Non-invasive sonodynamic chemotherapy

Abstract

A system for providing sonodynamic therapy is disclosed.SOLUTION: The system includes a transducer 150, a patient interface, and a controller coupled to the transducer. The patient interface is configured to acoustically couple the transducer to the patient. The controller is configured to generate an electrical drive signal with a frequency selected from a range of frequencies, modulate the drive signal, and drive the transducer with the modulated drive signal at the frequency to generate a modulated acoustic wave to generate an average acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment region without damaging healthy cells in the treatment region.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 62 / 805,186, filed February 13, 2019, and entitled NON-INVASIVE SONODYNAMIC THERAPY, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to a broadly applicable technology platform for treating lesions using sonodynamic therapy. More particularly, the present disclosure relates to devices, systems, and methods for treating tumors and cancers in body parts using sonodynamic therapy. [Background technology]

[0003] Sonochemotherapy is a proposed form of treatment that uses drugs that become cytotoxic only upon exposure to ultrasound. Because ultrasound can be focused into small tissue volumes within the body, this method offers a potential means of localizing treatment and reducing the risk of side effects elsewhere in the body. In this respect, sonochemotherapy is similar to photodynamic therapy, which uses light for drug activation, and several drugs have been shown to be sensitive to both light and sound. A significant potential advantage of sonochemotherapy over photodynamic therapy is that ultrasound can reach deeper tissues noninvasively compared to light.

[0004] The agents are sonosensitizing agents (i.e., sonosensitizers) that preferentially accumulate in lesional cells. When exposed to ultrasound energy, sonosensitizers initiate a cytotoxic response in target tissues. When activated by ultrasound energy, sonochemotherapeutic agents or "sound sensitizers" generate reactive oxygen species (ROS), which produce cytotoxic effects. The detailed mechanism of ROS generation is not fully understood, but some studies suggest that acoustic cavitation and associated thermal, chemical, or luminescent phenomena may be involved. Sonosensitizers can be used alone or in combination with other sonosensitizers, many of which are approved by the U.S. Food and Drug Administration (FDA) for use in neurosurgical diagnostic imaging or treatment of tumors throughout the body.

[0005] The promise of sonodynamic therapy is the ability to treat lesions, such as areas of organs or tissues damaged through injury or disease, e.g., wounds, ulcers, abscesses, or tumors, with ultrasound levels that are safe for healthy tissue but lethal to cells within the lesion that contain ultrasound sensitizers.

[0006] The contemplated minimally invasive sonochemical process allows for direct treatment of lesions with catheters placed in situ using a relatively simple procedure that mimics a biopsy. Obtaining stable, omnidirectional acoustic waves from a small, needle-like catheter device can present technical challenges in some cases. The small diameter of the catheter device required for minimally invasive procedures can limit the aperture size for any element that radiates acoustic waves axially from the tip. This can result in reduced field strength due to spherical divergence. Even acoustic waves emitted radially from a sufficiently long transducer experience cylindrical falloff.

[0007] Because acoustic intensity decreases due to divergence, acoustic waves near the catheter device may need to be relatively high to have sufficient acoustic intensity to activate ultrasound sensitizers several centimeters away from the catheter device. These higher intensities near the catheter device may even be sufficient to cause indiscriminate cell death near the catheter device and create a necrotic region around the catheter device. If this "necrotic" region of the catheter device were unavoidable, it could limit the body locations where the catheter device could be placed and limit the number of patients eligible for treatment.

[0008] High-intensity focused ultrasound (HIFU) is a 500W / cm 2 ~20,000W / cm 2 HIFU technology provides a non-invasive treatment of lesions by using an intensity of 1000 uV to cause thermal ablation of tissue. HIFU technology can ablate tissue non-invasively by heating the tissue to temperatures exceeding 42°C, causing necrotic cell death. The ultrasound levels used in this procedure are, by design, lethal to all cells within the ultrasound focus; therefore, this approach is unable to provide broad coverage to distinguish between healthy and diseased tissue.

[0009] A further challenge for non-invasive techniques utilizing sonodynamic therapy can be the strong attenuation and reflection of sound pressure from the patient's body, particularly the skull, when treating soft tissue and bone. The impedance mismatch between water / skin and bone is significant, resulting in strong reflections at the skin-bone and bone-brain interfaces. The attenuation coefficient of the skull can also be very high, resulting in losses due to absorption and scattering within the skull.

[0010] The following disclosure describes various sonodynamic therapy devices, systems, and methods for completely non-invasive treatments that can penetrate deep into the body. Summary of the Invention

[0011] An exemplary non-invasive approach to sonotherapy involves placing several ultrasound transducers or a single transducer with multiple elements on the outside of a body part, which are used to transmit acoustic waves through the skin into the body part. The size of the transducer allows the incident acoustic waves to be approximately planar and not suffer from the same divergence losses as cylindrical or spherical divergence. In one aspect, the acoustic waves generated by several ultrasound transducers or several elements of a single transducer converge, allowing the wavefronts to constructively interfere. Furthermore, the total surface area of ​​the acoustic elements allows energy transmission to be divided among many elements, instead of requiring all energy to come from a single element.

[0012] Clinically speaking, such a system can improve the patient experience. Because it is non-invasive, it eliminates the costs and risks of surgery, infection, and bleeding, significantly reducing the cost and complexity of healthcare. It can significantly reduce the time required to prepare patients for treatment. Treatments can last from 30 minutes to an hour in a non-surgical clinic setting, such as an oncology clinic. A single practitioner can monitor multiple patients simultaneously. The low device risks could open the door to more frequent treatments, earlier treatment within the disease progression, and treatment of less lethal diseases.

[0013] The exemplary non-invasive devices, systems, and methods described in the following disclosure can use relatively low acoustic intensities over a larger treatment area relative to conventional methods. The exemplary non-invasive techniques discussed below can provide approximately 0.1 W / cm over most or all of a body part being treated for a lesion, such as an area of ​​organ or tissue damaged through injury or disease, e.g., a wound, ulcer, abscess, or tumor. 2 ~about 50W / cm 2 , or about 0.2 W / cm 2 ~about 20W / cm 2 , or about 0.5 W / cm 2 ~approx. 8.0W / cm 2Unless otherwise specified, the terms "about" and "generally" in reference to values ​​mean within 10% of the nearest unit. For example, "about 0.1" means between 0.09 and 0.11. [Brief explanation of the drawings]

[0014] The following drawings illustrate certain aspects of the present disclosure and, therefore, do not limit the scope of the appended claims. The drawings are intended to be used in conjunction with the explanations in the following description. The disclosed aspects are described below in conjunction with the accompanying drawings, in which like numerals refer to like elements.

[0015] [Figure 1] FIG. 1 is a perspective view of a transcranial sonodynamic therapy device with a shell having multiple transducers and a cooling system positioned over a patient's head, according to at least one embodiment of the present disclosure.

[0016] [Figure 2] FIG. 1 is a perspective view of a transcranial sonodynamic therapy device with multiple transducers and a cooling system positioned over a patient's head, according to at least one embodiment of the present disclosure.

[0017] [Figure 3] FIG. 1 is a partial cutaway view of a transcranial sonodynamic therapy device positioned over a patient's head, showing a partial view of multiple transducers, according to at least one embodiment of the present disclosure.

[0018] [Figure 4] FIG. 1 is a schematic diagram of a transducer with a lens defining a concave surface, according to at least one embodiment of the present disclosure.

[0019] [Figure 5] FIG. 1 is a schematic diagram of a transducer with a lens defining a convex surface, according to at least one embodiment of the present disclosure.

[0020] [Figure 6] FIG. 1 is a schematic diagram of a transducer with multiple elements that can be individually excited to generate various acoustic waves, according to at least one embodiment of the present disclosure.

[0021] [Figure 7] FIG. 1B is a bottom view of a transducer having an internal element surrounded by concentric rings, according to at least one embodiment of the present disclosure.

[0022] [Figure 8] FIG. 1 is a bottom view of a transducer having internal elements arranged in a two-dimensional (2D) grid array, according to at least one embodiment of the present disclosure.

[0023] [Figure 9] FIG. 1 is a diagram of two constructively interfering acoustic ultrasound pulses without delay, in accordance with at least one embodiment of the present disclosure.

[0024] [Figure 10] 1 is a diagram of a pulse packet consisting of a sinusoidal signal modulated by a Gaussian pulse signal, in accordance with at least one aspect of the present disclosure.

[0025] [Figure 11] FIG. 1 is a partial cutaway view of a transcranial sonodynamic therapy device positioned over a patient's head, showing a partial view of the patient's skull and brain and multiple transducers, one transducer emitting energy into the patient's brain, in accordance with at least one embodiment of the present disclosure.

[0026] [Figure 12] 1 is a chart illustrating intensity transmittance across multiple frequencies, according to at least one embodiment of the present disclosure.

[0027] [Figure 13A] 1 is a chart showing transmittance and reflectance at 1 MHz versus skull thickness in millimeters, in accordance with at least one embodiment of the present disclosure.

[0028] [Figure 13B] 1 is a chart showing transmittance and reflectance at 1 MHz versus skull thickness in wavelength, in accordance with at least one embodiment of the present disclosure.

[0029] [Figure 14A] 1 is a chart illustrating intensity transmittance as a function of frequency, according to at least one embodiment of the present disclosure.

[0030] [Figure 14B] 1 is a chart illustrating reflectivity as a function of frequency, according to at least one embodiment of the present disclosure.

[0031] [Figure 15] 1 is a chart illustrating the field intensity of a plane wave incident on a multi-tissue skull model, in accordance with at least one embodiment of the present disclosure.

[0032] [Figure 16] 10 is a chart showing energy absorption rates of a freshly excised human skull at multiple frequencies, in accordance with at least one embodiment of the present disclosure.

[0033] [Figure 17] FIG. 1 is a partial cutaway view of a transcranial sonodynamic therapy device positioned over a patient's head, showing a partial view of multiple transducers and a general view of a cooling system, according to at least one embodiment of the present disclosure.

[0034] [Figure 18] FIG. 1 is a perspective view of a patient interface according to at least one embodiment of the present disclosure.

[0035] [Figure 19] 1 is a chart illustrating a relative sensitivity plot of an infrared (IR) temperature sensor according to at least one embodiment of the present disclosure.

[0036] [Figure 20]FIG. 1 is a block diagram of a general non-invasive sonodynamic therapy system in accordance with at least one embodiment of the present disclosure.

[0037] [Figure 21] FIG. 19 is an illustration of the sonodynamic treatment system shown in FIG. 18, according to at least one embodiment of the present disclosure.

[0038] [Figure 22] FIG. 20 is a schematic diagram of the sonodynamic treatment system shown in FIGS. 18 and 19, in accordance with at least one embodiment of the present disclosure.

[0039] [Figure 23] FIG. 1 is a schematic diagram of a sonodynamic therapy system with separate transmit and receive transducers, in accordance with at least one embodiment of the present disclosure.

[0040] [Figure 24] FIG. 1 is a schematic diagram of a sonodynamic therapy system with a single transmit and receive transducer, in accordance with at least one embodiment of the present disclosure.

[0041] [Figure 25] 1 is an overview of a sonodynamic therapy process according to at least one embodiment of the present disclosure.

[0042] [Figure 26] FIG. 1 is a diagram of a cancer cell illustrating the early stages of selective accumulation of a sensitizer, according to at least one embodiment of the present disclosure.

[0043] [Figure 27] FIG. 1 is a diagram of a cancer cell illustrating the selective increase in accumulation of a sensitizer, according to at least one embodiment of the present disclosure.

[0044] [Figure 28] FIG. 26 is a diagram of the cancer cells shown in FIGS. 24 and 25 undergoing sonochemotherapy, according to at least one embodiment of the present disclosure.

[0045] [Figure 29] FIG. 1 illustrates the process of sonoluminescence, according to at least one embodiment of the present disclosure.

[0046] [Figure 30] FIG. 1 is a schematic diagram of a cancer cell illustrating selective accumulation of a sensitizer, according to at least one embodiment of the present disclosure.

[0047] [Figure 31] FIG. 29 is a schematic diagram of the cancer cells shown in FIG. 28 undergoing sonochemotherapy, according to at least one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0048] The following detailed description is exemplary in nature and provides several practical illustrations and examples. Those skilled in the art will recognize that many of the described examples have a variety of suitable alternatives. Using the accompanying drawings as well as the description provided below, numerous different exemplary transcranial sonodynamic therapy devices are disclosed herein. Each of the aspects disclosed herein can be utilized independently or in combination with one or more (e.g., all) of the other aspects disclosed herein.

