Novel transfection and drug delivery device

Abstract

To provide an ultrasound transmitter device for treating a patient.SOLUTION: An ultrasound transmitter device includes an imaging probe; an imaging array; and a therapeutic ultrasound device, wherein the imaging probe is configured to guide the therapeutic ultrasound device to the patients treatment site by use of ultrasound imaging with the imaging array, wherein the therapeutic ultrasound device is configured to produce a controlled intensity of ultrasound energy for treating the patients treatment site, and wherein the imaging probe and the therapeutic ultrasound device are configured to work in conjunction with one another to apply therapeutic ultrasound to tissue or bone graft sites in the patient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Field of the Disclosure The present invention relates to devices, methods, and systems for effective tissue healing. More specifically, the disclosed devices, methods, and systems provide novel tissue healing through the use of ultrasound (US) to guide and promote allogeneic transfection and / or drug delivery. [Background technology]

[0002] Background of the Disclosure The following description contains information that may be useful in understanding the present invention. The following description is not an admission that any information provided herein is prior art or relevant to the claimed invention; nor is the following description an admission that any publication specifically or implicitly referenced is prior art.

[0003] Skeletal injuries, such as nonunion fractures and ligament / tendon ruptures, can have serious consequences for the quality of life of orthopedic patients. Current treatments for nonunion fractures include autografts, which can be associated with serious complications or side effects. Anterior cruciate ligament (ACL) or rotator cuff tears are often reconstructed with either autografts or allografts, which can lead to delayed healing times and reduced mobility.

[0004] Therefore, methods aimed at shortening patient recovery times from bone injuries and / or ligament / tendon ruptures are of great clinical importance. Summary of the Invention

[0005] Summary of the Disclosure With the current widespread use of bone and ligament repair, faster patient healing following a repair procedure would significantly reduce hospital and overall healthcare costs, as well as improve the patient experience.

[0006] There is an unmet need in the field of orthopedic medicine for novel therapies that can speed bone and ligament / tendon repair. The disclosed devices and methods provide an innovative means to effect more effective tissue healing through the use of ultrasound (US) to guide and promote allogeneic transfection and / or drug delivery.

[0007] Research experience has recently demonstrated that techniques can be used to induce bone regeneration by using allogeneic genes transfected in porcine models. Low-intensity pulsed ultrasound (LIPUS) has been known for many years to be effective in medicine both for diagnosis and bone healing, but it has also been shown to favorably affect the healing of autologous bone grafts.

[0008] In addition, delivery of bone morphogenetic protein (BMP) genes, achieved using viruses, has been shown to induce healing of nonunion fractures in rodents and large animals, and also enhance ligament integration in several animal models. Viral vectors are the most efficient gene delivery tools, but they also pose potential risks of tumorigenic and immunogenic reactions. Non-viral vectors are considered safer for use in humans, although they are much less efficient at gene expression. In vivo electroporation, used to deliver BMP genes to endogenous mesenchymal stem cells (MSCs) within nonunion fracture sites in rodents, has been shown to result in efficient fracture healing. Furthermore, an alternative physical method of gene transfection, called sonoporation, or the use of ultrasound for gene delivery, is particularly attractive for potential clinical applications, due to the widespread use of ultrasound in today's clinical practice.

[0009] However, while ultrasound has been successfully used for BMP gene delivery and ectopic bone formation in rodents, it was much less efficient than electroporation-mediated ectopic bone formation and did not lead to significant bone repair in a nonunion fracture model. Sonoporation and related protocols have now reached human trials for enhancing blood-brain barrier transport and treating acute myocardial infarction; however, sonoporation has not yet reached the level of use in preclinical large animal models and humans in regenerative medicine. In fact, it has been shown that sonoporation can be used to overexpress reporter genes in large animal fracture models. Recently, ultrasound-based BMP-6 gene delivery to endogenous MSCs led to complete repair of segmental bone defects in a minipig model. Furthermore, a similar approach was used to deliver plasmid BMP-2 into bone tunnels created for ACL reconstruction in the knee joints of minipigs.

[0010] Thus, disclosed are devices, methods and systems for the purpose of wound healing that utilize a practical and minimally invasive approach to expedite recovery times by conveniently combining at least one ultrasound probe with a system for transfecting genetic material and / or delivering drugs to a patient. Convenient, safe and reliable methods for providing genetic material and / or drugs directly to a target site in a patient are also disclosed.

[0011] The disclosed systems and methods provide a simple, safe, effective, and broadly applicable method-device for tissue healing through the use of US to guide and facilitate allogeneic transfection and / or drug delivery.

[0012] In addition, the systems and methods of the present disclosure may provide for precise allogeneic transfection through the use of ultrasound. For example, a combination of at least two ultrasound probes is disclosed for coordinated use in a procedure to guide and facilitate the transfection of genetic material into a patient for wound healing purposes.

