Patent Description:
The bioavailability of topically applied medicants is typically very low. For example, the bioavailability of topically applied lidocaine is approximately <NUM>%. See, <NPL>). In other words, more than <NUM> times the desired amount of lidocaine needs to be applied topically for the desired effect. In the case of an expensive medicant or a medicant having various side effects, it is undesirable to require application of such an excess of medicant in order to have the desired effect.

Low-frequency sonophoresis is a known method for enhancing transdermal drug delivery. However, these existing methods employ low-frequencies, low peak intensities, require long application times, or some combination of these to achieve improved transdermal drug delivery.

Microchannels can provide fluid communication between one side of a semi-permeable or impermeable membrane and an opposite side. However, transport of a transport target through a microchannel is slow and limited by diffusion and capillary forces. Document <CIT> relates to a method for conducting an ultrasound procedure using an ultrasound transmissive pad. Document <CIT> relates to an apparatus for tissue remodeling. Document <CIT> relates to an apparatus for oscillatory iontophoretic transdermal delivery of a therapeutic agent. Document <CIT> relates to microperforation of human skin for drug delivery.

Accordingly, a need exists for new systems and methods that overcome the aforementioned shortcomings.

The present disclosure overcomes the aforementioned drawbacks by presenting systems and methods (no methods are claimed) for material transport across an impermeable or semi-permeable membrane via artificially created microchannels.

In one aspect not being part of the invention, this disclosure provides a method for transporting a medicant across a stratum corneum layer of a skin and into a dermis layer of the skin. The method can include: contacting a top surface of the stratum corneum layer with the medicant; creating a microchannel in the membrane, the microchannel providing fluid communication between the top surface of the stratum corneum layer and an epidermis layer of the skin; directing a first acoustic energy field from an acoustic energy source or a first photon-based energy field from a photon-based energy source to the medicant, thereby driving the transport target through the microchannel and into the epidermis layer of the skin; and subsequent to the medicant being driven into the epidermis layer of the skin, applying a second acoustic energy field to the medicant, thereby driving the medicant from the epidermis layer of the skin and into the dermis layer of the skin.

In another aspect not being part of the invention, this disclosure provides a method for transporting a medicant across a stratum corneum layer of a skin and into a dermis layer of the skin. The method can include: inserting a hypodermic microneedle into the stratum corneum layer from a top surface, an interior of the hypodermic microneedle in fluid communication with a reservoir containing the medicant, the hypodermic microneedle providing fluid communication between the reservoir and the epidermis layer of the skin; directing a first acoustic energy field from an acoustic energy source or a first photon-based energy field from a photon-based energy source to the medicant, thereby driving the medicant through the microneedle and into the epidermis layer of the skin; and subsequent to the medicant being driven into the epidermis layer of the skin, applying a second acoustic energy field to the medicant, thereby driving the medicant from the epidermis layer of the skin and into the dermis layer of the skin.

In yet another aspect not being part of the invention, this disclosure provides a method for transporting a transport target across a membrane that is semi-permeable or impermeable to a transport target. The method can include: contacting a top surface of the membrane with the transport target; creating a microchannel in the membrane, the microchannel providing fluid communication between the top surface of the stratum corneum layer and an epidermis layer of the skin; directing a first acoustic energy field from an acoustic energy source or a first photon-based energy field from a photon-based energy source to the medicant, thereby driving the transport target through the microchannel and into the epidermis layer of the skin; and subsequent to the medicant being driven into the epidermis layer of the skin, applying a second acoustic energy field to the medicant, thereby driving the medicant from the epidermis layer of the skin and into the dermis layer of the skin.

In a further aspect not being part of the invention, this disclosure provides a method for transporting a transport target across a membrane that is semi-permeable or impermeable to a transport target. The method can include: inserting a hollow microneedle into the membrane from a top membrane surface, an interior of the hollow microneedle in fluid communication with a reservoir containing the transport target, the membrane having a bottom membrane surface opposite the top membrane surface, the hollow microneedle providing fluid communication between the reservoir and a first material layer contacting the bottom membrane surface; and directing a first acoustic energy field from an acoustic energy source or a first photon-based energy field from a photon-based energy source to the transport target, thereby driving the transport target through the microneedle and into the first material layer.

According to the invention, this disclosure provides a system according to claim <NUM>.

The foregoing and other aspects and advantage of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred aspect of the disclosure. Such aspect does not necessarily represent the full scope of the disclosure, however, and reference is made therefore to the claims and herein for interpreting the scope of the disclosure.

Before the present invention is described in further detail, it is to be understood that the invention is not limited to the particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. The scope of the present invention will be limited only by the claims. As used herein, the singular forms "a", "an", and "the" include plural embodiments unless the context clearly dictates otherwise.

Specific structures, devices, and methods relating to improved ultrasound treatment efficiency and operation are disclosed. It should be apparent to those skilled in the art that many additional modifications beside those already described are possible without departing from the inventive concepts. In interpreting this disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. Variations of the term "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, so the referenced elements, components, or steps may be combined with other elements, components, or steps that are not expressly referenced. Embodiments referenced as "comprising" certain elements are also contemplated as "consisting essentially of" and "consisting of" those elements.

When describing microneedles herein, it is contemplated that the disclosure encompasses solid microneedles, hollow microneedles, and hypodermic microneedles, unless the context clearly dictates otherwise.

This disclosure provides methods and systems for enhancing delivery of a transport target, such as a medicant, across a semi-permeable or impermeable membrane, such as the stratum corneum layer of skin, and into a first medium layer, such as an epidermis layer of skin. The systems and methods can also facilitate movement of the transfer target deeper into the first medium layer or into a second medium layer, such as the dermis layer of the skin, or a subsequent layer, such as subcutaneous tissue.

