CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of, and priority to, U.S. Provisional Application No. 63/272,393, filed October 27, 2021, and U.S. Provisional Application No. 63,350225, filed June 8, 2022, the content of each of which is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates to the field of ultrasound-mediated drug delivery systems, apparatuses, and methods for enhanced transmission of acoustic energy and volumetric production of cavitation in a body cavity, lumen, or orifice.

BACKGROUND

Low-frequency ultrasound (US) has been explored extensively for transdermal drug delivery of nucleic acids, peptides, proteins, as well as to significantly enhance the delivery of small molecules. The capacity for the delivery of a broad range of molecules has further motivated the exploration of this technology for drug delivery beyond the skin in areas such as the oral mucosal and the gastrointestinal (GI) tract. A short application of low frequency US to the GI tract has been shown to significantly enhance delivery of small molecule therapeutics and proteins in an ultra-rapid manner. Transient cavitation of large bubbles, which are produced in large quantities by an ultrasonic horn operating in low'-frequency, enables the disruption or permeabilization of cells and/or tissue membranes resulting in enhanced flux or transport across the biological barriers of these organs.

Ultrasonic energy is usually transmitted into an acoustic load or liquid medium using an ultrasonic radiator- waveguide (or waveguide-radiator) connected to a sandwiched electro-acoustic transducer (e.g., piezoelectric transducers). These devices are commonly known as sonotrodes (e.g., Langevin transducers) or ultrasonic horns and operate in the longitudinal mode at relatively high energy or intensity. The functions of the radiator- waveguide are to increase the transducer’s vibrational amplitude up to a specific magnitude necessary for a given application, to match the energy of a transducer to an acoustic propagating medium, to uniformly distribute radiated acoustic energy throughout the volume of the medium being treated, and, for the application of ultrasound- mediated drug delivery, to facilitate the desired or optimal production of cavitation. Maximum achievable ultrasonic amplitude depends, primarily, on the properties of the material from which an ultrasonic horn is made as well as on the shape of its longitudinal cross-section. Ultrasonic horns are constructed commonly from titanium alloys, such as Ti6A14V, or aluminum alloys, with a length equal to a multiple of half wavelength of the system and tend to be large when operating at low vibrational frequencies.

SUMMARY

Traditional sandwich ultrasonic transducers/horns have the advantages of a simple structure, adjustable performance, and high electro-acoustic efficiency. However, their radial dimension is required to be much smaller than 1/4 wavelength so that the power capacity, longitudinal radiation area, and output power of the transducers are all limited, which can further limit the direction and radiating surface area for generating cavitation to facilitate enhanced drug transport into or across a biological barrier. The vibration of the sandwich longitudinal transducer can be assumed to be one-dimensional longitudinal vibration if the lateral dimension of the sandwich transducer is less than a quarter of the wavelength. In this case, the vibration of the sandwich transducer is longitudinally dominant, and the ultrasound radiation is mainly in the longitudinal direction. These ultrasonic horns have shrinking cross-sectional areas that concentrate energy the radiated energy from a small tip area, resulting in a non-uniform acoustic field and localized cavitation near the tip. In terms of delivery to the GI and many body orifices, it would be advantageous to enhance drug transport using a cylindrical transmitter that emits ultrasonic energy radially as opposed to longitudinally. Systems and methods of the invention address many of the shortcomings of traditional sandwich ultrasonic transducers/horns by providing radial US energy useful in increasing cavitation in a body cavity, lumen, or orifice to aid in drug uptake as discussed below. The radial emission of 40 kHz US has been shown successfully deliver macromolecules locally in the colon of animals by directing cavitation toward the mucosa, representing a significant potential in novel probe design and ultrasonic energy transmission to facilitate use throughout the GI tract and in other parts of the body. In some embodiments, a radiator waveguide that emits US transversally as well as longitudinally to maximize the production of energy and cavitation exposure is desirable. The specific ultrasonic energy or power radiated by a waveguide into a liquid medium is proportional to the square of the amplitude of vibrations. In addition, the total acoustic power radiated into an acoustic load or liquid medium is proportional to the area of the radiating surface(s) of the radiator-waveguide. Therefore, the increase in the total radiated acoustic power at constant load and frequency can be achieved by increasing the amplitude of output vibrations of the radiator- waveguide or the area of the radiator-waveguide's radiating surface(s). However, the amplitude of output vibrations should not exceed the magnitude that corresponds to the fatigue strength of the radiator-waveguide material resulting in breakdown, shortening device durability, and US transmission inefficiency. Thus, the need exists for a low frequency ultrasound-mediated drug delivery device, producing large cavitation bubbles with minimal energy input, that incorporates a compact/small radiator- waveguide capable of operating in multiple of halfwavelength vibration mode with a large radiating surface(s), high gain factor, and efficient power transmission for optimal production of cavitation to facilitate drug transport into and/or through a biological membrane barrier of a body cavity, lumen, or orifice. Systems, methods, and devices of the invention address that need by providing a low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen, or orifice facilitated by cavitation generated by radially and/or longitudinally transmitted US radiation. In various embodiments, the system comprises at least one compact radiator- waveguide capable of radial and/or longitudinal emission or transmission of US energy into an acoustic load. In various embodiments, the drug delivery system comprises one or more transducers, one or more waveguide elements, one or more radiator elements, or combinations thereof. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial and/or longitudinal US energy from the radiator into an acoustic load. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial and longitudinal US energy from the radiator into an acoustic load. In various embodiments, the transducer is one or more PZT or magnetostrictive transducers. In various embodiments the waveguide comprises one or more combinations of cylindrical sections, variable cross-sections, or the like. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner diameter, and an outer diameter. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner diameter, an outer diameter, and a longitudinal radiation surface at the distal end. In various embodiments, one or more elements of the system is insertable into a body cavity, lumen, or orifice for generating cavitation in an acoustic liquid load of the cavity or lumen, preferable containing at least one chosen molecule, agent, or drug formulation, to facilitate drug delivery onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen (e.g., oral, ear, GI, colon, rectum, vagina, etc.), or orifice.

An object of the present disclosure is an ultrasound-mediated drug delivery apparatus for enhancing drug transport into or through a biological barrier in a body cavity, lumen, or orifice facilitated by cavitation generated by radially transmitted US radiation. In various embodiments, the apparatus comprises at least one compact radiator- waveguide capable of radial and/or longitudinal emission or transmission of US energy into an acoustic load. In various embodiments, the apparatus comprises at least one compact radiator-waveguide capable of radial emission and longitudinal transmission of US energy into an acoustic load. In various embodiments, the drug delivery apparatus comprises one or more transducers, one or more waveguide elements, one or more radiator elements, or combinations thereof. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial US energy from the radiator into an acoustic load. In various embodiments, the transducer is one or more PZT or magnetostrictive transducers. In various embodiments, the waveguide comprises one or more combinations of cylindrical sections, variable cross-sections, or the like. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner diameter and an outer diameter. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner diameter, an outer diameter, and a longitudinal radiation surface at the distal end. In various embodiments, the radiator comprises one or more semi-rectangular hollowed perforations distributed circumferentially and longitudinally from a proximal portion to a distal portion of the radiator. In various embodiments, one or more perforations enables flexural motion of the radiator material between each perforation to generate radial US energy from the surface of the radiator into an acoustic load. In various embodiments, the transducer excites one or more radial vibrational modes of the radiator- waveguide. In various embodiments, the transducer excites one or more radial vibrational modes of radiator material between each perforation to generate radial US energy from its surface into an acoustic load. In various embodiments, one or more elements of the apparatus is insertable into a body cavity, lumen, or orifice for generating cavitation in an acoustic liquid load, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, of the cavity or lumen to facilitate their transport onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen, or orifice.

An object of the present disclosure is an ultrasound-mediated drug delivery method for enhancing drug transport into or through biological barrier with a body cavity, lumen, or orifice facilitated by cavitation generated by radially transmitted US radiation. In various embodiments, the method comprises the use of radiator- waveguide capable of radial or longitudinal emission or transmission of US energy into an acoustic load. In various embodiments, the drug delivery method comprises using one or more transducers, one or more waveguide elements, one or more radiator elements, or combinations thereof to produce a specific amount, quantity, or volumetric measure of cavitation. In various embodiments, the method uses the transducer, waveguide element, and radiator combination and operate to produce radial US energy from the radiator into an acoustic load. In various embodiments, the method uses one or more PZT or magnetostrictive transducers. In various embodiments the method uses a waveguide comprising one or more combinations of cylindrical sections, variable cross-sections, or the like. In various embodiments, the method uses a radiator comprising a tubular element, the tubular radiator further comprising a length, an inner, and outer diameter. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner, outer diameter, and longitudinal radiation surface at the distal end. In various embodiments, the method uses a radiator comprising one or more semi -rectangular hollowed perforations distributed circumferentially and longitudinally from a proximal portion to a distal portion of the radiator. In various embodiments, one or more perforations enables flexural motion of the radiator material between each perforation to generate radial US energy from the surface of the radiator into an acoustic load. In various embodiments, the method uses said transducer to excite one or more radial vibrational modes of the radiator- waveguide. In various embodiments, the method uses the transducer to excite one or more radial vibrational modes of radiator material between each perforation to generate radial US energy from its surface into an acoustic load. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load at a specific operating mode, frequency, or the like. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load with more than one specific operating mode, frequency, combination of two or more operating modes or frequencies. In various embodiments, the method uses one or more elements of the system or apparatus is insertable into a body cavity, lumen (e.g., mouth, rectum, GI tract, etc.), or orifice for generating cavitation in an acoustic load, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, of the cavity or lumen to facilitate their transport into or across a biological barrier, cell, membrane, or tissue of the mammalian body cavity, lumen, or orifice.

An object of the present disclosure is a method for constructing compact low frequency radiator- waveguide capable of radial emission or transmission of US energy into an acoustic load via vibrational mode conversion. In various embodiments, the method comprises using one or more transducers to excite one or more longitudinal modes of a waveguide, the waveguide coupled to a tubular radiator, subsequently excite one or more radial modes of the coupled tubular radiator to produce a specific amount, quantity, or volumetric measure of cavitation. In various embodiments, the method uses the transducer, waveguide element, and radiator combination and operate to produce radial and/or longitudinal US energy from the radiator into an acoustic load. In various embodiments, the method uses one or more PZT or magnetostrictive transducers. In various embodiments the method uses a waveguide comprising one or more combinations of cylindrical sections, variable cross-sections, or the like. In various embodiments, the method uses a radiator comprising a tubular element, the tubular radiator further comprising a length, an inner, and outer diameter. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner, outer diameter, and longitudinal radiation surface at the distal end. In various embodiments, the method uses a radiator comprising one or more semi- rectangular hollowed perforations distributed circumferentially and longitudinally from a proximal portion to a distal portion of the radiator. In various embodiments, one or more perforations enables flexural motion of the radiator material between each perforation to generate radial US energy from the surface of the radiator into an acoustic load. In various embodiments, the method uses the transducer to excite one or more radial vibrational modes of radiator material between each perforation to generate radial US energy from its surface into an acoustic load. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load at a specific operating mode, frequency, or the like. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load with more than one specific operating mode, frequency, combination of two or more operating modes or frequencies. In various embodiments, the compact low frequency radiator- waveguide is constructed to operate at one or more low resonant frequencies by varying the length and/or diameter of the waveguide, the length of the tubular radiator, the ratio of the inner to the outer diameters of the tubular radiator, the dimension of at least one perforation of the tubular radiator, combinations thereof or the like.

