convergent / divergent / plane acoustic waves can be timed to converge at one location and interfere constructively. Divergent acoustic waves can be timed to converge at one location and interfere destructively. In yet another embodiment, a mixture of convergent / divergent / plane acoustic waves can converge at one, two, three, five, ten, or more locations and interfere constructively.

[0185] Control of the converging and diverging wavefronts generated by transducers 150, 400, and 450 can be considered as part of pretreatment planning. Based on input from the pretreatment planning process, the controller can adaptively modulate transducers 150, 400, and 450 to adjust the acoustic wavefront to preferentially target the desired treatment area. In one embodiment, digital imaging and communications (DICOM) images from computed tomography (CT) or other imaging sources can be input to the device controller to generate a customized modulation pattern that optimizes the treatment area for a particular patient. In one embodiment, DICOM images are used to determine the skull thickness and / or image processing is used to interpret the patient's mean skull thickness and calibrate one or more of the treatment intensity, amplitude, and frequency based on the skull thickness and / or mean skull thickness. In one embodiment, the patient's mean skull thickness is used to calibrate the treatment intensity. In one embodiment, the patient's mean skull thickness is used to calibrate the treatment amplitude. In one embodiment, the patient's mean skull thickness is used to calibrate the treatment frequency. In one embodiment, DICOM images are used to determine cranial density and / or image processing is used to interpret the patient's mean cranial density and calibrate one or more of the treatment intensity, amplitude, and frequency based on the cranial density and / or mean cranial density. In one embodiment, the patient's mean cranial density is used to calibrate the treatment intensity. In one embodiment, the patient's mean cranial density is used to calibrate the treatment amplitude. In one embodiment, the patient's mean cranial density is used to calibrate the treatment frequency. In another embodiment, pretreatment planning may include the selection of a preferred transducer type or transducer type arrangement that generates an optimized treatment area for a particular disease state. In another embodiment, the patient interface may be a variety of arrangements that can be selected during pretreatment planning to tune the transducers to a preferred arrangement for the procedure. In one embodiment, volume imaging data is acquired to plan the targeting of acoustic dynamics therapy.

[0186] In one embodiment, “non-focused” acoustic waves can be measured based on the volume of tissue being treated according to the number of nodes and antagonisms. An intensity or pressure histogram across a portion of the volume can be used to measure “non-focused” acoustic waves. In one embodiment, a dose-volume histogram can be used when planning acoustic dynamics therapy. Alternatively, a cumulative histogram may be used.

[0187] Figure 10 is a diagram of an acoustic pulse packet 480 comprising a repeating signal modulated by a Gaussian pulse signal, according to at least one aspect of the present disclosure. In one aspect, the acoustic wave generated by transducers 150, 400, 450 may be amplitude modulated. The acoustic pulse packet 480 can be generated by modulating a repeating signal, such as a sine wave, with a Gaussian pulse in which the repeating signal is independent of the Gaussian pulse. When transducers 150, 400, 450 are driven by the modulating signal, they generate sound pressure pulses 482 whose amplitude varies according to an envelope 484, which is in the form of a Gaussian pulse. In the illustrated example, the repeating signal is a sine wave, but the repeating signal can take many forms. The repeating signal may be modulated by a rectangular pulse, a triangular pulse, or a pulse of a predetermined mathematical shape. In addition to amplitude modulation, the repeating signal may be pulse width modulated, duty cycle modulated, phase modulated, frequency modulated, randomized phase modulated, or modulated using any suitable modulation technique to generate the desired acoustic pulse packet. The repeating signal may include variations between or within pulses. In various embodiments, the wave may include a square, rectangular, sinusoidal, triangular, or other waveform with randomized phase across all elements in the array, and the internal balance may have a slight delay during the last 45, 60, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 degrees or more of phase randomization. In various embodiments, the duty cycle is randomized for each pulse within the range of 10–50% (e.g., 10–40%, 10–20%, 10–30%, 10–20%, 12–36%, 12–24%, 12–18%, 15–30%, 15–60%). In various embodiments, the average duty cycle across randomized pulses is 5–60%, e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, and values ​​and ranges within that range.

[0188] Figure 11 is a partial fractured view of a transcranial acoustic therapy device positioned on the patient's head, showing a partial view of the patient's skull 510 and brain, as well as a plurality of transducers 150, each having one transducer that releases energy 200 into the patient's brain, relating to at least one aspect of the present disclosure. As shown in Figure 11, it may be possible to measure or obtain a rough image of the skull 510. This can be facilitated if the transducers 150 are fixed to a rigid shell and their relative positions and orientations are known. Rough measurements can be used to adjust the treatment algorithm by measurement parameters such as skull thickness "t" or skull density "ρ". Each transducer 150 can emit acoustic pulses and hear echoes. The echoes can be used to quickly estimate the skull thickness "t" or skull density "ρ" below each transducer 150. To treat tumors in other parts of the patient's body, the acoustic therapy device can be adapted and configured to bond to the patient's body.

[0189] In designs having transducers 150 with adjustable focus, the focus of each transducer 150 can be pre-set using a treatment plan. Alternatively, the transducers 150 can automatically adjust their focus based on head temperature readings or skull thickness "t" measurements. In one embodiment, temperature readings are used as feedback to increase or decrease intensity to remain within a safe thermal dose range for the tissue, such as temperatures below 35°C, including 44°C, 43°C, 42°C, 41°C, 40°C, 39°C, 38°C, 37°C, 36°C, or 45°C, and any range or value within those.

[0190] The amplitude of the electrically driven signal that drives the transducer 150 can be controlled or modulated. In some cases, it may be beneficial to modulate the electrically driven signal that drives the transducer 150 based on the temperature of the head or other body part being treated. For example, if a temperature sensor detects a rapid rise in temperature, the amplitude of the transducer 150 can be reduced, shut off for a period of time, or the duty cycle can be reduced. In some embodiments, the time-averaged acoustic intensity can be adjusted by modulating the intensity of the acoustic pulse to activate the sensitizer while maintaining the temperature of tumor cells below a temperature that can cause thermal damage to the cells and, in some situations, necrotic cell death (e.g., below 45°C, 44°C, 43°C, or 42°C, e.g., 41°C, 40°C, 39°C, 38°C, 37°C, 36°C, or 35°C, and any range or value within those). In another embodiment, acoustic dynamics therapy can function at various different frequencies. Each frequency can efficiently penetrate the skull 510 at a particular thickness of skull. Using a variety of frequencies can enable the non-invasive acoustic therapy device 100 to operate across a wide range of skull thicknesses "t".

[0191] In embodiments in which transducer 150 can operate at multiple frequencies, the frequency of each transducer 150 can be selected manually or automatically by the operator. As described above, transducer 150 can be driven at ultrasonic frequencies in the range of approximately 20.00 kHz to approximately 12.00 MHz, including, for example, 20 kHz, 50 kHz, 100 kHz, 250 kHz, 500 kHz, 1 MHz, 1.1 MHz, 1.2 MHz, 1.3 MHz, 1.4 MHz, 1.5 MHz, 2 MHz, 3 MHz, 4 MHz, 5 MHz, 10 MHz, 12 MHz, and any value and range therein. More specifically, transducer 150 may be driven at ultrasonic frequencies in the range of approximately 650.00 kHz to approximately 2.00 MHz. In one preferred range, the transducer 150 can be driven at ultrasonic frequencies in the range of about 900.00 kHz to about 1.20 MHz, more preferably (in some embodiments) about 1 MHz, 1.03 MHz, 1.06 MHz, 1.10 MHz, 1.20 MHz, etc. The frequency can be pre-selected by a physician. The frequency can be selected based on measurements of the anatomical structure of the head (e.g., skull thickness "t" or skull density "ρ"). For example, each transducer 150 can emit a series of pulses to measure the thickness of the skull 510 closest to it. Based on the results of the skull thickness "t" or skull density "ρ" measurement, an algorithm can be used to select a frequency from a set or range of frequencies that is most suitable for the skull thickness "t" or skull density "ρ", and excite the transducer 150 accordingly.

[0192] As shown in Figure 2, the size and shape of the transducer 150 can vary across the various disclosed embodiments. For cost-effective and simple systems, larger transducers 150 can be used, which may have directional acoustic waves and, if possible, have more directional acoustic waves. As further described elsewhere in this specification, the directivity of larger transducers 150 can be reduced by applying acoustic lenses that bend acoustic waves to each transducer 150. For systems that can be fitted into a skull, smaller transducers 150 can be used, which can radiate more widely than larger transducers 150. Such smaller transducers 150 may have a greater ability to image or beam steer as an array.

[0193] In some embodiments, the acoustic wave 200 is transmitted over an area such as a point, sphere, ellipse, or circle (e.g., 0.1-1 mm). 3 , 0.5~2mm 3 , 0.75~2.5mm 3 , 3-5mm 3 , 2-6mm 3 , 1mm 3 , 2mm 3 , 3mm 3 , 4mm 3 , 5mm 3 , 6mm 3 , 7mm 3 , 8mm 3 The acoustic waves are focused to a small area (for example, as shown in Figure 4) such as the values ​​and ranges of the brain, but instead of focusing the acoustic waves 200 to a small point, in some embodiments, as shown in Figures 5 and / or 6, the acoustic waves 200 are not focused to the brain (for example, over the entire volume of the brain, a part of the brain, 100 mm) 3 ~10,000mm 3 , 2000mm 3 ~6000mm 3 , 4000mm 3 ~8000mm 3 , 10,000mm 3 , 9000mm 3 , 8000mm 3, 7000 mm 3 , 6000 mm 3 , 5000 mm 3 , 6000 mm 3 , 3000 mm 3 , 2000 mm 3 , 1000 mm 3 , 500 mm 3 , 250 mm 3 , 100 mm 3 , or more), etc., can minimize the spatial variation of the acoustic wave intensity of body parts. The size and shape of the transducer 150 can non-focus or focus each transducer 150. The non-focused transducer can be formed using a transducer 150 having a convex radiation surface 310, as seen in FIG. 5. As seen in FIG. 4, the transducer design can focus the sound from each transducer 150 using a concave radiation surface 304 having a center of curvature where the sound can converge. As shown in FIG. 6, an array of transducers 150a - 150h can be used to generate convergent, divergent, or more complex acoustic waves. In various embodiments, the array has dimensions (such as length, width, diameter). In various embodiments, the transducers 150a - 150h and / or elements 452, 1302, 1308, 1326, 1327 have dimensions (such as length, radius, diameter) in the range of 0.5 mm to 20 mm, including 0.5 mm, 1 mm, 3 mm, 5 mm, 7 mm, 10 mm, 12 mm, 15 mm, 18 mm, and 20 mm, including any values and ranges therein. In various embodiments, the transducers 150a - 150h and / or elements 452, 1302, 1308, 1326, 1327 have dimensions (such as length, radius, diameter) in the range of 5 mm to 160 mm, including 5 mm, 10 mm, 30 mm, 50 mm, 70 mm, 100 mm, 120 mm, 130 mm, 140 mm, 150 mm, 150 mm, 170 mm, 180 mm, 190 mm, and 200 mm, including any values and ranges therein. In some embodiments, the diameter at the exit surface of the transducer is at least 10 - 50% (such as 10, 20, 30, 40, 50% and values and ranges therein) larger than the radius of curvature.

[0194] Each transducer 150 can repeat several frequencies such that at least one of the frequencies can be transmitted approximately optimally for a given skull thickness "t" or skull density "ρ". Each transducer 150 may also sweep sequentially from one frequency to another. The frequencies can be pre-selected for each transducer based on the thickness of the skull 510 closest to the transducer 150 (e.g., during treatment planning by a physician). Before treatment, each transducer 150 can transmit a test signal and monitor the reflected sound to automatically determine which frequency can best function for that frequency of the transducer 150. The test signal can be used to directly measure the skull thickness "t" or skull density "ρ" by measuring the delay of the pulse echo, or it can be used to detect the relative amount of reflected acoustic energy.

[0195] Each transducer 150 can consist of a wide-spectrum ultrasonic transducer or several smaller transducers (e.g., piezoelectric elements shown in Figures 6-8) designed to operate at specific frequencies. Each transducer 150 may have an element specifically designed to monitor waves reflected from the head. If transducer 150 is made up of several smaller transducers 150, while one transducer 150 is transmitting sound, the other transducers 150 can be used to transmit and / or monitor incoming acoustic pulses.

[0196] Of all the frequencies that function in acoustic dynamics therapy, a subset of frequencies can be selected to best cover a range of typical skull thicknesses "t". Frequencies that share many common factors (e.g., harmonics such as 1 MHz and 2 MHz) may not make a good selection for covering the maximum number of skull thicknesses because they may share many of the transmission peaks between the two frequencies. Frequencies without many or any common factors (e.g., coprime numbers) can make a good frequency selection because transmission peaks can occur at different skull thicknesses. In one embodiment, a sensor detects an ultrasonic signal, and the system re-examines the signal spectrum to identify harmonics, subharmonics, and / or superharmonics, and modifies the frequency, intensity, or other parameters of the ultrasonic signal.

[0197] Figure 12 is a chart 700 showing intensity transmittance ratios across multiple frequencies according to at least one aspect of the present disclosure. As shown in Figure 12, there are five different frequency transmissions across different skull thicknesses between 4 mm and 9 mm. These are a first frequency 702 at 1.107 MHz, a second frequency 704 at 1.052 MHz, a third frequency 706 at 1.000 MHz, a fourth frequency 708 at 0.961 MHz, and a fifth frequency at 0.898 MHz. Different skull thicknesses can be well covered. In this example, each skull thickness can have at least one frequency through which more than 75% of its energy can be transmitted. This can be achieved in frequencies as small as 0.2 MHz, from about 900 kHz to 1.1 MHz (e.g., 898 kHz and 1.107 MHz).

[0198] The transmission of sound through the absorbent layers of tissue may not decrease monotonically as a function of thickness. Instead, transmission can be increased when the thickness of the skull is a multiple of half the wavelength of the sound within that layer. Similarly, transmission can be reduced when the thickness of the skull is an odd multiple of a quarter wavelength (midway between A / 2).

[0199] Figure 13A is Chart 720 showing intensity transmittance and pressure reflectance ratios at 1 MHz for skull thickness in millimeters, according to at least one aspect of the present disclosure, and Figure 13B is Chart 730 showing transmittance and reflectance ratios at 1 MHz for skull thickness in wavelengths. The transmission of 1 MHz sound waves through various skull thicknesses is shown in Figures 13A and 13B. Figure 7A shows skull thickness in millimeters, and Figure 13B shows skull thickness at multiples of wavelength for intensity transmittance ratio 722 and reflectance ratio 724. The intensity transmittance ratio 722 can reach a peak whenever the skull is a multiple of half a wavelength. Similarly, the ratio of reflected sound, shown as the reflectance ratio 724, can be minimized whenever the skull is a multiple of half a wavelength.

[0200] The intensity transmittance ratio 722 and pressure reflectance ratio 724 can be functions of both skull thickness and frequency. Figure 14A is a chart 740 showing the intensity transmittance ratio 722 as a function of frequency, relating to at least one aspect of this disclosure, and Figure 14B is a chart 750 showing the reflectance ratio 724 as a function of frequency. To the right of chart 740 in Figure 14A is a scale 742 of the intensity transmittance ratio 722 ranging from 0.0 to 1.0, and to the right of chart 750 in Figure 14B is a scale of the reflectance ratio 724 ranging from -1.0 to +1.0. Figures 14A and 14B illustrate how the intensity transmittance ratio 722 and reflectance ratio 724 vary with skull thickness and frequency. Negative reflectance ratios can be achieved wherever peak transmission occurs. Negative reflectance ratios can indicate that the reflected wave can be phase-shifted by 180° relative to the incident wave. As shown in chart 740 of Figure 14A, the intensity transmittance ratio 722 has a maximum ratio of approximately 1.0 744 and a minimum ratio of approximately 0.4 746, which is consistent with the maximum / minimum ratios shown in charts 720 and 730 of Figures 13A and 13B. Chart 750 shown in Figure 14B shows that the reflectance ratio 724 has a minimum ratio of approximately 0.0 754 and a maximum ratio of approximately 0.8 756, which is consistent with the maximum / minimum ratios shown in charts 720 and 730 of Figures 13A and 13B.

[0201] Frequencies that differ only by irrational numbers can have peak transmissions at different thicknesses, accordingly enabling good selection. The golden ratio (e.g., "maximally irrational") can be useful for frequency selection. The transmission of the selected frequencies may not be sufficient to avoid peaks at the same skull thickness "t".

[0202] Although it may be acceptable for two frequencies to share a peak transmittance at a particular thickness, the shared peak occurs at a skull thickness "t" outside of the thicknesses expected to occur naturally. If the device can select the best frequency (e.g., maximum transmission ratio) at each skull thickness "t", the limited number of frequencies can serve to maximize the average transmittance of the best frequencies across many skull thicknesses "t" or to maximize the minimum transmittance of the best frequencies within the selected skull thicknesses "t" in order to obtain optimal coverage across many skull thicknesses "t".

[0203] To enable efficient transmission of sound into the brain, it may be necessary to shave or shorten the patient's head hair. Some embodiments can allow the hair to remain untouched. A comb-like structure can pass through the hair to contact the skull at many locations for sound transmission. The hair may also be wet and dulled to allow sound to transmit relatively unobstructed.