[0013] Transfection methods can include, for example, electroporation, cell squeezing, nanoparticles, magnetofection, microinjection, gene guns, impalefection, hydrostatic pressure, continuous injection, as well as sonication and chemicals such as lipofection.

[0014] Methods of drug delivery may include focused ultrasound, transient cavitation, and the like.

[0015] The devices of the present disclosure function as both imaging arrays and therapeutic devices, with the imaging array being used to guide the position of the therapeutic device, in some embodiments, the combination also provides the ability to precisely identify and simultaneously treat a treatment site.

[0016] In one aspect of the present disclosure, the disclosed ultrasound transmitting device includes at least two ultrasound probes, a first ultrasound probe configured to be an imaging array and a second ultrasound probe configured to be a therapeutic array guided by the first ultrasound probe to a treatment location within a patient's body.

[0017] The first ultrasonic probe and the second ultrasonic probe may be configured to be two detachable components joined together via a fastening mechanism, such as, for example, a clip, a fastener, a nail, and a lock. Alternatively, the two ultrasonic probes may be joined by an adhesive. In yet another embodiment, the two ultrasonic probes may be configured to be a single component permanently attached to each other.

[0018] In some embodiments, the treatment device of the present disclosure may include a gimbal positioner, a clamshell, and / or a therapeutic array cable. Alternatively, the therapeutic array may be cordless and include its own battery / power source.

[0019] The second ultrasonic probe may apply ultrasonic treatment to the treatment location once guided to the treatment location. The treatment device of the present disclosure may include a transfection device configured to perform allogeneic transfection to the treatment location. The treatment device of the present disclosure may further include a separate drug delivery device configured to perform effective drug delivery to the treatment location.

[0020] In some embodiments, the imaging array may be configured to guide and confirm the position of the therapeutic array. The therapeutic array may include a therapeutic ultrasound treatment device that emits a therapeutic beam (e.g., ultrasound) to a treatment site on the patient. The therapeutic beam may also guide a drug to the treatment site once the drug has been injected / absorbed by the patient.

[0021] In some embodiments, the imaging array may be configured to guide and confirm the position of the drug delivery device, which may include its own therapeutic array configured to emit a therapeutic beam to guide the drug to the treatment site.

[0022] The therapeutic beam may be distributed along the beamline in the azimuthal dimension, while also having the ability to dynamically reposition this azimuthally extended beam focus in the elevation dimension, allowing for the therapeutic beam to be systematically scanned over large areas of the patient treatment site, thereby providing relatively uniform insonification of the intended patient treatment area for the purpose of enhancing the allogeneic transfection process.

[0023] To achieve large array insonification, the expanded beam may be swept in any number of ways; these methods include (a) sweeping a concentrated focus slowly or quickly in both azimuth and elevation (e.g., raster scanning); (b) scanning an expanded focus slowly or quickly in elevation; or (c) a combination of (a) and (b) to produce the most effective insonification. Regardless of the focal geometry, the acoustic intensity of the beam can be adjusted to the desired intensity (typically around 30 mW / cm2). 2 ) may be maintained.

[0024] In one embodiment, the therapeutic array may be configured as a 1D array or a 2D array.

[0025] In yet other embodiments, the therapeutic array may be steered / directed, for example, automatically by a machine that detects the treatment site on the patient; mechanically by moving a second ultrasound probe; by the use of lenses; and by the use of multiple elements and electronic phasing.

[0026] The ultrasound transmitting devices of the present disclosure may be tailored to the needs of the patient: for example, the ultrasound transmitting device may be configured to be applied on a larger scale (e.g., an entire shoulder, an entire knee, etc.) or to treat on a smaller scale (e.g., a bone tunnel).

[0027] In another aspect of the present disclosure, the ultrasound transmitter of the present disclosure includes at least two probes, an imaging array and a therapeutic device, where the imaging array is configured to provide sufficient resolution to clearly image a bone tunnel or the like having a small hole of about 4 mm in diameter.

[0028] The ultrasound transmitter includes a highly adjustable arm configured to position the imaging array in a stationary position during ultrasound viewing of the bone tunnel site. The adjustable arm may hold the imaging array in a preformed "clamshell." The clamshell may hold the imaging array rigidly, but allow for removal and precise replacement of the imaging array whenever necessary. The arm holding the imaging array is first positioned to clearly view the bone tunnel, and then precisely positioned so that the bone tunnel ostium is centered with the array image, just a few millimeters from the face of the array.

[0029] The therapeutic device may emit a therapeutic ultrasound signal and may dynamically steer its beam energy so that the ultrasound signal is distributed in a time-averaged manner in the bone tunnel during the procedure. This second device may either be integrated with the imaging array or used separately. If used separately, the procedure may be performed as follows: first, the imaging array is positioned and centered on the bone tunnel; second, the imaging array is removed from its clamshell, and an imaging array mimic with a central hole to accommodate the therapeutic US device is used to replace the imaging array. In this way, the therapeutic ultrasound device is positioned directly at the bone tunnel without the need for imaging itself. The therapeutic ultrasound procedure may be performed with the cylindrical device, and an imaging probe may be used at any time to confirm the position of the therapeutic device in the proper position at the bone tunnel.