An object of the present disclosure is a low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a cavity, lumen, or orifice or lumen facilitated by cavitation generated by radially and/or longitudinally transmitted US radiation. In various embodiments, the system comprises at least one compact radiator- waveguide capable of radial and/or longitudinal emission or transmission of US energy into an acoustic load. In various embodiments, the endoscopic drug delivery system comprises a control body, ultrasound and fluid delivery controller, flexible insertion scope-tube, and a distal end of the scope-tube further comprising one or more low frequency transducers, one or more waveguide elements, one or more radiator elements, or combinations thereof. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial and/or longitudinal US energy from the radiator into an acoustic load in the proximity of one or more segments of an endoscope, preferably at the distal segment. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial and longitudinal US energy from the radiator into said acoustic load within a cavity, lumen, or orifice. In various embodiments, the transducer is one or more PZT or magnetostrictive transducers. In various embodiments the waveguide comprises one or more combinations of cylindrical sections, variable cross-sections, or the like. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner, and outer diameter. In various embodiments, the radiator comprises a tubular element, the tubular radiator further comprising a length, an inner, outer diameter, and longitudinal radiation surface at the distal end. In various embodiments, one or more elements of the system is insertable endoscopically into a cavity, lumen, or orifice for generating cavitation in an acoustic liquid load located in the proximity of one or more segments of a flexible tube of an endoscopic system or apparatus, preferably at the distal end for diagnostics and therapeutic applications. In various embodiments, the low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods enable targeted and/or precise delivery of at least one chosen molecule, agent, or drug formulation onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian cavity, lumen, or orifice (e.g., oral, ear, GI, colon, rectum, vagina, etc.) to treat, mitigate, or cure one or more diseases or conditions.

In summary, an object of the present disclosure is to provide a low frequency ultrasound- mediated drug delivery system using a compact radiator- waveguide, comprising one or more combinations of a transducer, solid cylindrical waveguide, and a tubular radiator capable of operating in multiple integer of half-wavelength longitudinal vibration mode while emitting radial and/or longitudinal US energy with a large radiating surface(s) and high gain factor for optimal production of cavitation in a liquid medium, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, to facilitate their transport into and/or through a biological barrier, cell, membrane, or tissue of a mammal body cavity, lumen, or orifice. The advantages of the radiator-waveguide, include but not limited to, compact form factor, more efficient radial and/or longitudinal US energy transfer into a liquid load, increased radiation surface and the uniformity of the distribution of acoustic energy throughout the volume of liquid load, increase intensity of acoustic radiation at lower device power consumption, and enabling standalone operation or targeted endoscopic drug delivery within mammalian body canal, tubes, orifice, glands, vessels, or cavity or lumen.

An object of the present disclosure may comprise a low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen, or orifice facilitated by cavitation generated by transverse and or longitudinally transmitted US radiation. In various embodiments, the system may comprise at least one compact radiator- waveguide capable of producing transverse, flexural, radial, and or longitudinal emission or transmission of US energy into and throughout an acoustic load. In various embodiments, the drug delivery system may comprise an ultrasonic horn containing one or more piezoelectric transducers, a half-wave extender, a waveguide element, or combinations thereof. In various embodiments, the ultrasonic horn or radiator, half-wave extender, and waveguide element, can be combined mechanically and actuated to produce at least one transverse, flexural, radial, or longitudinal direction US energy emission or transmission from at least one or all radiating surfaces into an acoustic load. In various embodiments, the transducer can comprise one or more non-limiting piezoelectric, electrostrictive, or magnetostrictive transducers. In various embodiments the US radiator- waveguide may comprise one or more combinations of a solid or hollow cylindrical rod portion, a solid or hollow variable cross-section portion, a solid or hollow half-wave extender, a solid or hollow thin rectangular plate waveguide, or the like. In various embodiments, the radiator- waveguide may comprise said thin rectangular plate waveguide having a defined length, height, and width and actuated to produce one or more transverse or flexural vibrational amplitudes at one or more nodes or antinodes along its length to radiate US energy in, into, within, or throughout an acoustic load. In various embodiments, the radiator- waveguide may comprise said thin rectangular plate having a defined length, thickness, and width and actuated to produce one or more transverse or flexural vibrational amplitudes at one or more nodes or antinodes along its length and emit or transmit longitudinal US energy from a distal surface. In various embodiments, one or more elements of the system may be insertable into a body cavity, lumen, or orifice and activated to generate cavitation in, into, within, or throughout an acoustic liquid load of the cavity or lumen, preferable containing at least one chosen molecule, agent, or drug formulation, to facilitate drug delivery onto, in, into, within, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen (e.g., oral, ear, GI, colon, rectum, vagina, etc.), or orifice.

An object of the present disclosure may comprise an ultrasound-mediated drug delivery apparatus for enhancing drug transport into or through a biological barrier within a body cavity, lumen, or orifice facilitated by cavitation generated by at least one transverse, flexural, radial, torsional, bending, tension, or longitudinal vibrational mode produced by a radiator- waveguide. In various embodiments, the apparatus may comprise at least one compact radiator- waveguide capable of producing US energy emission or transmission into, within, or throughout an acoustic load and generate cavitation within and or throughout said acoustic load. In various embodiments, the apparatus may comprise at least one compact radiator-waveguide capable of producing cavitation via at least one transverse, flexural, radial, torsional, bending, tension, or longitudinal vibrational mode to mediate drug delivery in, within, or throughout said acoustic load. In various embodiments, the drug delivery apparatus may comprise an ultrasound horn further comprising one or more transducers, said solid or hollow cylindrical radiator, said solid or hollow variable cross-section coupler, said solid or hollow half-wave extender, said thin rectangular plate waveguide, or combinations thereof. In various embodiments, the drug delivery apparatus may comprise an ultrasound horn further comprising one or more transducers, said solid or hollow cylindrical radiator, said solid or hollow variable cross-section coupler, said solid or hollow halfwave extender, two or more said thin rectangular plate waveguide, or combinations thereof. In various embodiments, said radiator-wave guide contains at least two thin rectangular plate waveguides configured relative to each other. In a preferred embodiment, the two said waveguides or straps may be configured to operate with their long axes and length protruding in orthogonal planes. In various embodiments, the transducer, horn, radiator, coupler, half-wave extender, and waveguide are combined and actuated to produce US energy emission or transmission into, within, or throughout an acoustic load. In various embodiments, the ultrasound horn or radiator comprises one or more non-limiting piezoelectric, electrostrictive, or magnetostrictive transducers. In various embodiments, the radiator- waveguide may comprise one or more combinations of radiator, horn, coupler, half-wave extender, thin rectangular plate waveguide, or the like. In various embodiments, the waveguide may comprise at least one rectangular plate having a defined length, thickness, and width to capable of being actuated to produce at least one transverse, flexural, radial, torsional, bending, or tension vibrational mode or deflection. In various embodiments, the waveguide may comprise two or more rectangular plate or strap having a defined length, height, and width to capable of being actuated and operating in two separate orthogonal planes to produce at least one transverse, flexural, radial, torsional, bending, or tension vibrational mode or deflection. In various embodiments, the transducer and horn excites one or more radial vibrational modes of the radiatorwaveguide. In various embodiments, the horn excites one or more transverse, radial, longitudinal, bending, or torsional vibrational modes or motions to generate radial US energy from at least one surface of the radiator- waveguide to generate cavitation, in, within or into an acoustic load. In various embodiments, the horn excites one or more transverse, radial, longitudinal, bending, or torsional vibrational modes or motions to generate radial US energy from one or more surfaces or a radiator- waveguide having two waveguides or straps configured to operate with their long axes protruding in two separate orthogonal planes to generate cavitation, in, into, within or throughout an acoustic load. In various embodiments, one or more elements of the apparatus can be insertable into a body cavity, lumen, or orifice for generating cavitation in, within, or throughout an acoustic liquid load, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, of the cavity or lumen to facilitate their transport onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen, or orifice.

An object of the present disclosure is an ultrasound-mediated drug delivery method for enhancing drug transport into or through biological barrier with a body cavity, lumen, or orifice facilitated by cavitation generated through at least one transverse, flexural, radial, longitudinal, bending, tension, or torsional mode of vibration of a radiator-waveguide. In various embodiments, methods may comprise the use of a radiator-waveguide capable of producing transverse, flexural radial, longitudinal, bending, tension, or torsional vibration or motion to emit or transmit US energy into, within or throughout an acoustic load. In various embodiments, the drug delivery method may comprise using an ultrasonic horn containing the one or more transducers, the one or more radiators, said variable cross-section coupler, said one or more half-wave extenders, said one or more thin rectangular plate waveguides, or combinations thereof to produce a variable or specific amount, quantity, or volumetric measure of cavitation in, into, within or throughout an acoustic load. In various embodiments, methods may use a combination of said horn, transducer, radiator, coupler, half-wave extender, and waveguide to produce US energy from the radiatorwaveguide for emission or transmission in, into, within, or throughout an acoustic load. In various embodiments, methods may use a combination of said horn, transducer, radiator, coupler, halfwave extender, and two or more waveguide or straps configured to operate with their long axes in two separate orthogonal planes to produce US energy from the radiator-waveguide for emission or transmission in, into, within, or throughout an acoustic load. In various embodiments, methods may use an ultrasonic horn containing one or more non-limiting piezoelectric, electrostrictive, or magnetostrictive transducers and mechanically or electrically coupled to form a radiatorwaveguide. In various embodiments, the radiator-waveguide may be actuated by said transducer and horn to produce or excite at least one transverse, flexural, radial, longitudinal, torsional, or bending deflection, motion, vibration, or vibrational mode along, on, or from a dimension, surface area, or volume of said radiator-waveguide. In various embodiments, methods may use said apparatus to generate cavitation in, into, within, or throughout an acoustic load at a variable or specific operating frequency, power, intensity, vibrational mode, the like, or combinations thereof. In various embodiments, methods may use said apparatus to generate cavitation in, into, within, or through an acoustic load with more than one variable or specific operating frequency, power, intensity, two or more vibrational modes, and more than one frequency. In various embodiments, methods may use said apparatus to generate cavitation in, into, within, or throughout an acoustic load by rotating one or more elements, preferably the half-wave extender and at least one thin rectangular plate waveguide to produce radial or circumferential emission or transmission of ultrasound energy. In various embodiments, methods may use said apparatus to generate cavitation in, into, within, or through an acoustic load with more than one variable or specific operating frequency, power, intensity, two or more vibrational modes, and more than one frequency. In various embodiments, methods may use one or more said elements of the system or apparatus that is insertable into a body cavity, lumen (e.g., mouth, rectum, GI tract, etc.), or orifice for generating cavitation in, into, within or throughout an acoustic load, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, of the cavity or lumen to facilitate their transport into or across a biological barrier, cell, membrane, or tissue of the mammalian body cavity, lumen, or orifice.