[0049] Before turning to the drawings, this disclosure first proceeds with a general description of various aspects of a non-invasive sonodynamic therapy system. In one aspect, this disclosure relates to a system for sonodynamic therapy. The system includes 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 electrical drive signal from a set of modulated acoustic wave parameters, modulate the drive signal, and use the modulated drive signal to drive the transducer at a frequency to generate modulated acoustic waves and generate an acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment region.

[0050] In another aspect, the present disclosure relates to another system for sonodynamic therapy. The system includes a first transducer, a second transducer, and a controller coupled to the first and second transducers. The controller is configured to generate a first electrical drive signal from a set of modulated acoustic wave parameters, generate a second electrical drive signal from the set of modulated acoustic wave parameters, drive the first transducer with the first electrical drive signal to generate a first acoustic wave, and drive the second transducer with the second electrical drive signal to generate a second acoustic wave. The first and second acoustic waves are combinable to generate an acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment region.

[0051] In yet another aspect, the present disclosure relates to yet another system for sonodynamic therapy, comprising a plurality of transducers and a controller coupled to the plurality of transducers, the controller configured to generate a plurality of electrical drive signals from a set of modulated acoustic wave parameters and drive the plurality of transducers with the plurality of electrical drive signals to generate a plurality of modulated acoustic waves, the plurality of modulated acoustic waves being combinable to generate an acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment region.

[0052] The following description provides an illustrative example of the application of noninvasive sonodynamic therapy techniques to treat tumors in the brain. However, it will be understood that such techniques are applicable to treating tumors in other body parts. Referring now to FIG. 1 , the human skull may vary depending on gender and anatomical location. One embodiment of the present disclosure provides a noninvasive sonodynamic therapy device 100, as shown in FIG. 1 . The noninvasive sonodynamic therapy device 100 may comprise a shell 110 with transducers 150 that can provide predictable and consistent sonication despite these variations. The shell 110 may comprise a rigid material. The known relative position of the transducers 150 allows for imaging of the head, even at low resolution with large transducers 150. The illustrated embodiment may require a mobile stand to be held in place on the patient while the patient is seated or supine. The rigid shell 110 may be a lightweight helmet that the patient can wear during treatment, allowing for predictable placement of the transducers 150 with little infrastructure requirements.

[0053] The non-invasive sonodynamic therapy device 100 can include a flexible shell 110 (e.g., a helmet) with transducers 150 positioned on a liquid-cooled skull cap 160, as further described elsewhere herein, requiring little infrastructure to support the array of transducers 150. A patient may be able to wear the skull cap 160 and shell 110 in any chair while waiting for the treatment to be completed. The lightweight design can minimize neck pain caused by the patient holding their head with the weight of the transducers 150 and cooling cap for extended periods of time. The flexible shell 110 can conform to the shape of each individual's skull. Such a device can accommodate subtle variations between treatments depending on the shape of each patient's head, further curving some transducers 150 inward or outward.

[0054] The non-invasive sonodynamic therapy device 100 can include a rigid or flexible patch having several transducers 150 that can be removably applied to the head. Such an embodiment may require the clinician to apply each patch individually. Having separate patches can allow for some treatment flexibility without having to individually plan and place each transducer 150. The exemplary non-invasive sonodynamic therapy device 100 can minimize pain caused by repeatedly applying patches to the head, which can be of particular concern for older and sicker patients.

[0055] The non-invasive sonodynamic therapy device 100 may include a patch with a single transducer 150 that can be removably applied to the head. An individual transducer 150 may provide the most treatment flexibility. Such a device may require a detailed process for planning the application of the transducer 150. By providing additional flexibility, the exemplary non-invasive sonodynamic therapy device 100 may accommodate greater usability risks.

[0056] As can be seen in FIG. 2 , the size and shape of the transducers 150 vary according to the various disclosed embodiments. For cost-effective and simple systems, larger transducers 150 that generate directional sound waves can be used. As further described elsewhere herein, the directionality of large transducers 150 can be reduced by applying an acoustic lens to each transducer 150, which bends the sound waves. For systems that can conform to the head, smaller transducers 150 that can radiate more widely than larger transducers 150 can be used. Such smaller transducers 150 may have greater imaging or beam steering capabilities as a single array.

[0057] 3 is a partial cutaway view of a transcranial sonodynamic therapy device 100 positioned over a patient's head, showing a partial view of multiple transducers 150, in accordance with at least one embodiment of the present disclosure. Instead of focusing the acoustic waves 200 to a small point, the acoustic waves 200 can be defocused to minimize spatial variations in acoustic wave intensity within the brain.

[0058] The size and shape of the transducers 150 can cause each transducer 150 to be defocused or focused. As used herein, the term focused refers to an acoustic wavefront that is more converging than the wavefront generated by a transducer 150 with a planar emission surface, and the term defocused refers to an acoustic wavefront that is more diverging than the wavefront generated by a transducer 150 with a planar emission surface. Whether the lens needs to be concave or convex to make the wave more divergent depends on whether the acoustic wave is transitioning from a region of low acoustic impedance to a region of high acoustic impedance, or whether the acoustic wave is transitioning from a region of high acoustic impedance to a region of low acoustic impedance. Here, if the lens is made of a material with a higher acoustic impedance than the target medium (water / tissue), the acoustic wave will originate from the high impedance material and transition into the target medium with low acoustic impedance. If the lens is concave, the lens will "focus" the acoustic wave, making it more convergent. If the lens is convex, the lens will "defocus" the acoustic wave, making it more divergent.

[0059] 4 is a schematic diagram of a transducer 150 having a lens 302 defining a concave surface 304, in accordance with at least one embodiment of the present disclosure. The lens 302 may be acoustically coupled to the transducer 150 or may be integrally formed therewith. In the illustrated example, the lens 302 is made of a material that has a higher acoustic impedance than the target medium (water / tissue) such that acoustic waves 306 originate from the high impedance material and transition into the target medium of low acoustic impedance, thereby "focusing" or converging the acoustic waves 306 onto the target tissue.

[0060] 5 is a schematic diagram of a transducer 150 having a lens 308 defining a convex surface 310, in accordance with at least one embodiment of the present disclosure. The lens 308 may be acoustically coupled to the transducer 150 or may be integrally formed therewith. In the illustrated example, the lens 308 is made from a material that has a higher acoustic impedance than the medium of interest (water / tissue). Thus, acoustic waves 312 originate from the high impedance material and transition to the target medium of low acoustic impedance, causing the acoustic waves 312 to "defocus" or diverge relative to the target tissue.

[0061] The focal point of the transducer 150 also depends on the material and shape of the lens (not shown). The use of lenses 302, 308 allows the transducer 150 to be flat, minimizing manufacturing costs. Both the lens 302 with concave surface 304 and the lens 310 with convex surface 310 may be configured to produce a fixed focal point.

[0062] It may be possible to manufacture a lens whose shape can be adjusted to create different focal points. It may be possible to create an elastic, fluid-filled pocket that acts as a lens. Fluid can be pumped in or out of the lens to adjust the shape of the pocket and therefore the focus of the transducer.

[0063] FIG. 6 is a schematic diagram of a transducer 150 having multiple elements 150a-150h that can be individually excited to generate various acoustic waves, in accordance with at least one embodiment of the present disclosure. As shown in FIG. 6, the multiple transducer elements 150a-150h can be arranged in an array to generate converging, diverging, or plane acoustic waves. For example, the transducer elements 150a-150h can be activated in a predetermined sequence to selectively generate converging, diverging, or plane acoustic waves, such as the converging acoustic wave 314 shown in FIG. 4 or the diverging acoustic wave 312 shown in FIG. 5. To generate the converging acoustic wave 314, for example, the outer transducer elements 150a and 150h are excited first, followed by the adjacent inner transducer elements 150b and 150g after a time delay. The next adjacent inner transducer elements 150c and 150f are then excited after a second time delay. Finally, the inner transducer elements 150d and 150e are excited after a third time delay. This pattern can be repeated to generate converging acoustic waves 314. The first, second, and third time delays can be equal or different to generate more complex acoustic waves. Alternatively, transducer elements 150a-150h can be excited in reverse order using equal or different time delays to generate diverging acoustic waves. Transducer elements 150a-150h can be interchangeably configured to transmit or receive acoustic waves.

[0064] FIG. 7 is a bottom view of a transducer 400 having an inner element 420 surrounded by concentric rings 410, according to at least one embodiment of the present disclosure. Each transducer 150 can be adapted and configured to generate acoustic waves with a variable focal point. One way to achieve this is for each transducer 400 to have concentric rings 410 (e.g., an annular array), as shown in FIG. 7. Each concentric ring 410 can be driven with a different signal. To focus the acoustic waves, the signal toward the inner element 420 can be gradually delayed relative to the outer concentric rings 410. The acoustic waves from each concentric ring 410 can converge at a point. To defocus the acoustic waves coming from the annular array, the acoustic waves outside the concentric rings 410 can be gradually delayed relative to the inner element 420. One way to form an annular array can be to use concentric rings 410 of equal area. In another embodiment, the annular array may include concentric rings 410 of unequal area.

[0065] FIG. 8 illustrates a bottom view of a transducer including internal elements 452 arranged in a two-dimensional (2D) grid array 450, in accordance with at least one embodiment of the present disclosure. Each internal element 452 of the 2D grid transducer array 450 can be driven with a different signal. To generate converging sound waves (e.g., "focused"), the signal applied to the internal element 454 can be gradually delayed relative to the signal applied to the outer element of the 2D grid transducer array 450. To generate diverging sound waves (e.g., "defocused"), the sound waves generated by the outer element 452 can be gradually delayed relative to the internal element 454. In one embodiment, each of the internal elements 452 of the 2D grid transducer array 450 can define an equal area. In another embodiment, each of the internal elements 452 of the 2D grid transducer 450 array can define unequal areas.

[0066] In one embodiment, the transducers 150, 400, 450 may be implemented as a single transducer with multiple piezoelectric elements having acoustically and electrically independent portions arranged in an array. In another embodiment, the transducers 150, 400, 450 may be implemented as different transducers operating in concert. From a physical perspective, there is little or no distinction between a single transducer having multiple elements and different transducers operating in concert. The elements of the array can be on the order of wavelengths. In one embodiment, the transducers 150, 400, 450 may be implemented as a single transducer with multiple elements implemented as an annular array, as shown in FIG. 7, or as a grid array, as shown in FIG. 8. In another embodiment, the transducers 150, 400, 450 may be implemented as multiple individual transducers.

[0067] In one embodiment, each of the transducers 150, 400, 450 or elements thereof shown in FIGS. 4-8 is non-invasive and can be implemented in a size and shape appropriate for a patient's body part. Additionally, the individual number and arrangement of transducer elements can be selected to fit the patient's body part. In one embodiment, the transducers 150, 400, 450 or elements thereof can be fabricated from piezoelectric or single-crystal materials that convert electrical energy into ultrasonic energy. The transducers 150, 400, 450 can also receive and convert ultrasonic energy into electrical energy. Each of the transducers 150, 400, 450 or elements thereof can be adaptively focused to generate acoustic waves through cooperative transducer performance. For example, each of the transducers 150, 400, 450 or elements thereof can be selectively controlled by a controller to operate as either a transmitter or a receiver, as described below. Additionally, each of the transducers 150, 400, 450 or elements thereof may be selectively excited and actuated to generate converging, diverging, or plane acoustic waves, as discussed in more detail below.

[0068] 4-8, in one aspect, the acoustic waves generated by the transducers 150, 400, 450 can be defined by vergent, a measure of the curvature of the acoustic wavefront. Negative vergent is when the acoustic wavefront propagates away from a point (i.e., diverging). Positive vergent is when the acoustic wavefront propagates toward a point (i.e., converging). Zero vergent is a planar acoustic wavefront that does not converge or diverge. Vergent is a characteristic of a single acoustic wavefront. A single converging / diverging acoustic wavefront can be generated by multiple elements of the transducers 150, 400, 450 (e.g., a transducer with an annular array 400 or a grid array 450).