[0030] In one embodiment, the ultrasound transmitter may include an imaging array with a central space to accommodate a therapeutic ultrasound device, or alternatively, the array may be a complete standard array held in a clamshell holder that can be replaced with an array mimic with a central hole to accommodate a therapeutic ultrasound device.

[0031] In one embodiment, the therapeutic device can use ultrasonic transmission with low frequency (1-2 MHz) emission signal in a typical therapeutic US procedure. US therapeutic procedures use a form of mechanical energy that is transmitted through and into living tissue as acoustic pressure waves. The therapeutic procedures generally utilize 20 minutes of treatment per day with 1 MHz waves, with an average intensity of 30 mW / cm2, pulse width of 200 microseconds, and repeating at 1 kHz. The therapeutic US wave guide device is made so that the ultrasonic energy is distributed in a uniform manner in the bone tunnel throughout the therapeutic procedure. To achieve this and maintain an atraumatic interface with the tissue, the device is made as follows, listed in order of importance:

[0032] 1. Generation of ultrasonic energy A simple piezoelectric transducer in the frequency range of 1-2 MHz can meet the requirements of therapeutic ultrasound. It can be a simple disk transducer without backing material and without substantial matching layer design, since the required bandwidth is small and the output power is very low. For a 5 mm diameter transducer, the expected electrical impedance is about 200 ohms and the transmission sensitivity is expected to be approximately 5 kPa / V. Therefore, the device is expected to require less than 10 V driving voltage and less than 250 mW power.

[0033] 2. Atraumatic transducer housing and placement for optimal ultrasound exposure to the treated tissue A material known to be ultrasonically transparent, such as polymethylpentene (TPX, a Mitsui Plastics trademark), may be used as a housing for the transducer. In this way, the transducer and its moving parts are completely housed. The housing tube may be placed with a rounded tip and positioned at or near the ostium of the bone tunnel during a therapeutic ultrasound procedure. If the imaging array has a central gap to accommodate an ultrasonic therapy device, a thin metal band may be fixed around the array housing tip to allow for increased visibility of the tip by the array for positioning in the bond tunnel. The use of a TPX shell tip, which is ultrasonically transparent, is being developed and is not believed to significantly impede the 1.5 MHz echo signal.

[0034] 3. Beam Steering With the therapeutic ultrasound power being applied at such a low frequency and so close to the tissue, the beam exists primarily as a radiating spherical wave until it is reflected from inside the bone tunnel into a more complex wave. If the tissue material inside the bone tunnel has similar ultrasonic attenuation properties as muscle and liver (i.e., 0.5 dB / cm / MHz), this means that the loss at the end of a 15 mm long bone tunnel is only about 1 dB (20% of the power). This is very little attenuation.

[0035] The ultrasound radiation pattern (also known as the "beam") is designed to produce a uniform time-averaged ultrasound exposure within the bone tunnel, and the beam may be steered to achieve this. The transducer may exist as a single element or multiple element device. The general direction of the beam may also be affected by mechanical rotation of the transducer or lens.

[0036] Oscillating the transducer may be accomplished by two means: either a mechanical wobbler or a rotating fixed lens. In the case of a mechanical wobbler, the transducer (either annular array or single element) may be mounted on a shaft made of a flexible elastomer that encapsulates the transducer wire and allows a tilt angle of 10-15 degrees from the central axis. The green tubular shaft rotates with a single offset ball that tilts the transducer as the tubular shaft rotates.

[0037] In using a lens, the lens may be made, for example of TPX (an exemplary material herein with a velocity of 2200 m / s), capable of steering the beam approximately 10-15 degrees off-axis. The lens may be bonded directly to the front face of the transducer; or alternatively, the lens may rotate within the tip while the transducer remains fixed in position. In the former case, the entire transducer and lens assembly rotates or rotates in an oscillating pattern of +180 degrees, -180 degrees.

[0038] The device may have no moving parts and therefore may not have problems with coupling with water or gel (in the transducer tube housing). The face of the therapeutic ultrasound transducer is flat, but is covered with an ultrasound compatible material to create a dome-shaped tip. The face of the transducer has only a few elements arranged in more of a matrix fashion, rather than arranged as an annular array. By selecting certain elements (rather than all), or alternatively by selecting all but with phase and / or amplitude modification, the beam can be altered enough to achieve the goal of uniform time-averaged ultrasound exposure throughout the tissue. Due to the size and frequency (1.5 MHz) of the elements of the present invention, sub-dicing of the elements may be required to prevent undesirable lateral resonances and promote only thickness mode resonances in each element. Sub-dicing is not difficult to perform.