[0204] FIG. 15 is a chart 760 showing the field intensity of a plane wave 762 into a multi-tissue skull model according to at least one embodiment of the present disclosure. Referring to FIG. 15, the skull can absorb most of the ultrasonic energy at short distances. The insertion loss 764 (the amount of energy that can be lost by applying an acoustic wave 200 to the skull) can be centered around about 12 dB. Each additional 3 dB of loss can correspond to a reduction of about half of the energy. A 12 dB loss can correspond to one sixteenth of the energy introduced at the surface of the skin remaining on the surface of the skull. Thus, the skull can be heated during transcranial acoustic mechanics therapy.

[0205] Table 1 outlines the parameters that can be used in the skull model. In addition to the intrinsic acoustic properties of the skull, the skin can be assumed to be 2.5 mm thick, and the skull can be assumed to be approximately 6.8 mm thick. Figure 15 shows the acoustic intensity with respect to the electric field intensity (dB) as a function of distance within the head model. The highlighted region of insertion loss 764 highlights the jump in energy lost at the interface and the abrupt decay within the skull.

[0206] JPEG0007884503000005.jpg91153

[0207] The model uses the average skull thickness of various humans. "The thicknesses of the frontal, parietal, and occipital bones were 6.58, 5.37, and 7.56 (in mm) for males; and 7.48, 5.58, and 8.17 for females, respectively." As stated elsewhere in this specification, human skulls vary considerably depending on sex and anatomical location. While the model can represent average attenuation, thicker parts of the skull may have greater attenuation. Generally, for every 2.7 mm equivalent increase in skull thickness, the attenuation can be increased by 3 dB (2x).

[0208] This model can be based on a simple plane wave model colliding with planar layers of tissue. Each layer of tissue can be assumed to be homogeneous and of uniform thickness. In this model, the effects of acoustic wavelengths (λ) that coincide with the varying thicknesses of the skull are ignored. It can also be assumed that all reflected waves are lost and do not re-enter the brain.

[0209] Pichardo et al. investigated the transmission of ultrasound through newly excised human skulls at various frequencies. They report the ratio of absorbed energy in seven skulls at several locations at frequencies of 0.270, 0.836, and 1.402 MHz. While they did not measure the energy lost specifically at 1 MHz, their study allows for interpolation and estimation that the insertion loss could be centered around approximately 12 dB. Their study also confirms that the insertion loss can vary depending on the skull and anatomical location.

[0210] Figure 16 is a chart 770 showing the energy absorption rates 772 of a newly excised human skull at multiple frequencies, relating to at least one aspect of the present disclosure. As shown in Figure 16, Pinton et al. also measured the attenuation at 1 MHz at nine points along an 8 mm thick portion of the skull and found an insertion loss of 12.6 ± 1.33 dB (higher loss due to the thicker skull portion). Both the simplified head model and measurements from different laboratories agree that the insertion loss (the amount of energy lost by adding the skull to the model) can be centered around approximately 12 dB (16 times), with considerable variation.

[0211] The energy lost as sound passes through the skull can be converted primarily into heat within the skull. The temperature of the skull begins to rise, and over time, the heat can dissipate to nearby tissues. Most of the heating originates from the outer surface of the skull and can dissipate to the skin and other layers of bone. Beyond a certain intensity, the blood may not be able to carry away enough heat, and the temperature of the bone and skin may rise to unsafe levels. Adding transducers to the system can reduce the intensity at which this threshold can be reached, as the blood is heated by each successive transducer it passes through and may lose its ability to absorb additional heat from the tissues.

[0212] Several methods can be used to counteract the effects of heating. In particular, cooling, intermittent treatment, monitoring, and transducer modulation can be used to reduce the consequences of heating.

[0213] Figure 17 is a partial breakaway view of a transcranial acoustic therapy device positioned over a patient's head, showing a partial view of a plurality of transducers 150 and an overall view of a cooling system 600, relating to at least one aspect of the present disclosure. The cooling system 600 shown in Figure 17 may be implemented to maintain the temperature of the skull and surrounding tissues within safe levels. A cooling layer (e.g., water) may be provided between the transducers 150 and the patient's head. The cooling layer may be made from a flexible membrane or balloon that can be adapted to each patient's head. Larger cooling layers may be reusable and therefore may include cleaning between each use.

[0214] The cooling system 600 can be made from a flexible cavity (not shown in Figure 17) having an inlet and outlet for the circulation of a coolant such as water. The patient's head can be inserted into a concave shape (e.g., a "bowl") having an elastic opening. The elastic opening can be sealed against the patient's head. Water can fill the space between the patient's head and the bowl.

[0215] Similar to a single-cavity design, water can be circulated to prevent the water temperature from rising. One advantage of such a system is that the water in the cooling system 600 can come into direct contact with the patient's head. The air around the patient's hair can be removed by the water, which can help to fuse the ultrasonic transducer 150 to the patient's head.

[0216] Figure 18A is a perspective view of a patient interface 650 relating to at least one aspect of the present disclosure. The cooling system 600 may be a cap 160 with cooling channels 630 distributed throughout. The cap 160 may have a single long loop of cooling channels 630, or it may have several independent loops. A system with several cooling loops may be connected to a single inlet and outlet pipe via a manifold, or they may be controlled independently. Water or other heat transfer fluid may be circulated through the cooling channels 630 to exchange heat generated by the transducer 150, the patient's body, or a combination thereof.

[0217] Figure 18B shows an embodiment of a patient interface 650 having an integrated cooling system 600. In one embodiment, a thin film conforming membrane 610 is flexible, elastic, and positioned across the surface of a transducer configured to conform to the shape of the patient's body for treatment. In one embodiment, the thin film conforming membrane 610 forms a fluid-filled pocket configured for thermal and / or acoustic coupling to a part of the patient's body. In one embodiment, the cooling system 600 includes the membrane 610 for providing active cooling to a part of the patient's body for treatment.

[0218] In one embodiment, the bonding membrane 610 is configured to capture a degassed circulating fluid (e.g., water, saline solution, cooling fluid, acoustic coupling material, gel) between the ultrasonic array and the patient. The degassed circulating fluid provides an acoustic coupling pathway from the individual ultrasonic elements to the surface of the membrane 610. The circulating fluid also provides active cooling, mitigating the potential for residual heat buildup at the patient entry surface and / or ultrasonic elements. A manifold with multiple nozzles can be incorporated into the membrane assembly to further guide the circulating fluid to the wetted surface of the bonding membrane, thereby increasing the direct cooling capacity at the patient interface.

[0219] In one embodiment, the fluid-backed bonding membrane 610 provides a conformable interface that molds to the shape of the local anatomical structure of the treatment site. In one embodiment, an ultrasonic bonding gel is further placed at the treatment site as part of the interface between the patient and the bonding membrane. The conformable fluid-filled membrane 610, together with the ultrasonic bonding gel, ensures good acoustic coupling between the transducer and the patient. The conformable fluid-filled membrane 610, together with the ultrasonic bonding gel, ensures good thermal coupling between the transducer and the patient.

[0220] In one embodiment, the binding membrane 610 is the sole component of the acoustic dynamics therapy device that comes into direct contact with the patient. The membrane 610 is made from a well-characterized elastomer having a known biocompatible profile for contact with the patient.

[0221] In one embodiment, the bonding membrane 610 can be removed and replaced as needed during patient use. In one embodiment, the bonding membrane 610 is attached to a detachable bezel or housing that can be detachably attached from the ultrasonic array (e.g., by one or more interfaces, locking mechanisms, latches, threads, etc.).

[0222] In various embodiments, a fluid (e.g., water) can flow through all areas of a body (e.g., head, torso, etc.) that can absorb heat. The fluid can be pumped to prevent an increase in fluid temperature that would reduce the cooling efficiency of the fluid. As with patches having multiple transducers 150, each patch can have its own cooling channel 630. The cooling channel 630 can be a fluid-filled tube, which may be larger and heavier than the wires leading to the transducers 150. The number of unique cooling channels 630 can be optimized to avoid excessive weight in the cooling layer.

[0223] The effects of heating can be easily monitored by a temperature sensor and mitigated by a fluid cooling system 600. A layer of cold, degassed water between the ultrasonic transducer 150 and the head can serve a dual function: coupling the head to the transducer 150 and controlling the skull temperature. Before any irradiation, the head can be cooled for several minutes with a constant flow rate of cold water. Once treatment begins, the skull temperature can be continuously monitored, and treatment can be adjusted across the entire skull, or each transducer 150 can be adjusted individually. Even without continuous monitoring of skull temperature, a safe treatment algorithm can be devised with intermittent treatment and continuous cooling, ensuring a safety margin for all patients. Intermittent treatment may also be more effective than the same effective treatment time performed continuously, due to the step of limiting the rate of oxygen diffusion around the ultrasonic sensitizer.

[0224] It may be necessary to monitor only surface temperature. In any case, it may be possible to monitor the temperature of the entire skull using various deep tissue temperature measurements. Any surface temperature measurements may need to be isolated from the water cooling layer to prevent the probe from being dominated by the cooling layer's effect.

[0225] In one embodiment, the temperature of the patient's head is monitored. A temperature sensor (not shown) is placed between the cooling layer and the head, and the temperature sensor can read the head temperature and / or the cooling layer temperature.

[0226] There are several ways in which temperature sensors can be isolated from the temperature of the cooling layer. An insulating layer can be placed between the cooling layer and each temperature sensor. In such a case, the area around each temperature sensor may receive little to no cooling.

[0227] Figure 19 is Chart 800 showing a relative sensitivity plot 802 of an infrared (IR) temperature sensor according to at least one aspect of the present disclosure. As shown in Figure 19, a temperature probe (not shown) that measures in only one direction (e.g., unidirectional) can be used. An example of a unidirectional temperature sensor can be an IR temperature sensor. An IR temperature sensor measures infrared light emitted by an object via blackbody radiation. An IR temperature sensor accepts radiation coming from a small range of angles (e.g., an accepting cone). In this application, one or more IR sensors can be oriented so that the accepting cone of each sensor can face the patient's head. One or more of the above methods can be combined to accurately monitor the temperature of a patient's head.

[0228] Figure 20 is a block diagram of a typical non-invasive acoustic dynamics therapy system 900 relating to at least one aspect of the present disclosure. The non-invasive acoustic dynamics therapy system 900 includes a controller 902 coupled to the ultrasonic transducer array 904 to control the operation of the ultrasonic transducer array 904 to generate appropriate ultrasonic acoustic waves. The ultrasonic transducer array 904 is coupled to a patient interface 906 to bind the ultrasonic acoustic waves generated by the ultrasonic transducer array 904 to a sensitizer 908 that accumulates in tumor cells in the patient's body. In one embodiment, the ultrasonic acoustic waves generate light through a process called sonoluminescence, which activates the sensitizer 908 and causes necrosis of tumor cells. In one embodiment, the ultrasonic acoustic waves generate light through a process called sonoluminescence. Sonoluminescence occurs when the ultrasonic acoustic waves collapse fluid bubbles, causing cavitation, and generate light in the process. The generation of light occurs far away from the ultrasonic transducers. The light generated by sonoluminescence activates protoporphyrin IX (PpIX) to produce ROS. Sonoluminescence can occur anywhere if the intensity of the ultrasound-acoustic waves is sufficient, which allows acoustic dynamics therapy to treat much deeper than photodynamic therapy. ROS species induce oxidative stress, leading to cancer cells undergoing programmed cell death (apoptosis). In one embodiment, ultrasound-acoustic wave treatment induces cavitation and microbubble formation, and their collapse generates photons within the tissue. In one embodiment, the photons activate sensitizers such as 5-aminolevulinic acid (5-ALA) and / or protoporphyrin-IX, thereby treating tumors or other undesirable tissues. The photons can have wavelengths and values ​​and ranges between approximately 250-750 nm, 300-700 nm, and 400-800 nm.

[0229] Acoustic dynamics therapy uses a drug called 908 sensitizer, which becomes cytotoxic only upon exposure to ultrasound. When activated, the acoustic dynamics drug, commonly called an "ultrasonic sensitizer," produces ROS that produce a cytotoxic effect that kills tumor cells. Acoustic dynamics therapy offers a much greater tissue depth that can be reached non-invasively by ultrasound compared to photodynamic therapy (which uses light only). In one embodiment, the sensitizer 908 may include 5-aminolevulinic acid (5-ALA), protoporphyrin IX (PpIX), hematoporphyrin, rose bengal, curcumin, titanium nanoparticles, chlorin e6, pheobromide-a, ATX-S10 (4-formyloxymethylidene-3-hydroxy-2-vinyl-duterioporfinyl(IX)-6,7-diaspartic acid), photophyllin, photophyllin II, DCPH-P-Na(I), NPe6 (mono-l-aspartylchlorin e6), polyhydroxyfullerene, hypocrelin-B, ZnPcS2P2, methylene blue, sinoporphyrin sodium, and any combination and derivatives thereof.

[0230] In one embodiment, the compound for 5-aminolevulinic acid (5-ALA) is represented by the following structure: JPEG0007884503000006.jpg1729

[0231] In one embodiment, the protoporphyrin IX (PpIX) compound is represented by the following structure: JPEG0007884503000007.jpg2930

[0232] In one embodiment, the heme b compound is represented by the following structure: Hem b JPEG0007884503000008.jpg2422

[0233] In one embodiment, the chemical compound for hematoporphyrin is represented by the following structure: JPEG0007884503000009.jpg2624

[0234] In one embodiment, the Rose Bengal compound is represented by the following structure: JPEG0007884503000010.jpg2524

[0235] In one embodiment, the compound for curcumin is represented by the following structure: JPEG0007884503000011.jpg2555

[0236] In one embodiment, the chlorin e6 compound is represented by the following structure: JPEG0007884503000012.jpg3229

[0237] In one embodiment, the sensitizer is administered orally to the patient. In one embodiment, the sensitizer is administered to the patient via a route other than intravenous and / or topical. In one embodiment, the sensitizer is administered to the patient by infusion. In some embodiments, one, two, or more sensitizers (such as 5-ALA alone or in combination with another compound) are administered orally, intratumorally, topically, intravenously, and / or intrathecally to the target. In some embodiments, ear drops or nasal drops and / or inhalation of one or more ultrasonic sensitizers are provided. Oral doses may include sublingual doses. In some embodiments, one, two, or more agents (such as 5-ALA) that enhance or elevate the sensitizer are administered together with the sensitizer (before, after, or simultaneously with the sensitizer). Examples of such drugs include, but are not limited to, vitamins (such as vitamin D3), tetracycline antibiotics (e.g., doxycycline, minocycline, etc.), deferoxamine, calcitriol, gefitinib, metformin, and imiquimod, as well as methotrexate. In one embodiment, 5-ALA and iron chelating agents are used. In some embodiments, one or more ultrasound sensitizers (such as 5-ALA) are administered to the patient (e.g., orally) without imaging the location of the ultrasound sensitizer or its products and / or metabolites (e.g., protoporphyrin IX (PpIX)) for, for example, tumor localization purposes. In one embodiment, one or more ultrasound sensitizers (e.g., 5-ALA) are administered to the patient (e.g., orally) without using the ultrasound sensitizer or its products and / or metabolites (e.g., protoporphyrin IX (PpIX)) for diagnostic purposes (e.g., administration of 5-ALA is therapeutic only).

[0238] In some embodiments, one or more ultrasound sensitizers (such as 5-ALA) are orally administered to the patient, and their products and / or metabolites (such as protoporphyrin IX (PpIX)) preferentially accumulate in tumor cells compared to non-tumor cells. Ultrasound is then used after this accumulation. Oral doses can be in the form of capsules, tablets, caplets, pills, oral strips, sublingual forms, gels, liquids, and powders (e.g., lyophilized powders that can be mixed with liquids such as water, saline, or juice for consumption by the patient). In some embodiments, liquid caps, liquid tablets, and / or gel caps are used. In various embodiments, the dose can be 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg per kg of patient body weight, as well as any value and range therein, and can be divided into two, three or more doses. Sustained-release and / or enteric-coated compositions and formulations are provided in embodiments. In some embodiments, orally ingested 5-ALA crosses the blood-brain barrier. In various embodiments, the ultrasound sensitizer is administered or directed to be administered 5, 10, 20, 30, 45, 60, 90, 120 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, or 48 hours before acoustic dynamics therapy.

[0239] In some embodiments, the acoustic dynamics processes described herein may include injecting or otherwise administering microbubbles into tumor tissue to “seed” cavitation, allowing bubbles to accumulate in tumor tissue, or injecting drugs to oxygenate tumor tissue. The acoustic dynamics therapy processes described herein may be combined with one or more other adjunctive therapies such as chemotherapy, immunotherapy, radiotherapy, and / or HIFU. In some embodiments, ultrasound is used therapeutically to act on PpIX (or another compound) to perform one or more therapeutic functions (e.g., further effects on the blood-brain barrier, angiogenesis, resistance to chemotherapy, metabolic pathways, etc.). HIFU, light, lasers, fluorescence, and other forms of light / illumination and / or other forms of energy delivery, cryotherapy, or mechanical / surgical procedures may be used in connection with the acoustic dynamics therapies disclosed herein. In some embodiments, only incoherent ultrasound is used herein to perform sonoluminescence. Non-invasive ultrasound is used in some embodiments that are extreme for the patient. In some embodiments, at least partially implantable ultrasound systems or devices are used. In some embodiments, non-implantable devices are used.