[0069] In one aspect, the acoustic waves generated by the transducers 150, 400, 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 (e.g., measured in degrees or radians) relative to their period. Delay is a measure of the amount of time shifted between two acoustic waves (e.g., measured in milliseconds). Delay and phase are often used interchangeably. For example, "delay" can be described in degrees or radians, but it is well understood that "delay" is an abbreviation for "phase delay." For a single acoustic pulse, it is clearer to discuss the delay between the peaks of two acoustic pulses in terms of time, since a phase shift requires a periodic signal. For repeating acoustic waves, the relative delay is often measured in terms of phase. For a continuous, periodic acoustic wave, by definition, delaying an integer number of periods should have no effect because a periodic signal exhibits symmetry across a full period shift. For pulses of repeating sound waves (e.g., a 1000-cycle sine wave), the sound waves can be delayed by an integer number of cycles. The beginning and end of the wave packet will have some edge effect if one signal starts / ends before the other. In the middle of two wave packets, there will be no effect (if the signals still overlap).

[0070] In one aspect, the transducers 150, 400, 450 may be adapted and configured to generate "focused" acoustic waves by generating converging acoustic waves that converge to a point. In another aspect, the transducers 150, 400, 450 may be adapted and configured to generate "defocused" acoustic waves, e.g., diverging acoustic waves. In other aspects, the transducers 150, 400, 450 may be adapted and configured to generate plane acoustic waves (e.g., zero vergences), where the acoustic waves are neither "defocused" nor "defocused."

[0071] In various embodiments, the transducers 150, 400, 450 may be driven at ultrasonic frequencies ranging from about 20.00 kHz to about 12.00 MHz. More specifically, the transducers 150, 400, 450 may be driven at ultrasonic frequencies ranging from about 650.00 kHz to about 2.00 MHz. In a preferred range, the transducers 150, 400, 450 may be driven at ultrasonic frequencies ranging from about 900.00 kHz to about 1.20 MHz, more preferably about 1.06 MHz.

[0072] FIG. 9 is a diagram 470 of two acoustic ultrasonic pulses 472, 474 that constructively interfere without delay, according to at least one embodiment of the present disclosure. As previously described, the transducers 150, 400, 450 can be adapted and configured to generate "focused" acoustic waves by time-coordinating multiple acoustic wavefronts to generate constructively interfering wavefronts. The coordination of the acoustic wavefronts is independent of the vergence of the acoustic wavefronts. The point at which the wavefronts converge can be adjusted by delaying one signal relative to another. The diagram 470 shown in FIG. 9 illustrates two pulses 472, 474 generated without a relative delay. The two pulses 472, 474 can be said to constructively interfere upon reaching the center and then converge at the center to generate a composite pulse 474. If the left acoustic pulse 472 is delayed relative to the right acoustic pulse 474, the two pulses 472, 474 will meet at a point to the left of center, thus shifting the point of constructive interference to the left of center. Similarly, if the right acoustic pulse 474 is delayed relative to the right acoustic pulse 474, the two pulses 472, 474 will meet at a point to the right of center, thus shifting the point of constructive interference to the right of center.

[0073] In another embodiment, a mix of converging / diverging / plane sound waves can be timed to meet and constructively interfere at one location, and diverging sound waves can be timed to meet and destructively interfere at one location.

[0074] Control of the converging and diverging wavefronts generated by the transducers 150, 400, 450 can be considered as part of pre-treatment planning. Based on input from the pre-treatment planning process, the controller can adaptively modulate the transducers 150, 400, 450 so that the acoustic wavefronts coordinate to preferentially target the desired treatment region. In one aspect, digital imaging and communications (DICOM) images from a computed tomography (CT) or other imaging source can be input to the device controller to generate customized modulation patterns that optimize the treatment region for a specific patient. In another aspect, pre-treatment planning can include selection of a preferred transducer type or arrangement of transducer types that creates a treatment region optimized for a specific disease state. In another aspect, the patient interface can be a variety of arrangements that can be selected during pre-treatment planning that coordinate the transducers in a preferred arrangement for treatment.

[0075] The "defocused" acoustic waves can be measured based on the volume of tissue being treated according to the number of nodes and antinodes. A histogram of intensity or pressure over a volume can be used to measure the "defocused" acoustic waves. In one aspect, a dose-volume histogram can be used in planning sonochemotherapy. Alternatively, a cumulative histogram can be used.

[0076] FIG. 10 is a diagram of an acoustic pulse packet 480 consisting of a repetitive signal modulated by a Gaussian pulse signal, in accordance with at least one embodiment of the present disclosure. In one embodiment, the acoustic wave generated by the transducer 150, 400, 450 may be amplitude modulated. The acoustic pulse packet 480 may be generated by modulating a repetitive signal, such as a sine wave, with a Gaussian pulse, where the repetitive signal is independent of the Gaussian pulse. When the transducer 150, 400, 450 is driven by the modulated signal, it generates an acoustic pressure pulse 482 whose amplitude varies according to an envelope 484 in the form of a Gaussian pulse. In the illustrated example, the repetitive signal is a sine wave, but the repetitive signal can take many forms. The repetitive 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 repetitive 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. A repetitive signal may include pulse-to-pulse or intra-pulse variations.

[0077] FIG. 11 is a partial cutaway view of a transcranial sonodynamic therapy device positioned on a patient's head in accordance with at least one embodiment of the present disclosure, showing a partial view of the patient's skull 510 and brain, and multiple transducers 150, with one transducer emitting energy 200 into the patient's brain. As shown in FIG. 11 , it may be possible to take measurements or obtain a rough image of the skull 510. This may 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 treatment algorithms according to measured parameters, such as the skull thickness "t." Each transducer 150 can emit an acoustic pulse and listen for echoes. The echoes can be used for a quick estimation of the skull thickness "t" below each transducer 150. To treat tumors in other parts of the patient's body, the sonodynamic therapy device may be adapted and configured to couple to the patient's body.

[0078] For designs with transducers 150 with adjustable foci, the focus of each transducer 150 can be preset with a treatment plan, or the transducers 150 can automatically adjust the transducer focus based on head temperature readings or based on measurements of skull thickness "t."

[0079] The amplitude of the electrical drive signal driving the transducer 150 can be controlled or modulated. In some cases, it may be beneficial to modulate the electrical drive signal driving the transducer 150 based on the temperature of the head or other body part being treated. For example, if a temperature sensor detects a sudden increase in temperature, the amplitude of the transducer 150 can be reduced, turned off for a period of time, or the duty cycle can be reduced. By modulating the intensity of the acoustic pulse, the time-averaged acoustic intensity can be adjusted to activate the sensitizer while maintaining the temperature of the tumor cells below a temperature (e.g., below 42°C) that can cause thermal damage to the cells and possibly necrotic cell death. In another aspect, sonodynamic therapy can work at a variety of different frequencies. Each frequency can efficiently penetrate the skull 510 for a particular skull thickness. By using various frequencies, the noninvasive sonodynamic therapy device 100 can operate over a wide range of skull thicknesses "t."

[0080] In embodiments in which the transducers 150 are capable of operating at multiple frequencies, the frequency of each transducer 150 can be selected manually or automatically. As noted above, the transducers 150 may be driven at an ultrasonic frequency ranging from approximately 20.00 kHz to approximately 12.00 MHz. More specifically, the transducers 150 may be driven at an ultrasonic frequency ranging from approximately 650.00 kHz to approximately 2.00 MHz. In a preferred range, the transducers 150 may be driven at an ultrasonic frequency ranging from approximately 900.00 kHz to approximately 1.20 MHz, more preferably at approximately 1.06 MHz. The frequencies may be preselected by a physician. The frequencies may be selected based on measurements of the anatomy of the head (e.g., skull thickness "t"). For example, each transducer 150 may emit a series of pulses to measure the thickness of the skull 510 closest to each transducer. Based on the measurement of skull thickness "t", an algorithm can be used to select a frequency from a set or range of frequencies that may be best suited to skull thickness "t" and excite transducer 150 accordingly.

[0081] As can be seen in FIG. 2 , the size and shape of the transducers 150 vary according to the various disclosed embodiments. For cost-effective and simple systems, larger transducers 150 can be used, which may have directional sound waves. As further described elsewhere herein, the directionality of large transducers 150 can be reduced by applying an acoustic lens to each transducer 150, which bends the sound waves. For systems that can conform to the skull, smaller transducers 150 can be used, which can radiate more widely than larger transducers 150. Such smaller transducers 150 may have greater imaging or beam steering capabilities as a single array.

[0082] Instead of focusing the sound waves 200 to a small point, the sound waves 200 can be defocused to minimize spatial variations in sound wave intensity within the brain, as shown in FIG. 4. The size and shape of the transducers 150 can be varied to allow each transducer 150 to be defocused or focused. Defocused transducers can be formed using transducers 150 with convex emission surfaces 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 emission surface 304 with a center of curvature at which the sound can be focused. As shown in FIG. 6, an array of transducers 150a-150h can be used to generate converging, diverging, or more complex sound waves.

[0083] Each transducer 150 may cycle through several frequencies so that at least one of the frequencies provides near-optimal penetration for a given skull thickness "t." Each transducer 150 may also continuously sweep from one frequency to another. Frequencies may be selected in advance (e.g., during treatment planning by a physician) for each transducer 150 based on the thickness of the skull 510 closest to each transducer. Prior to treatment, each transducer 150 may transmit a test signal and monitor the reflected sound to automatically determine which frequency will work best for that transducer 150. The test signal may be used to directly measure skull thickness "t" by measuring pulse-echo delay, or it may be used to detect the relative amount of reflected acoustic energy.

[0084] Each transducer 150 can be a broad spectrum ultrasound transducer, or it can be made up of several smaller transducers (e.g., the piezoelectric elements shown in Figures 6-8) designed to operate at specific frequencies. Each transducer 150 can have an element specifically designed to monitor waves reflected from the head. If the transducer 150 is made up of several smaller transducers 150, one transducer 150 can transmit sound while the remaining transducers 150 are used to monitor incoming acoustic pulses.

[0085] Of all the frequencies that work in sonodynamic therapy, a subset of frequencies can be selected to best cover a range of common skull thicknesses "t." Frequencies that share many common denominators (e.g., harmonics such as 1 MHz and 2 MHz) may not be a good choice to cover the most skull thicknesses, since many of the transmission peaks between the two frequencies may be shared. Frequencies that do not have many or no common denominators (e.g., relatively prime numbers) may be a good choice of frequencies, since transmission peaks may occur at different skull thicknesses.

[0086] FIG. 12 is a chart 700 illustrating intensity transmission across multiple frequencies, according to at least one embodiment of the present disclosure. As shown in FIG. 12, five different frequencies are transmitted through different skull thicknesses, ranging from 4 mm to 9 mm: a first frequency 702 of 1.107 MHz, a second frequency 704 of 1.052 MHz, a third frequency 706 of 1.000 MHz, a fourth frequency 708 of 0.961 MHz, and a fifth frequency 709 of 0.898 MHz. This provides excellent coverage across different skull thicknesses. In this example, each skull thickness can have at least one frequency that can transmit 75% or more of its energy. This can be achieved over a frequency range of 898 kHz to 1.107 MHz, a range of just 0.2 MHz.

[0087] The transmission of sound through an absorbing layer of tissue may not decrease monotonically as a function of thickness. Instead, transmission can be increased if the skull thickness is a multiple of half the wavelength of sound in that layer. Similarly, transmission can be reduced if the skull thickness is an odd multiple of a quarter wavelength (halfway between A / 2).

[0088] FIG. 13A is a chart 720 illustrating intensity transmittance and pressure reflectance at 1 MHz versus skull thickness in millimeters, and FIG. 13B is a chart 730 illustrating transmittance and reflectance at 1 MHz versus skull thickness in wavelength, according to at least one embodiment of the present disclosure. As shown in FIGS. 13A and 13B, a 1 MHz sound wave is transmitted through various skull thicknesses. With regard to intensity transmittance 722 and reflectance 724, FIG. 7A illustrates skull thickness in millimeters, while FIG. 13B illustrates skull thickness in multiples of wavelengths. Intensity transmittance 722 can peak whenever the skull is a multiple of a half wavelength. Similarly, the proportion of reflected sound, shown as reflectance 724, can be lowest whenever the skull is a multiple of a half wavelength.