An object of the present disclosure is a method for constructing compact low frequency radiator- waveguide capable of emitting or transmitting US energy in, into, within or throughout an acoustic load via vibrational mode conversion. In various embodiments, methods may comprise using an ultrasound horn, further comprising one or more transducers operating in a longitudinal vibrational mode to excite one or more transverse or flexural vibrational modes of a thin rectangular plate waveguide or strap, the waveguide or strap is mechanically coupled to said horn or radiator. In various embodiments, said waveguide or strap is coupled to said radiator via a halfwave extender. In various embodiments, said transducer and radiator horn may excite one or more transverse or flexural vibrational modes within said waveguide or strap to produce a variable or specific amount, quantity, or volumetric measure of cavitation. In various embodiments, methods can use the transducers, radiator, horn, coupler, extender, at least one waveguide, a combination of two waveguides or straps configured to operate with their long axes projecting in two separate orthogonal planes, or combinations thereof, for actuation of the radiator-waveguide strap to produce, emit, or transmit US energy from the radiator- waveguide in, into, within, or throughout an acoustic load. In various embodiments, methods can use the horn or radiator comprising the one or more ultrasound transducers or the present disclosure. In various embodiments methods may use a radiator- waveguide that comprises one or more combinations of a solid or hollow cylindrical radiator portion, a variable cross-section coupling portion, a half-wave extender portion, at least one thin rectangular plate waveguide, a combination of two or thin rectangular plate waveguides, or the like. In various embodiments, methods may use an ultrasonic horn comprising at least one piezoelectric transducer mechanically coupled to a half-wave extender via a variable cross-section coupler portion, said extender mechanically attached or coupled to a proximal portion said waveguide, said waveguide having a variable circular cross section proximal portion that transitions toward a distal end into a thin rectangular plate having a length, thickness, and width. In various embodiments, said ultrasonic horn comprises two waveguides having a variable circular cross section proximal portion that transitions toward a distal end into a thin rectangular plate having a length, thickness, and width. In various embodiments, the thin rectangular plate portion of said waveguide are mechanically coupled off-axis with respect to the main longitudinal axis of said half-wave extender portion. In an alternative embodiment, two thin rectangular plate portions are mechanically coupled off-axis with respect to the main longitudinal axis of said half-wave extender portion, said plate portions or straps configured to operate with their long axes projecting in two separate orthogonal planes. In various embodiments, the actuation of said transducer and horn produces longitudinal vibration within said half-wave extender portion and off-axis coupling to variable circular cross-section portion of said waveguide produces transverse or flexural vibrations or deflection at one or more antinodes of said one or more thin rectangular plate portions of said waveguide. In various embodiments, methods may allow for the generation, production, emission, or transmission of US energy from at least one, node, antinode, amplitude deflection, distal tip, or surface of radiator-waveguide in, into, or within an acoustic load. In various embodiments, methods can use said apparatus to generate cavitation in, into, within, or throughout an acoustic load at a variable or specific operating power, intensity, frequency, mode, the like, or combinations thereof. In various embodiments, methods may use said apparatus to generate cavitation in, into, within, or throughout an acoustic load with more than one variable or specific operating mode, frequency, combination of two or more operating modes or frequencies. In various embodiments, the compact low frequency ultrasound radiatorwaveguide is constructed to operate at one or more low resonant frequencies by varying at least one dimension of the radiator- waveguide.

An object of the present disclosure is a low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a cavity, lumen, or orifice or lumen facilitated by cavitation generated by a radiator- waveguide using at least one transverse, flexural, radial, longitudinal, bending, tensional, or torsional vibrational mode. In various embodiments, the system may comprise at least one compact radiator-waveguide capable of producing, emitting, or transmitting US energy in, into, within, or throughout an acoustic load using at least one transverse, flexural, radial, longitudinal, bending, tensional, or torsional vibrational mode. In various embodiments, the endoscopic drug delivery system may comprise a control body, ultrasound and fluid delivery controller, flexible insertion scope-tube, and a distal end of the scope-tube further comprising one or more low frequency ultrasound radiator-waveguides of the present disclosure, or combinations thereof. In various embodiments, the transducer, horn radiator, the one or more half-wave extenders, variable circular cross-section portion and thin rectangular plate portion of said waveguide are combined and actuated to produce US energy from the radiator- waveguide in, into, within, or throughout an acoustic load in the proximity of one or more segments of an endoscope, preferably at the distal segment. In various embodiments, the transducer, horn radiator, extender, and waveguide are combined and actuated to produce US energy from the radiatorwaveguide in, into, within, or throughout said acoustic load within a cavity, lumen, or orifice. In various embodiments, the transducer and horn can be the one or more ultrasound transducers and horns of the present disclosure. In various embodiments the radiator- waveguide may comprise one or more combinations of said horn, radiator, and waveguide, strap, or the like. In various embodiments the radiator-waveguide may comprise one or more combinations of said horn, radiator, and waveguide, strap, said waveguide further comprising two thin rectangular plates or straps configured to operate with their long axes projecting in two separate orthogonal planes. In various embodiments, one or more elements of the system may be insertable endoscopically into a cavity, lumen, or orifice for generating cavitation in, into, within, or throughout an acoustic liquid load located in the proximity of one or more segments of a flexible tube of an endoscopic system or apparatus, preferably at the distal end for diagnostics and therapeutic applications. In various embodiments, the low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods enable targeted and or precise delivery of at least one chosen molecule, agent, or drug formulation onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian cavity, lumen, or orifice (e.g., oral, ear, GI, colon, rectum, vagina, etc.) to treat, mitigate, or cure one or more diseases or conditions.

In summary, an object of the present disclosure is to provide a low frequency ultrasound- mediated drug delivery system using a compact radiator- waveguide, comprising one or more combinations of a transducer, horn, radiator, half-wave extender, and waveguide or strap, having a variable circular cross section portion and a thin rectangular plate portion capable of producing at least one transverse, flexural, radial, longitudinal, bending, tensional, or torsional vibration mode to produce, emit, or transmit omni-directional US energy with a large radiating surface and high gain factor for optimal production of cavitation in an acoustic load or liquid medium, said load preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, to facilitate their transport into and or through a biological barrier, cell, membrane, or tissue of a mammal body cavity, lumen, or orifice. The advantages of the radiatorwaveguide, include but not limited to, compact form factor, more efficient US energy transfer into a liquid load, increased radiation surface, omni-directional distribution of acoustic energy throughout the volume of a liquid load, increased intensity of acoustic radiation at lower device power consumption, and enabling standalone operation or targeted endoscopic drug delivery within a mammalian body canal, tubes, orifice, glands, vessels, or cavity or lumen.

BRIEF DESCRIPTION OF DRAWINGS

The above and other objects, features and advantages of the present disclosure will be more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. l is a functional block diagram of a low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen, or orifice facilitated by cavitation generated by radially transmitted US radiation, in accordance with certain aspects of the present disclosure;

FIG. IB is a functional block diagram of a low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen, or orifice facilitated by cavitation generated by radially AND longitudinally transmitted US radiation, in accordance with certain aspects of the present disclosure;

FIG. 2 is a computer aided design drawing of a tubular radiator, in accordance with certain aspects of the present disclosure;

FIG. 3 is computer aided design drawing of a tubular radiator of one embodiment, in accordance with certain aspects of the present disclosure;

FIG. 4 is computer aided design drawing of a tubular radiator of another embodiment, in accordance with certain aspects of the present disclosure;

FIG. 5 is a map of longitudinal normalized vibrations of a tubular radiator in accordance with certain aspects of the present disclosure; FIG. 6 is computer aided design drawing of a tubular radiator having perforations for radial mode conversion, in accordance with certain aspects of the present disclosure;

FIG. 7 is a map of radial normalized vibrations of a tubular radiator containing one or more longitudinal slits in accordance with certain aspects of the present disclosure;

FIG. 8 is an experimental setup for evaluating a Finite Element model and apparatus in accordance with certain aspects of the present disclosure;

FIG. 9 is an ultrasound-mediated endoscopic drug delivery system in accordance with certain aspects of the present disclosure.

FIG. 10 is a computer-aided design rendering of a standalone low frequency ultrasound- mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen, or orifice facilitated by cavitation generated by radially transmitted US radiation, in accordance with certain aspects of the present disclosure.

FIG. 11A is a computer aided design drawing of a strap waveguide, in accordance with certain aspects of the present disclosure.

FIG. 1 IB is a computer aided design drawing of a waveguide having two straps, in accordance with certain aspects of the present disclosure.

FIG. 12 is computer aided design drawing of a cross-section view of a waveguide according to one embodiment, in accordance with certain aspects of the present disclosure.

FIG. 13 A is an engineering sketch of a waveguide, in accordance with certain aspects of the present disclosure.

FIG. 13B is an engineering sketch of a waveguide comprising two straps, in accordance with certain aspects of the present disclosure.

FIG. 14 is an FEA simulation output of a computer model of the drug device of the present disclosure, in accordance with certain aspects of the present disclosure.

FIG. 15 is another FEA simulation output of a computer model of the drug device of the present disclosure, in accordance with certain aspects of the present disclosure.

FIG. 16 is a pictorial of an in vitro experimental setup, in accordance with certain aspects of the present disclosure. FIGS. 17A, 17B, 17C, 17D, and 17E are graphs of in vitro experimental results obtained using the drug delivery device of the present disclosure, in accordance with certain aspects of the present disclosure.

FIG. 18 is an ultrasound-mediated endoscopic drug delivery system in accordance with certain aspects of the present disclosure.

DETAILED DESCRIPTION

It should be appreciated that all combinations of the concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. It also should be appreciated that terminology explicitly employed herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the concepts disclosed herein.

It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes. The present disclosure should in no way be limited to the exemplary implementation and techniques illustrated in the drawings and described below.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed by the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed by the invention, subject to any specifically excluded limit in a stated range. Where a stated range includes one or both endpoint limits, ranges excluding either or both of those included endpoints are also included in the scope of the invention.

As used herein, “exemplary” means serving as an example or illustration and does not necessarily denote ideal or best.

As used herein, the term “includes” means includes but is not limited to, the term “including” means including but not limited to. The term “based on” means based at least in part on. As used herein, "US device" refers to any device or machine comprising a transducer capable of emitting US energy (e.g., waves). US devices are well-known in the art and include the US devices described in International Publication No. WO 2016/164821.