[0240] In one embodiment, 5-aminolevulinic acid (5-ALA) can be provided in any pharmaceutically acceptable formulation, and can be provided as a free acid, a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester. In some embodiments, 5-ALA is sterilized, for example, by irradiation or another sterilization process (such as gamma irradiation). In some embodiments, ultrasound is delivered to the subject several hours after the sensitizer (such as 5-ALA) has been delivered to enhance efficacy (e.g., 1–24 hours, 1–5 hours, 2–4 hours, and values ​​and ranges within thereof). In various embodiments, the dose of the ultrasound sensitizer is administered or directed to be administered 5, 10, 20, 30, 45, 60, 90, 120 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, or 48 hours before acoustic dynamic therapy. In one embodiment, multiple doses of a sensitizer (such as 5-ALA) are delivered periodically (for example, at intervals between doses ranging from 1 minute to 1 hour, or 1 to 6 hours).

[0241] In some embodiments, sensitizers are used that exhibit further selectivity for tumor tissue to enhance stability and / or permeability, including but not limited to 5-ALA, linear, unsubstituted alkyl 5-ALA esters, or PpIX. 5-ALA or its methyl or hexyl esters and / or branched alkyl 5-ALA esters and substituted benzyl 5-ALA esters may be used herein. In one embodiment, compounds having a hydrolyzable group at carbon 4 of 5-aminolevulinic acid may be used. In some embodiments, hydrophobic sensitizers are used. For example, in one embodiment, an ultrasonic sensitizer is provided inside or on the surface of a microbubble. In one embodiment, a microbubble complex is provided comprising a sensitizer and another agent (e.g., an activator, enhancer, chemotherapeutic agent, etc.) bound to a microbubble, which can be directly or indirectly bound via a linker. In one embodiment, 5-ALA leads to the accumulation of PpIX in cancer through one or more mechanisms. Firstly, cancer cells preferentially transport 5-ALA across the cell membrane due to the overexpression of peptide transporter 2 (PEPT2). Secondly, cancer cells accumulate PpIX because ferrochelatase (FECH) expression is reduced and heme group synthesis is completed. These two mechanisms result in increased PpIX concentrations in tumor cells, while they remain low in healthy cells. In one embodiment, during acoustic dynamics therapy, PpIX acts as a catalyst, converting molecular oxygen from a low-energy state to a high-energy state. These high-energy oxygen molecules are highly reactive and damage cellular components. In particular, these reactive oxygen species (ROS) damage the mitochondria of cancer cells, where the highest concentrations of PpIX are generated.

[0242] The non-invasive acoustic dynamics therapy system 900 can be used to treat a variety of tumors, whether malignant or non-malignant, and to treat the area surrounding the tumor cavity. The area surrounding the tumor cavity contains cells that cause recurrence and eventual death in malignant tumors. In one embodiment, the non-invasive acoustic dynamics therapy system 900 can be configured, for example, to treat prostate cancer via transrectal ultrasound acoustics and to treat cervical cancer via transvaginal ultrasound acoustics. In one embodiment, the treatment relates to neuromodulatory applications such as spasticity, pain, or disorders related to bodily coordination or movement.

[0243] In one embodiment, the controller 902 may be configured to drive the ultrasonic transducer array 904. The controller 902 may be configured to perform one or more control algorithm setting / reflection evaluations and adjust the drive frequency with respect to skull thickness. This can be done automatically. In one embodiment, the control algorithm may be configured to pulse or control the "duty cycle" of the drive waveform of the ultrasonic transducer array 904 to generate a high time-peak acoustic intensity of an ultrasonic acoustic wave with a time-averaged acoustic intensity low enough to activate the sensitizer 908 while preventing thermal necrosis of tumor cells in the treatment area. In another embodiment, the control algorithm may be configured to generate delayed wave packets that overlap with the tumor. In yet another embodiment, the control algorithm may be configured to control the intensity of the ultrasonic acoustic wave.

[0244] In another embodiment, the control algorithm may be configured to control the phase of the ultrasound-acoustic wave. In yet another embodiment, the control algorithm may be configured to randomize the phase of the ultrasound-acoustic wave. Modulating the acoustic wave with phase randomization facilitates broad and consistent coverage across the treatment area, where the acoustic wavefront constructively couples at various pseudo-random locations within the treatment area, rather than at the exact same location in each cycle. This control scheme provides a more uniform treatment area, supporting a broad and consistent treatment range and avoiding sub-treatment dead spots within the treatment area. Phase randomization offers further benefits in adapting to the treatment environment. Repeating the exact same excitation pattern in some types of acoustic environments can form standing waves. Standing waves are inherently dangerous because they can deliver unintended therapeutic energy to the patient. A control scheme that provides phase randomization of the acoustic waveform can mitigate the risk of repetitive excitations that could lead to standing waves.

[0245] The feedback loop is returned to the controller 902, which can adjust the drive signal to the ultrasound transducer array 904 based on in situ variables such as tissue depth, tissue thickness, tissue volume, skull thickness, and temperature, among other variables. In one embodiment, the controller 902 may be located within the ultrasound generator or elsewhere. In various embodiments, the in-situ variables may include disease state or in-vivo location. Disease state may include alternative treatment ultrasound transducer probes that are driven differently for each disease state. Examples of the feedback loop are described below in relation to Figures 22–24.

[0246] In one embodiment, the ultrasound transducer array 904 can be configured according to the transducers 150, 400, and 450 described above. However, in various embodiments, the form factor of the ultrasound transducer array 904 may be configured to couple ultrasound waves at various locations on the patient's body other than the head. For example, the ultrasound transducer array 904 may be configured to generate ultrasound waves that activate a sensitizer 908 to treat tumors in the brain, such as glioblastoma, spine, lung, breast, mouth, tongue, stomach, liver, pancreas, intestine, rectum, colon, vagina, ovary, testis, leukemia, and lymphoma, regardless of whether the tumor is malignant or non-malignant.

[0247] In various configurations, the ultrasound transducer array 904 generates ultrasound-acoustic waves that are non-invasive and can reach target tumor cells non-invasively. As described above, the ultrasound transducer array 904 may be configured as a ring array, a two-dimensional grid array, a linear array, etc., to generate adaptively focused ultrasound-acoustic waves optimized based on in situ variables such as tissue depth, tissue thickness, tissue volume, and skull thickness, among other variables. In other embodiments, the ultrasound transducer array 904 can adaptively focus or adjust the ultrasound-acoustic waves based on pretreatment planning or safety. In one embodiment, the controller 902 executes a control algorithm for generating selectively converging / diverging ultrasound-acoustic waves, including adaptive focus for coordinated transducer performance. The ultrasound-acoustic array 904 may be configured to perform transmitter and receiver functions that can be controlled by the controller 902.

[0248] The ultrasonic transducer array 904 is coupled to a patient interface 906 to facilitate acoustic coupling of the ultrasonic vibrations generated by the ultrasonic transducer array 904 into the patient's body. The patient interface 906, like the ultrasonic transducer array 904, is non-invasive. In one embodiment, the patient interface 906 may be configured to remove air between the ultrasonic transducer array 904 and the patient's body to facilitate acoustic coupling. In one embodiment, the patient interface 906 may be configured to remove excess heat from the patient's body. In some configurations, the patient interface 906 may be equipped with various sensors, such as temperature sensors. Signals from such sensors can be provided as feedback to a controller 902 (see, for example, Figure 22). Such feedback may be used to control the ultrasonic transducer array 904 to generate desired ultrasonic acoustic waves. The patient interface 906 may also include a gel or hydrogel layer to improve acoustic coupling between the ultrasonic transducer array 904 and the patient's body. In one embodiment, the patient interface 1022 may be configured to apply cooling locally. In one embodiment, the patient interface 1022 may be configured for sensor feedback to the processing unit 902.

[0249] Finally, the non-invasive acoustic dynamics therapy system 900 includes a sensitizer 908 that can be absorbed by tumor cells. In one embodiment, acoustic dynamics therapy may include a combination of a sensitizer 908, such as a sensitizer, ultrasound generated by an ultrasound transducer array 904 coupled to the patient's body by a patient interface 906, and molecular oxygen. These components are individually nontoxic, but when combined, they generate cytotoxic ROS to kill tumor cells. Acoustic dynamics therapy can be configured to provide ultrasound penetration through the patient's body and can be used to treat widespread, deep, and hard-to-reach tumors.

[0250] Figure 21 is an explanatory diagram 1000 of the acoustic dynamics therapy system 900 shown in Figure 20, relating to at least one aspect of the present disclosure. In one aspect, the acoustic dynamics therapy system 900 comprises a controller 902 which may be located within an ultrasound generator 1002. The ultrasound generator 1002 comprises a controller 1012, a user interface 1004, a foot switch 1006 for operating the controller 1012, and a cap or helmet 1008 positioned over the patient's head. A cable 1010 carrying electrical signals to and from an ultrasound transducer array 904 connects the transducer array 904 and the ultrasound generator 1002. The ultrasound transducer array 904 comprises an array of ultrasound transducers 150, 400, 450 positioned on a patient interface 906 such as a skull cap 160. The ultrasonic generator 1002 drives ultrasonic transducers 150, 400, and 450 to generate ultrasonic acoustic waves 200, which are coupled to the patient's body and excite sensitizers 908 that the patient has ingested and absorbed by tumor cells. The controller 1012 shapes the acoustic waves to achieve convergence, divergence, or plane acoustic waves or more complex acoustic waves. As described above, in one embodiment, the sensitizer 908 may include, for example, an ALA sensitizer that is activated in the sonoluminescence process.

[0251] Figure 22 is a schematic diagram 1100 of the acoustic dynamics therapy system 900 shown in Figures 20 and 21, relating to at least one aspect of the present disclosure. The controller 902 of the acoustic dynamics therapy system 900 comprises a user interface 1102 coupled to a processing unit 1104 and configured to receive input from a user and provide output to the user. The processing unit 1104 may be a processor or microcontroller coupled to memory (e.g., a memory circuit), a control circuit, or a combination thereof. The ultrasonic transducer array 904 comprises one or more ultrasonic transducers 1114 and one or more monitoring ultrasonic transducers 1116. It will be understood that the same ultrasonic transducer elements may be configured to implement ultrasonic transmitter and receiver functions (see, for example, Figure 24). The patient interface 906 comprises one or more temperature sensors 1118 for monitoring the temperature of the patient 1122. The patient interface 906 also comprises a cooling system 1120 for lowering the temperature of the patient 1122. In one embodiment, the patient interface 906 may be configured to eliminate the gap between the transducer 1114 and the patient 1122 in order to enable acoustic coupling.

[0252] The processing unit 1104 is configured to execute machine-executable instructions to implement various control algorithms as described above. The processing unit 1104 may have memory for storing such machine-executable instructions and processing engines for executing control algorithms. The processing unit 1104 may also be implemented in hardware having digital and analog electronic components. The processing unit 1104 is coupled to a power supply 1106 suitable for driving the multiplexing system 1112 and the ultrasonic transducer 1114.

[0253] The ultrasonic transducer 1114 is coupled to the body of the patient 1122 to activate the sensitizer 908 administered to the patient 1122. In one aspect, at least one ultrasonic sensitizer 908 can be configured to preferentially accumulate in the selected tissue of the patient 1122. The monitoring ultrasonic transducer 1116 monitors the acoustic feedback from the patient 1122 and generates a signal that is provided as feedback to the processing unit 1104 via an analog-to-digital converter 1110 (ADC). In addition to the acoustic feedback, the power monitoring device 1108 monitors the power supply 1106 and provides feedback to the processing unit 1104 via the ADC 1110. The processing unit 1104 controls the ultrasonic transducer drive signal based on the acoustic feedback signal and / or the power monitoring signal to achieve the desired ultrasonic acoustic wave in the body of the patient 1122. In one aspect, at least one ultrasonic transducer 1114 is configured to output acoustic waves that selectively converge and diverge. The transducer 1114 may be configured as an annular array or a grid array. The transducer 1114 may be configured to have a plurality of electrodes. The transducer 1114 may be configured to receive reflected acoustic signals.

[0254] The processing unit 1104 is coupled to the temperature sensor 1118 and receives the patient's temperature feedback via the ADC 1010. The processing unit 1104 controls the cooling system 1120 based at least in part on the patient temperature feedback signal.

[0255] In one aspect, the processing unit 1102 has a time-average intensity output that is 1 to 30, 1 to 20, 1 to 10, 2 to 30, 2 to 20, 2 to 25, 2 to 20, 2 to 15, 2 to 10, 2 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15 W / cm 2 and values therein, such as 30 W / cm 2 , 25 W / cm 2 , 20 W / cm 2 , 15 W / cm 2 , 10 W / cm 2 or less, 8 W / cm2 Less than (for example, 7.0 W / cm²) 2 6.5W / cm² 2 6.0W / cm² 2 5.5 W / cm² 2 , 0.05 W / cm 2 4.5 W / cm² 2 4.0 W / cm² 2 3.5 W / cm² 2 3.0 W / cm² 2 , 2.5W / cm 2 , 2.0W / cm 2 , 1.5W / cm 2 , 1.0 W / cm 2 , 0.5W / cm 2 , 0.4 W / cm 2 , 0.3 W / cm 2 , 0.2 W / cm 2 , 0.1 W / cm 2 , 0.05 W / cm 2 ), and are configured to generate pulsed acoustic signals having any value and range within them. In various embodiments, acoustic intensity is generated from each active element in the array. In one embodiment, intensity is generated from one or more active elements in the array. The processing unit 1102 is adapted to apply amplitude-modulated acoustic signals that include constructive interference across multiple wave cycles. The processing unit 1102 may be further configured to output packets of acoustic waves in various delay sequences to provide diffused tissue coverage. The processing unit 1102 may be configured to run a frequency-adaptive algorithm to optimize the transmission of the acoustic signal. The processing unit 1102 may be configured to control the stepwise randomization of the acoustic signal.

[0256] In various embodiments, the Disclosure provides an acoustic dynamics therapy apparatus comprising a transducer 904, a patient interface 906, and a controller 902 adapted to activate a sensitizer 908 within the body of a patient 1122. The transducer 904 may comprise one or more transducers 1114, 1116, and the controller 902 is configured to drive the transducer 904 and generate a broadband range of ultrasonic frequencies to produce divergent, convergent, or plane acoustic waves.

[0257] In one embodiment, the patient interface 906 is configured to transmit acoustic waves generated by the transducer 904 into the body of the patient 1122, thereby acoustically coupling the transducer 904 to the patient 1122. In one embodiment, the patient interface 906 provides a cooling system 1120 for removing excess heat that accumulates in the patient 1122 as a result of coupling acoustic energy to the patient 1122's body. In one embodiment, the patient interface 906 may comprise an integrated cooling system 1120. The patient interface 906 may comprise a hydrogel cap filled with gel or a water-filled cap having a cooling channel. In one embodiment, the patient interface 906 comprises one or more sensors 1118 for providing feedback to the processing unit 1104 of the controller 902. The sensors 1118 may include, for example, a temperature sensor, an optical temperature sensor for measuring temperature in a particular direction, or an acoustic sensor which may include the same transducer 904 used to transmit acoustic signals. The patient interface 906 may be configured to remove air from the patient interface 906 in order to improve the acoustic coupling between the transducer 904 and the patient 1122's body. In another embodiment, the patient interface 906 may be configured to cool the patient 1122. In yet another embodiment, the patient interface 906 may be configured to cool the transducer 904, for example, to keep the transducer at the same temperature to achieve frequency stability.

[0258] In one embodiment, the patient interface 906 may be adapted and configured to conform to various patient anatomical structures. For example, the patient interface 906 may be adapted and configured to conform to the patient's anatomical structure for acoustic dynamics therapy, which is particularly adapted to treat tumors located in, for example, the brain, lungs, breasts, stomach, liver, pancreas, intestines, rectum, colon, vagina, and testes. The acoustic dynamics therapy device may be adapted to wrap around the patient's torso or limbs and / or be used to treat osteosarcoma in bone. The controller 902 may be adapted to detect either the patient interface 906 or the acoustic dynamics therapy device, such as the transducer 904 or the patient interface 906, and to select a therapeutic algorithm for generating acoustic waves optimized for treating various tumors. The transducer 904 or the patient interface 906 may be identified using, for example, identification (ID) circuits 1115, 1119, which have single-wire serial EEPROM. The EEPROM of the ID circuits 1115, 1119 may include both a pre-programmed unique serial number and a memory section. One or all of the memory sections may be permanently locked by the end device manufacturer to enable product tracking and attachment identification. Other identification techniques may include detecting the impedance of the transducer 904 or the patient interface 906 and associating the impedance with a therapeutic algorithm.