[0089] The intensity transmittance 722 and pressure reflectance 724 can be a function of both skull thickness and frequency. FIG. 14A is a chart 740 showing intensity transmittance 722 as a function of frequency, and FIG. 14B is a chart 750 showing reflectance 724 as a function of frequency, according to at least one embodiment of the present disclosure. To the right of the chart 740 in FIG. 14A is a scale 742 of intensity transmittance 722 ranging from 0.0 to 1.0, and to the right of the chart 750 in FIG. 14B is a scale of reflectance 724 ranging from −1.0 to +1.0. FIGS. 14A and 14B show how the intensity transmittance 722 and reflectance 724 vary with skull thickness and frequency. A negative reflectance can be achieved whenever peak transmission occurs. A negative reflectance can indicate that the reflected wave may be phase shifted 180° relative to the incident wave. As shown in chart 740 of Figure 14A, the intensity transmittance 722 has a maximum percentage 744 of about 1.0 and a minimum percentage 746 of about 0.4, which matches the maximum / minimum percentages shown in charts 720, 730 of Figures 13A and 13B. Chart 750 shown in Figure 14B indicates that the reflectance 724 has a minimum percentage 754 of about 0.0 and a maximum percentage 756 of about 0.8, which matches the maximum / minimum percentages shown in charts 720, 730 of Figures 13A and 13B.

[0090] Frequencies that differ by irrational numbers may be a good choice because they can have peak transmissions at different thicknesses. The golden ratio (e.g., the "most irrational number") may be useful for frequency selection. The transmission of the selected frequencies may not be sufficient to avoid peaks at the same skull thickness "t".

[0091] It may be acceptable for two frequencies to share a peak transmittance at a particular thickness, but the shared peak shall occur at a skull thickness "t" outside of those expected to occur naturally. If the device is capable of selecting the best frequency (e.g., maximum transmittance) at each skull thickness "t," obtaining optimal coverage over many skull thicknesses "t" with a limited number of frequencies can mean maximizing the average transmittance of the best frequency at the selected skull thickness "t" or maximizing the minimum transmittance of the best frequency within the selected skull thickness "t."

[0092] To allow for efficient transmission of sound into the brain, the hair on the patient's head may need to be shaved or shortened. In some embodiments, it may be possible to leave the hair intact. The comb-like structure can pass through the hair and contact the skull in multiple locations to allow sound transmission. The hair may also be wet and matted to allow for relatively unimpeded transmission of sound.

[0093] FIG. 15 is a chart 760 illustrating the field intensity of a plane wave 762 incident on a multi-tissue skull model, according to at least one embodiment of the present disclosure. Referring to FIG. 15, the skull can absorb a large portion of the ultrasound energy over a short distance. The insertion loss 764 (the amount of energy that can be lost by adding the skull to the acoustic wave 200) can be centered around 12 dB. Every additional 3 dB of loss can correspond to a reduction in approximately half of the energy. A 12 dB loss can correspond to one-sixteenth of the energy introduced to the surface of the skin remaining on the skull. As a result, the skull can heat up during transcranial sonodynamic therapy.

[0094] Table 1 summarizes the parameters that may be used in the skull model. In addition to the inherent acoustic properties of the skull, the skin may be assumed to be 2.5 mm thick, and the skull may be assumed to be approximately 6.8 mm thick. Figure 15 shows the acoustic intensity in terms of field strength (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 rapid attenuation within the skull.

[0095] [Table 1]

[0096] This model uses average skull thicknesses for various humans. The thicknesses of the "frontal, parietal, and occipital bones" were "6.58, 5.37, and 7.56 (in mm), respectively, for males, and 7.48, 5.58, and 8.17 (in mm), respectively, for females." As noted elsewhere herein, human skulls vary considerably by gender and anatomical location. While the model can represent average attenuation, thicker parts of the skull may have greater attenuation. In general, for every additional 2.7 mm of skull, attenuation may increase by 3 dB (doubling).

[0097] This model can be based on a simple plane wave model impinging on a plane layer of tissue. Each layer of tissue can be assumed to be homogeneous and of uniform thickness. This model ignores the effect of the sound wavelength (λ), which corresponds to the varying thickness of the skull. It can also be assumed that all reflected waves are lost and do not re-enter the brain.

[0098] Pichardo et al. investigated the transmission of ultrasound at various frequencies through freshly excised human skulls. They reported the percentage of energy absorbed by seven skull bones at several locations at frequencies of 0.270, 0.836, and 1.402 MHz. Although they did not specifically measure the energy lost at 1 MHz, their study allows for interpolation and estimation that insertion loss may be centered around 12 dB. Their study also confirms that insertion loss is predictable and varies by skull and anatomical location.

[0099] 16 is a chart 770 illustrating the energy absorption coefficient 772 of a freshly excised human skull at multiple frequencies, in accordance with at least one embodiment of the present disclosure. As shown in FIG. 16, Pinton et al. also measured the attenuation at 1 MHz at nine points along an 8 mm thick section of skull and found an insertion loss of 12.6 ± 1.33 dB (higher loss than that attributed to the thicker skull section). Both simplified head models and measurements obtained from different laboratories agree that the insertion loss (the amount of energy lost by adding the skull to the model) is centered around 12 dB (1 / 16) and can vary considerably.

[0100] The energy lost as sound passes through the skull may be converted primarily to heat within the skull. As the skull begins to heat up, the heat may dissipate to nearby tissue over time. Most of the heat may originate on the exterior of the skull and dissipate into other layers of skin and bone. Beyond a certain point, the blood may not be able to carry away enough heat, and bone and skin temperatures may rise to unsafe levels. Adding transducers to a system may reduce the rate at which this threshold can be reached, as the blood warms with each successive transducer that passes and may lose its ability to absorb additional heat from tissue.

[0101] There may be several ways to combat the effects of fever: cooling, intermittent therapy, monitoring, and transducer modulation, among others, may be used to reduce the consequences of fever.

[0102] FIG. 17 is a partial cutaway view of a transcranial sonodynamic therapy device positioned on a patient's head, showing a partial view of multiple transducers 150 and a full view of a cooling system 600, according to at least one embodiment of the present disclosure. The cooling system 600 shown in FIG. 17 can be implemented to maintain the temperature of the skull and surrounding tissue within safe levels. A cooling layer (e.g., water) can be provided between the transducers 150 and the patient's head. The cooling layer can be made from a flexible membrane or balloon that can conform to each patient's head. Large cooling layers can be reusable and therefore may require cleaning between uses.

[0103] The cooling system 600 can be made from a flexible cavity (not shown) with an inlet and an outlet for circulating a coolant, such as water. The patient's head can be inserted into a concave shape (e.g., a "bowl") with a resilient opening. The resilient opening can seal against the patient's head. Water can fill the space between the patient's head and the bowl.

[0104] As with the single cavity design, the water can be circulated to prevent the water temperature from rising. One advantage of such a system may be that the water in the cooling system 600 can be in direct contact with the patient's head. Air around the patient's hair can be removed by the water, which can help couple the ultrasound transducer 150 to the patient's head.

[0105] 18 is a perspective view of a patient interface 650 according to at least one embodiment of the present disclosure. The cooling system 600 can be a cap 160 with cooling channels 630 distributed throughout. The cap 160 can have a single long loop of cooling channels 630, or it can have several independent loops. A system with several cooling loops can be connected to a single inlet and outlet tube via a manifold, or they can be independently controlled. Water or other heat transfer fluid can circulate through the cooling channels 630 to exchange heat generated by the transducer 150, the patient's body, or a combination thereof.

[0106] The water can flow through all areas of the head that can absorb heat. The water can be pumped to prevent the water temperature from rising, which would reduce the cooling efficiency of the water. As with patches with multiple transducers 150, each patch can have its own cooling channel 630. The cooling channel 630 can be a water-filled tube that can be larger and heavier than the wires going to the transducers 150. The number of unique cooling channels 630 can be optimized to avoid excessive weight of the cooling layer.

[0107] The effects of heat generation can be easily monitored with temperature sensors and reduced with a fluid cooling system 600. A layer of cold, degassed water between the ultrasound transducer 150 and the head can serve the dual function of coupling the head to the transducer 150 and controlling the temperature of the skull. Prior to insonification, the head can be cooled for several minutes with a constant flow of cold water. Once treatment begins, skull temperature can be continuously monitored and treatment can be adjusted across the skull or for each transducer 150 individually. Even without continuous skull temperature monitoring, a safe treatment algorithm can be devised involving intermittent treatment and continuous cooling with a safety margin for all patients. Intermittent treatment may also be more effective than the same effective treatment time delivered continuously due to the rate-limiting step of oxygen diffusion around the ultrasound sensitizer.

[0108] It may be possible that only surface temperature monitoring is required. In either case, it may be possible to monitor the temperature throughout the skull using various deep tissue temperature measurements. Any surface measurements of temperature may need to be insulated from the cooling layer of water to prevent the probe from being dominated by the cooling layer's effects.

[0109] It may be necessary to monitor the temperature of the patient's head. If a temperature sensor (not shown) were simply placed between the cooling layer and the head, the temperature sensor would likely read some combination of the head temperature and the cooling layer temperature.

[0110] There may be several ways in which the temperature sensors can be isolated from the temperature of the cooling layer. An insulating layer may be placed between the cooling layer and each temperature sensor. In such a case, the area around each temperature sensor may receive less or no cooling.

[0111] FIG. 19 is a chart 800 illustrating a relative sensitivity plot 802 of an infrared (IR) temperature sensor, according to at least one embodiment of the present disclosure. As shown in FIG. 19, a temperature probe (not shown) that measures in only one direction (e.g., unidirectional) can be utilized. 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., acceptance cone). In the present application, one or more IR sensors can be oriented such that the acceptance 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.

[0112] 20 is a block diagram of a general non-invasive sonodynamic therapy system 900 according to at least one embodiment of the present disclosure. The non-invasive sonodynamic therapy system 900 includes a controller 902 coupled to an ultrasound transducer array 904 to control the operation of the ultrasound transducer array 904 to generate appropriate ultrasound waves. The ultrasound transducer array 904 is coupled to a patient interface 906, which couples the ultrasound waves generated by the ultrasound transducer array 904 to a sensitizer 908 that accumulates in tumor cells within the patient. Through a process called sonoluminescence, the ultrasound waves activate the sensitizer 908, producing light that causes necrosis of the tumor cells.

[0113] Sonochemotherapy treatment utilizes sensitizer 908 drugs that become cytotoxic only upon exposure to ultrasound. Upon activation, sonochemotherapy drugs, commonly referred to as "ultrasound sensitizers," generate ROS, which produce cytotoxic effects that kill tumor cells. Compared to photodynamic therapy, sonochemotherapy allows for much greater tissue depth to be reached noninvasively by ultrasound. In one embodiment, the sensitizer 908 may include 5-aminolevulinic acid (5-ALA), among other sensitizers 908, such as hematoporphyrin, Rose Bengal, curcumin, titanium nanoparticles, chlorine e6, and any combination thereof. Additionally, the sonochemical process may include injecting microbubbles into tumor tissue to "seed" cavitation, allowing bubbles to accumulate in the tumor tissue, or injecting drugs to oxidize the tumor tissue. The sonochemotherapy process described herein can be combined with one or more other adjunctive therapies, such as chemotherapy, immunotherapy, radiation therapy, and / or HIFU.

[0114] The non-invasive sonodynamic therapy system 900 can be utilized to treat a variety of tumors, whether malignant or non-malignant, and to treat the area surrounding the tumor cavity, which contains cells that cause recurrence and eventual death in malignant tumors. In one aspect, the non-invasive sonodynamic therapy system 900 can be configured to treat prostate cancer via transrectal sonodynamic therapy and cervical cancer via transvaginal sonodynamic therapy, for example.

[0115] In one aspect, the controller 902 may be configured to drive the ultrasound transducer array 904. The controller 902 may be configured to run one or more control algorithms to set / evaluate reflections and adjust the drive frequency for skull thickness. This may be done automatically. In one aspect, the control algorithm may be configured to pulse or control the "duty cycle" of the drive waveform of the ultrasound transducer array 904 to generate ultrasound waves with high time-peak acoustic intensity and low time-average acoustic intensity sufficient to activate the sensitizer 908 while preventing thermal necrosis of tumor cells in the treatment area. In another aspect, the control algorithm may be configured to generate packets of waves delayed to overlap with the tumor. In another aspect, the control algorithm may be configured to control the intensity of the ultrasound waves.