[0039] The proposed device has great potential to shorten the recovery time of patients from bone injury or ligament / muscle rupture.The proposed device may also be used in any treatment site where ultrasound may be interfered with from bone structures, such as the brain (interference from the skull), ear canal, intraorbital cavity, dental pulp, bone marrow, heart and lung (interference from the ribs), spinal cord and intervertebral disc (interference from the vertebrae), and cartilage.Also advantageously, the disclosed device and method may be used in combination with allogeneic transfection or drug delivery.

[0040] Implementation of these devices and methods is believed to result in measurable improved outcomes, including reduced patient recovery time, increased patient comfort and autonomy, reduced caregiver time, and reduced daily suction sets, among other things. [Brief description of the drawings]

[0041] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate aspects of the present invention and, together with the description herein, explain and illustrate the principles of the invention. The drawings are intended to illustrate major features of exemplary aspects in a diagrammatic format. The drawings are not intended to depict every feature of the actual aspects or the relative dimensions of the depicted elements, and are not drawn to scale.

[0042] [Figure 1] FIG. 1 illustrates an example system for healing through ultrasound in accordance with the principles of the present disclosure. [Figure 2A] 1A-1C show different examples of steerable therapeutic arrays according to the principles of the present disclosure. [Figure 2B] 1A-1D illustrate different examples of steerable therapeutic arrays according to the principles of the present disclosure. [Figure 2C] 1A-1C show different examples of steerable therapeutic arrays according to the principles of the present disclosure. [Figure 2D] 1A-1C show different examples of steerable therapeutic arrays according to the principles of the present disclosure. [Diagram 3] 3A-3D are diagrams illustrating another example of a steerable therapeutic array according to the principles of the present disclosure. [Figure 4] FIG. 13 illustrates yet another example of a steerable therapeutic array according to the principles of the present disclosure. [Diagram 5] 5A and 5B show an example of a treatment device constructed according to the principles of the present disclosure, respectively, and further another example of a treatment device constructed according to the principles of the present disclosure. [Figure 6] 6A-6G are diagrams illustrating different example ultrasound radiation patterns emitted by a therapeutic device constructed according to the principles of the present disclosure. [Figure 7] FIG. 1 shows an example of a solid-state array according to the principles of the present disclosure.

[0043] In the drawings, for ease of understanding and convenience, the same reference numbers and initial letters identify elements or acts that are the same or similar in structure or functionality. To easily identify the description of a particular element or act, the most significant digits in the reference numbers indicate the figure number in which that element is first introduced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Detailed Description The present disclosure and its various features and advantageous details will be described in more detail with reference to non-limiting embodiments and examples described and / or illustrated in the accompanying drawings and detailed in the following description. It should be noted that the features illustrated in the drawings are not necessarily to scale, and that features of one embodiment may be used with other embodiments, even if not explicitly stated herein, as would be recognized by a person skilled in the art. Descriptions of well-known components and processing techniques may be omitted so as not to unnecessarily hinder the implementation of the present disclosure. The examples used in this specification are merely intended to facilitate understanding of how the present disclosure can be realized, and to further enhance the ability of a person skilled in the art to realize the embodiments of the present disclosure. Therefore, the examples and embodiments in this specification should not be interpreted as limiting the scope of the present disclosure.

[0045] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.Szycher's Dictionary of Medical Devices CRC Press, 1995 may provide useful guidance for many terms and phrases used herein.Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the realization of the present invention.In fact, the present invention is not limited in any manner to the methods and materials specifically described.

[0046] In some embodiments, characteristics such as dimensions, shapes, and relative positions used to describe and claim particular embodiments of the invention should be understood as being modified by the term "about."

[0047] Various embodiments of the present invention are described below. The following description provides specific details for a thorough understanding and enabling description of these embodiments. However, those skilled in the relevant art will understand that the present invention can be practiced without many of these details. Similarly, those skilled in the relevant art will also understand that the present invention may include many other obvious features that are not detailed herein. In addition, some well-known structures or functions may not be presented or detailed below in order to avoid unnecessarily obscuring the relevant description.

[0048] The terminology used below should be interpreted in its broadest reasonable manner, even when used in conjunction with the detailed description of certain embodiments of the invention. In fact, certain terms may even be emphasized below; however, any terminology that is intended to be interpreted in any limited manner is expressly and specifically so defined in this detailed description section.

[0049] Although the present specification contains details of many specific embodiments, these should not be interpreted as limitations on the scope of any invention or what may be claimed, but rather as descriptions of features specific to particular embodiments of a particular invention. Certain features described herein in the context of separate embodiments may also be implemented in combination in a single embodiment. Conversely, various features described in the context of a single embodiment may also be implemented in multiple embodiments separately or in any suitable subcombination. Furthermore, although features may be described above as acting in a particular combination, or even initially claimed as such, one or more features in a claimed combination may in some cases be deleted from the combination, and the claimed combination may be directed to a subcombination or a variation of the subcombination.