[0259] In one embodiment, the controller 902 is configured to generate an electrically driven signal to activate one or more ultrasonic transducers 904, which generate acoustic waves to activate a sensitizer 908 placed in the body of the patient 1122. In one embodiment, the electrically driven signal generated by the controller 902 can activate one or more ultrasonic transducers 904 to generate acoustic waves of varying intensities, amplitudes, or frequencies. In another embodiment, the acoustic waves may be amplitude-modulated, frequency-modulated, phase-modulated, continuous, discontinuous, pulsed, randomized, or a combination thereof. In yet another embodiment, the acoustic waves may be generated in packets of wave cycles, the number of cycles per packet may be predetermined to achieve a desired result different from, for example, focused ultrasonic pulses. In yet another embodiment, the controller 902 is configured to generate a frequency-modulated signal to generate frequency-modulated acoustic waves. In one embodiment, the controller may be configured to generate intra-pulse or inter-pulse variation signals that can be used to reduce standing acoustic waves.

[0260] In one embodiment, the controller 902 is configured to apply an amplitude-modulated acoustic-ultrasonic signal that constructively interferes across multiple wave cycles. In one embodiment, the intensity of each of the multiple acoustic waves remains within a safe range, ensuring that the ultrasonic energy carried by each of the multiple acoustic waves is safe for the patient's tissues, such as the brain or other body parts. In one embodiment, the controller 902 may be configured to drive the transducer 904 to generate amplitude-modulated acoustic waves that produce a constructive wavefront. In one embodiment, the ultrasound modifies the blood-brain barrier (BBB). In one embodiment, the ultrasound facilitates the delivery of drugs and / or ultrasound sensitizers across the blood-brain barrier. In one embodiment, the ultrasonic energy causes vibrations that induce transient disruption of the blood-brain barrier.

[0261] In one embodiment, the acoustic dynamics therapy device comprises a single transducer 904, and the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate a long acoustic ultrasonic packet. In one embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic ultrasonic wave packet consisting of a sinusoidal amplitude modulated by a Gaussian pulse (see, for example, Figure 10). In another embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic ultrasonic wave packet consisting of a sinusoidal amplitude modulated by a rectangular pulse. In yet another embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic ultrasonic wave packet consisting of a sinusoidal amplitude modulated by a triangular pulse. The ultrasonic ultrasonic wave packet may include intrawave or interwave packet variation. In one embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an acoustic ultrasonic pulse. The acoustic wavefront of an ultrasonic pulse may either converge to focus the ultrasonic energy into a specific region, or diverge to spread the ultrasonic energy over a larger region.

[0262] In other embodiments, the acoustic dynamics therapy device may comprise two or more transducers 904, and the controller 902 may be configured to generate drive signals for activating the two or more transducers 904 to generate acoustic ultrasonic pulses, where the individual wavefronts, whether convergent or divergent, converge at the same location simultaneously to focus the ultrasonic energy. In one embodiment, the controller 902 can adapt the frequency drive for each transducer 904.

[0263] Figure 23 is a schematic diagram of an acoustic dynamics therapy system 920 having a separate transmitter transducer 930 and a receiver transducer 934, relating to at least one aspect of the present disclosure. The acoustic dynamics therapy system 920 includes a system controller 922 for controlling a signal generator 924 to generate an electrical signal for driving the transmitter transducer 930. The electrical signal is amplified by an amplifier 926, and the drive signal is coupled to the transmitter transducer 930 by a matching network 928 to maximize the power transmitted to the transmitter transducer 930. The transmitter transducer 930 transmits acoustic waves to tissue 932 (e.g., a lesion) within the treatment area. The receiver transducer 934 detects the acoustic waves radiated by the tissue 932. The output of the receiver transducer 934 is a weak electrical signal provided to an electronic preamplifier 936, which converts a weak electrical signal into an output signal that is noise-resistant and strong enough to undergo further processing, such as filtering by a filter 938. The output of filter 938 is supplied to an analog-to-digital converter 940 (ADC) which provides the feedback signal in digital format to the system controller 922. Based on the feedback signal received from receiver transducer 934, the system controller 922 can adjust the drive signal applied to transmitter transducer 930. The adjustment may include adjusting the modulation, intensity, frequency, phase, or randomization of the drive signal, or any combination thereof. The feedback signal may represent tissue depth, tissue thickness, tissue volume, skull thickness, temperature, distance to the treatment area, or a combination thereof.

[0264] Figure 24 is a schematic diagram of an acoustic dynamics therapy system 950 having a single transmit-and-receiver transducer 962, relating to at least one aspect of the present disclosure. The acoustic dynamics therapy system 950 includes a system controller 952 for controlling a signal generator 954 to generate an electrical signal for driving the transducer 962 in transmitter mode. The electrical signal is amplified by an amplifier 956 and applied to a transmitter / receiver (T / R) switch 958. When the transducer 962 is in transmitter mode, the T / R switch 958 couples the drive signal to the transducer 962 via a matching network 960 to optimize the power transmitted to the transducer 962. In transmitter mode, the transducer 962 transmits acoustic waves to tissue 964 (e.g., a lesion) within a treatment area. In receiver mode, the transducer 962 detects acoustic waves radiated by the tissue 964. The output of the transducer 962 is a weak electrical signal coupled to the T / R switch 958 by the matching network 960. The T / R switch 958 provides a weak electrical signal to the electronic preamplifier 966, which converts the weak electrical signal into an output signal strong enough to be noise-resistant and strong enough for further processing, such as filtering by the filter 968. The output of the filter 968 is provided to the ADC 970, which provides a feedback signal in digital form to the system controller 952. Based on the feedback signal received from the transducer 962 in receiver mode, the system controller 952 can adjust the drive signal applied to the transducer 962 in transmitter mode. The adjustment may include adjusting the modulation, intensity, frequency, phase, or randomization of the drive signal, or any combination thereof. The feedback signal may represent tissue depth, tissue thickness, skull thickness, temperature, distance to the treatment area, or a combination thereof.

[0265] Having described various aspects of the acoustic dynamics therapy systems 900, 920, 950, 1000, 1100 and their components, this disclosure now moves on to describing various aspects of irradiation drive patterns for generating an incoherent field for distributing low-intensity energy. In various embodiments, the low-intensity energy is 15 W / cm². 2 , 10W / cm 2 , 8W / cm 2 7.0W / cm² 2 6.5W / cm² 2 6.0W / cm² 2 5.5 W / cm² 2 , 0.05 W / cm 2 4.5 W / cm² 2 4.0 W / cm² 2 3.5 W / cm² 2 3.0 W / cm² 2 , 2.5W / cm 2 , 2.0W / cm 2 , 1.5W / cm 2 , 1.0 W / cm 2 , 0.5W / cm 2 , 0.4 W / cm 2 , 0.3 W / cm 2 , 0.2 W / cm 2 , 0.1 W / cm 2 , 0.05 W / cm 2 and among them 0.01 W / cm² 2 Including any value and range up to 20 W / cm² 2 ~0.01 W / cm 2 The irradiation driving pattern can be generated using a plurality of ultrasonic transducer elements arranged in a preferred array or subarray structure for generating an incoherent field. The number of ultrasonic transducer elements and the arrangement of the array are solutions for position dependence for each disease state. Various embodiments of the ultrasonic transducer array are described herein in relation to Figures 1 to 24, and more specifically in relation to Figures 29 to 42B.

[0266] Having described various aspects of the acoustic dynamics therapy systems 900, 920, 950, 1000, 1100 and their components, this disclosure now moves on to describing various aspects of the shape, element arrangement, element shape, and lens design for activating the ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy. The described aspects of the ultrasonic transducer array contribute to an incoherent pressure field having a preferred energy profile for activating the ultrasonic sensitizer. It will be understood that the acoustic dynamics therapy systems 900, 920, 950, 1000, 1100 and their components can be adapted and configured to drive the ultrasonic transducer arrays described below in relation to the aspects shown in Figures 25-35 and 37-38.

[0267] In another aspect, the disclosure relates to an irradiation-driven pattern applied as pulse therapy based on a rate-limiting step that depletes the local oxygen supply when an ultrasonic sensitizer is activated and generates reactive oxygen species.

[0268] In another aspect, the disclosure relates to an irradiation driving pattern that includes phase randomization between ultrasonic transducer elements for generating an incoherent distributed acoustic field.

[0269] In another embodiment, the disclosure relates to an irradiation drive pattern including element weighting between ultrasonic transducer elements, wherein the selected elements are driven at increased or decreased frequencies and / or amplitudes to generate an incoherent distributed acoustic field.

[0270] In another embodiment, the present disclosure relates to an irradiation driving pattern which may also include frequency, amplitude, and / or phase modulation within each element pulse to generate an incoherent distributed field.

[0271] In another aspect, the disclosure may also include decontamination or standard apodization techniques across an array or subarray element pattern to generate an incoherent distributed field.

[0272] In another embodiment, the disclosure relates to irradiation drive patterns, which may also include alternating drive patterns that utilize only a subset of elements as a subarray for applying energy to specific locations within a distribution field. The intensity, amplitude, and frequency of the irradiation drive pattern, as well as the resulting peak negative pressure, are delivered within a range that contributes to a cavitation environment safe for healthy tissue within the surgical field being treated.

[0273] This disclosure relates to various embodiments of irradiation drive patterns for activating an ultrasonic sensitizer to provide acoustic dynamics therapy. The irradiation drive pattern generates an incoherent field for distributing low-intensity energy. In one embodiment, the drive pattern includes a plurality of ultrasonic transducer elements arranged in a preferred array or sub-array structure. The number of ultrasonic transducer elements and the arrangement of the array structure are solutions for position dependence for each disease state. Due to differences in the positions of spatial elements within the array, coherence occurs only at specific locations in the treatment surgical field. As used herein, coherence can be used to describe the characteristics of the interrelationships between sound waves generated by a disease-specific array.

[0274] Coherence is a measure of the correlation between one wave and another wave or another part of the same wave. Temporal coherence is the degree to which a wave can be shifted in time and still correlate well with another wave. Two waves that are continuous, have a constant phase difference, and have the same frequency will remain correlated even when shifted in time relative to each other. Spatial coherence is the degree to which a wave can be shifted in space and still correlate well with another wave or another part of the same wave. Coherence between two waves can be measured as the spatial difference between the sources of the two waves, as the time difference between the two waves such that one wave is delayed relative to the other, or as a combination thereof. Two waves can be considered coherent if they have a constant relative phase, or if they have a phase difference of zero or constant and the same frequency. As an example and not an limitation, the properties of a coherent light source can include, for example, waves having a constant phase difference (e.g., being in phase with each other) and the same frequency. At the same frequency, the phases of two waves are randomized while maintaining the same phase difference and preventing phase coupling due to constructive or canceling interference. Wave amplitude does not necessarily contribute to wave coherence, but it is possible to manipulate the amplitude to achieve a more diffuse acoustic field.

[0275] Figures 20–24 show various acoustic dynamics therapy systems 900, 1000, 1100, 920, and 950 for generating irradiation drive patterns for acoustic dynamics therapy. The acoustic dynamics therapy systems 900, 1000, 1100, 920, and 950 can be adapted and configured to drive an array of ultrasonic transducer elements to generate incoherent irradiation drive patterns for activating ultrasonic sensitizers in conjunction with providing acoustic dynamics therapy.

[0276] In various embodiments, cancerous tissues of the lungs, breasts, colorectal region, prostate, and pancreas can be treated using, for example, one or more ultrasound sensitizers with ultrasound parameters described herein, using some of the embodiments described herein. Tumors that are difficult to access, including those surrounded by bone structures, are treated in various embodiments, including, but not limited to, brain tumors or spinal tumors. Treatment of unwanted tissues in joints and other orthopedic applications are also provided herein. In some embodiments, acoustic dynamics therapy is used to improve the efficiency of chemotherapy molecules, sonoporation, and / or gene delivery. In various embodiments, 8, 10, 15, and 20 W / cm² are applied to cancerous tissue. 2 Less than (for example, 0.1-8 W / cm²) 2 , 0.1~4W / cm 2 , 0.5~5W / cm 2 Acoustic therapy using an ultrasound array that delivers time-averaged intensity output (such as) can be used to induce and activate ultrasound sensitizers at relatively deep depths within the patient's body, with or without cavitation, thereby activating the ultrasound sensitizers and triggering thermal effects, oxygen species, and / or free radicals in a cascade of events that damage cancer cells. In various embodiments, acoustic therapy can be used with or without photodynamic therapy.

[0277] Some embodiments described herein are used synergistically with other cancer therapies, including, for example, radiation, chemotherapy, immunotherapy, and cell therapy. In one embodiment, the combination of ultrasound and ultrasound sensitizer described herein reduces or eliminates the need for one or more additional complementary therapies. For example, when treating cancerous tissue with the combination of ultrasound and ultrasound sensitizer described herein, lower doses or fewer additional therapies such as chemotherapy, radiation, and cell therapy may be required, thus enhancing patient care and reducing side effects.

[0278] Figure 25 shows a diagram of a coherent acoustic field 1200 generated by an array of coherent ultrasonic transducer elements according to at least one aspect of the present disclosure. The coherent acoustic field 1200 includes, or essentially consists of, a plurality of waveforms 1202, 1204, 1206, 1208, 1210 having the same frequency, phase, and amplitude, for example. Examples of ultrasonic transducer elements are described in relation to Figures 29 to 42B.

[0279] An incoherent light source is the exact opposite of a coherent light source. An incoherent light source emits an irradiation drive pattern that randomizes the phase difference across the entire ultrasonic transducer array. Furthermore, the frequency and / or amplitude within the irradiation drive pattern may also be modulated to achieve an incoherent light source.

[0280] Figure 26 shows a diagram of an incoherent acoustic field 1220 generated by an array of incoherent ultrasonic transducer elements according to at least one aspect of the present disclosure. The incoherent acoustic field 1220 includes, or essentially consists of, a plurality of waveforms 1222, 1224, 1226, and 1228 that are in different phases relative to each other. As shown in the example in Figure 26, waveforms 1222-1228 are generated in bursts that are out of phase with each other. Examples of ultrasonic transducer elements are described in relation to Figures 29-42B. In some embodiments, the burst frequencies are 0.3-3 MHz (e.g., 0.5-1.5, 0.6-1.8, 0.7-1.1, 0.5-2.0 MHz, etc.).

[0281] In one embodiment, the independent emission of an incoherent field-driven pattern contributes to a favorable cavitation environment for activating the ultrasound sensitizer and promoting acoustic dynamics therapy. The intensity, amplitude, and frequency of the sound wave sensitization driving pattern, as well as the resulting variable peak negative pressure, are further important contributing factors to the cavitation environment for activating the ultrasound sensitizer. In another embodiment, the independent emission of an incoherent field-driven pattern contributes to a favorable environment for activating the ultrasound sensitizer and promoting acoustic dynamics therapy without cavitation. The intensity, amplitude, and frequency of the irradiation driving pattern, as well as the resulting variable peak negative pressure, further contribute to the environment for activating the ultrasound sensitizer. Furthermore, the incoherent field-driven pattern can continuously shift the energy collection point within the therapeutic working field, thereby gradually saturating a large therapeutic volume with ultrasonic pressure after many cycles of the driving pattern, thereby broadly activating the ultrasound sensitizer. This ensures that exogenous cancer cells throughout the target therapeutic site and its surroundings are treated. In some cases, anatomical structures may disrupt and / or attenuate ultrasound pressure within the desired treatment area. If known disturbances may occur in the desired treatment area, the irradiation drive pattern can be used with a combination of coherent and incoherent drive patterns to selectively deliver energy to any weak points in the treatment field.

[0282] According to one embodiment, the irradiation-driven pattern is applied as pulsed therapy. According to another embodiment, the irradiation-driven pattern is applied as continuous therapy. Applying a pulsed-driven pattern instead of a continuous wave has inherent patient safety advantages. This avoids the accumulation of energy as heat, particularly in areas where significant reflections can occur. The pulsed-driven pattern also dramatically reduces the ability to form standing waves, thereby mitigating the risks associated with the continuous wave pattern. The pulsed-driven pattern is also important in some embodiments to allow for broad activation of the ultrasound sensitizer. In one embodiment of acoustic dynamics therapy, there is a rate-limiting step when the ultrasound sensitizer is activated and generates reactive oxygen species, a process that instantaneously depletes the local oxygen supply. The pulsed-driven pattern allows the local oxygen supply to be resaturated, thereby allowing subsequent ultrasound sensitizer activation to occur during subsequent pulses. In one embodiment, the continuous wave-driven pattern may not only result in a significant increase in potential patient safety risks, but may also be detrimental to the effective administration of acoustic dynamics therapy because the continuous wave-driven pattern may not allow for broad restoration of the local oxygen supply.

[0283] Figure 27A shows a diagram of a pulse therapy 1230 according to at least one aspect of the present disclosure. An enable / delivery pulse 1232 activates a drive waveform 1234 over a period (beat) with a predetermined duty cycle defined as the ratio of pulse width to period. The drive waveform 1234 has the same pulse width as the enable / delivery pulse 1232 and repeats over the same period. The drive waveform 1234 is also defined by its magnitude (amplitude) and burst count—the number of cycles of the period wave per pulse width 1232.