[0116] In another aspect, the control algorithm may be configured to control the phase of the ultrasound waves. In another aspect, the control algorithm may be configured to randomize the phase of the ultrasound waves. Modulating the acoustic waves with phase randomization promotes broad and consistent coverage across a treatment region, where the acoustic wavefronts combine constructively at various pseudo-random locations within the treatment region rather than at the exact same location each cycle. This control scheme provides a more uniform treatment region, supporting broad and consistent treatment coverage and avoiding subtherapeutic dead spots within the treatment region. Phase randomization offers additional benefits in adapting to the treatment environment. Repeating the exact same excitation pattern in some types of acoustic environments can result in the formation of 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 can lead to standing waves.

[0117] A feedback loop can be fed back to the controller 902 to 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, temperature, among other variables. In one aspect, the controller 902 may be located within the ultrasound generator or elsewhere. In various aspects, the in situ variables may include disease states or internal body locations. Disease states may include alternative therapeutic ultrasound transducer probes that are driven differently for each disease state. Examples of feedback loops are described below in connection with FIGS. 22-24.

[0118] In one embodiment, the ultrasound transducer array 904 may be configured according to the transducers 150, 400, 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 a 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, such as glioblastoma, of the brain, lung, breast, stomach, liver, pancreas, intestine, rectum, colon, vagina, and testes, among others, whether the tumor is malignant or non-malignant.

[0119] In various configurations, the ultrasound transducer array 904 is non-invasive and generates ultrasound waves that can non-invasively reach targeted tumor cells. As described above, the ultrasound transducer array 904 may be configured as an annular array, a 2D grid array, a linear array, etc. to generate adaptively focused ultrasound waves optimized based on in situ variables such as tissue depth, tissue thickness, tissue volume, skull thickness, among other variables. In other aspects, the ultrasound transducer array 904 can adaptively focus or adjust ultrasound waves based on pre-treatment planning or safety. In one aspect, the controller 902 executes control algorithms to generate selectively converging / diverging ultrasound waves, including adaptive focusing for cooperative transducer performance. The ultrasound acoustic array 904 may be configured to perform transmitter and receiver functions that may be controlled by the controller 902.

[0120] 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 aspect, 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 aspect, the patient interface 906 may be configured to remove excess heat from the patient's body. In some configurations, the patient interface 906 may include various sensors, such as temperature sensors. Signals from such sensors can be provided as feedback to the controller 902 (see, for example, FIG. 22 ). Such feedback can be utilized to control the ultrasonic transducer array 904 to generate desired ultrasound 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 aspect, the patient interface 1022 may be configured to locally apply cooling. In one aspect, the patient interface 1022 may be configured for sensor feedback to the processing unit 902.

[0121] Finally, the noninvasive sonodynamic therapy system 900 includes a sensitizer 908 that can be absorbed by tumor cells. Sonodynamic therapy requires the combination of a sensitizer 908, such as a sensitizing drug, ultrasound generated by an ultrasound transducer array 904 coupled into the patient's body by a patient interface 906, and molecular oxygen. While these components are non-toxic individually, when combined together, cytotoxic ROS are generated to kill tumor cells. Sonodynamic therapy can be configured to provide ultrasound that penetrates the patient's body and can be used to treat deep, difficult-to-access tumors over a wide area.

[0122] FIG. 21 is an illustration 1000 of the sonodynamic therapy system 900 shown in FIG. 20 , in accordance with at least one embodiment of the present disclosure. In one embodiment, the sonodynamic therapy system 900 includes a controller 902 that can be located within an ultrasound generator 1002. The ultrasound generator 1002 includes a controller 1012, a user interface 1004, a foot switch 1006 for activating the controller 1012, and a cap or helmet 1008 that is placed on the patient's head. A cable 1010 that carries electrical signals to and from the ultrasound transducer array 904 couples the transducer array 904 to the ultrasound generator 1002. The ultrasound transducer array 904 includes an array of ultrasound transducers 150, 400, 450 that are placed on a patient interface 906, such as a skull cap 160. The ultrasound generator 1002 drives the ultrasound transducers 150, 400, 450 to generate ultrasound waves 200 that are coupled into the patient's body to excite the sensitizer 908 that has been ingested by the patient and absorbed into tumor cells. The controller 1012 shapes the acoustic waves to achieve converging, diverging, or plane acoustic waves, or more complex acoustic waves. As previously mentioned, in one aspect, the sensitizer 908 may include, for example, an ALA sensitizer that is activated by the sonoluminescence process.

[0123] FIG. 22 is a schematic diagram 1100 of the sonodynamic therapy system 900 shown in FIGS. 20 and 21 , in accordance with at least one embodiment of the present disclosure. The controller 902 of the sonodynamic therapy system 900 includes 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, control circuitry, or a combination thereof. The ultrasound transducer array 904 includes one or more ultrasound transducers 1114 and one or more monitoring ultrasound transducers 1116. It will be appreciated that the same ultrasound transducer element may be configured to perform ultrasound transmitter and receiver functions (see, for example, FIG. 24 ). The patient interface 906 includes one or more temperature sensors 1118 for monitoring the temperature of the patient 1122. The patient interface 906 also includes a cooling system 1120 for reducing the temperature of the patient 1122. In one aspect, the patient interface 906 may be configured to eliminate an air gap between the transducer 1114 and the patient 1122 to allow for acoustic coupling.

[0124] The processing unit 1104 is configured to execute machine-executable instructions for implementing various control algorithms as described above. The processing unit 1104 may include memory for storing such machine-executable instructions and a processing engine for executing the 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 multiplexing system 1112 and a power supply 1106 suitable for driving the ultrasound transducer 1114.

[0125] The ultrasound transducer 1114 is coupled to the body of the patient 1122 to activate a sensitizing agent 908 administered to the patient 1122. In one aspect, the at least one ultrasound sensitizing agent 908 may be configured to preferentially accumulate in selective tissues of the patient 1122. The monitoring ultrasound transducer 1116 monitors 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, a power monitor 1108 monitors the power supply 1106 and provides feedback to the processing unit 1104 via the ADC 1110. The processing unit 1104 controls the ultrasound transducer drive signal based on the acoustic feedback signal and / or the power monitoring signal to achieve desired ultrasound waves within the patient 1122. In one aspect, the at least one ultrasound transducer 1114 is configured to output selectively converging and diverging acoustic waves. The transducer 1114 may be configured as an annular array or a grid array. The transducer 1114 may be configured to have multiple electrodes. The transducer 1114 may be configured to receive reflected acoustic signals.

[0126] The processing unit 1104 is coupled to the temperature sensor 1118 and receives patient 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.

[0127] In one embodiment, the processing unit 1102 is configured to provide 8 W / cm 2The processing unit 1102 is configured to generate a pulsed acoustic signal having a time-averaged intensity output of less than 1 / 2 s. The processing unit 1102 is adapted to apply an amplitude-modulated acoustic signal comprising constructive interference over multiple wave cycles. The processing unit 1102 may be further configured to output packets of acoustic waves in various delayed sequences to provide wide tissue coverage. The processing unit 1102 may be configured to perform a frequency adaptation algorithm to optimize the transmission of the acoustic signal. The processing unit 1102 may be configured to control the gradual randomization of the acoustic signal.

[0128] In various aspects, the present disclosure provides a sonodynamic therapy device comprising a transducer 904, a patient interface 906, and a controller 902 adapted to activate a sensitizer 908 within a patient 1122. The transducer 904 can comprise one or more transducers 1114, 1116, and the controller 902 is configured to drive the transducer 904 to generate a broadband range of ultrasound frequencies to generate diverging, focusing, or plane acoustic waves.

[0129] In one aspect, the patient interface 906 is configured to transmit acoustic waves generated by the transducer 904 into the body of the patient 1122 and acoustically couple the transducer 904 to the patient 1122. In one aspect, the patient interface 906 provides a cooling system 1120 to remove any excess heat that accumulates within the patient 1122 as the acoustic energy couples into the patient's 1122 body. In one aspect, the patient interface 906 may include an integrated cooling system 1120. The patient interface 906 may include a gel-filled hydrogel cap or a water-filled cap with cooling channels. In one aspect, the patient interface 906 includes 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, an acoustic sensor that may include the same transducer 904 used to transmit the acoustic signal. The patient interface 906 may be configured to remove air from the patient interface 906 to improve acoustic coupling between the transducer 904 and the body of the patient 1122. 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.

[0130] In one aspect, the patient interface 906 may be adapted and configured to fit various patient anatomies. For example, the patient interface 906 may be adapted and configured to fit various patient anatomy, e.g., for sonodynamic therapy specifically adapted to treat tumors located in the brain, lung, breast, stomach, liver, pancreas, intestine, rectum, colon, vagina, and testicles, among others. The sonodynamic therapy device may be adapted to encase the patient's torso or limbs and / or utilized to treat osteosarcoma within the bone. The controller 902 may be adapted to detect either the patient interface 906 or a sonodynamic therapy device, such as the transducer 904 or patient interface 906, and select a treatment algorithm for generating acoustic waves optimized to treat various tumors. The transducer 904 or patient interface 906 can be identified using an identification (ID) circuit 1115, 1119, e.g., comprising a single-wire serial EEPROM. The EEPROM of the ID circuit 1115, 1119 may include both a preprogrammed unique serial number and a memory portion. Any or all of the memory sections may be permanently locked by the end device manufacturer to allow for product tracking and attachment identification. Other identification techniques may include detecting the impedance of the transducer 904 or patient interface 906 and correlating the impedance with a treatment algorithm.

[0131] In one aspect, the controller 902 is configured to generate an electrical drive signal to activate one or more ultrasound transducers 904 to generate acoustic waves and activate a sensitizer 908 located within the patient 1122. In one aspect, the electrical drive signal generated by the controller 902 can activate one or more ultrasound transducers 904 to generate acoustic waves of various intensities, amplitudes, or frequencies. In another aspect, the acoustic waves can be amplitude modulated, frequency modulated, phase modulated, continuous, discontinuous, pulsed, randomized, or combinations thereof. In other aspects, the acoustic waves can be generated in packets of wave cycles, and the number of cycles per packet can be predetermined to achieve a desired result different from, for example, a focused ultrasound pulse. In other aspects, the controller 902 is configured to generate a frequency modulation signal to generate frequency-modulated acoustic waves. In one aspect, the controller can be configured to generate an intra-pulse or inter-pulse variation signal that can be used to reduce standing acoustic waves.

[0132] In one aspect, the controller 902 is configured to apply amplitude-modulated acoustic ultrasound signals that constructively interfere over multiple wave cycles. In one aspect, the intensity of each of the multiple acoustic waves remains within a safe range where the ultrasound energy carried by each of the multiple acoustic waves is safe for tissue of the patient 1122, such as the brain or other body parts. In one aspect, the controller 902 may be configured to drive the transducer 904 to generate amplitude-modulated acoustic waves that generate constructive wavefronts.

[0133] In one embodiment in which the sonodynamic therapy device includes a single transducer 904, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate a long acoustic ultrasonic wave packet. In one embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic wave packet comprised of a sinusoidal amplitude modulated by a Gaussian pulse (see, e.g., FIG. 10 ). In another embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic wave packet comprised of a sinusoidal amplitude modulated by a rectangular pulse. In another embodiment, the controller 902 may be configured to generate a drive signal to activate the transducer 904 to generate an ultrasonic wave packet comprised of a sinusoidal amplitude modulated by a triangular pulse. The ultrasonic wave packet may include intra- or inter-wave packet variation. In one aspect, 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 the ultrasonic pulse may either converge to focus the ultrasonic energy in a particular area or diverge to spread the ultrasonic energy over a larger area.

[0134] In other aspects, if the sonodynamic therapy device includes two or more transducers 904, the controller 902 may be configured to generate drive signals to activate the two or more transducers 904 to generate acoustic ultrasound pulses, with individual wavefronts, whether converging or diverging, meeting at the same time and location to focus the ultrasound energy. In one aspect, the controller 902 can adapt the frequency drive for each transducer 904.