As used herein, "in combination with," when referring to administration of a pharmaceutical agent and/or an US enhancing agent and delivery of US to a subject, a region of a subject, a tissue of a subject or a portion of a subject's tissue, includes delivery of US followed by administration of the pharmaceutical agent and/or US enhancing agent, concurrent delivery of US and administration of the pharmaceutical agent and/or US enhancing agent, and administration of the pharmaceutical agent and/or US enhancing agent followed by delivery of US. Preferably, administration of the pharmaceutical agent and/or US enhancing agent follows delivery of US or delivery of US and administration of the pharmaceutical agent and/or US enhancing agent are concurrent (though not necessarily of identical duration). Concurrent delivery of US and administration of the pharmaceutical agent and/or US enhancing agent merely implies that there is overlap between the time period during which US is delivered and the pharmaceutical agent and/or US enhancing agent is administered, and includes delivery of US that precedes, but overlaps with, administration of the pharmaceutical agent and/or US enhancing agent, administration of the pharmaceutical agent and/or US enhancing agent that precedes, but overlaps with, delivery of US, and delivery of US and administration of the pharmaceutical agent and/or US enhancing agent that begin and/or end at the same or substantially the same time, or any combination of the foregoing.

As used herein, the term “acoustic cavitation” or “cavitation” is the generation of gaseous voids (cavities, bubbles) in a liquid by an acoustic or ultrasonic wave. Acoustic cavitation refers specifically to bubbles generated within a medium that is exposed to acoustic radiation, of sufficient intensity. Such bubbles nucleate at impurities, including microscopic and sub- microscopic gas inclusions.

As used herein, the term “low frequency ultrasound” is sound generate in the range of 20- 200 kHz.

Exemplary embodiments of the present disclosure provide a system, apparatus, and methods for enhancing US radial and/or longitudinal emission into an acoustic liquid load, containing at least one treatment or therapeutic agent, using a radiator-waveguide, comprising combination of a transducer, solid cylindrical waveguide, and a tubular radiator capable of operating in at least one multiple integer of half-wavelength longitudinal vibration mode while emitting radial (2- dimensional) and longitudinal US energy via mode conversion with large radiating surfaces and high gain factor for optimal production of cavitation in a liquid medium to facilitate drug transport into and/or through a biological barrier, cell, membrane, or tissue of a mammal body cavity, lumen, orifice. The advantages of the radiator- waveguide, include but not limited to, compact form factor, more efficient radial US energy transfer into a liquid load, increased radiation surface and the uniformity of the distribution of acoustic energy throughout the volume of liquid load, increase intensity of acoustic radiation at lower device power consumption, and enabling standalone operation or targeted endoscopic drug delivery within mammalian body canal, tubes, orifice, glands, vessels, or cavity or lumen.

In general, various embodiments of the present disclosure comprise acoustic tooling methods that takes longitudinal motion from the transducer and converts it to useful motion in the radial direction via the radiator- waveguide. The designs are effective by maximizing longitudinal to radial direction motion gain and radial direction surface area. In one acoustic tooling a bell horn is designed that maximizes radial emission through the longitudinal half-wave mode shape (at a frequency). The design maximizes the above effect by causing the longitudinal mode nodal area to radially move with maximum gain and surface area. The key dimensions to maximize the effect are Outer Diameter(OD)/Inner Diameter ratio, and taper angle. In another acoustic tooling method, a bell horn with slits is designed to maximize radial emission by causing slit elements to flex with resulting amplitude in the radial direction.

Turning now descriptively to the drawings, in which the same reference characters denote the same elements throughout the several views, FIG. 1 depicts a functional block diagram 100 of a standalone low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen or orifice facilitated by cavitation generated by radially transmitted US radiation. In various embodiments, the system comprises at least one compact radiator- waveguide 102 capable of radial emission or transmission of US energy into an acoustic load 104. In various embodiments, the drug delivery system comprises one or more transducers 106, one or more waveguide elements 108, one or more radiator elements 110. In various embodiments, transducer 106, waveguide 108, and radiator 110 are combined and actuated to produce radial US energy 112 from the radiator 110 into an acoustic load 104. In various embodiments, transducer 106 is one or more PZT or magnetostrictive transducers. In various embodiments waveguide 108 comprises one or more combinations of cylindrical section 114, variable cross-section 116, or the like. In various embodiments, radiator 110 comprises a tubular element, the tubular radiator further comprising a length 118, an inner diameter 120, and outer diameter 122. In various embodiments, one or more elements of the system is insertable into a body cavity or lumen for generating cavitation in an acoustic liquid load of the cavity or lumen, preferable containing at least one chosen molecule, agent, or drug formulation, to facilitate drug delivery onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen (e.g., oral, ear, GI, colon, rectum, vagina, etc.), or orifice.

Referring now to FIG. IB depicts a functional block diagram 100b of a standalone low frequency ultrasound-mediated drug delivery system for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen or orifice facilitated by cavitation generated by radially and longitudinally transmitted US radiation. In various embodiments, the system comprises at least one compact radiator- waveguide 102b capable of radial and longitudinal emission or transmission of US energy into an acoustic load 104b. In various embodiments, the drug delivery system comprises one or more transducers 106b, one or more waveguide elements 108b, one or more radiator elements 110b further comprising a distal cap 112b. In various embodiments, transducer 106b, waveguide 108b, radiator 110b, and distal cap 112b are combined and actuated to produce radial US energy 114b from the radiator 110b and longitudinal US energy 116b, from the surface of distal cap 112b, into an acoustic load 104b. In various embodiments, transducer 106b is one or more PZT or magnetostrictive transducers. In various embodiments waveguide 108b comprises one or more combinations of cylindrical section 118b, variable cross-section 120b, or the like. In various embodiments, radiator 110b comprises a tubular element, the tubular radiator further comprising a length 122b and a distal cap 112b with an outer diameter 124b. In various embodiments, one or more elements of the system is insertable into a body cavity or lumen for generating cavitation in an acoustic liquid load of the cavity or lumen, preferable containing at least one chosen molecule, agent, or drug formulation, to facilitate drug delivery onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity or lumen (e.g., oral, ear, GI, colon, rectum, vagina, etc.).

Referring now to FIG. 2, a computer aid design drawing 200 of a tubular radiator is shown, according to various embodiments. In one embodiment, shown in FIG. 2 A, tubular radiator 110 of FIG. 1 comprises a cylindrical section 202, a cross-section variable section 204, a second cylindrical section 206, preferably shorter in length than cylindrical section 202, and a third cylindrical section 208. In various embodiments, cylindrical section 202 comprises a distal opening 210 with a diameter defined by one or more variable inner diameters 120 and outer diameters 122 of FIG. 1. In various embodiments, shown in FIG. 2B, tubular radiator 110 of FIG. 1 comprises an internal hollow section 212, an internal conical section 214 that terminates at a hemi- spherical section 216. In various embodiments, one or more dimensions of said sections are varied to fabricate a tubular radiator capable of operating at one or more resonant modes or resonant frequencies to emit ultrasound emission, energy, or intensity radially from the longitudinal actuation of the radiator.

Referring now to FIG. 3, a computer-aided-design CAD) drawing 300 of a tubular radiator is shown, according to one preferred embodiment. In one embodiment, cylindrical section 202 of FIG. 2 comprises a distal opening diameter of 0.394 inches and a length 304 0.781 inches. In one embodiment, cross-section variable section 204 of FIG. 2 comprises a length 306 of 0.889 and an internal conical angle 308 of 10 degree with reference to longitudinal axis of its outer wall. In one embodiment, the hemi -spherical section 214 of FIG. 2 comprises a radius 310 of 0.03 inches. In one embodiment, cylindrical section 206 of FIG. 2 comprises an outer diameter 312 of 0.250 inches. In one embodiment, cylindrical section 208 of FIG. 2 comprises an outer diameter 314 of 0.104 inches.

Referring now to FIG. 4, a computer-aided-design CAD) drawing 400 of a tubular radiator is shown, according to one preferred embodiment. In one embodiment, cross-sectional view, tubular radiator of FIG. 3 comprises a total length 402 of 2.17 inches. In one embodiment, the combined length 404 of cylindrical section 202, cross section variable section 204, cylindrical section 206 of FIG. 2 is 1.92 inches. In one embodiment, the length 406 of cylindrical section 206 of FIG. 2 is 0.126. In one embodiment, the length 408 of cylindrical section 208 of FIG. 2 is 0.200 inches. In one embodiment, tubular radiator of FIG. 3 comprises a short cylindrical section 410 connecting cylindrical section 206 to cylindrical section 208 of FIG. 2 having a length 410 of 0.05 inches. In a preferred embodiment, cylindrical section 208 of FIG. 2 is threaded with a 412 dimension of 6-32.

The Finite Element Method (FEM) enables engineers to model, analyzed, and predicts the performance of real physical systems. It is well known that the numerical method is a useful tool in the analysis of complex vibration systems. It can give the vibrational modal shape, modal analysis, the natural frequency, the electro-mechanical impedance curve and radiated sound field of the vibrational system. The benefit for the design of a radiator- waveguide is less use of material as well as iterations and error time. Modal analysis computes the shape and frequency of modes and displays a magnitude of displacement or stress. Referring now to FIG. 5, a map of longitudinal vibration 500 of a tubular radiator is shown. In one simulation, vibrational modal analysis reveals one or more regions of relative radial deflection (x-axis radial deformation) amplitude, normalized to the mass matrix, at one or more nodal or antinodal locations, generated by tubular radiator with one or more preferred dimensions of CAD drawing 300 of FIG. 3, operating at 55 kHz. As evident, a relative negative radial deflection region 502 is achieved at the distal end of the cylindrical section 202 of FIG. 2. In a similar manner, a relative positive radial max-deflection region 504 is achieved at mid-region of the cylindrical section. One or more varying positive radial deflection regions 506, 508 are also produced by said tubular radiator. A relative negative radial deflection region 510 is also achieved at the proximal region of the cylindrical section 206 of FIG. 2.

Referring now to FIG. 6, a CAD diagram 600 of a tubular radiator is shown according to various embodiments. In various embodiments, tubular radiator 602 comprises one or more semi- rectangular hollowed perforations 604 or slits distributed circumferentially and longitudinally from a proximal portion 604 to a distal portion 608 of radiator 602. In various embodiments, one or more perforations enable flexural motion of the radiator material between each perforation to generate radial US energy from the surface of the radiator into an acoustic load, for example acoustic load 104 of FIG. 1. In various embodiments, the transducer 106 of FIG. 1 excites one or more radial vibrational modes of the radiator- waveguide 602. In various embodiments, the transducer excites one or more radial vibrational modes of radiator material between each perforation 604, 610 to generate radial US energy from its surface into an acoustic load. In a preferred embodiment, tubular radiator 602 comprises a hollow cylindrical section with a distal opening diameter 612 of 0.186 inches, with a length 614 of 2.01 inches. In another embodiment, the cylindrical section is connected at the distal end to a solid cylindrical section with having a diameter 616 of 0.118 inches. The combined length 618 of said two section is 2.01 inches. In yet another embodiment, the solid cylindrical section is connected to a cross-section variable section having a radius 620 of 0.05 inches, thickness 622 0.001 inches, and the widest cross-section diameter 624 of 0.250 inches. In yet another embodiment, the cross-section variable section is connected to two solid cylindrical sections having a total length 626 of 0.188 inches. In one embodiment, one solid cylindrical section connected distal to said cross-section variable section has a diameter 628 of 0.150 inches. In another embodiment, the other solid cylindrical section has a diameter 630 of 0.190 inches. In various embodiments, one or more elements of the apparatus is insertable into a body cavity, lumen, or orifice for generating cavitation in an acoustic liquid load, preferably containing at least one small molecule, macromolecule, peptide, nucleic acid, agent, or the like, of the cavity or lumen to facilitate their transport onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen, or orifice.