[0284] The pulse characteristics of the drive pattern for enabling the activation of the ultrasonic sensitizer can be defined by the pulse width of the pulse drive waveform 1234 pattern. Each pulse width includes a burst 1236 of the drive pattern cycle. In one embodiment, this burst 1236 of the drive pattern creates a favorable cavitation environment for activating the ultrasonic sensitizer. In one embodiment, this burst 1236 of the drive pattern creates a non-cavitation environment for activating the ultrasonic sensitizer. Applying pulse bursts 1236 of the drive pattern allows for the application of relatively high peak intensity while still maintaining low time intensity. Each pulse width preferably includes bursts 1236 of 10 to 1000 drive pattern cycles to create a favorable activation profile for the ultrasonic sensitizer. The time between bursts 1236 1238 can be manipulated to account for the recovery of local oxygen supply and further manage temperature and safety concerns in a highly reflective environment.

[0285] Figure 27B shows a diagram of a pulse therapy 1230 according to at least one aspect of the present disclosure, which includes a pulse-driven waveform 1234 pattern having a variable duration followed by a periodic pause or quiescence cycle 1238. In various embodiments, the time delay is within the range of 0.1μs to 100s, including 0.1μs, 0.2μs, 0.3μs, 0.4μs, 0.5μs, 1μs, 5μs, 10μs, 15μs, 20μs, 25μs, 30μs, 35μs, 40μs, 50μs, 60μs, 70μs, 80μs, 90μs, 0.1ms, 0.2ms, 0.3ms, 0.4ms, 0.5ms, 1ms, 5ms, 10ms, 50ms, 100ms, 500ms, 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s and any values ​​and ranges within those ranges. In various embodiments, the pause or suspension cycle is within the range of 0.1μs to 100s, including 0.1μs, 0.2μs, 0.3μs, 0.4μs, 0.5μs, 1μs, 5μs, 10μs, 15μs, 20μs, 25μs, 30μs, 35μs, 40μs, 50μs, 60μs, 70μs, 80μs, 90μs, 0.1ms, 0.2ms, 0.3ms, 0.4ms, 0.5ms, 1ms, 5ms, 10ms, 50ms, 100ms, 500ms, 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s and any values ​​and ranges within those ranges.

[0286] In one embodiment, each pulse may generate cavitation bubbles, which may accumulate in a cloud that could interfere with or attenuate subsequent pulses. To improve the dissipation of the cavitation cloud before subsequent pulses, various combinations of different period lengths and pause / pause cycles can be utilized. These pulse parameters also provide additional means for managing and preventing temperature increases in patient tissue exposed to the ultrasound field.

[0287] Figure 27B illustrates a pulse therapy according to at least one aspect of the present disclosure, comprising an initial period A before repeating a pulse sequence, followed by a slightly longer period B, and then a pause or quiescent period. Periods A and B may be followed by further subsequent periods of continuously varying lengths. In various embodiments, the length of the periods and the pause / quiescent intervals may provide additional benefits for activating the ultrasound sensitizer by providing additional time for the restoration of local oxygen supply beneficial to acoustic dynamics therapy. In one embodiment, the period defines the pulse repetition frequency. In one embodiment, when an ultrasound transducer is pulsed at a uniform pulse repetition frequency, it generates high-pitched audible noise. Such audible noise may be unacceptable in a clinical setting while treating a patient, particularly in brain cancer applications where the transducer is coupled to the head, which can amplify the audible noise from the patient's perspective. In one embodiment, the period length is randomized pulse by pulse to reduce the audible noise output from the transducer. In various embodiments, period A, period B, and pause (pause) period 1238 are 0.1μs, 0.2μs, 0.3μs, 0.4μs, 0.5μs, 1μs, 5μs, 10μs, 15μs, 20μs, 25μs, 30μs, 35μs, 40μs, 50μs, 60μs, 70μs, 80μs, 90μs, 0.1ms, 0.2ms, 0.3 The time range is 0.1μs to 100s, including ms, 0.4ms, 0.5ms, 1ms, 5ms, 10ms, 50ms, 100ms, 500ms, 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s, and any value and range within those ranges.In various embodiments, the period pause or suspension cycle 1238 is 0.1μs, 0.2μs, 0.3μs, 0.4μs, 0.5μs, 1μs, 5μs, 10μs, 15μs, 20μs, 25μs, 30μs, 35μs, 40μs, 50μs, 60μs, 70μs, 80μs, 90μs, 0.1ms, 0.2ms, 0.3ms, The values ​​are within the range of 0.1μs to 100s, including 0.4ms, 0.5ms, 1ms, 5ms, 10ms, 50ms, 100ms, 500ms, 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s, and any value and range within these ranges. In one embodiment, the pulse treatment is 0.1μs and the pause or suspension cycle 1238 is 0.1μs. In one embodiment, the pulse treatment is 0.1μs and the pause or suspension cycle 0.2μs. In one embodiment, the pulse treatment is 0.1μs and the pause or suspension cycle 0.5μs. In one embodiment, the pulse treatment is 1μs and the pause or suspension cycle 1μs. In one embodiment, the pulse treatment is 1 μs and the pause or suspension cycle is 2 μs. In one embodiment, the pulse treatment is 1 μs and the pause or suspension cycle is 5 μs. In one embodiment, the pulse treatment is 1 ms and the pause or suspension cycle is 1 ms. In one embodiment, the pulse treatment is 1 ms and the pause or suspension cycle is 2 ms. In one embodiment, the pulse treatment is 1 ms and the pause or suspension cycle is 5 ms. In one embodiment, the pulse treatment is 1 s and the pause or suspension cycle is 1 s. In one embodiment, the pulse treatment is 1 s and the pause or suspension cycle is 2 s. In one embodiment, the pulse treatment is 1 s and the pause or suspension cycle is 5 s.

[0288] In one embodiment, the pattern of the pulse-driven waveform 1234 includes discrete frequency bursts, such as in the range of approximately 20.00kHz to approximately 12.00MHz, including any value and range among them such as 20kHz, 50kHz, 100kHz, 250kHz, 400kHz, 500kHz, 550kHz, 600kHz, 650kHz, 700kHz, 750kHz, 800kHz, 850kHz, 900kHz, 950kHz, 1MHz, 1.1MHz, 1.2MHz, 1.3MHz, 1.4MHz, 1.5MHz, 2MHz, 3MHz, 4MHz, 5MHz, 10MHz, 12MHz, and 0.5~1.5MHz, 0.6~1.4MHz, 0.7~1.1MHz, 0.8~1.2MHz, 1~5MHz. More specifically, transducers 150, 400, and 450 may be driven at ultrasonic frequencies in the range of approximately 650.00 kHz to approximately 2.00 MHz. In one preferred range, transducers 150, 400, and 450 may be driven at ultrasonic frequencies in the range of approximately 500 kHz to approximately 1.3 MHz, approximately 700 kHz to approximately 1.1 MHz, 900.00 kHz to approximately 1.20 MHz, and 975 kHz to 1.1 MHz, for example, in one embodiment they may be driven at approximately 1 MHz, 1.03 MHz, 1.06 MHz, 1.10 MHz, 1.20 MHz, etc. In one embodiment, the pattern of the pulse-driven waveform 1234 includes bursts of 0.1MHz, 0.2MHz, 0.4MHz, 0.5MHz, 0.6MHz, 0.7MHz, 0.8MHz, 0.9MHz, 1.0MHz, 1.1MHz, 1.2MHz, 1.3MHz, 1.4MHz, 1.5MHz, 1.6MHz, 1.7MHz, 1.8MHz, 1.9MHz, 2.0MHz, 2.5MHz, 3.0MHz, 3.5MHz, 4.0MHz, 4.5MHz, 5.0MHz, 6MHz, 7MHz, 8MHz, 9MHz, 10MHz, and any value or range within these ranges.In one embodiment, the pattern of the pulse-driven waveform 1234 includes one, two, three or more discrete bursts of any value or range therein, such as 0.1MHz, 0.2MHz, 0.4MHz, 0.5MHz, 0.6MHz, 0.7MHz, 0.8MHz, 0.9MHz, 1.0MHz, 1.1MHz, 1.2MHz, 1.3MHz, 1.4MHz, 1.5MHz, 1.6MHz, 1.7MHz, 1.8MHz, 1.9MHz, 2.0MHz, 2.5MHz, 3.0MHz, 3.5MHz, 4.0MHz, 4.5MHz, 5.0MHz, 6MHz, 7MHz, 8MHz, 9MHz, 10MHz, and any value or range therein, and includes random bursts, sequentially advancing bursts, sequentially decreasing bursts, skip bursts, and other burst patterns. In various embodiments, the repeating signal may be pulse-width modulated, duty cycle modulated, phase modulated, frequency modulated, randomized phase modulated, or modulated using any suitable modulation technique to generate desired acoustic pulse packets. In one embodiment, all elements in the array fire simultaneously. In one embodiment, all elements in the array fire sequentially. In one embodiment, all elements in the array fire randomly. In one embodiment, all elements in the array fire incrementally at 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 MHz and any value within those frequencies. In one embodiment, an inverse incremental sequence is used. In one embodiment, lower frequencies result in less cavitation. In one embodiment, lower frequencies offer a greater chance of bursting bubbles. In one embodiment, higher frequencies offer a greater chance of more cavitation.

[0289] The irradiation drive pattern includes phase randomization between ultrasonic transducer elements according to one embodiment. The phase difference between the generated waves is randomized. This drive pattern provides an important aspect in creating a non-coherent, dispersed therapeutic surgical field. The randomization technique may utilize a normal distribution, or in other embodiments, it may be advantageous to set random phases from various random distributions. In one embodiment, the method covers 0° to 220° (e.g., 0° to 45°, 0° to 90°, 1° to 135°, 0° to 180°, 0° to 200°, 45° to 90°, 45° to 135°, 45° to 180°, 45° to 220°, 90° to 135°, 90° to 180°, 90° to 220°, 120° to 220°, 120° to 180°, 120° to The phase of each element in the entire array is selected in a randomized manner between phases of 150°, 180°–220°, and / or 200°–220°, followed by a variance adjustment to select the remaining group of elements in the 140°–360° range (e.g., 140°–300°, 140°–270°, 140°–225°, 140°–180°, 140°–150°).

[0290] According to one embodiment, the irradiation drive pattern can include frequency modulation within each element pulse to enhance the incoherent distribution field. Varying the frequency within the burst of wave packets blurs the wavefront, thereby providing a more uniform therapeutic action field. Widely and uniformly spreading the energy is necessary for the robust activation of the ultrasound sensitizer.

[0291] The irradiation drive pattern can include inverse apodization profiles and standard apodization profiles across the array elements, as well as a planar apodization profile according to one embodiment. Time-based apodization profiles within the drive pattern cycle are also a means that can be used to enhance the incoherent distribution field. Apodization is an ultrasonic imaging technique that typically involves varying the amplitude across the aperture of an ultrasonic transducer so that transducer elements at the center of the probe head are electrically excited with a larger amplitude voltage than transducer elements at the edges. Ultrasonic imaging apodization attempts to reduce the amplitude of the side lobes for better overall image resolution. The inverse of this drive pattern can be uniquely applied to direct energy to a therapeutic surgical field to activate an ultrasonic sensitizer, according to one embodiment. Inverse apodization for acoustic dynamics therapy provides greater energy to ultrasonic transducer elements at the outer edges of the array compared to those near the center of the array axis. Therefore, inverse apodization broadens the beam width and results in a deeper irradiation area. The excitation scheme may include smooth and / or discrete steps that help collect and distribute energy across the treatment surgical field. In the context of this treatment device, array or subarray-based apodization can be utilized to concentrate energy into a smaller treatment surgical field. This may be useful, for example, when optimizing the treatment surgical field in response to changes in skull thickness.

[0292] According to one embodiment, the irradiation drive pattern is likely to include an alternating drive pattern. Furthermore, some alternating drive patterns utilize only a subset of elements as a subarray for adding energy to specific locations within the distribution field. This is achieved by a selection process that coherently selects elements that are directional to the location of interest, and then provides phase randomization across those subarray elements to have the most incoherent field possible at the location of interest. The pulse characteristics of preferred drive patterns for acoustic dynamics therapy have been previously disclosed. Each pulse may contain the same burst of the drive pattern, or additionally, several alternating frequencies of the pulse may provide an alternating drive pattern. The alternating drive pattern provides a means of further saturating the treatment surgical field with preferred waveform characteristics for activating the ultrasonic sensitizer. The alternating drive pattern may use all ultrasonic transducer elements in the array, while other alternating drive patterns may use only a subset of transducer elements in the array as a subarray. The alternating drive patterns within the subarray allow energy to be applied to specific weak points in the surgical field without the use of any kind of coherent focusing drive pattern.

[0293] Figure 28 is a logic flowchart 1240 for generating an irradiation drive pattern for acoustic dynamics therapy, according to at least one aspect of the present disclosure. The logic flowchart 1240 illustrates a method for generating an acoustic irradiation drive pattern for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy. The acoustic irradiation drive pattern generates an incoherent acoustic field for distributing low-intensity energy. According to the method, a first signal is generated to drive a first ultrasonic transducer element to generate a first acoustic irradiation drive pattern having a first phase, a first frequency, and a first amplitude (1242). A second signal is generated to drive a second ultrasonic transducer element to generate a second acoustic irradiation drive pattern having a second phase, a second frequency, and a second amplitude (1244). At least one of the relative phase difference, frequency, and amplitude of the first and second signals is selected to generate a third incoherent acoustic irradiation pattern for activating an ultrasonic sensitizer located in patient tissue.

[0294] Figures 29 to 42B illustrate various embodiments of ultrasonic transducer arrays and techniques for packing elements of ultrasonic transducer arrays according to various embodiments. The ultrasonic transducer arrays can be driven by acoustic dynamics therapy systems 900, 1000, 1100, 920, and 950, shown in Figures 20 to 24. These acoustic dynamics therapy systems 900, 1000, 1100, 920, and 950 can be adapted and configured to drive the ultrasonic transducer arrays described below to generate irradiation drive patterns for acoustic dynamics therapy.

[0295] An ultrasonic transducer, according to one embodiment, is a device capable of generating and receiving ultrasonic vibrations. The ultrasonic transducer comprises an active element, which is a piezoelectric material or a single-crystal material that converts electrical energy into ultrasonic energy.

[0296] Various embodiments of ultrasound array shapes for acoustic dynamics therapy may, according to one embodiment, include a large opening that closely conforms to the contours of the body and / or the body. The large opening is defined as being the same size as or larger than the lesion being treated. The aspect ratio of the opening to the lesion size allows for the initiation of a wide, incoherent field to ensure that the lesion and surrounding tissues are treated. In one embodiment, the array is in close contact with the body. For example, in the brain cancer embodiment, the array may be a fitted helmet or individual elements arranged in an array pattern directly on the head. In one embodiment, ultrasound modifies the blood-brain barrier (BBB). In one embodiment, ultrasound facilitates the delivery of drugs and / or ultrasound sensitizers that cross the blood-brain barrier.

[0297] The geometric shapes of the ultrasonic transducer element arrays include, but are not limited to, one, some, or all of the following: close-fitting helmets, dome helmets, individual elements positioned on the head or body, flat arrays, hemispherical arrays, and / or curved linear arrays, according to various embodiments.

[0298] In various embodiments, the ultrasonic transducer elements constituting the array may consist of linear arrays, rectangular arrays, circular arrays, concentric circular arrays, helical arrays, Archimedes spiral arrays, or sunflower spiral arrays, or any combination thereof, or sparser variations thereof, as described herein according to various embodiments. The ultrasonic transducer elements configured in such arrangements may be packed according to a predetermined element packing density or distribution. In addition to the linear rectangular arrays shown in Figures 6 and 8 and the concentric circular arrays shown in Figure 7, various embodiments of ultrasonic element array shapes for acoustic dynamics therapy may also include ultrasonic transducer elements arranged in an Archimedes spiral, or known as a linear array. The Archimedes spiral has the property that any ray from the origin intersects the continuous spiral of the spiral at a point having a constant separation distance (equal to 2πb when θ is measured in radians), and is therefore named the "arithmetic spiral." The active transducer elements are arranged along the Archimedean spiral at various predetermined element packing densities, including sparse Archimedean spiral arrays.

[0299] Figure 29 shows an array 1300 of ultrasonic transducer elements 1302 arranged in an Archimedean spiral (linear spiral) according to at least one aspect of the present disclosure. In the illustrated example, the overall diameter of the Archimedean spiral array 1300 is, but is not limited, about 150 mm, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited. In various embodiments, the ultrasonic transducer elements 1302 have dimensions (e.g., length, radius, diameter) in the range of 0.5 mm to 20 mm, 1 mm to 10 mm, 3 mm to 7 mm, and 4 mm to 6 mm, including any values ​​and ranges therein, such as 0.5 mm, 1 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 10 mm, 12 mm, 15 mm, 18 mm, and 20 mm.

[0300] More specifically, according to one embodiment, the diameter of the ultrasonic transducer element 1302 can be selected based on the wavelength of 1.5 MHz ultrasound propagating through water at the speed of sound (approximately 1,480 meters / second). Wavelength λ is the ratio of the speed of sound to frequency. At these values, the nominal diameter of the ultrasonic transducer element 1302 is approximately 1 mm. The diameter of the ultrasonic transducer element 1302 may be selected in the range of 0.5λ to 20λ (e.g., 0.5 mm to 20 mm). In one embodiment, each of the ultrasonic transducer elements 1302 may have the same diameter, and in other embodiments, the ultrasonic transducer elements 1302 may have different diameters selected within the range described herein.