[0135] 23 is a schematic diagram of a sonodynamic therapy system 920 having separate transmitter transducer 930 and receiver transducer 934, according to at least one embodiment of the present disclosure. The sonodynamic therapy system 920 includes a system controller 922 for controlling a signal generator 924 to generate an electrical signal to drive 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 delivered 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 emitted by the tissue 932. The output of the receiver transducer 934 is a weak electrical signal provided to an electronic preamplifier 936, which converts the weak electrical signal into a noise-resistant and sufficiently strong output signal for further processing, such as filtering by a filter 938. The output of the filter 938 is provided to an analog-to-digital converter 940 (ADC), which provides a feedback signal in digital form to the system controller 922. Based on the feedback signal received from the receiver transducer 934, the system controller 922 can adjust the drive signal applied to the transmitter transducer 930. The adjustment can include adjusting the modulation, intensity, frequency, phase, or randomization of the drive signal, or any combination thereof. The feedback signal can represent tissue depth, tissue thickness, tissue volume, skull thickness, temperature, distance to the treatment area, or a combination thereof.

[0136] 24 is a schematic diagram of a sonodynamic therapy system 950 having a single transmit and receive transducer 962 in accordance with at least one embodiment of the present disclosure. The sonodynamic 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 through a matching network 960 to optimize the power delivered to the transducer 962. In transmitter mode, the transducer 962 transmits acoustic waves to tissue 964 (e.g., a lesion) within the treatment area. In receiver mode, the transducer 962 detects acoustic waves emitted 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 the weak electrical signal to an electronic preamplifier 966, which converts the weak electrical signal into an output signal that is noise-resistant and strong enough for further processing, such as filtering by a filter 968. The output of the filter 968 is provided to an ADC 970, which provides a feedback signal to the system controller 952 in digital form. 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 can include adjusting the modulation, intensity, frequency, phase, or randomization of the drive signal, or any combination thereof. The feedback signal can represent tissue depth, tissue thickness, skull thickness, temperature, distance to the treatment area, or a combination thereof.

[0137] Having described various aspects of the sonodynamic treatment systems 920, 950, 1100 and the components of the sonodynamic treatment systems 920, 950, 1100, the present disclosure now turns to a description of the sonodynamic treatment process that may be implemented in the sonodynamic treatment systems 920, 950, 1100 described hereinabove. For brevity and clarity of disclosure, the sonodynamic treatment process according to Figures 25-31 below will be described in conjunction with Figures 20-24.

[0138] 25 is an overview of a sonochemical therapy process 1200 according to at least one embodiment of the present disclosure. In a first stage 1202 of the sonochemical therapy process, a patient is administered a sonochemical sensitizer 908 described herein and wears an ultrasound transducer array 904 comprising a plurality of ultrasound transducers 150. The sonochemical sensitizer 908 can be administered orally or via other natural orifices, by injection, intravenously, topically, or by other suitable techniques. In a second stage 1204 of the sonochemical therapy process, the sonochemical sensitizer 908 accumulates in tumor cells 1206. In a third stage 1208 of the sonochemical therapy process 1200, ultrasound waves 1210 generated by the ultrasound generator 1002 activate the sonochemical sensitizer 908. In a fourth stage 1212 of the sonochemical therapy process 1200, the sonochemical sensitizer 908 causes a series of deaths of the tumor cells 1206.

[0139] FIG. 26 is a diagram 1300 of tumor cells 1206 illustrating the early stages of selective accumulation of a sensitizer 908, according to at least one embodiment of the present disclosure. In the illustrated example, the sensitizer 908 is taken up into mitochondria 1304 of the cancer cells 1206 at 1302. The patient is orally administered a prodrug 5-ALA sensitizer 908, putting the heme 1306 biosynthetic pathway 1316 into overdrive. Generally, the body's natural feedback mechanism prevents excess heme 1306 production. Heme 1306 reduces the activity of the aminolevulinic acid synthase (ALAS) enzyme, which produces 5-ALA endogenously. Even though the ALAS enzyme is inactivated by exogenously introducing the sensitizer 908, heme 1306 biosynthesis continues. As a result, protoporphyrin IX (PpIX) 1308 preferentially accumulates in many types of cancer cells 1206, including glioblastoma multiforme (GBM). PpIX 1308 is a catalyst that converts dissolved molecular oxygen into ROS by absorbing photons. Protoporphyrin IX 1308 is in the same class of molecules as chlorophylls (i.e., porphyrins) and can convert light into chemical energy.

[0140] 27 is a diagram 1320 of cancer cells 1206 illustrating the selective increase in accumulation 1322 of sensitizer 908, according to at least one embodiment of the present disclosure. As shown in FIG. 27, PpIX 1308 is the active compound and the penultimate intermediate in the biosynthetic pathway 1316 of heme 1306. The accumulation of PpIX 1308 in the mitochondria 1304 of cancer cells 1206 is due to the increased accumulation 1322 of 5-ALA sensitizer 908 and the decreased conversion of PpIX 1308 to heme 1306 (decreased expression of ferrochelating enzymes).

[0141] FIG. 28 is a diagram 1330 of the cancer cells 1206 shown in FIGS. 26 and 27 undergoing sonochemotherapy, according to at least one embodiment of the present disclosure. The ultrasound transducer 904 generates ultrasound waves 200 that penetrate the cancer cells 1206 and mitochondria 1304. The ultrasound waves 200 generate light 1312 through a process called sonoluminescence. Sonoluminescence occurs when the ultrasound waves 200 collapse fluid bubbles 1332, causing cavitation 1334 and generating light 1312 in the process. The generation of light 1312 occurs remotely from the ultrasound transducer 904. The light 1312 generated by sonoluminescence activates PpIX 1308, generating ROS 1336. Sonoluminescence can occur anywhere the ultrasound waves 200 are strong enough, allowing sonochemotherapy to treat much deeper tissue than photodynamic therapy. ROS 1336 species cause oxidative stress, and as a result, cancer cells 1206 undergo programmed cell death 1314 (apoptosis), which is equivalent to photodynamic therapy.

[0142] 29 is a diagram 1400 illustrating the sonoluminescence process, according to at least one embodiment of the present disclosure. Diagram 1400 can be found in Detlef Lohse, Sonoluminescence, Inside a micro-reactor, Nature, Vol. 418, pp. 381-383 (2002), which is incorporated herein by reference. At low acoustic pressures, standing ultrasound 200 causes the bubble 1402 to expand dramatically until the increase in acoustic pressure causes the bubble 1402 to collapse. When the temperature within the bubble 1402 rises above 10,000 K, the gas within the bubble 1402 partially ionizes, forming plasma 1404. Finally, recombination of electrons and ions results in light emission 1406.

[0143] 30 is a schematic diagram 1500 of a cancer cell 1502 illustrating the selective accumulation of a sensitizer 908, according to at least one embodiment of the present disclosure. In the illustrated example, the 5-ALA sensitizer 908 is administered systemically to the cancer cell 1502 and absorbed into the mitochondria 1504 of the cancer cell 1502. The 5-ALA sensitizer 908 is administered orally to a patient, putting the heme 1506 biosynthetic pathway into overdrive. A natural feedback mechanism in the patient's body prevents excess heme 1506 from being produced. Heme 1506 reduces the activity of the aminolevulinic acid synthase (ALAS) enzyme, which endogenously produces 5-ALA. By exogenously introducing the ALA sensitizer 908, the ALAS enzyme is inactivated, but heme 1506 biosynthesis continues. As a result, PpIX 1508 preferentially accumulates in many types of cancer cells 1502, including glioblastoma multiforme (GBM).

[0144] PpIX 1508 is the active compound and the penultimate intermediate in the biosynthetic pathway 1510 of heme 1506. The accumulation of PpIX 1508 in the mitochondria 1504 of cancer cells 1502 is due to increased uptake of 5-ALA sensitizer 908, decreased conversion of PpIX 1508 to heme 1506, and decreased expression of ferrochelating enzyme 1512.

[0145] Protoporphyrin IX 1508 is a catalyst that converts dissolved molecular oxygen into ROS by absorbing photons. Protoporphyrin IX 1508 is a molecule in the same class as chlorophylls (i.e., porphyrins) and can convert light into chemical energy.

[0146] FIG. 31 is a schematic diagram 1600 of the cancer cells 1502 shown in FIG. 30 undergoing sonochemotherapy, according to at least one embodiment of the present disclosure. An ultrasound transducer 904 generates ultrasound waves 200 that penetrate the cancer cells 1502 and mitochondria 1504. The ultrasound waves 200 generate light 1602 via a process called cavitation 1606 and sonoluminescence 1604. The generation of light 1602 occurs remotely from the ultrasound transducer 904. The light 1602 generated by sonoluminescence 1604 activates PpIX 1508, generating ROS 1608. Sonoluminescence 1604 can occur anywhere the ultrasound waves 200 are strong enough, allowing sonochemotherapy to treat much deeper tissue than photodynamic therapy. ROS 1608 species cause oxidative stress, and as a result, cancer cells 1502 undergo programmed cell death 1610 (apoptosis), similar to photodynamic therapy.

[0147] The interaction of acoustic waves 200 with the aqueous medium can result in cavitation 1606. Under appropriate ultrasonic conditions, cavitation 1606 involves the nucleation, growth, and implosive collapse of gas-filled bubbles. In sonoluminescence 1604, inertial cavitation 1606 involves bubbles growing to near-resonant size and expanding to a maximum before violently collapsing. The energy released by this implosion results in temperatures of up to 10,000 K and pressures of up to 81 MPa in the surrounding microenvironment. These extreme temperatures and pressures create a sonochemical reactor at the point of implosion. Cavitation 1606 generates ROS 1608 in sonodynamic therapy under two mechanisms of action:

[0148] One possible mechanism of action is sonoluminescence 1604. Sonoluminescence is the process by which light 1602 is generated upon exposure of cancer cells 1502 to energy generated by acoustic waves 200. Another possible mechanism of action may be thermolysis. Thermolysis is a process in which the local temperature increase that occurs simultaneously with inertial cavitation 1606 decomposes the sensitizer 908, generating free radicals that can react with other endogenous substances to generate ROS 1608. While ROS 1608 plays an important role in SDT, in some embodiments, sonodynamic therapy may be based on a sonomechanical mechanism. This conclusion was based on the observation that HP-sensitized cells can be sensitive to acoustic waves 200 at intensities that have been shown not to induce inertial cavitation.

[0149] In various embodiments of the present disclosure, sonodynamic therapy can be performed using one or more sensitizers 908. Such sensitizers 908 used in sonodynamic therapy can be selected from a variety of compounds. These compounds include, but are not limited to, porphyrins such as Photofrin, protoporphyrin IX precursors, xanthene-based sensitizers 908 such as Rose Bengal and its derivatives, acridine orange, methylene blue, curcumin, hypocrellin, indocyanine green, and nanoparticle / microparticle sensitizer conjugates. Further information regarding sonodynamic therapy can be found in David Costley et al., Treating Cancer With Sonodynamic Therapy: A Review, pp. 107-117, received October 17, 2014, accepted November 23, 2014, and published online January 13, 2015, which is incorporated herein by reference in its entirety. In various embodiments, the sonodynamic therapy techniques described in the present disclosure can be applied to animals as well as humans. In one aspect, the sonodynamic therapy techniques described in this disclosure can be applied to mammals, and in this regard, use of the term "patient" throughout this disclosure is intended to encompass humans and animals alike.

[0150] In various aspects, the sonodynamic therapy techniques described in this disclosure may be adapted to other parts of the body. These other parts of the body may be accessed through natural orifices (mouth, nasal passages, anus, vagina) or minimally invasive processes such as intravascular access. The sonodynamic therapy device may be specifically adapted to have a flexible and steerable catheter shaft to reach tumors in specific organs, such as the liver, stomach, breast, or lungs. The sonodynamic therapy device may be adapted to encase the torso or limbs and may be utilized to treat osteosarcoma within the bone.

[0151] In various aspects, the sonodynamic therapy techniques described herein may be adapted for use with adjuvant therapies. The disclosed sonodynamic therapy techniques can be utilized with other cancer treatments, including chemotherapy, immunotherapy, radiation therapy, and HIFU / hyperthermia. Furthermore, the disclosed sonodynamic therapy techniques utilize additional agents that increase oxygen in the brain or increase oxygen in brain tumors to preferential oxygen concentrations to provide effective sonodynamic therapy. The disclosed sonodynamic therapy techniques can utilize sensitizers modified or encapsulated to effectively target tumors. The disclosed sonodynamic therapy techniques can deliver O2 to the entire body using a nose tube. The disclosed sonodynamic therapy techniques can utilize multiple sensitizers in combination and include introducing gas bubbles into the tumor to oxygenate the tumor, create more cavitation, and provide a possible contrast mechanism for imaging.