An object of the present disclosure is a method for constructing compact low frequency radiatorwaveguide capable of radial emission or transmission of US energy into an acoustic load via vibrational mode conversion. In various embodiments, the method comprises using one or more transducers 106 of FIG. 1 to excite one or more longitudinal modes of waveguide 102 of FIG. 1, the waveguide coupled to tubular radiator 110 of FIG. 1, subsequently excite one or more radial modes of the coupled tubular radiator to produce a specific amount, quantity, or volumetric measure of cavitation. In various embodiments, the method comprises using one or more transducers 106 of FIG. 1 to excite one or more longitudinal modes of waveguide 102 of FIG. 1, the waveguide coupled to tubular radiator 110 of FIG. 1, subsequently excite one or more radial modes and one or more longitudinal modes of the coupled tubular radiator, comprising distal cap 112b of FIG. IB, to produce a specific amount, quantity, or volumetric measure of cavitation. In various embodiments, the method uses the transducer, waveguide element, and radiator combination and operate to produce radial US energy from the radiator into an acoustic load. In various embodiments, the method uses the transducer, waveguide element, and radiator with distal cap combination and operate to produce radial and longitudinal US energy from the radiator into an acoustic load. In various embodiments, the method uses one or more PZT or magnetostrictive transducers. In various embodiments the method uses a waveguide comprising one or more combinations of cylindrical sections, variable cross-sections, or the like, constructed preferably using Titanium 6AL 4V, having dimensions disclosed within FIG. 3 and FIG. 4, but not limited to. In various embodiments, the method uses a radiator comprising a tubular element, the tubular radiator further comprising a length, an inner, and outer diameter as shown in FIG. 1. In various embodiments, the method uses a radiator comprising a tubular element, the tubular radiator further comprising a length and a distal cap as shown in FIG. IB. In various embodiments, the method uses a radiator comprising one or more semi-rectangular hollowed perforations or slits distributed circumferentially and longitudinally from a proximal portion to a distal portion of the radiator. In various embodiments, one or more said perforations or slit enables flexural motion of the radiator material between each perforation or slit to generate radial US energy from the surface of the radiator into an acoustic load as shown in FIG. 6, but not limited to. In various embodiments, the method uses a radiator comprising one or more semi -rectangular hollowed perforations or slits distributed circumferentially and longitudinally from a proximal portion to a distal portion of the radiator combined with a distal cap as shown in FIG. IB. In various embodiments, one or more perforations or slits enables flexural motion of the radiator material between each perforation or slit to generate radial US energy 112 of FIG. 1 from the surface of the radiator and longitudinal US 116b of FIG. IB, into an acoustic load. In various embodiments, the method uses the transducer to excite one or more radial vibrational modes of radiator material between each perforation or slit to generate radial US energy from its surface into an acoustic load. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load at a specific operating mode, frequency, or the like. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load in the frequency range of 20-200 kHz, preferably 20-100 kHz, most preferably between 20 kHz to 60 kHz. In various embodiments, the apparatus generates cavitation in an acoustic load with one or more input intensities, but not limited to, 0.5 Watt per squarecentimeter to 50 Watt per square centimeter, preferably 5 Watt per square centimeter to 25 Watt per square centimeter, most preferably the minimal intensity required to produce cavitation sufficient to deliver a therapeutic amount determined by one or more in vitro or in vivo measurement methods or techniques. In various embodiments, the apparatus generates cavitation in an acoustic load with one or more output intensities, but not limited to, 0.5 Watt per squarecentimeter to 50 Watt per square centimeter, preferably 5 Watt per square centimeter to 25 Watt per square centimeter, most preferably the minimal output intensity required to produce cavitation sufficient to deliver a therapeutic amount determined by one or more in vitro or in vivo measurement methods or techniques. In various embodiments, the method uses said apparatus to generate cavitation in an acoustic load with more than one specific operating mode, frequency, combination of two or more operating modes or frequencies. In various embodiments, the compact low frequency radiator- waveguide is constructed to operate at one or more low resonant frequencies by varying the length and/or diameter of the waveguide, the length of the tubular radiator, the ratio of the inner to the outer diameters of the tubular radiator, the dimensions (e.g., length, width, etc.) of at least one perforation or slit of the tubular radiator, combinations thereof, or the like. In various embodiments, the compact low frequency radiator-waveguide is constructed to operate at one or more low resonant frequencies by varying the length and/or diameter the distal cap of the tubular radiator, combinations thereof, or the like. In various embodiments, the compact low frequency radiator- waveguide is constructed to operate with waveguide, radiator, or the total radiator- waveguide at half-or full wavelength or combinations thereof. In various embodiments, the compact low frequency radiator- waveguide is constructed to produce one or more relative radial, positive or negative, deflections of high amplitude at one or more antinodes along one or more tubular radiator segments of approximately 1 to 100 microns, preferably 1-50 microns, more preferably 1- 10 microns, peak-to-peak. In various embodiments, the compact low frequency radiator- waveguide is constructed to produce one or more longitudinal deflection amplitudes of approximately 1 to 100 microns, preferably 1-50 microns, more preferably 1- 10 microns. In various embodiments, the compact low frequency radiator- waveguide is constructed to produce one or more gain ratios between the waveguide and tubular radiator. In various embodiments, one or more longitudinal inputs to a waveguide produces one or more radial output ratios, preferably 0.1 to 0.5, more preferably 0.5-0.75, most preferably, 0.75 - 1.00.

The characterization of the dynamic behavior of the tubular radiator of FIG. 6 can be performed to reduce the time and cost involved the mechanical and electrical design process using numerical and experimental approaches. Modal and dynamic analyses can be carried out by means of CAE software programs available from ANSYS (Canonsburg, PA). The relationships of the longitudinal-radial resonance frequency and amplitude versus sizes of diagonal slits can be studied to verify that the longitudinal vibration can be converted into the radial vibration within the tubular radiator with one or more longitudinal slits. In general, the input to a model includes the horn’s material and properties such density, Poisson’ s ratio, and Young’ s modulus. Referring now to FIG. 7, a map of radial normalized vibration simulation 700 of a tubular radiator containing one or more longitudinal slits 702 is shown. In one simulation, modal analysis reveals one or more regions of deflection or deformation, at one or more nodal and antinodal locations, generated by tubular radiator with one or more preferred dimensions of CAD drawing 600 of FIG. 6, operating at 40 kHz. As evident, one or more relative negative high-deflection regions 704, 706, 708 are generated from the proximal to distal end of the tubular radiator. In a similar manner, one or more relative positive high-deflection regions 710, 712, 714 708 are generated from the proximal to distal end of the tubular radiator.

The accuracy of the Finite Element model can be confirmed by comparing numerically and experimentally determined resonant characteristics using, for example, a ID or 3D laser Doppler vibrometer (Polytec, 3D CLV-3D), while the detected frequency response functions, with a frequency range of 0 and 100 kHz, can be recorded through Signal Calc ACE data acquisition software (Data Physics Corp). Referring now to FIG. 8, diagram 800 of an experimental setup for evaluating a FE model and apparatus of the present disclosure is shown. An experimental setup comprises a signal generator 802 that provide one or more voltage sine waves at a chosen frequency. The sine wave amplitude is boosted in magnitude by an amplifier 804 to a chosen amplitude to excite harmonically an ultrasound transducer 806 which can be transducer 106 of FIG. 1 or an equivalent of the present disclosure. In various embodiments, an impedance-matching instrument can be connected between amplifier 804 and said transducer. The voltage applied to transducer 806 can be observed and measured as current flow/draw across resistor 810 which through current channel 812, as well as voltage channel 814, can both be observed using oscilloscope 816. A multimeter 818 enables measurement of the voltage of the signal from amplifier 804. The velocity or displacement response of a radiator- waveguide device can be measured at the distal end or one or more antinodes along the length of the tubular radiator using a ID or 3D laser Doppler vibrometer. The vibration velocities can be measured over a grid of points located on the tubular using a 3D laser Doppler vibrometer, while the detected frequency response functions, with a frequency range of 0 and 80 kHz, are recorded through a data acquisition system/software and imported for modal analysis and validation. In various embodiments, data acquisition and processing software (SignalCalc, Data Physics) can be employed to calculate the Frequency Response Functions (FRF) from the input and output signals of the ultrasonic transducer and to apply curve-fitting routines to extract the frequency, magnitude, phase data, radial, and longitudinal deflection of one or more surfaces of said tubular radiator for device performance validation.

An object of the present disclosure is a low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a cavity, lumen, or orifice or lumen facilitated by cavitation generated by radially and/or longitudinally transmitted US radiation. Referring now to FIG. 9, an ultrasound-mediated endoscopic drug delivery system 900 is shown, according to various embodiments. The endoscopic drug delivery system 900 comprises at least one compact transducer-radiator-waveguide 902 capable of radial and/or longitudinal emission or transmission of US energy into an acoustic load. In various embodiments, the endoscopic drug delivery system 900 comprises a control body 904, flexible insertion scope-tube 906, and a distal end of the scopetub 908 further comprising one or more low frequency transducers 902a, one or more waveguide elements 902b, one or more radiator elements 902c, or combinations thereof. In various embodiments, the endoscopic drug delivery system 900 further comprises an ultrasonic drug delivery controller 910 having one or more electrical connection means 912 to enable the delivery of electrical energy to actuate transducer 902a, said connection means configured within or external to control body 904, flexible insertion scope-tube 906, and a distal end of the scope-tub 908. In various embodiments, the endoscopic drug delivery system 900 further comprises an ultrasonic drug delivery controller 910 having one or more electrical connection means 912 to enable the delivery of electrical energy to actuate transducer 902a, said connection means configured within or external to control body 904, flexible insertion scope-tube 906, and a distal end of the scope-tub 908. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce radial and/or longitudinal US energy from the radiator into an acoustic load in the proximity of one or more segments of an endoscope (i.e., comprising a control body 904, flexible insertion scope 906, and steerable distal end 908), preferably at the distal segment, more preferably at the distal end 908. In various embodiments, the transducer-radiator- waveguide 902, equivalent to a low frequency ultrasound-mediated drug delivery system of FIG. 1, is excited or actuated to produce radial US energy from the radiator into said acoustic load within a cavity, lumen, or orifice. In alternative embodiments, the transducer-radiator-waveguide 902, equivalent to a low frequency ultrasound-mediated drug delivery system of FIG. IB, is excited or actuated to produce radial and longitudinal US energy from the radiator into said acoustic load within a cavity, lumen, or orifice. In various embodiments, one or more elements of the endoscopic drug delivery system 900 is insertable endoscopically into a cavity, lumen, or orifice for generating cavitation in an acoustic liquid load located in the proximity of one or more segments of flexible tube 906 of an endoscopic system or apparatus, preferably at the distal end 908 for diagnostics and therapeutic applications. In various embodiments, the endoscopic drug delivery system 900 further comprises an ultrasonic drug delivery controller 910 having one or more fluidic connection means 914 to enable the delivery of diagnostic, therapeutic agent, or drug containing fluid media or mixture to endoscope lumen 916, said connection means configured within or external to control body 904, flexible insertion scope-tube 906, and a distal end of the scope-tub 908, with termination connection into endoscopic lumen 916. In various embodiments, endoscopic lumen 916 enables fluid delivery into the interior of tubular radiator 902c and ultimately dispersed into an acoustic load. In various alternative embodiments, endoscopic lumen 916 enables fluid delivery to the exterior of tubular radiator 902c and ultimately dispersed into an acoustic load. In various embodiments, transducer-radiator-waveguide 902 is configured to operate in conjunction with one or more elements of an endoscopic diagnostic or treatment system, including but not limited to, illumination, light source, camera, diagnostic sensor, biopsy port, biopsy device, biopsy channel, forceps, suction, inflation device, internal/external tracker, gripper, GI track attachment, clip, positioning system, surgical instrument, the like, or combinations thereof. In various embodiments, the low frequency ultrasound-mediated endoscopic drug delivery system 900, apparatus, and methods enable targeted and/or precise delivery of at least one chosen molecule, agent, or drug formulation onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian cavity, lumen, or orifice (e.g., oral, ear, GI, colon, rectum, vagina, joint, etc.) to treat, mitigate, intervene, or cure one or more diseases or conditions.