[0050] Similarly, although operations may be depicted in a particular order in the figures, this should not be understood as requiring that such operations be performed in that particular or sequential order, or that all of the operations shown be performed, to achieve desirable results. In certain situations, multitasking and parallel processing may be advantageous. Furthermore, the separation of various system components in the above-described embodiments should not be understood as requiring such separation in all embodiments, and it should be understood that the program components and systems described herein may generally be integrated together in a single software product or packaged in multiple software products.

[0051] 1 illustrates an example of an application of the therapy device 110, showing the therapy array 120 aimed at a complex bone defect repair site 130 involving both the tibia and fibula. An imaging probe 140 guides and confirms the position of the therapy array 120. For simplicity, the gimbal positioner, clamshell, and therapy array cables are omitted from the drawing. The therapy device 110 includes an imaging array that detects the repair site and guides the therapy array 120, which applies ultrasound therapy at a predetermined (or dynamically changing based on conditions) wavelength.

[0052] The therapeutic device 110 may also include a transfection device or system (not shown) for transfecting genetic material onto the repair site once such site has been identified and located by the imaging probe.

[0053] Transfection methods / systems can include, for example, electroporation, cell squeezing, nanoparticles, magnetofection, microinjection, gene guns, impalefection, hydrostatic pressure, continuous injection, as well as sonication and chemicals such as lipofection.

[0054] 2A-2D show different examples of steerable ultrasound beams emanating from a therapeutic device constructed according to the principles of the present disclosure. FIG. 2A shows an example of a steerable therapeutic array 200 with a long axis shape and array elements 210 generally described in random (but known) positions across the array surface. As shown, a large therapeutic array may include small elements 210 arranged in a random fashion to help prevent undesirable grating lobes when the primary focus is steered away from a geometric center focal region 220.

[0055] In Figure 2B, an imaging array 230 has been added, shown aligned along the central axis of the therapeutic array 200. As shown, a key design aspect of this large array 230 is its long azimuthal dimension (rather than being a strictly spherical surface); this is done to enhance the array's ability to create an extended focus in the azimuthal direction. Another key aspect is the housing (central cavity) for the imaging array.

[0056] 2C shows the imaging plane 240 and the cylindrical region 250 that is the expanded focal region created by the therapeutic array 200. In addition to using a relatively standard imaging array for guidance, a key aspect of the device is the ability to create a beam that is distributed along the beamline in the azimuth dimension, while also having the ability to dynamically reposition this azimuthally expanded beam focus in the elevation dimension. In this manner, very large areas can be systematically scanned, allowing for relatively uniform insonification of the intended area for the purpose of enhancing the allogeneic transfection process. To achieve large array insonification, the expanded beam may be swept in any number of ways; these methods include (a) sweeping a concentrated focus slowly or quickly in both azimuth and elevation (e.g., raster scanning); (b) scanning an expanded focus slowly or quickly in elevation; or (c) a combination of (a) and (b) to produce the most effective insonification. Regardless of the focal geometry, the acoustic intensity of the beam can be adjusted to the desired intensity (typically around 30 mW / cm2). 2 ) may be maintained.

[0057] FIG. 2D shows that the extended focal region (e.g., as shown in FIG. 2C) may be steered in the elevation plane, allowing for a larger net array of therapeutic ultrasound exposure.

[0058] 3A-3B show examples of planar therapeutic arrays that may be realized as 1D or 2D arrays. The therapeutic US beam may be very broadly focused during steering, so a large number of elements and small size of array elements are not necessarily required. Steerable therapeutic arrays are shown as relatively planar devices with elements distributed in a manner that allows the 1D or 2D array to act as a low intensity beam transmitter. In FIG. 3A, a planar 1D array is configured with a central slot for a guiding imaging transducer; in FIG. 3B, the array is shown with the imaging transducer array in place; and in FIG. 3C, a 2D segmented array is shown with elements that are coarse enough to allow low channel counts, but sophisticated enough to allow proper beam steering to insonify the intended area.

[0059] FIG. 4 shows an example of a steerable therapeutic array based on the principles of the present disclosure. A steerable therapeutic array (as shown) with a curvature and radius of curvature appropriate for the application (e.g., a ROC in the range of 50-75 mm is appropriate for a knee application as depicted in FIG. 1). Because the therapeutic array of the present invention does not provide high intensity, the therapeutic array element area 410 is relatively small, but allows each element to be phased for low frequency steering in virtually any direction. The wide gaps between the four groups of therapeutic subarrays create "grating lobes," but these are believed to have little effect; this is a general design example, so the exact number and distribution of elements is flexible. The imaging elements (yellow) allow imaging at 6 MHz, which allows good focusing in both azimuth and elevation to a depth of up to 10 cm. The imaging plane may be phased for elevation focusing to facilitate + / -15 degrees elevation steering; this may be increased as necessary by either lowering the imaging frequency or reducing the elevation pitch. Imaging in this design, as shown here, may be achieved with a standard moving aperture of a linear array or by combining sub-apertures in a synthetic aperture implementation.