[0152] In various aspects, the sonodynamic therapy techniques described in this disclosure can be adapted for use with ultrasound imaging, a process that may include adding contrast agents for ultrasound directed to the tumor.

[0153] As used herein, a processor or processing unit is an electronic circuit that performs operations on some external data source, usually memory or some other data stream. The term is used herein to refer to a system that combines several specialized "processors" or to the central processor (Central Processing Unit) within a computer system, especially a System-on-Chip (SoC).

[0154] As used herein, a system-on-chip or system-on-chip (SoC or SOC) is an integrated circuit (also known as an "IC" or "chip") that integrates all the components of a computer or other electronic system. It can include digital, analog, mixed-signal, and often radio frequency functions all on a single substrate. An SoC integrates a microcontroller (or microprocessor) with advanced peripherals such as a graphics processing unit (GPU), Wi-Fi module, or coprocessor. An SoC may or may not include built-in memory.

[0155] As used herein, a microcontroller or controller is a system that integrates a microprocessor with peripheral circuits and memory. A microcontroller (or MCU for microcontroller unit) may be implemented as a small computer on a single integrated circuit. This may be similar to an SoC. An SoC may include a microcontroller as one of its components. A microcontroller may include one or more core processing units (CPUs) along with memory and programmable input / output peripherals. Program memory in the form of ferroelectric RAM, NOR flash, or OTP ROM is often also included on the chip, as well as a small amount of RAM. In contrast to microprocessors used in personal computers or other general-purpose applications that consist of various discrete chips, microcontrollers can be utilized in embedded applications.

[0156] As used herein, the term controller or microcontroller can be a standalone IC or chip device that interfaces with a peripheral device. It can also be the link between two parts of a computer or controller on an external device that manages the operation (and connections) of that device.

[0157] Any processor or microcontroller described herein may be implemented by any single-core or multi-core processor, such as those known by Texas Instruments under the trademark ARM Cortex. In one aspect, the processor may be an LM4F230H5QR ARM Cortex-M4F processor core available from Texas Instruments, including, for example, 256 KB of on-chip memory, such as 256 KB of single-cycle flash memory or other non-volatile memory up to 40 MHz, a prefetch buffer to improve performance above 40 MHz, 32 KB of single-cycle serial random access memory (SRAM), internal read-only memory (ROM) loaded with StellarisWare® software, 2 KB of electrically erasable programmable read-only memory (EEPROM), one or more pulse-width modulation (PWM) modules, one or more quadrature encoder input (QEI) analogs, and one or more 12-bit analog-to-digital converters (ADCs) with 12 analog input channels, details of which are available in the product data sheet.

[0158] In one aspect, the processor can include a safety controller, which includes two controller-based families such as the TMS 570 and RM4x, also known under the trademark Hercules ARM Cortex R4, manufactured by Texas Instruments. The safety controller can be specifically configured for IEC 61508 and ISO 26262 safety-critical applications to provide, among other things, advanced integrated safety features while offering scalable performance, connectivity, and memory options.

[0159] As used herein, terms such as “component,” “system,” and “module” can refer to any computer-related entity, including hardware, a combination of hardware and software, software, or software in execution, in addition to electromechanical devices. For example, a component can be, but is not limited to, a process running on a processor, a processor, an object, an executable, a thread of execution, a program, and / or a computer. By way of example, both an application running on a computer and a computer can be a component. One or more components can reside within a process and / or thread of execution, and a component can be localized on one computer and / or distributed between two or more computers. The term “exemplary” is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs.

[0160] As used herein, the term control circuit may refer to any standalone or combinational electronic circuit, such as, for example, a processing unit, processor, microcontroller, microcontroller unit, controller, digital signal processor (DSP), programmable gate array (PGA), field programmable gate array (FPGA), programmable logic device (PLD), system on chip (SoC), application specific integrated circuit (ASIC), graphics processing unit (GPU), etc. According to various aspects, the process flow diagrams described herein may be implemented by a digital device, such as a control circuit.

[0161] While various aspects of the present disclosure describe instruction processing and distribution in the context of execution units and logic circuitry, other aspects of the present disclosure may be achieved by data and / or instructions stored on a machine-readable tangible medium that, when executed by a machine, causes the machine to perform functions consistent with at least one aspect. In one aspect, relevant functionality of the present disclosure is embodied in machine-executable instructions. The instructions can be used to cause a general-purpose or special-purpose processor programmed with the instructions to perform the steps of the functions described in the present disclosure. Aspects of the present disclosure may be provided as a computer program product or software, which may include a machine- or non-transitory computer-readable medium having instructions stored thereon that can be used to program a computer (or other electronic device) to perform one or more operations according to aspects of the present disclosure. Alternatively, functionality according to the present disclosure may be performed by specific hardware components that contain fixed-function logic for performing the functions, or by any combination of programmed computer components and fixed-function hardware components.

[0162] The instructions used to program the logic to execute the various disclosed aspects can be stored in memory within the system, such as DRAM, cache, flash memory, or other storage device. Additionally, the instructions can be distributed over a network or via other computer-readable media. Thus, a machine-readable medium can include any mechanism for storing or transmitting information in a form readable by a machine (e.g., a computer), including, but not limited to, a floppy diskette, an optical disk, a compact disk, a read-only memory (CD-ROM), a magneto-optical disk, a read-only memory (ROM), a random access memory (RAM), an erasable programmable read-only memory (EPROM), an electrically erasable programmable read-only memory (EEPROM), a magnetic or optical card, a flash memory, or any tangible machine-readable storage device used to transmit information over the Internet via electrical, optical, acoustic, or other forms of propagated signals (e.g., carrier waves, infrared signals, digital signals, etc.). Accordingly, non-transitory computer-readable media includes any type of tangible machine-readable medium suitable for storing or transmitting electronic instructions or information in a form readable by a machine (e.g., a computer).

[0163] Various examples have been described with reference to particular disclosed aspects. The various aspects are presented for purposes of illustration and not limitation. Those skilled in the art will recognize that various changes, adaptations, and modifications may be made without departing from the scope of the disclosure or the appended claims.

Claims

1. A transducer; a patient interface for acoustically coupling the transducer to a patient; a controller coupled to the transducer; wherein the controller generating an electrical drive signal from the set of modulated acoustic wave parameters; modulating the drive signal; and Driving the transducer at a frequency with the modulated drive signal to generate modulated acoustic waves that generate sufficient acoustic intensity to activate an ultrasound sensitizer within the treatment area.

1. A system for sonodynamic therapy, comprising:

2. The system of claim 1 , wherein the acoustic wave is a wave packet.

3. 3. The system of claim 1, wherein the transducer is configured to generate focused acoustic waves that are modulated by the controller to preferentially target the treatment area.

4. The system of claim 3 , wherein the transducer comprises a concave acoustic lens for generating the focused acoustic waves.

5. 5. A system according to any one or more of claims 3 to 4, wherein the transducer comprises a plurality of elements operable in a predetermined sequence to generate the focused acoustic waves.

6. The system of claim 1 , wherein the transducer is configured to generate diverging acoustic waves modulated by the controller to preferentially target the treatment area.

7. The system of claim 6 , wherein the transducer comprises a convex acoustic lens for generating diverging acoustic waves.

8. 8. A system according to any one or more of claims 6 to 7, wherein the transducer comprises a plurality of elements operable in a predetermined manner to generate the diverging acoustic waves.

9. 9. The system of claim 1, wherein the transducer comprises a flat surface for generating plane acoustic waves.

10. 9. The system of claim 1, wherein the transducer comprises an annular array of transducer elements.

11. 9. The system of claim 1, wherein the transducer comprises a grid array of transducer elements.

12. 12. A system according to any one or more of the preceding claims, comprising a shell, the transducer being fixed to the shell to determine the position and orientation of the transducer.

13. The system of claim 12 , wherein the shell is made from a rigid material.

14. The system of claim 12 , wherein the shell is made from a flexible material.

15. The modulated acoustic waves have a power of about 0.1 W / cm within the treatment area. 2 ~ about 50.0 W / cm 2 15. The system of claim 1 , wherein the system generates a time-averaged acoustic intensity of

16. The modulated acoustic waves have a power of about 0.2 W / cm within the treatment area. 2 ~ about 20.0 W / cm 2 The system of claim 15, wherein the system generates a time-averaged acoustic intensity of

17. The modulated acoustic waves have a power of about 0.5 W / cm within the treatment area. 2 ~ Approximately 8.0 W / cm 2 The system of claim 16, wherein the system generates a time-averaged acoustic intensity of

18. 18. The system of any one or more of the preceding claims, wherein the frequency is selected from the range of ultrasonic frequencies from about 20.00 kHz to about 12.00 MHz.

19. 20. The system of claim 18, wherein the frequency is selected from a range of ultrasonic frequencies from about 650.00 kHz to about 3.00 MHz.

20. 20. The system of claim 19, wherein the frequency is selected from a range of ultrasonic frequencies between about 900.00 kHz and 1.20 MHz.

21. 21. The system of claim 1, wherein the controller is configured to determine in situ variables and adaptively modulate the acoustic wave parameters to generate an optimized acoustic wave based on the in situ variables.

22. 22. The system of claim 1, wherein the controller is configured to determine in situ variables and adaptively adjust the time-averaged acoustic intensity to generate optimized sound waves based on the in situ variables.

23. 23. The system of any one or more of claims 1 to 22, wherein the controller is configured to determine in situ variables and adaptively modulate the acoustic waves to preferentially target treatment areas based on the in situ variables.

24. 24. The system of any one or more of claims 1 to 23, wherein the controller is configured to determine an in situ variable selected from tissue depth, tissue thickness, tissue volume, skull thickness, temperature, distance to the treatment area, or a combination thereof.

25. 25. The system of any one or more of claims 1 to 24, wherein the patient interface comprises a cooling system.

26. 26. The system of claim 25, wherein the patient interface comprises cooling channels for circulating a fluid.

27. 27. The system of any one or more of claims 1 to 26, wherein the patient interface comprises a gel.

28. 28. The system of any one or more of claims 1 to 27, wherein the patient interface is configured to assist in transducer alignment to preferentially target the treatment area.

29. 29. The system of any one or more of claims 1 to 28, wherein the patient interface is configured to adaptively adjust to fit different patient anatomies.

30. 30. The system of any one or more of the preceding claims, wherein the patient interface comprises a sensor coupled to the controller.

31. 31. The system of claim 30, wherein the sensor is a temperature sensor.

32. 32. The system of any one or more of claims 1 to 31, wherein the modulated drive signal is an amplitude modulated drive signal for generating amplitude modulated sound waves.

33. 32. The system of any one or more of claims 1 to 31, wherein the modulated drive signal is modulated by a pulse signal to generate pulsed acoustic waves.

34. 32. The system of claim 1, wherein the modulated drive signal is packetized with a predetermined number of cycles per packet to generate packets of acoustic waves.

35. 32. The system of any one or more of claims 1 to 31, wherein the modulated drive signal is a frequency modulated drive signal for generating frequency modulated acoustic waves.

36. 36. The system of claim 35, wherein the frequency modulated drive signal includes intra-pulse variations.

37. 37. The system of any one or more of claims 35 to 36, wherein the frequency modulated drive signal includes pulse-to-pulse variation.

38. 32. The system of claim 1, wherein the modulated drive signal is a duty cycle modulated drive signal for generating a duty cycle modulated acoustic wave.

39. 39. The system of any one or more of claims 1 to 38, wherein the controller is configured to detect the transducer and select a treatment algorithm according to the transducer.

40. 40. The system of any one or more of claims 1 to 39, wherein the controller is configured to detect the patient interface and select a treatment algorithm according to the patient interface.

41. 41. The system of any one or more of claims 1 to 40, wherein the controller is configured to drive the transducer at the frequency with the modulated drive signal to generate modulated acoustic waves that produce a time-averaged acoustic intensity that does not cause thermal or other damage to healthy cells within the treatment area.

42. 42. The system of claim 41, wherein the controller is configured to drive the transducer at the frequency with the modulated drive signal to generate modulated acoustic waves that produce a time-averaged acoustic intensity that does not cause the temperature of healthy tissue in the treatment area to rise above 42°C.