Exemplary embodiments of the present disclosure provide a system, apparatus, and methods for enhancing ultrasound emission or transmission of transverse, flexural, radial, longitudinal, bending, tension, torsional vibration mode energy into, within, or throughout an acoustic liquid load, containing at least one treatment or therapeutic agent, using a radiatorwaveguide, comprising combination of a transducer, horn, radiator, extender, and a thin rectangular plate waveguide capable of operating in at least one vibration mode while emitting a combination of transverse, flexural, and longitudinal US energy via mode conversion with large radiating surfaces and high gain factor for optimal production of cavitation in a liquid medium to facilitate drug transport into and or through a biological barrier, cell, membrane, or tissue of a mammal body cavity, lumen, orifice. The advantages of the radiator- waveguide , include but not limited to, compact form factor, more efficient multi or omni-directional US energy transfer into a liquid load, increased radiation surface and the uniformity of the distribution of acoustic energy throughout the volume of liquid load, increase intensity of acoustic radiation at lower device power consumption, and enabling standalone operation or targeted endoscopic drug delivery within mammalian body canal, tubes, orifice, glands, vessels, or cavity or lumen.

In general, various embodiments of the present disclosure comprise acoustic tooling methods that takes longitudinal motion from an ultrasonic horn and converts it to useful motion with multi-modal vibration, including but not limited to, transverse, flexural, radial, longitudinal, bending, tensional, or torsional vibration mode, via the radiator-waveguide. The designs are effective by maximizing longitudinal to multi-modal vibration conversion with motion gain for multi-directional emission. In one acoustic tooling a radiator- waveguide strap is designed to maximize transverse, flexural, radial, and longitudinal emission. In another acoustic tooling a radiator- waveguide containing two straps is designed to maximizes transverse, flexural, radial, and longitudinal emission.

Turning now descriptively to the drawings, in which the same reference characters denote the same elements throughout the several views, FIG. 10 depicts a computer-aided design rendering of a standalone low frequency ultrasound-mediated drug delivery system 1100 for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a body cavity, lumen or orifice facilitated by cavitation generated by transverse, flexural, and longitudinally transmitted US radiation. In various embodiments, the drug delivery device 1102 may comprise an ultrasonic horn 1104 containing one or more piezoelectric transducers 1106, variable cylindrical cross-section radiator 1108, said ultrasonic horn mechanically coupled to a half-wave extender 1110, which is mechanically attached to waveguide 1112. In various embodiments, one or more transducers 1106, ultrasonic horn or radiators 1108, half-wave extenders 110, and waveguides 1112, can be combined mechanically and actuated to produce at least one transverse, flexural, radial, or longitudinal direction US energy emission or transmission from at least one or all radiating surfaces into an acoustic load. The transducer 1106 can comprise one or more non-limiting piezoelectric, electrostrictive, or magnetostrictive transducers, preferable a ceramic lead zirconate titanate (PZT) piezoelectric transducer. In various embodiments, ultrasonic horn, or radiator 1108 can be a Langevin transducer, Langevin horn, or the like. In various embodiments, the US radiator- waveguide may comprise one or more combinations of a solid or hollow cylindrical rod portion, a solid or hollow variable cylindrical cross-section portion, a solid or hollow half-wave extender 1110, a solid or hollow waveguide 1112 having a variable cross-section proximal portion and a thin rectangular plate portion, or the like. In various embodiments, the radiator- waveguide may comprise said thin rectangular plate waveguide 1112 portion having a defined length, height, and width and actuated to produce one or more transverse or flexural vibrational amplitudes at one or more nodes or antinodes along its length to radiate US energy emission or transmission into, within, or throughout an acoustic load. In various embodiments, the radiator- waveguide may comprise said thin rectangular plate having a defined length, height, and width and actuated to produce one or more transverse or flexural vibrational amplitudes at one or more nodes or antinodes along its length and emit or transmit longitudinal US energy from a distal surface. In various embodiments, one or more elements of the system 1100 may be insertable into a body cavity, lumen, or orifice and activated to generate cavitation in, into, within, or throughout an acoustic liquid load of the cavity or lumen, preferable containing at least one chosen molecule, agent, or drug formulation, to facilitate drug delivery onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian body cavity, lumen (e.g., oral, ear, GI, colon, rectum, vagina, etc.), or orifice.

Referring now to FIG. 11, a computer-aided design drawing of a waveguide 1200 is shown, according to various embodiments. In various embodiments, the waveguide, equivalent to waveguide 1112 of FIG. 10, may comprise one or more portions, including but not limited to, a threaded portion 1202, a solid or cylindrical portion 1204, a variable semi-cylindrical cross-section portion 1206, and a thin rectangular plate portion 1208, said portion preferable having an elliptical cross-section. In various, embodiments, threaded portion 1202 is machined or fabricated to enable mechanical attachment to half-wave extender 1110 of FIG. 10. In various embodiments, variable cylindrical cross-section portion 1206 is machined or fabricated with two or more convex surfaces, via non-limiting CNC fillet milling, each surface having varying radius of curvature. In various embodiment, variable cylindrical cross-section portion 1206 is machined or fabricated with a hollow and threaded distal end to accommodate mechanical attachment to thin rectangular plate portion 1208 of waveguide 1112 of FIG. 10. In an alternative embodiment, threaded portion 1202, solid or cylindrical portion 1204, variable cylindrical cross-section portion 1206, and thin rectangular plate portion 1208 is machined or fabricated as a single waveguide.

Referring now to FIG. 1 IB, a computer- aided design drawing of a waveguide 1200b with two straps is shown, according to various embodiments. In various embodiments, the waveguide, equivalent to waveguide 1112 of FIG. 10, may comprise one or more portions, including but not limited to, a threaded portion 1202b, a solid or cylindrical portion 1204b, first strap portion 1206b, a second strap portion 1208b, said first strap portion 1206b further comprising a variable semi- cylindrical cross-section portion 1210b, and a thin rectangular plate portion 1214b, said portion 1214b preferable having an elliptical cross-section, and said second strap portion 1208b further comprising a variable semi-cylindrical cross-section portion 1212b, and a thin rectangular plate portion 1216b, said portion 1216b preferable having an elliptical cross-section. In various embodiments, first strap portion 1206b is configured physically to operate with its long axis 1218b in a plane orthogonal to second strap portion 1208b. In various embodiments, similarly second strap portion 1208b is configured physically to operate with its long axis 1220b in a plane orthogonal to first strap portion 1206b. In various embodiments, the two said straps are mechanically or physically connected to the distal surface of portion 1204b, preferably with longitudinal axis 1218b and longitudinal 1220b off axis relative to the longitudinal axis and vibrational direction of portion 1204b, to enable longitudinal to flexural mode conversion. In various alternative embodiments, first strap portion 1206b is configured to operate with longitudinal axis 1218b projected along one or more planes relative to a plane operation of second strap portion 1208b at a non-limiting angle, ranging from 1 degree to 90 degree, relative to each other. In various alternative embodiments, the two said straps are mechanically or physically connected side by side or physically separated at their proximal bases. In various, embodiments, threaded portion 1202b is machined or fabricated to enable mechanical attachment to half-wave extender 1110 of FIG. 10. In various embodiments, variable cylindrical cross-section portion 1210b and 1212b are machined or fabricated with two or more convex surfaces, via non-limiting CNC fillet milling, each surface having varying radius of curvature. In various embodiment, the variable cylindrical cross-section portion 1210b and 1212b are machined or fabricated with a hollow and threaded distal end to accommodate mechanical attachment to thin rectangular plate portion 1206b and 1208b. In an alternative embodiment, threaded portion 1202b, solid or cylindrical portion 1204b, variable cylindrical cross-section portion 1210b, 1212b and thin rectangular plate portions 1206b, 1208b is machined or fabricated as a single waveguide.

Referring now to FIG. 12, a computer- aided design drawing 1300 of a cross-section view of a waveguide is shown, according to various embodiments. Cross-section view of drug delivery device 1102 of FIG. 10 comprises further details on the mechanical connection between various portions of said device. The distal of the device comprises an ultrasonic horn 1302, equivalent to horn 1104 of FIG. 10, further comprising a metallic backing portion 1302a, a piezoelectric stack 1302b, a cylindrical variable cross-section radiator 1302c, and a hollow threaded distal tip 1302d. In various embodiments, ultrasonic horn 1302 is assembled with 1302a, 1302b, and 1302c as a Langevin horn capable of operating one or more longitudinal vibrational modes. In various embodiments, hollow threaded distal tip 1302d enables mechanical attachment to a proximal threated portion of half-wave extender 1304, equivalent to extender 1110 of FIG. 10. In various embodiments, extender 1304 comprises a threaded proximal portion 1304a capable of mating with 1302d of horn 1302 as a threated male-female joint. In various embodiments, extender 1304 comprises a hollow threaded distal tip 1304a to accommodate mechanical attachment to a proximal portion of waveguide 1306, equivalent to waveguide 1112 of FIG. 10. In various embodiments, waveguide 1306 comprises a threaded proximal portion 1306a capable of mating with 1304b of extender 1304 as a threated male-female joint. In various embodiments, ultrasonic horn 1302, extender 1304, and waveguide 1306 may be fabricated from metal, including but limited to titanium, steel, aluminum, the like, or combinations thereof.