[0060] 5A and B show different examples of therapeutic devices constructed according to the principles of the present disclosure. This first device may be an ultrasound imaging probe with sufficient resolution to clearly image a bone tunnel or the like with a small hole of about 4 mm in diameter. This device is supported on a highly adjustable arm (e.g., as shown in FIG. 5A) that positions the imaging array in a stationary position while the site of the bone tunnel is viewed with ultrasound. The adjustable arm may hold the imaging array in a preformed "clamshell" (e.g., as shown in FIG. 5b). The clamshell holds the array rigidly but allows removal and precise replacement of the imaging array whenever necessary. The arm holding the imaging array may be first positioned to clearly view the bone tunnel, and then precisely positioned so that the small hole of the bone tunnel is centered with the array image, just a few millimeters from the face of the array. The second device emits a therapeutic ultrasound signal and can dynamically steer its beam energy so that the ultrasound signal is distributed in a time-averaged manner in the bone tunnel during the procedure. This second device may be either integrated with the imaging array or used separately. When used separately, the procedure is performed as follows: first, the imaging array is positioned and centered on the bone tunnel; second, the imaging array is removed from its clamshell (e.g., as shown in FIG. 5B), and an imaging array mimic with a central hole to accommodate the therapeutic US device is used to replace the imaging array. In this way, the therapeutic ultrasound device is directly positioned at the bone tunnel without the need for imaging itself. The therapeutic ultrasound procedure is performed with the cylindrical device, and an imaging probe may be used at any time to confirm the position of the therapeutic device to be in the proper position at the bone tunnel.

[0061] Figures 6A-6G show different examples of ultrasound radiation patterns emitted by a therapeutic device constructed according to the principles of the present disclosure. Design variations for therapeutic ultrasound transducer devices are shown. In Figures 6A-6D, a TPX shell covers the therapeutic transducer assembly. In Figure 6A, a single disk transducer with a fixed position is used; this single element may also be wobbled as in Figure 6C. In Figure 6B, an annular array is shown that can generate beams of various widths as shown in Figures 6E-6G. The beam may be wobbled mechanically as in Figure 6C, or wobbled by a lens as in Figure 6D.

[0062] Oscillating the transducer may be achieved by two means: either a mechanical wobbler or a rotating fixed lens. In the case of a mechanical wobbler (see, for example, FIG. 2C), the transducer (either annular array or single element) may be mounted on a shaft (shown in yellow) made of a flexible elastomer that encapsulates the transducer wire and allows a tilt angle of 10-15 degrees from the central axis. A green tubular shaft rotates, along with a single offset ball that tilts the transducer as the tubular shaft rotates.

[0063] In using a lens as shown in (d), a lens may be made of TPX (an exemplary material herein with a velocity of 2200 m / s) that can steer the beam approximately 10-15 degrees off-axis. The lens may be bonded directly to the front face of the transducer; or alternatively, the lens may rotate within the tip while the transducer remains fixed in position. In the former case, the entire transducer and lens assembly rotates or rotates in an oscillating pattern of +180 degrees, -180 degrees.

[0064] Ultimately, the most reliable device would have no moving parts and therefore no problems with coupling with water or gel (in the transducer tube housing). The face of the therapeutic US transducer is flat, but is covered with an ultrasound compatible material to create a dome-shaped tip. The transducer face has only a few elements arranged in a more matrix fashion, rather than arranged as an annular array. By selecting specific elements (rather than all), or alternatively by selecting all but with phase and / or amplitude modification, the beam can be altered enough to achieve the goal of uniform time-averaged ultrasound exposure throughout the tissue. Due to the size and frequency (1.5 MHz) of the elements of the present invention, sub-dicing of the elements may be necessary to prevent undesirable lateral resonances and promote only thickness mode resonances in each element. Sub-dicing is not difficult to do. An example of a face of a solid aperture is shown in FIG. 7.

[0065] An example of a solid-state array based on the principles of the present disclosure is shown in Figure 7. A solid-state array with nine elements is shown (a), which may be phased or weighted as necessary to create beams of varying directionality while maintaining a constant power density for therapeutic US purposes. A simpler, but likely equally effective, version for signal energy transfer and beam steering is shown in (b), which uses only four phased elements.