43. a first transducer; a second transducer; and a controller coupled to the first and second transducers; wherein the controller: generating a first electrical drive signal from the set of modulated acoustic wave parameters; generating a second electrical drive signal from the set of modulated acoustic wave parameters; Driving a first transducer with a first electrical drive signal to generate a first acoustic wave; Driving a second transducer with a second electrical drive signal to generate a second acoustic wave. wherein the first and second acoustic waves are combinable to generate an acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment area.

44. 44. The system of claim 43, wherein the first and second acoustic waves are combinable to produce a converging acoustic wave at a predetermined distance from the first and second transducers.

45. 44. The system of claim 43, wherein the first and second acoustic waves are combinable to produce a diverging acoustic wave.

46. 44. The system of claim 43, wherein the first and second acoustic waves are combinable to produce a plane acoustic wave.

47. 47. The system of any one or more of claims 43 to 46, wherein the controller is configured to modulate the first electrical drive signal with a first modulating signal and modulate the second electrical drive with a second modulating signal to drive the first and second transducers to generate first and second modulated acoustic waves.

48. 48. The system of claim 47, wherein the controller is configured to amplitude modulate the first and second electrical drive signals to generate first and second amplitude-modulated acoustic waves.

49. 49. The system of any one or more of claims 47 to 48, wherein the controller is configured to frequency modulate the first and second electrical drive signals to generate first and second frequency-modulated acoustic waves.

50. 50. The system of any one or more of claims 47 to 49, wherein the controller is configured to phase modulate the first and second electrical drive signals to generate first and second phase-modulated acoustic waves.

51. 51. The system of claim 50, wherein the controller is configured to phase modulate the first and second electrical drive signals to generate phase-randomized acoustic waves.

52. 52. The system of any one or more of claims 43 to 51, wherein the controller is configured to delay either the first or second electrical drive signal to produce a relative delay of the corresponding first or second acoustic wave.

53. 53. The system of any one or more of claims 43 to 52, wherein the first electrical drive signal has a first frequency and the second electrical drive signal has a second frequency.

54. 54. The system of claim 53, wherein the frequency is selected from a range of ultrasonic frequencies from about 20.00 kHz to about 12.00 MHz.

55. 55. The system of claim 54, wherein the frequency is selected from a range of ultrasonic frequencies from about 650.00 kHz to about 3.00 MHz.

56. 55. The system of claim 54, wherein the frequency is selected from a range of ultrasonic frequencies between about 900.00 kHz and 1.20 MHz.

57. 57. The system of any one or more of claims 43 to 56, wherein at least one of the first or second transducers comprises an annular array of transducer elements.

58. 57. The system of any one or more of claims 43 to 56, wherein at least one of the first or second transducers comprises a grid array of transducer elements.

59. 59. The system of any one or more of claims 43 to 58, comprising a shell, the first and second transducers being fixed to the shell to determine the position and orientation of the first and second transducers.

60. 60. The system of claim 59, wherein the shell is made from a rigid material.

61. 60. The system of claim 59, wherein the shell is made from a flexible material.

62. The modulated acoustic waves have a power of about 0.1 W / cm within the treatment area. 2 ~ about 50.0 W / cm 2 62. The system of any one or more of claims 43 to 61, wherein the system generates a time-averaged acoustic intensity of

63. The modulated acoustic waves have a power of about 0.2 W / cm within the treatment area. 2 ~ about 20.0 W / cm 2 63. The system of claim 62, wherein the system generates a time-averaged acoustic intensity of

64. The modulated acoustic waves have a power of about 0.5 W / cm within the treatment area. 2 ~ Approximately 8.0 W / cm 2 64. The system of claim 63, wherein the system generates a time-averaged acoustic intensity of

65. 65. The system of any one or more of claims 43 to 64, comprising a patient interface for acoustically coupling the first and second transducers to a patient.

66. 66. The system of claim 65, wherein the patient interface comprises a cooling system.

67. 67. The system of claim 66, wherein the patient interface comprises cooling channels for circulating a fluid.

68. 66. The system of claim 65, wherein the patient interface comprises a gel.

69. 69. The system of any one or more of claims 65 to 68, wherein the patient interface is configured to assist in transducer alignment to preferentially target the treatment area.

70. 69. The system of any one or more of claims 65 to 68, wherein the patient interface is configured to adaptively adjust to fit different patient anatomies.

71. 71. The system of any one or more of claims 65 to 70, wherein the patient interface comprises a sensor coupled to the controller.

72. 72. The system of claim 71, wherein the sensor is a temperature sensor.

73. 73. The system of any one or more of claims 65 to 72, wherein the controller is configured to detect the patient interface and select a treatment algorithm according to the detected patient interface.

74. 74. The system of any one or more of claims 43 to 73, wherein the controller is configured to determine in situ variables and adaptively modulate acoustic wave parameters to generate optimized acoustic waves based on the in situ variables.

75. 75. The system of any one or more of claims 43 to 74, wherein the controller is configured to determine in situ variables and adaptively adjust the time-averaged acoustic intensity to generate optimized sound waves based on the in situ variables.

76. 76. The system of any one or more of claims 43 to 75, wherein the controller is configured to determine in situ variables and adaptively modulate the acoustic waves to preferentially target treatment areas based on the in situ variables.

77. 77. The system of any one or more of claims 43 to 76, wherein the controller is configured to determine an in situ variable selected from tissue depth, tissue thickness, tissue volume, skull thickness, temperature, distance to the treatment area, or a combination thereof.

78. 78. The system of any one or more of claims 43 to 77, wherein the controller is configured to detect at least one of the first or second transducers and select a treatment algorithm according to the detected first and second transducers.

79. 79. The system of any one or more of claims 43-78, wherein the first and second modulated acoustic waves are combinable to produce a time-averaged acoustic intensity that does not cause thermal or other damage to healthy cells within the treatment area.

80. 80. The system of claim 79, wherein the first and second modulated acoustic waves are combinable to produce a time-averaged acoustic intensity that does not cause the temperature of healthy tissue in the treatment region to rise above 42°C.

81. a plurality of transducers; a controller coupled to the plurality of transducers; wherein the controller: generating a plurality of electrical drive signals from the set of modulated acoustic wave parameters; Driving the plurality of transducers with the plurality of electrical drive signals to generate a plurality of modulated acoustic waves. wherein the plurality of modulated acoustic waves are combinable to generate an acoustic intensity sufficient to activate an ultrasound sensitizer in the treatment area.

82. 82. The system of claim 81, wherein the multiple acoustic waves are combinable to produce a focused acoustic wave at a predetermined distance from the multiple transducers.

83. 82. The system of claim 81, wherein the multiple acoustic waves are combinable to produce diverging acoustic waves.

84. 82. The system of claim 81, wherein the multiple acoustic waves are combinable to produce a plane acoustic wave.

85. 85. The system of any one or more of claims 81 to 84, wherein the controller is configured to modulate each of the plurality of electrical drive signals with a modulating signal to drive the plurality of transducers to generate a plurality of modulated acoustic waves.

86. 86. The system of claim 85, wherein the controller is configured to amplitude modulate the plurality of electrical drive signals to generate a plurality of amplitude-modulated acoustic waves.

87. 87. The system of any one or more of claims 85 to 86, wherein the controller is configured to frequency modulate the plurality of electrical drive signals to generate a plurality of frequency-modulated acoustic waves.

88. 88. The system of any one or more of claims 85 to 87, wherein the controller is configured to phase modulate the plurality of electrical drive signals to generate a plurality of phase-modulated acoustic waves.

89. 89. The system of claim 88, wherein the controller is configured to phase modulate the plurality of electrical drive signals to generate phase-randomized acoustic waves.

90. 90. The system of any one or more of claims 81 to 89, wherein the controller is configured to delay at least one of the plurality of electrical drive signals relative to the remaining electrical drive signals to generate an acoustic wave having a delay relative to the remaining acoustic waves.

91. 91. The system of any one or more of claims 81 to 90, wherein the at least one electrical drive signal of the plurality of electrical drive signals has a different frequency than the remaining electrical drive signals.

92. 92. The system of claim 91, wherein the frequencies of the at least one electrical drive signal and the remaining electrical drive signals are selected from a range of ultrasonic frequencies from about 20.00 kHz to about 12.00 MHz.

93. 93. The system of claim 92, wherein the frequencies of the at least one electrical drive signal and the remaining electrical drive signals are selected from a range of ultrasonic frequencies from about 650.00 kHz to about 3.00 MHz.

94. 94. The system of claim 93, wherein the frequencies of the at least one electrical drive signal and the remaining electrical drive signals are selected from a range of ultrasonic frequencies between approximately 900.00 kHz and 1.20 MHz.

95. 95. The system of any one or more of claims 81 to 94, wherein the plurality of transducers are arranged in an annular array of transducer elements.

96. 95. The system of any one or more of claims 81 to 94, wherein the plurality of transducers are arranged in a grid array of transducer elements.

97. 97. A system according to any one or more of claims 81 to 96, comprising a shell, the plurality of transducers being fixed to the shell to determine the position and orientation of each of the plurality of transducers.

98. 98. The system of claim 97, wherein the shell is made from a rigid material.

99. 98. The system of claim 97, wherein the shell is made from a flexible material.

100. The plurality of modulated acoustic waves has a frequency of about 0.1 W / cm within the treatment area. 2 ~ about 50.0 W / cm 2 100. The system of any one or more of claims 81 to 99, combinable to produce a time-averaged acoustic intensity of

101. The plurality of modulated acoustic waves has a power of about 0.2 W / cm within the treatment area. 2 ~ about 20.0 W / cm 2 101. The system of claim 100, combinable to generate a time-averaged acoustic intensity of

102. The plurality of modulated acoustic waves has a power of about 0.5 W / cm within the treatment area. 2 ~ Approximately 8.0 W / cm 2 102. The system of claim 101, combinable to generate a time-averaged acoustic intensity of

103. 103. The system of any one or more of claims 81 to 102, comprising a patient interface for acoustically coupling the plurality of transducers to a patient.

104. 104. The system of claim 103, wherein the patient interface comprises a cooling system.

105. 105. The system of claim 104, wherein the patient interface comprises cooling channels for circulating a fluid.

106. 106. The system of any one or more of claims 103 to 105, wherein the patient interface comprises a gel.

107. 107. The system of any one or more of claims 103 to 106, wherein the patient interface is configured to assist in transducer alignment to preferentially target the treatment area.

108. 108. The system of any one or more of claims 103 to 107, wherein the patient interface is configured to adaptively adjust to fit different patient anatomies.

109. 109. The system of any one or more of claims 103 to 108, wherein the patient interface comprises a sensor coupled to the controller.

110. 110. The system of claim 109, wherein the sensor is a temperature sensor.

111. 111. The system of any one or more of claims 103 to 110, wherein the controller is configured to detect the patient interface and select a treatment algorithm according to the patient interface.

112. 112. The system of any one or more of claims 81 to 111, wherein the controller is configured to determine in situ variables and adaptively modulate acoustic wave parameters of the plurality of electrical drive signals to generate optimized acoustic waves based on the in situ variables.

113. 113. The system of any one or more of claims 81 to 112, wherein the controller is configured to determine in situ variables and adaptively adjust the time-averaged acoustic intensity of the combined multiple modulated sound waves to generate an optimized sound wave based on the in situ variables.

114. 114. The system of any one or more of claims 81 to 113, wherein the controller is configured to determine in situ variables and adaptively modulate the acoustic waves to preferentially target treatment areas based on the in situ variables.

115. 115. The system of any one or more of claims 81 to 114, wherein the controller is configured to determine an in situ variable selected from tissue depth, tissue thickness, tissue volume, skull thickness, temperature, distance to the treatment area, or a combination thereof.

116. 116. The system of any one or more of claims 81 to 115, wherein the controller is configured to detect at least one of the plurality of transducers and select a treatment algorithm according to the detected transducer.

117. 117. The system of any one or more of claims 81 to 116, wherein the multiple acoustic waves are combinable to produce a time-averaged acoustic intensity that does not cause thermal or other damage to healthy cells within the treatment area.

118. 118. The system of claim 117, wherein the multiple acoustic waves are combinable to produce a time-averaged acoustic intensity that does not cause the temperature of healthy tissue in the treatment area to rise above 42°C.

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