[0301] Other embodiments of ultrasonic element array shapes for acoustic dynamics therapy may also include ultrasonic transducer elements arranged in a sunflower spiral pattern or grid according to various predetermined element packing density techniques, including sparse sunflower spiral arrays. Figure 30 shows a sunflower spiral array 1304 of ultrasonic transducer elements 1302 arranged on a grid according to at least one embodiment of the present disclosure. As previously stated, the diameter of the sunflower spiral array 1304 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameters of the ultrasonic transducer elements 1302 may be the same or different within the dimensional range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended. The sunflower spiral is a special case of the Fermat spiral, defined by the divergence angle that determines the angular distance between two consecutive elements. The radial position of each element is determined by the square root of its angular position.

[0302] Other variations of the sunflower spiral array 1304 shown in Figure 30 include variations including a sparse sunflower spiral array and a sunflower spiral array, as shown in Figures 31 to 37, which include additional transducer elements arranged on specific rings of the sunflower spiral array according to a predetermined element packing density.

[0303] The sunflower helical array offers advantages over other sparse array configurations in terms of beamforming performance and array uniformity. The sunflower array is known for its good element packing characteristics and beam pattern with low sidelobe energy. Furthermore, since the sunflower pattern is considered to have the highest density among helical patterns, selecting active ultrasonic transducer elements from a sunflower helical array is advantageous.

[0304] This disclosure describes several configurations of sparse helical arrays of active ultrasonic transducer elements arranged on a sunflower helical grid according to various packing densities according to various embodiments. Algorithms are also disclosed for generating various sparse helical arrays arranged on a sunflower helical grid at various packing densities using the same number of active ultrasonic transducer elements, in order to simplify the electronic circuits for driving the ultrasonic transducer elements to achieve desired acoustic therapy.

[0305] The sunflower spiral array pattern of ultrasonic transducer elements can be generated according to the following algorithm, function, or pseudocode.

[0306] The following is exemplary code for generating sunflower spirals according to various embodiments. α = 137.51° #Magic or Golden Angle N_e=128 #Number of active elements multiplier=3 # Number of elements to skip N = N_e * multiplier # All elements, including skipped elements D=150 #Actual array diameter l_0 = D / (sqrt((N-1)*α)) #From equation 16 by Yoon et al. n=1:N #Element Index φ = n * α # Polar angle of each element r = l_0 * sqrt.(φ) # Polar radius of each element #Create an array of Cartesian positions C = polar2cart.(φ,r); C=hcat(C...)'; #Create a position vector inds=1: Multiplier: N x,y=C[inds,1],C[inds,2] #Actual elements xx,yy=C[:,1],C[:,2] #All elements, including those that were skipped #plot scatter(xx,yy,ma=0.5,markercolor=:white, markerstrokealpha=0.2,markerstrokecolor=:grey) scatter!(x,y,markercolor=:blue) plot!(aspect_ratio=:equal,size=(500,500),title=''$(N)skipping every $(multiplier)elements=128'') savefig(''sunflower_$(N)_skip$(multiplier).png'') The following are exemplary equations that can be used to generate sunflower lattice points according to various embodiments. α ≈ 137.51° i=1 … N JPEG0007884503000013.jpg13153 θi = iα JPEG0007884503000014.jpg11153 Xi = ri cos(θi) yi=ri sin(θi) The above equation defines the grid points of the sunflower array in polar coordinates (θi,ri) and Cartesian coordinates (xi,yi) confined to a diameter D. The sunflower grid points are arranged incrementally around the polar axis by an angle α defined to be the golden angle of approximately 137.51°. The sunflower grid points are gradually arranged radially in steps of length I defined to confine the points to the diameter D. The sunflower grid point index i is an integer from 1 to N, where N is the number of grid points. Sparse rectangular and spiral arrays are presented in Yoon, Hansol, and Tai-kyong Song, "Sparse Rectangular and Spiral Array Designs for 3D Medical Ultrasound Imaging," Sensors (Basel, Switzerland) 20(2020):n.page., which is incorporated herein by reference.

[0307] Referring to Figure 31, an array 1306 of ultrasonic transducer elements 1302 defining an internal sunflower spiral is shown according to at least one aspect of the present disclosure, with additional ultrasonic transducer elements 1308 arranged in the outer region of the sunflower spiral array. As previously stated, the diameter of the sunflower spiral array 1304 is approximately 150 mm, but is not limited, and the diameters of the ultrasonic transducer elements 1302, 1308 can be selected in the range of 0.5 mm to 20 mm, depending on the frequency of the excitation signal and the speed of sound in water, but is not limited. As previously stated, the diameters of the ultrasonic transducer elements 1302, 1308 may be the same as or different from the diameters of the transducer elements 1302, 1308 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302, 1308 may be suspended.

[0308] Figure 32 shows a sparse sunflower helical array 1310 comprising 128 active ultrasonic transducer elements 1302 arranged on a grid of 256 elements skipping every two elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1310 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0309] Figure 33 shows a sparse sunflower helical array 1312 comprising 128 active ultrasonic transducer elements 1302 arranged on a grid of 384 elements skipping every three elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1312 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0310] Figure 34 shows a sparse sunflower helical array 1314 comprising 128 active ultrasonic transducer elements 1302 arranged on a grid of 512 elements skipped every four elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1314 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0311] Figure 35 shows a sparse sunflower helical array 1316 comprising 640 active ultrasonic transducer elements 1302 arranged on a grid of 128 elements skipping every five elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1316 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0312] Figure 36 shows a sparse sunflower helical array 1318 comprising 768 active ultrasonic transducer elements 1302 arranged on a grid of 128 elements skipped every six elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1318 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0313] Figure 37 shows a sparse sunflower helical array 1320 comprising 128 active ultrasonic transducer elements 1302 arranged on a grid of 896 elements skipped every seven elements, according to at least one aspect of the present disclosure. As previously stated, the diameter of the sunflower helical array 1320 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0314] Figure 38 shows an array 1322 comprising 128 randomly arranged and irregularly distributed active ultrasonic transducer elements, relating to at least one aspect of the present disclosure. As previously stated, the diameter of the random array 1322 is approximately 150 mm, but is not limited, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, but is not limited, depending on the frequency of the excitation signal and the speed of sound in water. As previously stated, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be suspended.

[0315] In various embodiments, the shape of the ultrasonic transducer element includes, for example, a circular or disk shape and a concentric ring, as well as Figures 1 to 3 and Figure 7. Figure 39A shows an array 1324 of concentrically arranged active ultrasonic transducer elements 1302, with additional active ultrasonic transducer elements 1326 according to at least one embodiment of the disclosure arranged on the outer portion of the outer ring. As previously stated, the diameter of the array 1324 is, but not limited to, about 150 mm, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, depending on the frequency of the excitation signal and the speed of sound in water, but not limited to. As previously stated, the diameters of the ultrasonic transducer elements 1302, 1326 may be the same as or different from the diameters of the transducer elements 1302, 1326 selected within the range described in the disclosure. It will be understood that some of the ultrasonic transducer elements 1302, 1326 may be suspended.

[0316] Figure 39B shows an array 1327 of concentrically arranged ultrasonic transducer elements 1302 according to at least one aspect of the present disclosure. In various embodiments, the overall diameter of the array 1324 is in the range of approximately 100 mm to 200 mm, including but not limited to 100 mm, 125 mm, 150 mm, 165 mm, 175 mm, 200 mm and any value therein, and the diameter of the ultrasonic transducer elements 1302 can be selected in the range of 0.5 mm to 20 mm, including 0.5 mm, 1 mm, 3 mm, 5 mm, 7 mm, 10 mm, 12 mm, 15 mm, 18 mm, and 20 mm, depending on the frequency of the excitation signal and the speed of sound in water. In various embodiments, the diameter of the ultrasonic transducer elements 1302 may be the same as or different from the diameter of the transducer elements 1302 selected within the range described in the present disclosure. It will be understood that some of the ultrasonic transducer elements 1302 may be activated or deactivated collectively, in groups, or individually. In various embodiments, the array 1327 includes 1 to 1024 ultrasonic transducer elements 1302, each containing 1, 2, 4, 8, 16, 32, 64, 128, 256, 384, 512, 640, 678, 896, or 1024 elements. In various embodiments, the array 1327 includes 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 ultrasonic transducer elements 1302. In one embodiment, the array 1327 has 256 transducer elements 1302, each having a diameter of 5 mm. In one embodiment, the spacing between adjacent elements is constant. In one embodiment, the spacing between adjacent elements gradually increases outward from the center of the array toward the outer diameter of the array, and the spacing between adjacent valence and / or concentric rings of elements gradually increases from the center of the array toward the outer diameter or periphery of the array. In another embodiment, the spacing between adjacent elements gradually decreases outward from the center of the array toward the outer diameter of the array, and the spacing between adjacent valence and / or concentric rings of elements gradually decreases from the center of the array toward the outer diameter or periphery of the array.

[0317] Figure 40 shows several uniform element packing techniques 1328 for arranging ultrasonic transducer elements according to at least one aspect of the present disclosure. In various aspects, ultrasonic transducer elements constituting an array such as linear, rectangular, circular, concentric, helical, Archimedean spiral, or sunflower spiral, or any combination thereof, or sparse variations thereof, as described herein, may be packed according to a predetermined element packing density or distribution. A regular element packing density or distribution is an arrangement of circular active transducer elements (equal or varying in size) on a given surface such that there is no overlap between transducer elements and that circular transducer elements cannot be expanded without overlap. The relevant packing density η of the arrangement is the percentage of the surface covered by circles. Conventional element packing is further described at https: / / en.wikipedia.org / wiki / Circle_packing#Uniform_packings, which is incorporated herein by reference.

[0318] Figures 4 and 5 show different embodiments of transducer lenses defining concave and convex surfaces, respectively, according to various embodiments. Generating a broad diffusion field through the skull presents several challenges. The skull attenuates a significant amount of ultrasonic energy. Geometrically focusing the ultrasonic transducer elements to the same point helps overcome the attenuation from the skull. This geometric focus of the array receives energy from all elements in the array. Points close to the array (e.g., inside the skull) may be too off-axis to receive much energy from many elements due to the directivity of the individual elements. While the skull still attenuates a considerable portion of the energy from any one element, the total amount of energy between the point close to the array and the focus is high. Therefore, the geometric focus helps to compensate for the transmission loss through the skull.

[0319] This geometric focusing is costly because it naturally restricts the size of the field compared to a flat array. In other words, geometric focusing helps to transfer sufficient energy but prevents the field from diffusing as widely as possible. Furthermore, in many arrays, the geometric focus is fixed because the position and orientation of the elements are fixed within the array.

[0320] To help mitigate this trade-off, lenses, such as those shown in Figures 4 and 5, can be added to the radiating plane of the array according to various embodiments. The lenses can manipulate the direction of the field of view and the fergentz. In some embodiments, lenses are added to change the geometric focus of the array. For example, lenses can be added to a transducer to bring the focus closer to the array. In another embodiment, lenses can be added to a transducer to disperse the energy beam from each element in the array. This beam dispersion may not change the geometric focus of the array, but a point closer to the array can receive energy from more elements.

[0321] In one embodiment, a large acoustic lens material piece can be formed to create a lens array. In some cases, the lens array can be rearranged to move the array relative to the light-emitting element. In some embodiments, the lenses can be rotated along a single axis. For example, the lens array can be rotated 180° from an "off" position to an "on" position with respect to an Archimedean spiral array. In the off position, the outer surface of the lens array directly above the element is parallel to the element's radiating plane. This parallel plane does not significantly alter the direction or fergents of the ultrasound. In this off position, the region of the lens array that alters the ultrasonic field is arranged around an Archimedean spiral alternating with the spiral on which the element is positioned. In the on position, the lens array is rotated so that the spiral crossing the effective lens region and the spiral crossing the element position overlap.

[0322] In some embodiments, there may be several positions that provide different degrees of focus. The lens array can be rearranged to a finite number of positions, each having a different effect on the resulting field. In some cases, the lens array may be rotated to any intermediate position (infinitely many positions). For example, the lens array may be shaped to have a series of helical valleys that can be rotated to many relative positions with respect to the element helix. When the bottom of a groove is aligned with the element helix, there is one effect on the array's focus and the element's dispersion. When the vertex between two grooves is aligned with the element helix, there is another effect on the array's focus and the element's dispersion. Similarly, the lens array can be rotated so that the forward slope between the peaks and valleys is aligned with the element helix. The backward slope between the valleys and peaks can be aligned with the helical element. All intermediate positions provide a different effect on the resulting field.

[0323] In some embodiments, the lens can rotate with three degrees of freedom (spherical kinematic pairs).

[0324] To spread the acoustic beam generated by each element, dispersion lenses can also be applied to the elements. These dispersion lenses can be appropriately integrated into the acoustic stack design, or achieved by a plastic (e.g., Pebax 300 series) overlay that mats onto the surface of a transducer array coupled in an appropriate manner. This type of overlay can be interchangeable, allowing different dispersion lenses to be created to optimize the treatment surgical field for various skull sizes and thicknesses.

[0325] In another embodiment, this dispersion lens may have a beam spreading effect on each element to a greater or lesser extent in order to randomize the sum of acoustic beams from various elements. This dispersion randomization can be applied at the local element subarray level to enhance the overlap of acoustic beams from adjacent elements, or a patterned randomization can be applied across the entire array. For example, more beam spreading can be applied to elements closer to the array center, and less beam spreading to outer array elements to compensate for geometrical acoustic beam spreading to elements further away from the target brain tissue treatment area, i.e., outer elements.

[0326] Elements positioned along a concave surface allow for an energy sum close to the geometric focus of the concave surface; however, in this application, it may also be advantageous to add an entire array dispersion lens to reduce the effects of geometric focusing and reduce geometric sidelobe focusing. This functionality is intended to enhance the ability to broaden the therapeutic surgical field. In one embodiment, this may include a small randomized acoustic delay, applied as part of the transducer acoustic stack design or as a separate overlay lens, as described herein. This technique is analogous to electron transmit pulse phase randomization, but it should be noted that the acoustic properties of the element beam profile can be modified by introducing this physical acoustic offset. This acoustic offset can be modeled and optimized to provide the best overall acoustic beam performance.

[0327] This overlay lens can also be used to focus the energy of a standard array closer or further away, allowing for better optimization of the surgical field for different skull sizes and / or thicknesses.

[0328] In another embodiment, this overlay lens can be used to focus different regions of an array at different depths, similar to an annular array. For example, the outer array elements can be focused to a deeper depth, the inner array elements to a closer depth, and the intermediate array elements to a depth between these two extremes to extend and expand the surgical field for treatment.

[0329] In another embodiment, focusing may be enhanced so that the outer elements focus closer and the inner elements focus deeper, ensuring overlap of energy profiles across the targeted therapeutic area of ​​the brain. These examples demonstrate that this type of array focusing overlay lens can be generalized to any subarray or entire array focusing mechanism (e.g., Fresnel lenses).

[0330] Figure 41 shows a 3 mm diameter transducer aperture element 1330 replaced by four 1 mm diameter aperture elements 1332 according to at least one aspect of the present disclosure. With respect to array element grouping, several different techniques can result in improvements to the overall therapeutic surgical field. In a first element grouping technique, smaller ultrasonic transducer elements 1332 replace larger ultrasonic transducer elements 1330. In this case, the larger ultrasonic transducer element 1330 is replaced by an array of smaller elements 1332 to broaden the entire acoustic beam generated by the element. (Smaller elements generally have a wider beam pattern and better angular response compared to larger elements.) For example, as shown in Figure 38 according to at least one aspect of the present disclosure, a 3 mm circular element 1330 can be replaced by four 1 mm elements 1332. In one aspect, these four 1 mm elements 1332 can be combined into a subarray and connected to each other to form an equivalent 3 mm aperture element 1330. On the other hand, this might be desirable as a practical solution to limit system requirements, but it is not a requirement.

[0331] Figure 42A is a side view of a 2D matrix array 1334 of ultrasonic transducer elements configured to generate a steering beam 1336, according to at least one aspect of the present disclosure, and Figure 42B is an end view of the 2D matrix array 1334 shown in Figure 42A, according to at least one aspect of the present disclosure. The techniques shown in Figures 42A to 42B utilize a 2D matrix array 1334 of ultrasonic transducer elements. Rather than relying on the geometric focus of a larger concave ultrasonic transducer, the 2D matrix array 1334 provides ultrasonication of a volume 1338 of the skull 1340 due to its ability to steer in three dimensions. This 2D matrix array 1334 may be implemented as a sub-array configuration (a group of individual elements linked together in the sub-array formation, driven by a single source), a sparse array configuration (to limit the number of elements and / or driving array electronics), or a combination of both sub-array and sparse array configurations. Further enhancement of the therapeutic surgical field provided by the 2D matrix array 1334 of ultrasonic transducer elements can be provided by the dispersion lens technology described above. It should be noted that the 2D matrix array 1334 can be circular or elliptical in configuration, as these configurations may be superior to the square or rectangular 2D array 1334 shown in Figures 42A-42B for illustrative purposes only. The diameters of the individual ultrasonic transducer elements in the 2D matrix array 1334 can be selected as described above. For example, the diameter of the 2D matrix array 1334 may be approximately 150 mm, but is not limited, and the diameters of the ultrasonic transducer elements in the 2D matrix array 1334 may be selected in the range of 0.5 mm to 20 mm, depending on the frequency of the excitation signal and the speed of sound in water, but is not limited. As described above, the diameters of the ultrasonic transducer elements may be the same as or different from the diameters of the transducer elements selected within the range described in this disclosure. It will be understood that some of the ultrasonic transducer elements may be suspended.