[0066] Aspects Aspect 1. An imaging probe; an imaging array; and Therapeutic ultrasound devices and Including, The imaging probe is configured to guide the therapeutic ultrasound device to a treatment site on a patient through the use of ultrasound imaging by the imaging array; and The therapeutic ultrasound device is configured to generate ultrasonic energy of controlled intensity for treating a treatment site on the patient. An ultrasound transmitting device for treating a patient. Embodiment 2. The ultrasound transmitting device of embodiment 1, wherein the imaging probe and the therapeutic ultrasound device are configured to be aligned together once the imaging probe identifies a treatment site on the patient. Aspect 3. The ultrasound transmitting device of aspect 1, wherein the therapeutic ultrasound device includes at least one of an ultrasound emitter, a lens, other elements necessary for application of ultrasound energy, and phase adjustment. Embodiment 4. The ultrasonic transmitting device of embodiment 3, wherein the ultrasonic energy is directed by at least one of mechanically moving the ultrasonic emitter, the use of lenses, and the use of multiple elements and electronic phasing. Embodiment 5. The ultrasound transmitting device of embodiment 1, further comprising a transfection device configured to transfect genetic material onto a treatment site in a patient. Embodiment 6. The ultrasound transmitting device of embodiment 5, wherein the transfection is performed by at least one of electroporation, cell squeezing, nanoparticles, magnetofection, microinjection, gene gun, impalefection, hydrostatic pressure, continuous injection, and sonication and chemicals. Embodiment 7. The suction tube of embodiment 1, wherein the suction section is slidably connected to an outer portion of the intestinal tube such that the suction tube can slide longitudinally relative to the intestinal tube. Embodiment 8. The ultrasonic transmitting device of embodiment 1, wherein the ultrasonic energy is configured to enhance drug delivery onto the treatment site by transient cavitation. Aspect 9. An imaging probe; an imaging array; and Therapeutic ultrasound devices and Including, the imaging probe is configured to guide the therapeutic ultrasound device to a treatment site on a patient through the use of ultrasound imaging by the imaging array; the therapeutic ultrasound device is configured to generate ultrasonic energy of controlled intensity for treating a treatment site on the patient; and the imaging probe and the therapeutic ultrasound device are configured to work in conjunction with one another to apply therapeutic ultrasound to an implant site in the patient's tissue or bone. An ultrasound transmitting device for treating a patient. Embodiment 10. The ultrasound transmitting device of embodiment 9, configured to operate to form an ultrasound focal point used to insonify a region of tissue or bone by controlled ultrasound energy generating means. Embodiment 11. The ultrasound transmitting device of embodiment 10, wherein the ultrasound focus includes at least one of a point focus, distributed foci, or a combination. Embodiment 12. The ultrasound transmitting device of embodiment 11, configured to move the ultrasound focus to insonify a region of tissue by distributing the focused energy of the ultrasound beam over a three-dimensional volume in a sweeping manner, multiple simultaneous focusing manner, wide area focusing manner, or a combination of these manners. Embodiment 13. The ultrasound transmitting device of embodiment 9, wherein the therapeutic ultrasound is configured to enhance drug delivery onto the treatment site by transient cavitation. Embodiment 14. The ultrasound transmitting device of embodiment 9, configured to monitor cavitation at a treatment site on a patient. Embodiment 15. The ultrasonic transmitting device of embodiment 14, configured to determine stable cavitation. Embodiment 16. The ultrasound transmitting device of embodiment 14, further configured to adjust treatment based on the determination of stable cavitation. Embodiment 17. The ultrasound transmitting device of embodiment 14, configured to construct a three-dimensional map of cavitation on a treatment site of a patient. Embodiment 18. The ultrasound transmitting device of embodiment 14, configured to construct a one-dimensional map, a two-dimensional map, or a four-dimensional map of cavitation on a treatment site of a patient. Aspect 19. An imaging probe; an imaging array; and Therapeutic ultrasound devices and providing an ultrasonic transmitting device comprising: guiding the therapeutic ultrasound device to a treatment site on a patient by using ultrasound imaging emitted from the imaging array configured to be placed on or adjacent to the imaging probe; and generating ultrasonic energy of controlled intensity to treat a treatment site on said patient; A method for treating a patient comprising: Embodiment 20. The method of embodiment 19, wherein the imaging probe and the therapeutic ultrasound device are configured to be aligned together once the imaging probe identifies a treatment site on the patient.

[0067] conclusion The various methods and techniques described above provide multiple ways to carry out the present invention. Of course, it should be understood that not all of the objectives or advantages described herein can necessarily be realized based on any particular embodiment described herein. Thus, those skilled in the art will recognize that the method of the present invention may be carried out in a manner that achieves or optimizes one advantage or a group of advantages as taught herein, but does not necessarily achieve other objectives or advantages as taught or suggested herein. Various alternatives are mentioned herein. It should be understood that some embodiments specifically include one, another, or more features; other embodiments specifically exclude one, another, or more features; and still other embodiments include one, another, or more advantageous features, thereby relieving a particular feature.