An object of the present disclosure is a method for constructing a compact low frequency radiator- waveguide capable of emitting or transmitting US energy in, into, within or throughout an acoustic load via vibrational mode conversion. Referring now to FIG. 13 A, an engineering sketch 1400 of a waveguide is shown, according to various embodiments. The sketch comprises detail dimensions, shown with a side view 1400 A and top view 1400B of a preferred embodiment of waveguide 1112 of FIG. 10. It is understood that the dimensions are approximates and nonlimiting for fabrication. Waveguide 1112 of FIG. 10 comprises a threaded proximal portion 1402, equivalent to 1306a of FIG. 12, having a threaded outer diameter of approximately 0.315 inches and total length of approximately 0.188 inches. The threaded proximal portion or post is necked down to an approximately 0.150 in outer diameter at approximately 0.138 inches from its most proximal surface. In various embodiments, waveguide 1112 comprises a cylindrical portion 1404, equivalent to cylindrical portion 1204 of FIG. 11, having a length of approximately 0.251 inches and an outer diameter of approximately 0.315 inches. In various embodiments, the waveguide comprises a variable semi-cylindrical cross-section portion 1406, equivalent to variable crosssection portion 1206 of FIG. 11. Portion 1406 comprises a symmetrical necked down feature approximately 0.063 inches from its proximal end, said necked down feature having a length of approximately 0.125 inches as shown with side view 1400B. In various embodiments, variable semi-cylindrical cross-section portion 1406 is fabricated to have two distinct convex surfaces. In a preferred embodiment, portion 1406 comprises a first surface 1406a fabricated with a convex surface having a curvature radius of approximately 0.010 inches and height of approximately 0.213 inches. In addition, surface 1406a may be tapered elliptically, from proximal to distal, toward the center axis of waveguide 1112 with a lateral dimension of approximately 0.75 inch. Portion 1406 further comprises a second surface 1406b may be fabricated via an approximate 0.275 inches by 0.175 fillet milling technique. Waveguide 1112 of FIG. 10 further comprise a thin rectangular plate portion 1408, equivalent to 1208 of FIG. 11 having a thickness dimension of approximately 0.40 ± 0.002 inches and a width of approximately 0.165 ± 0.002 inches. In various embodiments, portion 1408 comprises a proximal reference point 1408a and a distal tip 1408a with details of said distal shown in closeup 1410. In various embodiments, portion 1408 has rounded side edges a long its length with details shown in closeup 1412 from proximal reference point 1408a to distal tip 1408b. In various embodiments, said waveguide with these dimensions may be fabricated with metal, preferably titanium 6AL 4V, free of sharp edges (0.005 inches) and finished to be free of burs as a single waveguide. Without limitation, the constructed compact low frequency radiatorwaveguide the may generate US energy or mechanical wave while operating or vibrating in the frequency in the range of about 5 kHz to about 500 kHz, from about 10 kHz to about 500 kHz, from about 20 kHz to about 500 kHz, from about 5 kHz to about 1 MHz, from about 10 kHz to about 1 MHz, from about 20 kHz to about 1 MHz, from about 5 kHz to about 2 MHz, from about 10 kHz to about 2 MHz, from about 20 kHz to about 2 MHz, from about 2 MHz to 200 MHz, from 200M to 2 GHz, or from 2GHz to 10 GHz.

Referring now to FIG. 13B, an engineering sketch 1400b of a waveguide with two straps is shown, according to various embodiments. The sketch comprises detail dimensions, shown with a side view 1400 Ab and top view 1400Bb of an alternative preferred embodiment of waveguide 1112 of FIG. 10. It is understood that the dimensions are approximates and non-limiting for fabrication. Waveguide 1112 of FIG. 10 comprises a threaded proximal portion 1402b, equivalent to 1306a of FIG. 12, having a threaded outer diameter of approximately 0.190 inches and total length of approximately 0.188 inches. The threaded proximal portion or post is necked down to an approximately 0.150 in outer diameter at approximately 0.138 inches from its most proximal surface. In various embodiments, waveguide 1112 of FIG. 10 comprises a cylindrical portion 1404b, equivalent to cylindrical portion 1204 of FIG. 11A, having a length of approximately 0.250 inches and an outer diameter of approximately 0.315 inches. In various embodiments, the waveguide comprises two straps, equivalent to strap 1206b and 1208b of FIG. 1 IB, one configured with a variable semi-cylindrical cross-section portion 1406b and the other with a variable semi- cylindrical cross-section portion 1408b. In various embodiments, variable semi-cylindrical crosssection portion 1406b and 1408b are fabricated to have two distinct convex surfaces. In a preferred embodiment, portion 1406b and 1408b each comprises a first surface fabricated with a convex surface having a curvature radius of approximately 0.010 inches and height of approximately 0.213 inches. In addition, said surface may be tapered elliptically, from proximal to distal, toward the center axis of the waveguide with a lateral dimension of approximately 0.75 inch. Portions 1406b and 1408b further comprises a second surface that may be fabricated via an approximate 0.275 inches by 0.175 fillet milling technique. In various embodiments, one or more said convex surfaces enables the reduction of material stress. Each strap of waveguide 1112 of FIG. 10 further comprise a thin rectangular plate portion 1410b having a thickness dimension of approximately 0.040 inches and a width of approximately 0.140 inches. In a preferred embodiment, the combined or total length of cylindrical portion 1404b, 1406b, and 1410b may be approximately or exactly 1.80 inches. Similarly, the combined or total length of cylindrical portion 1404b, 1406b, and 1412b may be approximately or exactly 1.80 inches. In various embodiments, said waveguide with these dimensions many be fabricated with metal, preferably titanium 6AL 4V, free of sharp edges (0.005 inches) and finished to be free of burs as a single waveguide. Without limitation, the constructed compact low frequency radiator- waveguide the may generate US energy or mechanical wave while operating or vibrating in the frequency range of about 5 kHz to about 500 kHz, from about 10 kHz to about 500 kHz, from about 20 kHz to about 500 kHz, from about 5 kHz to about 1 MHz, from about 10 kHz to about 1 MHz, from about 20 kHz to about 1 MHz, from about 5 kHz to about 2 MHz, from about 10 kHz to about 2 MHz, from about 20 kHz to about 2 MHz, from about 2 MHz to 200 MHz, from 200M to 2 GHz, or from 2GHz to 10 GHz.

The Finite Element Analysis (FEA) enables engineers to model, analyzed, and predicts the performance of real physical systems. It is well known that the numerical method is a useful tool in the analysis of complex vibration systems. It can give the vibrational modal shape, modal analysis, the natural frequency, the electro-mechanical impedance curve, and radiated sound field of the vibrational system. The benefit for the design of a radiator- waveguide is less use of material as well as iterations and error time. Modal analysis computes the shape and frequency of modes and displays a magnitude of displacement or stress. Referring now to FIG. 14, an FEA simulation output 1500 of a computer model of device 1102 of FIG. 10 is shown. The FEA computer model comprises a model 1502 of horn 1104 of FIG. 10 and model 1504 of waveguide 1112 of FIG. 10. In various embodiments, said computer model is used to analyze one or more transverse or flexural deflections 1506 of waveguide 1112. In a simulation, a model 1508 of piezo stack, equivalent to piezo transducer 1106 of FIG. 10, is performed with said stack actuated at a frequency of 40 kHz to create longitudinal motion, 4.38-micron peak-to-peak, in the long axis direction of horn 1104 of FIG. 10. The results show that the longitudinal motion creates a 30.36-micron peak-to-peak orthogonal motion at the tip of waveguide 1112 of FIG. 10 with 4 additional antinodes of activity. The model demonstrates that longitudinal to transverse mode conversion is achievable for device 1102 of FIG. 10 with a gain of approximately 7.

The characterization of the dynamic behavior of the waveguide 1112 of FIG. 10 can be performed to reduce the time and cost involved the mechanical and electrical design process using numerical and experimental approaches. Modal and dynamic analyses can be carried out by means of CAE software programs available from ANSYS (Canonsburg, PA). The relationships of the longitudinal to transverse mode conversion and resultant amplitude generated by said wave can be studied with varying simulation model inputs. Referring now to FIG. 15, another FEA simulation output 1600 of a computer model of device 1102 of FIG. 10 is shown. In various embodiments, said computer model is used to analyze one or more acoustic pressures 1600 of waveguide 1112 of FIG. 10. In a simulation, a model of piezo stack 1508 of FIG. 14 is performed with said stack actuated at a frequency of 40 kHz to create longitudinal motion in the long axis direction of horn 1104 of FIG. 10. The results show that the longitudinal to subsequent transverse mode conversion of waveguide 1112 of FIG. 10 can create one or more acoustic negative pressure amplitudes 1602 and one or more acoustic positive pressure amplitudes 1604 along the length and surfaces of said waveguide. In certain embodiments, the positive pressures 1604 and negative pressures 1602 are harmonically alternating. In certain embodiments, with an input of 5.8-micron peak-to-peak deflection of horn 1104 of FIG. 10, a minimum amplitude of -123.5 psi at 1602 and a maximum amplitude of 162.76 psi at 1604 in a plane normal to said waveguide is obtained. In some embodiments, with an input of 7-micron peak-to-peak deflection of horn 1104 of FIG. 10, negative pressures 1602 and positive pressures 1605 in excess of 24 psi may be obtained with 24 psi being the threshold for ultrasonic cavitation. The ability for waveguide 1112 of FIG. 10 to deliver drugs can be evaluated by in vitro experimentations. Referring now to FIG. 16 a pictorial 1700 of an in vitro experimental setup is shown in various embodiments. The experimental set up comprises a beaker 1702 which holds a liquid medium or drug mixture. A “L” bracket 1704 is configured and a cut piece of gastrointestinal tissue 1706 mounted, with one or more washers and screws, parallel to the long axis of said bracket and a shorter portion 1706b of said tissue is mounted in the perpendicular direction parallel to the base of said bracket. An ultrasound drug delivery device 1708, equivalent to device 1102 of FIG. 10 is position, in proximity to the mounted tissue 1706 and tissue portion 1706b, within beaker 1702 and immersed in the liquid medium containing a drug mixture, for example, mesalamine for treating ulcerative colitis. In various experiments, said drug mixture may comprise but not limited to, 10 to 100% DC Perrigo. In various embodiments, mounted tissue 1706 may provide data for the delivery or transport of drug from the axially produced energy by drug delivery device 1708 while mounted tissue portion 1706b provides data for the delivery or transport of drug from radially produced energy from said device. In a preferred embodiment, drug delivery device 1708 is positioned at a controlled distance between waveguide 1710, equivalent to waveguide 1112 of FIG. 10 and tissue 1706. In various experiments, the control radial distance can range from 3 mm to 15 mm. Drug delivery device 1708 is then configured electronically to emit US energy into the liquid mixture at one or more specific frequencies (e.g., 40 kHz +/- 250 Hz), powers (e.g., 20-25 Watt), intensities, and duty cycles (e.g., 10-100%). Upon completion of an experimental run, tissue 1706 is removed and processed for the determination of the amount drug delivered into said tissue.