[0332] The 2D matrix array 1334 or the individual ultrasonic transducer elements of the array 1334 may include automated movement (lateral, axial, and rotational) to further distribute the incoherent field for the desired activation of the sensitizer according to various embodiments.

[0333] Having described various aspects of the Acoustic Dynamics Therapy Systems 900, 920, 950, 1000, 1100 and their components, this disclosure now moves on to describing various aspects of apparatus, systems, and methods for selectively positioning and holding an ultrasonic transducer array in a preferred location for therapeutic purposes and coupling the array to the patient's head or other body part for efficient and safe energy transmission, as well as transcranial optimization routines that consider and compensate for variations in transmission through the skull to enable a therapeutic surgical field with an appropriate energy profile for activating an ultrasonic sensitizer.

[0334] In various embodiments, a wearable receptacle, called a patient interface, is positioned above / on the patient's head or other body part and is attached to the patient's head or other body part. The patient interface provides alignment between the patient's specific anatomical structure and an ultrasound transducer array that is detachably coupled to or integrated with the patient interface, guiding the placement and positioning of the therapeutic surgical field for providing acoustic dynamics therapy.

[0335] In various embodiments, the patient interface includes one or more alignment and / or orientation mechanisms that establish true alignment. The alignment and / or orientation mechanisms are shaped and / or sized to bond with and accept bone landmarks on the head, such as the zygomatic arch, mastoid process, mastoid process of the temporal bone, lateral eye, and central arch of the brow, in order to establish true alignment for providing acoustic mechanical therapy. In one embodiment, the patient interface includes a alignment and / or orientation mechanism that is shaped and sized to accept at least two anatomical features on the patient's head. In one embodiment, a targeting template is placed on the patient to facilitate the alignment of the transducer to various treatment sites. In various embodiments, the targeting template is a wearable elastic template with markers to facilitate treatment, such as by isolating markings on the skin with a grid, anatomical structure-based positioning, or indicators. In one embodiment, the targeting template is a cap. In one embodiment, the targeting template is a band configured to wrap around the head, neck, chest, torso, back, waist, legs, buttocks, genital area, or other body part. In one embodiment, the targeting template is drawn on the body. In one embodiment, the targeting template includes a measurement gradient that allows the user to customize the treatment location to the patient's specific anatomical size. In some embodiments, the targeting template remains in place during ultrasound treatment. In some embodiments, the targeting template is made removable before ultrasound treatment.

[0336] Once the patient interface is properly aligned and positioned on the patient, it can be effectively secured in place by straps, adhesives, tapes, or any other suitable fasteners that firmly secure the patient interface to the patient. In certain embodiments, the patient interface is coupled to a robotic arm capable of making minor and / or major adjustments to the position of the patient interface relative to the patient's head. In at least one example, the robotic arm is detached from the patient interface once it is fixed to the patient's head in a preferred therapeutic position.

[0337] In various embodiments, the patient interface provides a receptacle for receiving a preferred ultrasound probe configured for acoustic dynamics therapy. Thus, the ultrasound probe treatment position is established by the patient interface device. This position ultimately determines the arrangement of the treatment surgical field for providing acoustic dynamics therapy. Alternatively, the patient interface may include multiple receptacles for receiving multiple ultrasound probes and / or for carefully navigating a single probe through multiple defined treatment positions. The preferred treatment positions may be a fixed, predetermined pattern or may be customized based on the specific disease location of each patient.

[0338] In certain embodiments, the patient interface includes structures and / or mechanisms that guide the placement of an ultrasonic transducer array to a preferred position for activating an ultrasonic sensitizer. In certain embodiments, the patient interface includes multiple structures or mechanisms that guide the placement of multiple transducer arrays to a preferred position for activating an ultrasonic sensitizer.

[0339] In other embodiments, the patient interface provides the progression of discrete steps using a single array continuously across preferred therapeutic locations. In certain embodiments, the patient interface includes an array holder that can be automatically or manually adjusted to move the array to preferred therapeutic locations. Preferred therapeutic locations for the array may include regions on the skull that better facilitate acoustic coupling based on geometric shape, anatomical structure, and / or preferred anatomical attenuation. Preferred therapeutic locations may also be indexed to or correlated with CT or other imaging data that provide known anatomical inputs for guiding array placement and / or therapeutic parameters. Furthermore, preferred therapeutic locations may also take disease location as input, thereby positioning the array to ensure that ultrasound energy is directed to the diseased area and surrounding tissues.

[0340] In various embodiments, a controller, such as controller 902, can receive imaging data, such as CT scans, or other imaging data that provides known anatomical inputs for guiding array placement and / or treatment parameters. Based on the imaging data, controller 902 can select a preferred treatment position for the ultrasound transducer array. In certain embodiments, the array holder is operably coupled to a motor. In such embodiments, controller 902 can cause the motor to move the array holder relative to the patient interface to the selected treatment position. In various embodiments, controller 902 can cause user interface 1004 to communicate the selected treatment position to the user.

[0341] In another embodiment, the ultrasound transducer array is integrated with the patient interface such that positioning and locating the patient interface is also positioning and locating the array.

[0342] Once the array is positioned appropriately for treatment, according to one embodiment, the array is appropriately coupled to the patient for transmission. In the case of brain cancer patients, all hair is removed so as not to interfere with acoustic coupling. Acoustically conductive gels are common in the industry. In various embodiments, an acoustic coupling membrane is attached to the exit surface of the ultrasonic transducer array. The acoustic coupling membrane can be selectively expanded and contracted to further guide the positioning and placement of the ultrasonic transducer array and further guide the positioning of the treatment surgical field. In various embodiments, the acoustic coupling membrane comprises an elastic material having acoustically neutral properties to provide minimal ultrasonic attenuation.

[0343] In various embodiments, the acoustic coupling membrane defines a cavity having a patient interface. The ultrasound transducer array may protrude from the patient interface toward the cavity. To fill the cavity to a predetermined volume, an acoustic coupling agent, such as degassed water, may be used. The volume of the acoustic coupling agent contained within the membrane can be selectively adjusted to reposition the ultrasound array. Selective control of the array's position using the coupling membrane allows for selective guidance of the treatment surgical field. The membrane's compliance allows it to conform to the patient's anatomical structure at the treatment site for acoustic coupling.

[0344] According to one embodiment, any suitable valve can be used to insert and / or remove the acoustic coupling agent into the cavity in order to expand and / or contract the acoustic coupling membrane. One or more sensors, such as a pressure sensor, can be used by the controller 902 to evaluate the volume of the acoustic coupling agent in the cavity.

[0345] In certain embodiments, the volume of the acoustic coupling membrane can be selectively adjusted to reposition the ultrasonic transducer array. Selective control of the array position using a coupling membrane allows for selective guidance of the treatment surgical field according to one embodiment. In certain embodiments, expansion and / or contraction of the acoustic coupling membrane can be used in cooperation with the array holder to control the position and distance of the array from the skull. This distance can be discretely or dynamically adjusted according to one embodiment to change the position and penetration depth of the treatment surgical field during treatment.

[0346] In certain embodiments, the acoustic coupling agent is circulated to remove residual heat from the surgical field during treatment. In certain embodiments, the acoustic coupling agent is also cooled to remove residual heat from the surgical field during treatment. In certain embodiments, the temperature of the acoustic coupling agent is monitored as a safety measure. For example, the patient interface may include one or more temperature sensors according to one embodiment. In one example, as described elsewhere in this specification, the processing unit 1104 is coupled to a temperature sensor 1118 and receives patient temperature feedback via the ADC 1010. The processing unit 1104 controls the cooling system 1120 at least in part based on the patient temperature feedback signal.

[0347] Transcranial ultrasound delivery presents numerous challenges. The skull acts as a strong reflector, as well as a scatterer and absorber of ultrasound energy. There are also known large patients with varying cranial attenuation characteristics. Patient-specific information is desirable to optimize the therapeutic surgical field for activating the ultrasound sensitizer, taking into account variations in transmission through the patient's skull. Patient-specific information can be input from CT or MRI or other image files, including location-based cranial thickness data. The output of individual ultrasound elements, and / or the entire array, and / or subsections of the array, can be adjusted based on input from CT, MRI, or other image files. Additionally or alternatively, the acoustic dynamics therapy system itself (e.g., system 900, described in more detail in relation to Figures 21 and 22) can be used to collect patient-specific transcranial transmission data for calibrating the optimal ultrasound array output.

[0348] In various examples, an acoustic dynamics therapy system (e.g., system 900, which is described in more detail in relation to Figures 21 and 22) includes one or more transcranial optimization routines for calibrating an ultrasonic transducer array 904 to patient-specific attributes in order to establish appropriate ultrasonic irradiation parameters according to one embodiment. According to one embodiment, the controller 902 may be configured to execute one or more control algorithms to calibrate the ultrasonic transducer array 904 to patient-specific attributes, such as skull thickness. Furthermore, the controller may be configured to activate an ultrasonic sensitizer in the therapeutic area within an anatomical structure for each ultrasonic irradiation parameter established by calibrating the ultrasonic transducer array to patient-specific attributes. In one embodiment, the patient-specific attributes are anatomical. In another embodiment, the patient-specific attributes are non-anatomical.

[0349] In certain cases, the controller 902 can determine whether the skull thickness measurement is within an acceptable nominal range according to one embodiment. In one embodiment, digital imaging and communications (DICOM) images from computed tomography (CT) or other imaging sources can be input to the device controller 902. The imaging data can be analyzed by the controller 902 to determine whether the skull thickness measurement is within an acceptable nominal range. Thus, the controller 902 can use imaging data, such as CT scans, as a screening tool, thereby indicating only patients whose skull thickness measurement is within the nominal or specified range for treatment. The imaging data indicating skull thickness can also be used to optimize the frequency and array position for the most beneficial surgical field for treatment.

[0350] Additionally or alternatively, in a calibration algorithm according to one embodiment, the controller 902 may cause the ultrasonic transducer array 904 to generate pulses to examine the skull at several different frequencies. The controller 904 then evaluates the proportion of reflected energy at various frequencies. In some cases, the frequency with the lowest relative reflected energy correlates with the frequency with the highest transmitted energy through the skull. In at least one example, the calibration process includes measuring the distance to the skull using time of flight (with short pulses). It may also be possible to measure the tilt of the skull relative to various elements. If the skull is tilted too much relative to nearby elements, in one embodiment, the controller 902 is configured to limit the energy directed toward those elements.

[0351] As described in more detail above, according to one embodiment, it may be possible to perform measurements of the skull 510 or obtain a rough image, as shown in Figure 11. This can be facilitated if the transducers 150 are fixed to a rigid shell and their relative positions and orientations are known. The rough measurements can be used to adjust the treatment algorithm by measurement parameters such as skull thickness "t" or skull density "ρ". Each transducer 150 can emit acoustic pulses and hear echoes. The echoes can be used to quickly estimate the skull thickness "t" or skull density "ρ" below each transducer 150. To treat tumors in other parts of the patient's body, the acoustic dynamics therapy system 900 can be adapted and configured to bond to the patient's body.

[0352] In addition to the above, the calibration process may include confirmation that the probe is properly coupled to the patient by a bubble / bubble ultrasound detection technique according to one embodiment.

[0353] In various embodiments, one or more calibration algorithms that can be executed by the controller 902 include a chirp signal input, which can be analogous to a sine wave having a continuously changing frequency. An example of a chirp signal is shown in Figure 46. Multiple overlapping echoes of a chirp signal can be separated in time. A sine wave cannot be easily separated in time because it is identical for a one-period shift. In other words, the autocorrelation of a sine wave has a periodic peak in time for a one-cycle interval. The fluctuating frequency of the chirp signal aligns the peaks and troughs of the chirp signal in only one direction, and the autocorrelation has a single peak. In various embodiments, the chirp signal can be a signal with a longer duration than a short "ping," so that more energy can be used as input for performing calibration. In certain examples, the chirp signal is shaped using an envelope function to have a gradually increasing and decreasing peak as in one embodiment. An exemplary enveloped chirp signal is shown in Figure 47. A chirp signal with a rectangular envelope has abrupt changes. Rapid changes in the echoes returned from a rectangular envelope chirp can be attributed to the input signal or the image being captured. To investigate transmissions across multiple frequencies in a single integration, the received chirp signal can be integrated in the frequency domain. Furthermore, the received chirp signal can be convolved with the time-reversed transmitted chirp signal to accurately calculate the cranial boundary.

[0354] Additionally or alternatively, an impulse input signal may be used in the calibration process according to one embodiment. The impulse input signal may include pulses that rapidly increase or decrease. An example of an impulse input signal is shown in Figure 50. This short signal facilitates temporal echo resolution. Typically, impulses do not contain large amounts of energy and are limited by duration and peak pressure. Therefore, a series of impulses separated by x nsec can be used for applications targeting integrated time energy. Figure 51 shows an impulse input signal and the resulting echo. Other input signals may be used. The delay between two echoes indicates skull thickness. The delay from the impulse input signal to the first echo signal indicates the distance to the skull surface.

[0355] Additionally or alternatively, in a calibration process according to one embodiment, a ping input signal may be utilized. A ping is defined by a short burst of pulses of a specific frequency. Examples of squared and smoothed ping signals are shown in Figures 48 and 49, respectively. Ping input signals typically contain lower frequency content than chirp input signals. Because the input pulse correlates with itself at several locations, distinguishing return echoes is more difficult. Additionally or alternatively, per-element frequency-modified pulse bursts may be utilized in the calibration process. This may include outer elements that utilize lower frequencies than inner elements. If the outer array elements are further from the desired therapeutic surgical field, this can improve the energy available from the outer elements. Furthermore, element frequencies are optimized for skull penetration, either directly related to skull thickness or related to frequency-dependent transmission efficiency. Furthermore, similar to chirps, randomized local frequency content, in which temporally overlapping frequencies are transmitted within the brain, may be utilized in the calibration process. In one embodiment, randomization can be extended across local subarrays (nearest neighbor elements), and in another embodiment, frequency randomization can be deployed across the entire array to optimize the surgical field for treatment.

[0356] In addition to the above, in various examples, the calibration process includes one or more combinations of chirp, ping, and / or impulse input signals at various appropriate frequencies and / or amplitudes according to one embodiment. In at least one example, short pings are used to examine the skull at several different frequencies and / or amplitudes. This overcomes one of the drawbacks of short pings, i.e., low-frequency content. Additionally or alternatively, amplitude-modulated pulse bursts can be used. Along with the length of the pulse burst, the amplitude can vary. This has the effect of moving energy to deeper or shallower or different parts of the treatment surgical field, for example, when applied on a subarray basis to target specific regions of the brain based on prior knowledge of skull topology and thickness.

[0357] In various examples, the calibration process evaluates the location of target tissue, such as a tumor within an anatomical structure, that comes into contact with the patient interface of the acoustic dynamics therapy system according to one embodiment. For example, the controller 904 may utilize external imaging data and / or ultrasound imaging data collected by the acoustic dynamics therapy system itself. The controller 904 may adjust the output of various elements of the ultrasound transducer array based on the relative position of the individual elements to the target tissue. In at least one example, outer elements further away from the target tissue are tuned to lower frequencies than inner elements that are enclosed within the target tissue. Additionally or alternatively, the calibration process optimizes the output of the elements for skull penetration, which is either directly related to the local thickness of the skull or related to frequency-dependent transmission efficiency.

[0358] Furthermore, in certain examples, the calibration process, according to one embodiment, uses randomized local frequency content in which frequencies similar to chirps but with temporal overlap are transmitted to the brain. In various embodiments, the randomization can be extended across local subarrays that may include the nearest or adjacent elements. In another example, frequency randomization can be deployed across the entire array to optimize the therapeutic surgical field.

[0359] The controller 902 can determine the distance to the skull surface of a patient (e.g., skull 510 shown in Figure 11) wearing the acoustic dynamics therapy system 900 according to one embodiment, using one or more of the aforementioned optimization techniques of the calibration process. In one example, the time of flight is used to estimate the distance from the transducer 150 to the skull 510. Furthermore, the controller 902 can also estimate the skull thickness based on echoes received from the outer and inner surfaces of the skull. The difference in the time of flight of these two echoes can indicate the approximate skull thickness.