[0068] Further, those skilled in the art will recognize the applicability of various features according to different embodiments. Similarly, the various elements, features, and steps described above, and other known equivalents to each such element, feature, or step, may be utilized in various combinations by those skilled in the art to perform methods based on the principles described herein. In various embodiments, some of the various elements, features, and steps will be specifically included and others will be specifically excluded.

[0069] Although the present application has been disclosed in the context of particular embodiments and examples, it will be appreciated by those skilled in the art that the aspects of the present application extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses and modifications, and their equivalents.

[0070] In some embodiments, the terms "a," "an," and "the," and similar references, when used in the context of describing certain embodiments of the present application (especially in the context of certain claims in the appended claims), may be considered to include both the singular and the plural. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise stated herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "such as") provided herein with respect to certain embodiments is intended only to make the application more clear and does not pose a limitation on the scope of the application as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present application.

[0071] Certain aspects of the present application have been described herein. Variations to those aspects will become apparent to those of skill in the art upon reading the foregoing description. It is anticipated that those of skill in the art will be able to utilize such variations as appropriate, and the present application may be implemented in ways other than as specifically described herein. Accordingly, many aspects of the present application include all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, unless otherwise indicated herein or clearly contradicted by context, any combination of the above-described elements in all possible variations is encompassed by the present application.

[0072] Specific embodiments of the subject matter of the present invention have been described. Other embodiments are within the scope of the appended claims. In some cases, the acts recited in the claims can be performed in a different order and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results.

[0073] All patents, patent applications, patent application publications, and other materials, such as articles, books, specifications, publications, documents, and / or articles, referenced herein are hereby incorporated by reference in their entirety for all purposes, except for any prosecution file history relating thereto, which may conflict or be in conflict with this document, or which may have a limiting effect on the broadest scope of any claims now or later associated with this document. By way of example, if any inconsistency or conflict exists between the explanations, definitions, and / or use of terms associated with any of the incorporated materials and those associated with this document, the explanations, definitions, and / or use of terms in this document will control.

[0074] Finally, it should be understood that the aspects of the present application disclosed herein are illustrative of the principles of the aspects of the present application. Other modifications that may be used may fall within the scope of the present application. Thus, by way of example, but not of limitation, alternative configurations of the aspects of the present application may be utilized in accordance with the teachings herein. Thus, the aspects of the present application are not limited to that precisely as shown and described.

Claims

1. an imaging array including a set of imaging subarrays; a therapeutic transducer array including a set of therapeutic subarrays; Transfection Devices and 1. An ultrasound transmitting device for treating a patient, comprising: the imaging array is configured to guide the therapeutic transducer array to a treatment site on a patient through the use of ultrasound imaging by the imaging array; the therapeutic transducer array is configured to generate ultrasonic energy of controlled intensity for treating a treatment site on the patient; the imaging array and the therapeutic transducer array are configured to work in conjunction with one another to apply therapeutic ultrasound to a treatment site on the patient; and the transfection device is configured to transfect genetic material onto a treatment site in the patient; The transfection is performed by at least one of electroporation, cell squeezing, nanoparticles, magnetofection, microinjection, gene gun, and impalefection; Ultrasonic transmitting device.

2. 10. The ultrasound transmitting device of claim 1 configured to operate to form an ultrasound focal point used to insonify an area of ​​a treatment site on the patient by controlled ultrasound energy generating means.

3. 3. The ultrasound transmitting device of claim 2, wherein the ultrasound focus comprises at least one of a point focus, a distributed focus, or a combination thereof.

4. 4. The ultrasound transmitting device of claim 3, configured to move an ultrasound focus to insonify an area of ​​the patient treatment site by distributing the focused energy of the ultrasound beam over a three-dimensional volume in a sweeping manner, in multiple simultaneous focusing manner, in a wide-area focusing manner along an azimuth or elevation angle relative to the direction of ultrasound propagation, or a combination of these manners.

5. 10. The ultrasound transmitting device of claim 1, wherein the therapeutic ultrasound is configured to enhance drug delivery onto a treatment site in the patient by transient cavitation.

6. 13. The ultrasound transmitting device of claim 1 configured to monitor cavitation at a treatment site on a patient.

7. 7. The ultrasound transmitting device of claim 6, configured to determine stable cavitation at a treatment site on a patient.

8. 7. The ultrasound transmitting device of claim 6, further configured to adjust ultrasound intensity generated by the therapeutic transducer array based on a determination of stable cavitation at a treatment site on a patient.

9. 7. The ultrasound transmitting device of claim 6, configured to construct a three-dimensional map of cavitation on a treatment site on a patient.

10. 7. The ultrasound transmitting device of claim 6, configured to construct a one-dimensional map, a two-dimensional map, or a four-dimensional map of cavitation on a treatment site on a patient.

11. 13. The ultrasound transmitting device of claim 1, wherein the therapeutic transducer array is integrated with the imaging array.

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