Referring now to FIG. 17 A, a graph of experimental results obtained using the drug delivery device of the present disclosure. In an experiment, data was obtained for the drug mesalamine delivered or transported radially or transversely into tissue 1706 or axially or longitudinally into tissue portion 1706B of FIG. 16. The results show that the amount (approximately 600 ng mesalamine average per mg of GI tissue) of drug delivered radially is greater than the amount (approximately 250 ng mesalamine average per mg of tissue) of drug delivered through the axial or longitudinal vibrational mode of device operation. In general, the closer the waveguide 1112 of FIG. 10 is to tissue than the more drug is delivered or uptake into tissue. These in vitro results demonstrated the effectiveness of the drug delivery device of the present disclosure. Referring now to FIG. 17B, a graph of experimental results obtained using the drug delivery device of the present disclosure. In various experiments using in vitro experimental setup described in pictorial 1700 of FIG. 16, data were obtained for the delivery or transport of fluorescent dextran microparticles delivered or transported radially or transversely into tissue 1706 or axially or longitudinally into tissue portion 1706b of FIG. 16. In one experiment, drug delivery device 1708 of FIG. 16 was positioned at a specific distance from said tissue and tissue portion and configured to expose 20-25 Watt of power into beaker 1702 of FIG. 16 with a solution containing 0.5 pgram of fluorescent (680 nm wavelength) dextran microparticles per mL of saline. The data shows that dextran microparticles can be transported into tissue 1706 and portion 1706b of FIG. 16 at approximately 3.34 times greater amount compared to control. In addition, adjusted for tissue surface area, it appears that the axial and radial transport using the drug delivery device of the present disclosure is approximately equal and the combined amount of tissue surface area exposure achieved for delivery is greater than a conventional Langevin horn.

Referring now to FIG. 17C, a graph of experimental results obtained using the drug delivery device of the present disclosure. In various experiments using in vitro experimental setup described in pictorial 1700 of FIG. 16, data were obtained for the delivery or transport of fluorescent dextran microparticles delivered or transported radially or transversely into tissue 1706 or axially or longitudinally into tissue portion 1706b of FIG. 16. In another experiment, drug delivery device 1708 of FIG. 16 was positioned at several controlled distances (3 mm, 4mm, 5mm) from said tissue and tissue portion to expose 20-25 Watt of power into beaker 1702 of FIG. 16 with a solution containing 0.5 pgram of fluorescent (680 nm wavelength) dextran microparticles per mL of saline. The data shows that dextran microparticles can be transported into tissue 1706 and portion 1706b of FIG. 16 at approximately 2.74 (at 3 mm distance), 3.02 (at 4mm distance), and 2.50 (at 5 mm distance) times greater amount compared to control. In addition, adjusted for tissue surface area, it appears that the combined amount of axial and radial transport using the drug delivery device of the present disclosure is relatively insensitive to distance in the range of 3 to 5 mm under the experimental conditions.

Referring now to FIG. 17D, a graph of experimental results obtained using the drug delivery device of the present disclosure. In various experiments using in vitro experimental setup described in pictorial 1700 of FIG. 16, data were obtained for the delivery or transport of fluorescent dextran microparticles delivered or transported radially or transversely into tissue 1706 or axially or longitudinally into tissue portion 1706b of FIG. 16. In yet another experiment, the effect of varying the operating duty cycle of drug delivery device 1708 of FIG. 16 for exposing 20-25 Watt of power into beaker 1702 of FIG. 16 with a solution containing 0.5 pgram of fluorescent (680 nm wavelength) dextran microparticles per mL of saline was examined. The data shows that dextran microparticles can be transported into tissue 1706 and portion 1706b of FIG. 16 of 1.92 (using 1 minute, 100% duty cycle), 2.94 (using 2-minutes, 50% duty cycle), and 1.62 (using 1-minute, 50% duty cycle) times greater amount compared to control. In addition, adjusted for tissue surface area, it appears that the combined amount of axial and radial transport using the drug delivery device of the present disclosure is greatest by using a 50% duty cycle for a duration of 2 minutes under the experimental conditions.

Referring now to FIG. 17E, a graph of experimental results obtained using the drug delivery device of the present disclosure. In various experiments using in vitro experimental setup described in pictorial 1700 of FIG. 16, data were obtained for the delivery or transport of fluorescent dextran microparticles delivered or transported radially or transversely into tissue 1706 or axially or longitudinally into tissue portion 1706b of FIG. 16. In yet another experiment, the effect of varying the amount of power (Watt (W)) delivered, using a duty cycle of 50% with an exposure duration of 2 minutes, by drug delivery device 1708 of FIG. 16 into beaker 1702 of FIG. 16 with a solution containing 0.5 pgram of fluorescent (680 nm wavelength) dextran microparticles per mL of saline and the amount dextran transported was examined. The data shows that dextran microparticles can be transported into tissue 1706 and portion 1706b of FIG. 16 of 2.05 (at 2.6 W delivered), 2.51 (at 5.77 W delivered), 2.35 (at 10 W delivered), 3.00 (at 14.2 W delivered), and 3.00 (at 18.37 W delivered) times greater amount compared to control. In addition, corrected for tissue surface area, it appears that the combined amount of axial and radial transport using the drug delivery device of the present disclosure increases with wattage and reaches a plateau of 3 times greater than control under the experimental conditions.

An object of the present disclosure is a low frequency ultrasound-mediated endoscopic drug delivery system, apparatus, and methods for enhancing drug transport on, into, or through a biological barrier, cell, membrane, or tissue within a cavity, lumen, or orifice or lumen facilitated by cavitation generated by radially and or longitudinally transmitted US radiation. Referring now to FIG. 18, an ultrasound-mediated endoscopic drug delivery system 1900 is shown, according to various embodiments. The endoscopic drug delivery system 1900 comprises at least one compact transducer-radiator- waveguide 1902 capable of producing in one or more transverse, flexural, radial, or longitudinal directions, US energy emission or transmission in, into, within or throughout an acoustic load. In various embodiments, the endoscopic drug delivery system 1900 comprises a control body 1904, flexible insertion scope-tube 1906, and a distal end of the scope-tub 1908 further comprising one or more low frequency transducer stacks 1902a, one or more radiators 1902b one or more waveguides 1902c, or combinations thereof. In various embodiments, the endoscopic drug delivery system 1900 further comprises an ultrasonic drug delivery controller 1910 having one or more electrical connection means 1912 to enable the delivery of electrical energy to actuate transducer stack 1902a, said connection means configured within or external to control body 1904, flexible insertion scope-tube 1906, and a distal end of the scope-tub 1908. In various embodiments, the endoscopic drug delivery system 1900 further comprises an ultrasonic drug delivery controller 1910 having one or more electrical connection means 1912 to enable the delivery of electrical energy to actuate transducer 1902a, said connection means configured within or external to control body 1904, flexible insertion scope-tube 1906, and a distal end of the scopetub 1908. In various embodiments, the transducer, waveguide element, and radiator are combined and actuated to produce in one or more transverse, flexural, radial, or longitudinal directions, US energy emission or transmission from the delivery device into an acoustic load in the proximity of one or more segments of an endoscope (i.e., comprising a control body 1904, flexible insertion scope 1906, and steerable distal end 1908), preferably at the distal segment, more preferably at the distal end 1908. In various embodiments, the transducer-radiator-waveguide 902, equivalent to a low frequency ultrasound-mediated drug delivery device 1102 of FIG. 10, is excited or actuated to produce radial US energy from the radiator into said acoustic load within a cavity, lumen, or orifice. In alternative embodiments, the transducer-radiator-waveguide 1902, equivalent to a low frequency ultrasound-mediated drug delivery system of FIG. 1, is excited or actuated to produce in one or more transverse, flexural, radial, or longitudinal directions, US energy emission or transmission from said device in, into, within or throughout said acoustic load within a cavity, lumen, or orifice. In various embodiments, one or more elements of the endoscopic drug delivery system 900 is insertable endoscopically into a cavity, lumen, or orifice for generating cavitation in an acoustic liquid load located in the proximity of one or more segments of flexible tube 1906 of an endoscopic system or apparatus, preferably at the distal end 1908 for diagnostics and therapeutic applications. In various embodiments, the endoscopic drug delivery system 1900 further comprises an ultrasonic drug delivery controller 1910 having one or more fluidic connection means 1914 to enable the delivery of diagnostic, therapeutic agent, or drug containing fluid media or mixture to endoscope lumen 1916, said connection means configured within or external to control body 1904, flexible insertion scope-tube 1906, and a distal end of the scope-tub 1908, with termination connection into endoscopic lumen 1916. In various embodiments, endoscopic lumen 1916 enables fluid delivery into the interior or exterior of device 1902 and ultimately dispersed into an acoustic load. In various embodiments, transducer-radiator-waveguide 1902 is configured to operate in conjunction with one or more elements of an endoscopic diagnostic or treatment system, including but not limited to, illumination, light source, camera, diagnostic sensor, biopsy port, biopsy device, biopsy channel, forceps, suction, inflation device, internal/external tracker, gripper, GI track attachment, clip, positioning system, surgical instrument, the like, or combinations thereof. In various embodiments, the low frequency ultrasound-mediated endoscopic drug delivery system 1900, apparatus, and methods enable targeted and or precise delivery of at least one chosen molecule, agent, or drug formulation onto, into, or across a biological barrier, cell, membrane, or tissue of a mammalian cavity, lumen, or orifice (e.g., oral, ear, GI, colon, rectum, vagina, joint, etc.) to treat, mitigate, intervene, or cure one or more diseases or conditions.

An object of the present disclosure is one or more low frequency ultrasound-mediated endoscopic drug delivery apparatuses and methods for the treatment, mitigation, intervention, or cure one or more diseases or conditions. In various embodiments, the apparatus is broadly employed to inspect and operate on organs, airways, and vessels of the body to diagnose and treat various diseases in a minimally invasive manner. In various embodiments, the apparatus enables controlled, targeted, or precise delivery and amount of the drug to be delivered to an intended region of the body. In various embodiments, the one or more apparatuses can be configured or modified for targeted or precise drug delivery concomitant or relating to one or more clinical procedures, including but not limited, neuroendoscopy, sinuscopy, laryngoscopy, bronchoscopy, thorascopy, esophagoscopy, gastroscopy, colonoscopy, laparoscopy, cystoscopy, nephroscopy, nephrolectomy, arthroscopy, otoscopy, colposcopy, hysteroscopy, amnioscopy, fetoscopy, and falloscopy. In various embodiments, the one or more apparatuses can be configured or modified for targeted, precise, and localized drug delivery in combination with standard endoscopy, navigated endoscopy, robotic endoscopy, or future endoscopic system incorporating intelligent technologies, including but not limited to, smart video, augmented reality, surgical tracking and navigation, advanced robotics, and multifunctional theranostics.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” As used herein, the terms “right,” “left,” “top,” “bottom,” “upper,” “lower,” “inner” and “outer” designate directions in the drawings to which reference is made.

The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

The present disclosure includes that contained in the appended claims as well as that of the foregoing description. Although this invention has been described in its exemplary forms with a certain degree of particularity, it is understood that the present disclosure of has been made only by way of example and numerous changes in the details of construction and combination and arrangement of parts may be employed without departing from the spirit and scope of the invention.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. EQUIVALENTS

Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.