[0360] Within the transducer frequency bandwidth, some frequencies may have lower reflected energy characteristics and, correspondingly, better cranial penetration characteristics, which may be beneficial for optimizing the treatment surgical field according to one embodiment. In particular, one frequency may result in lower reflected energy. In some cases, this frequency having the lowest relative reflected energy correlates with the frequency having the highest transmitted energy through the skull. Thus, the controller 902 can use one or more of the aforementioned optimization techniques of the calibration process to investigate the skull 510 at different frequencies and compare the energy reflected by the skull for each frequency to determine the frequency having the highest cranial penetration rate in order to maximize the amount of energy transmitted through the skull. Furthermore, in certain examples, the controller 902 can also use one or more of the aforementioned optimization techniques of the calibration process to maximize the size of the treatment surgical field by changing pulses or system components for treating brain cancer.

[0361] In various embodiments, ultrasound array acoustic dynamics therapy can treat cancerous tissue throughout the body using, for example, one or more ultrasound sensitizers with ultrasound parameters described herein, using some of the embodiments described herein. In some embodiments, acoustic dynamics therapy is used to improve the efficiency of sonoporation, gene therapy, and / or chemotherapy treatments. In various embodiments, acoustic dynamics therapy is used to activate ultrasound sensitizers inside or on the surface of the patient's body. In various embodiments, acoustic dynamics therapy can be used with or without photodynamic therapy. Some embodiments described herein can be used synergistically with other cancer therapies, including, for example, radiation, chemotherapy, immunotherapy, and cell therapy.

[0362] Figure 43 is a logic flowchart of a process showing a control program or logic configuration for calibrating an ultrasonic transducer array of an acoustic dynamics therapy system (e.g., system 900) according to at least one aspect of the present disclosure. The calibration process in Figure 43 includes selecting elements of the ultrasonic transducer array 904, generating ultrasonic pulses using these elements, and detecting reflections of pulses on all elements of the ultrasonic transducer array 904. The calibration process in Figure 43 further includes calculating a minimum distance from one of the elements to the skull, where the minimum distance is the distance from one of the elements to a portion of the skull adjacent to or below that element, and the controller is configured to calculate the skull thickness in the skull portion. The calibration process in Figure 43 further includes comparing the calculated skull disease with imaging data of the patient's skull, such as a CT scan. The calibration process in Figure 43 further includes setting or modifying the amplitude and frequency of the active elements to maximize the ultrasonic transmission or efficiency through the skull. Additionally or alternatively, the calibration process in Figure 43 further includes modifying the amplitude and frequency of the active elements to minimize cranial heating during acoustic dynamics therapy performed by the system 900. In a particular embodiment, the calibration process in Figure 43 is repeated until all or at least a predetermined subset of the elements of the ultrasonic transducer array 904 are calibrated to maximize cranial transmission and / or minimize cranial heating.

[0363] Maximizing cranial permeability and / or minimizing cranial heating is evaluated based on predetermined thresholds according to one embodiment. For example, the acceptable maximum cranial permeability is a value greater than or equal to a predetermined threshold indicating cranial permeability. Similarly, the acceptable minimum cranial heating is a value less than or equal to a predetermined threshold indicating cranial heating.

[0364] Figure 44 is a logic flowchart of a process showing a control program or logic configuration for calibrating an ultrasonic transducer array of an acoustic dynamics therapy system according to at least one aspect of the present disclosure. The calibration process in Figure 44 includes selecting elements of the ultrasonic transducer array 904, generating a frequency sweep using these elements, and detecting the amplitude of reflected energy at each frequency of the frequency sweep. The calibration process in Figure 44 further includes calculating an optimal frequency for the elements, the optimal frequency being the frequency that minimizes the amount of energy reflected above a predetermined threshold. The calibration process in Figure 44 further includes setting the elements to the optimal frequency. In a particular aspect, the calibration process in Figure 44 is repeated until all or at least a predetermined subset of the elements of the ultrasonic transducer array 904 are calibrated to the optimal frequency.

[0365] Figure 45 is a logic flowchart of a process showing a control program or logic configuration for calibrating an ultrasonic transducer array of an acoustic dynamics therapy system according to at least one aspect of the present disclosure. The calibration process of Figure 45 includes selecting elements of the ultrasonic transducer array 904, generating a question signal using these elements, and detecting a reflected signal in response to the question signal, wherein the reflected signal is reflected by the patient's skull. The calibration process of Figure 45 further includes calculating in-situ variables based on the reflected signal. In some cases, the calibration process of Figure 45 further includes comparing the in-situ variables calculated by the controller with external data. The calibration process of Figure 45 further includes adjusting the irradiation pattern or array configuration of the ultrasonic transducer array 904, or both, based on the in-situ variables. If the in-situ variables are compared with external data, the calibration process includes adjusting the irradiation pattern or array configuration of the ultrasonic transducer array 904, or both, based on the results of the comparison. In a particular embodiment, the calibration process shown in Figure 45 is repeated until all or at least a predetermined subset of the elements of the ultrasonic transducer array 904 are calibrated to the optimal frequency.

[0366] One or more of the calibration processes shown in Figures 43-44 can be performed by a control circuit. In another embodiment, one or more of the calibration processes shown in Figures 43-44 can be performed by a combinational logic circuit. In yet another embodiment, one or more of the calibration processes shown in Figures 43-44 can be performed by a sequential logic circuit. However, these examples are not limiting. The calibration processes shown in Figures 43-44 may include various hardware and / or software components and can be performed by circuits that are located in or associated with various suitable systems described herein.

[0367] Upon administration of an ultrasound sensitizer, the controller 902 can utilize a combination of different ultrasound treatments at different time points according to one embodiment. For example, it may be beneficial to apply an initial ultrasound treatment immediately after administration of the ultrasound sensitizer to help promote further uptake of the ultrasound sensitizer. Based on the duration since the initial ultrasound treatment or other means, if the uptake of the ultrasound sensitizer is considered to be within an optimal window, additional ultrasound treatments can then be initiated. Applying different ultrasound treatments at different time points after administration of the ultrasound sensitizer promotes further uptake of the ultrasound sensitizer and enhances the overall therapeutic effect. In another embodiment, instead of initiating ultrasound treatment based on the duration since administration of the ultrasound sensitizer and / or ultrasound treatment, the device may be used to directly monitor patient-specific uptake of the ultrasound sensitizer and then apply ultrasound treatment when the uptake is considered to be within an optimal range.

[0368] Studies have shown that acoustic dynamics therapy relies on the generation of reactive oxygen species. These reactive oxygen species react with other molecules and damage the organelles of cancer cells. To enhance oxidative damage within cancer cells, patients may be monitored for the amount of dissolved oxygen within cancer cells, and / or alternatively, for peripheral capillary oxygen saturation levels according to one embodiment. Oxygen monitoring is then used as additional patient-specific input to guide the application of ultrasound therapy when the parameters are considered to be within an optimal range.

[0369] Having described various aspects of the Acoustic Dynamics Therapy Systems 900, 920, 950, 1000, 1100 and their components, this disclosure now moves on to describing various aspects of enhancing Acoustic Dynamics Therapy treatments, which can be attenuated and augmented to further generate complementary adjuvant effects that enhance the destruction of target cells and / or tissues according to various embodiments.

[0370] According to some non-limiting aspects of this disclosure, the above-described apparatus, systems, and methods for enhancing acoustic dynamics therapy can be attenuated and augmented to further generate complementary adjuvant effects that enhance the destruction of target cells and / or tissues. For example, the therapies disclosed herein can reduce the level of ultrasonic energy required to destroy target cells and / or tissues, and thus limit subsequent damage to healthy cells of surrounding organs. Accordingly, the apparatus, systems, and methods disclosed herein offer numerous technical improvements, including efficient use of resources (e.g., ultrasonic energy) and advantageous capabilities for maintaining the patient's overall health (e.g., elimination of destructive cells and preservation of healthy cells). According to some non-limiting aspects of this disclosure, therapies disclosed herein can bring about such improvements by utilizing complementary therapies (e.g., supplemental oxygenation, immunotherapy, anti-inflammatory therapy, microbubble-enhanced cavitation, electromagnetic energy, magnetic energy, one or more bipolar electrodes, electrode arrays, thermotherapy, hypothermia, and ultrasonic sensitizers including alternative ultrasonic sensitizers and / or nanoparticle additives) to enhance the effectiveness of acoustic dynamics therapy itself. In one embodiment, electromagnetic energy (e.g., light) complements acoustic dynamics therapy. In another embodiment, magn...

Claims

1. An ultrasonic transducer system that generates an incoherent sound pressure field for activating an ultrasonic sensitizer, in conjunction with providing acoustic dynamics therapy to a patient, An ultrasonic transducer array including multiple ultrasonic transducer elements, A cooling system including a patient interface configured to (i) remove excess heat from the patient and (ii) acoustically couple at least a portion of the patient to the ultrasonic transducer array, Equipped with, The patient interface includes a flexible membrane, The plurality of ultrasonic transducer elements are configured to generate at least two acoustic driving patterns, including random phase differences, in order to generate the incoherent sound pressure field having an energy profile for activating the ultrasonic sensitizer placed in the patient's tissue. The plurality of ultrasonic transducer elements have a random phase difference across the plurality of ultrasonic transducer elements, The modulation frequency across the plurality of ultrasonic transducer elements, and Modulation amplitude across the plurality of ultrasonic transducer elements At least one of the following, Driven by multiple signals including, The at least two acoustic driving patterns include alternating driving patterns, each of which utilizes a subset of the plurality of ultrasonic transducer elements to generate the incoherent sound pressure field. Ultrasonic transducer system.

2. The incoherent sound pressure field is administered non-invasively. The ultrasonic transducer system according to claim 1.

3. The energy profile is driven by multiple ultrasonic frequencies in the range of 20 kHz to 2 MHz. The ultrasonic transducer system according to claim 1.

4. The aforementioned incoherent sound pressure field is 1 to 20 W / cm². 2 Including the intensity output, The ultrasonic transducer system according to claim 1.

5. The ultrasonic sensitizer is selected from the group consisting of 5-aminolevulinic acid (5-ALA), protoporphyrin IX (PpIX), hematoporphyrin, rose bengal, curcumin, titanium nanoparticles, and chlorin e6. The ultrasonic transducer system according to claim 1.

6. Each of the ultrasonic transducer elements includes an opening of a size and configuration that conforms to the contour of the patient's body and / or adheres closely to the patient's body. The ultrasonic transducer system according to any one of claims 1 to 5.

7. The size of the opening is selected such that the aspect ratio of the opening to the size of the lesion being treated is the same size as the lesion or larger than the lesion, so as to enable the initiation of a wide incoherent sound pressure field to treat the lesion and surrounding tissue. The ultrasonic transducer system according to claim 6.

8. The ultrasonic transducer elements are arranged in one of the following configurations: a helical configuration, a rectangular array, a concentric array, or a randomly and irregularly arranged heterogeneous distribution. The ultrasonic transducer system according to any one of claims 1 to 5.

9. The plurality of ultrasonic transducer elements include 128 to 1024 active ultrasonic transducer elements. The ultrasonic transducer system according to any one of claims 1 to 5.

10. The ultrasonic transducer array includes a rectangular array shape, The ultrasonic transducer system according to any one of claims 1 to 5.

11. The plurality of ultrasonic transducer elements are arranged in an array that is placed in a helmet configured to be coupled to the patient's head. The ultrasonic transducer system according to any one of claims 1 to 5.

12. The plurality of ultrasonic transducers are arranged in an array that is positioned toward a flexible patient interface configured to be coupled to the patient's head. The ultrasonic transducer system according to any one of claims 1 to 5.

13. The plurality of ultrasonic transducer elements are arranged in a hemispherical array. The ultrasonic transducer system according to any one of claims 1 to 5.

14. The plurality of ultrasonic transducer elements are arranged in a curved linear array. The ultrasonic transducer system according to any one of claims 1 to 5.

15. The plurality of ultrasonic transducer elements are arranged in a 2D matrix array. The ultrasonic transducer system according to any one of claims 1 to 5.

16. The dimensions of the ultrasonic transducer array are in the range of 100 mm to 200 mm. The ultrasonic transducer system according to any one of claims 1 to 5.

17. The dimensions of each ultrasonic transducer element of the plurality of ultrasonic transducer elements are in the range of 0.5 mm to 20 mm. The ultrasonic transducer system according to any one of claims 1 to 5.

18. It is configured to activate the ultrasound sensitizer without focusing the ultrasound waves. The ultrasonic transducer system according to any one of claims 1 to 5.

19. It is configured to treat cancerous tissue of the brain, spine, mouth, lungs, breast, colorectal region, testes, vagina, liver, stomach, prostate, and pancreas. The ultrasonic transducer system according to any one of claims 1 to 5.

20. It is configured for acoustic dynamics therapy comprising at least one of the group consisting of radiation, chemotherapy, and cell therapy. The ultrasonic transducer system according to any one of claims 1 to 5.

21. The ultrasonic sensitizer is configured for oral administration to the patient. The ultrasonic transducer system according to any one of claims 1 to 5.

22. The ultrasonic sensitizer is selected from the group consisting of 5-aminolevulinic acid (5-ALA), protoporphyrin IX (PpIX), hematoporphyrin, rose bengal, curcumin, titanium nanoparticles, chlorin e6, pheobromide-a, ATX-S10 (4-formyloxymethylidene-3-hydroxy-2-vinyl-duterioporfinyl(IX)-6,7-diaspartic acid), photophyllin, photophyllin II, DCPH-P-Na(I), NPe6 (mono-l-aspartylchlorin e6), polyhydroxyfullerene, hypocrelin-B, ZnPcS2P2, methylene blue, and sinoporphyrin sodium. The ultrasonic transducer system according to any one of claims 1 to 5.

23. The aforementioned ultrasonic transducer array is minimally invasive. The ultrasonic transducer system according to any one of claims 1 to 5.

24. The ultrasonic transducer array is configured to be inserted into the mouth, nasal cavity, ear, anus, or vagina. The ultrasonic transducer system according to any one of claims 1 to 5.

25. The plurality of ultrasonic transducer elements are configured to be acoustically coupled to the patient through fluid-filled cavities. The ultrasonic transducer system according to any one of claims 1 to 5.

26. The patient interface further comprises a flexible membrane configured to bind to a portion of the patient, The ultrasonic transducer system according to any one of claims 1 to 5.

27. An ultrasonic transducer system that generates an incoherent sound pressure field for activating an ultrasonic sensitizer in conjunction with providing acoustic dynamics therapy, A cooling system configured to remove excess heat from the patient, A plurality of ultrasonic transducer elements are arranged in an array configured to generate at least two acoustic driving patterns including random phase differences, in order to generate an incoherent sound pressure field having an energy profile for activating an ultrasonic sensitizer placed in the patient's tissue, Equipped with, Each of the plurality of ultrasonic transducer elements includes an emission surface configured to emit acoustic waves. The plurality of ultrasonic transducer elements are driven by a plurality of signals, the plurality of signals include a random phase difference across the plurality of ultrasonic transducer elements. The at least two acoustic driving patterns include alternating driving patterns, each of which utilizes a subset of the plurality of ultrasonic transducer elements to generate the incoherent sound pressure field. Ultrasonic transducer system.

28. The energy profile is driven by multiple ultrasonic frequencies in the range of 20 kHz to 12 MHz. The ultrasonic transducer system according to claim 27.

29. The plurality of ultrasonic transducer elements are configured to generate the incoherent sound pressure field through openings of a size and configuration based on an energy profile that saturates a large treatment volume, thereby activating the ultrasonic sensitizer placed within the patient's tissue, and ensuring treatment of target lesions of cancer cells present in the patient's tissue and exogenous cancer cells. The ultrasonic transducer system according to claim 27.

30. Each of the plurality of ultrasonic transducer elements has dimensions, the opening includes an opening size, the target lesion of cancer cells includes a lesion size, the opening size is selected to be larger than the lesion size, and the aspect ratio of the opening size to the lesion size enables the initiation of the incoherent sound pressure field for treating the target lesion of cancer cells present in the patient's tissue and exogenous cancer cells. The ultrasonic transducer system according to claim 29.

31. The plurality of signals are configured to minimize spatial fluctuations in acoustic wave intensity, and the acoustic waves activate the ultrasonic sensitizer in the target lesion of the cancer cells. The ultrasonic transducer system according to claim 29.

32. The plurality of ultrasonic transducer elements are arranged in a hemispherical shape. An ultrasonic transducer system according to any one of claims 27 to 31.

33. Further including therapies selected from radiation, chemotherapy, immunotherapy, radiotherapy, and hyperthermia, An ultrasonic transducer system according to any one of claims 27 to 31.

34. The plurality of ultrasonic transducer elements are acoustically coupled to the patient through fluid-filled cavities. An ultrasonic transducer system according to any one of claims 27 to 31.

35. It is configured to treat cancerous tissue of the brain, lungs, breasts, liver, stomach, prostate, vagina, testes, pancreas, or intestines. An ultrasonic transducer system according to any one of claims 27 to 31.

36. The ultrasonic sensitizer is selected from the group consisting of aminolevulinic acid (ALA), hematoporphyrin, rose bengal, curcumin, titanium nanoparticles, and chlorin e6. An ultrasonic transducer system according to any one of claims 27 to 31.

37. The plurality of ultrasonic transducer elements include 128 to 1024 ultrasonic transducer elements. An ultrasonic transducer system according to any one of claims 27 to 31.

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