As will be described with respect to <FIG>, <FIG>, a delivery system <NUM> which is not part of the invention can include an ultrasound probe <NUM> and one or more microneedles <NUM> projecting from a bottom or other ultrasound probe surface <NUM>. The delivery system <NUM> can be positioned atop and coupled to an impermeable or semi-permeable membrane <NUM> having a top membrane surface <NUM>. The membrane <NUM> can be located above a first material layer <NUM> and an optional second material layer <NUM>. One or more optional subsequent material layers can also be present beneath the second material layer <NUM>. A region of interest <NUM> can be any contiguous location within the illustrated first material layer <NUM> or second material layer <NUM>, or within an unillustrated subsequent material layer. The ultrasound probe <NUM> can include an ultrasound source <NUM>, which can include one or more transducers <NUM>. The ultrasound source <NUM> and transducers <NUM> can be any of a variety of ultrasound sources or transducers known to one of skill in the art or developed in the future to be suitable for producing the ultrasound characteristics described herein. The one or more transducers <NUM> can each independently be a single transduction element, an array of transduction elements, or a group of arrays of transduction elements. The ultrasound probe <NUM> can be coupled to a power supply <NUM> and electronics <NUM> sufficient for the operation of an ultrasound system. The power supply <NUM> can be any power supply known to one of skill in the art to be suitable for powering an ultrasound probe. The electronics <NUM> can be those electronics known to one of skill in the art to be suitable for operating an ultrasound probe. The ultrasound probe <NUM> can be coupled to a control module <NUM> adapted to control the emission of ultrasound from the ultrasound probe <NUM>. The control module <NUM> can be a control module or controller known to one of skill in the art to be suitable for controlling the emission characteristics of an ultrasound probe <NUM>.

Examples of suitable power supplies <NUM> can include, but are not limited to, one or more direct current (DC) power supplies, single-use or rechargeable batteries, or other power supplies configured to provide electrical energy to the ultrasound probe <NUM>, including to the ultrasound source <NUM>, transducers <NUM>, electronics <NUM>, control modules <NUM>, or any other aspect of the ultrasound probe <NUM> that requires electrical energy. Associated sensors for monitoring the performance of the power supplies <NUM> are contemplated, such as current sensors, power sensors, and the like.

Examples of suitable electronics <NUM> can include, but are not limited to, amplifiers or drivers, such as multi-channel or single channel power amplifiers or drivers; power converters configured to adjust voltages; open-loop feedback systems; closed-loop feedback systems; filters, such as harmonic filters or matching filters; and the like.

Control modules <NUM> can include components suitable for controlling the emission characteristics of the ultrasound probe <NUM>, including but not limited to, a computing system adapted to control the ultrasound probe <NUM>; timing circuits; software and algorithms to provide control and user interfacing; input controls, such as switches, buttons, touchscreens, and the like; outputs, such as lighting or audio signals or displays; storage elements, such as memory to store calibration and usage data; and the like.

The delivery system <NUM> can also include sensors suitable for measuring certain aspects of the delivery system <NUM>. Examples of sensors include, but are not limited to, temperature sensors, motion sensors, location sensors, coupling sensors, such as capacitive or acoustic coupling sensors, and the like.

The transducer <NUM> can be configured as a spherically-focused single element transducer, an annular/multi-element transducer, an annular array having an imaging region, a line-focused single-element transducer, a one-dimensional linear array, a one-dimensional curved linear array, a two-dimensional array with a mechanical focus, a convex lens focus, a concave lens focus, a compound lens focus, or a multiple lens focus, a two-dimensional planar array, or other transducer arrangements suitable for producing the ultrasound energy described herein and corresponding effects.

Referring to <FIG>, the delivery system <NUM> is illustrated positioned above the top membrane surface <NUM>. A layer of coupling medium <NUM> is positioned atop the top membrane surface <NUM>. The coupling medium <NUM> can include a transport target <NUM>. In some aspects, the transport target <NUM> can be dispersed or dissolved in the coupling medium <NUM>. In some aspects, the coupling medium <NUM> itself can be the transport target <NUM>.

Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the delivery system <NUM> has been coupled to the top membrane surface <NUM>, and the microneedles <NUM> have punctured the membrane <NUM>, thereby creating microchannels <NUM> in the membrane <NUM>, and the ultrasound probe <NUM> has begun emitting a first ultrasound energy field <NUM>. The microchannels <NUM> extend over the full depth of the membrane <NUM>. The first acoustic energy field <NUM> can penetrate at least through the membrane <NUM> and at least partially into the first material layer <NUM>. In response to the first acoustic energy field <NUM>, the transport target <NUM> can be driven from above the top membrane surface <NUM>, into or through the microchannels <NUM>, and into the first material layer <NUM>.

It should be appreciated that there exist intermediate states between the state of the arrangement in <FIG> and that illustrated in <FIG>, where the delivery system <NUM> is positioned between the illustrated positions. There also exist intermediate states where the first acoustic energy field <NUM> penetrates only partially into the membrane <NUM>, or penetrates throughout the membrane <NUM>, but not into the first material layer <NUM>, or penetrates throughout the membrane <NUM> and partially into the first material layer <NUM> to a depth different than that illustrated. In similar intermediate states, the transport target <NUM> can penetrate only partially into the microchannels <NUM>, or penetrates throughout the microchannels <NUM>, but not into the first material layer <NUM>, or penetrates throughout the microchannels <NUM> and partially into the first material layer <NUM> to a depth different than that illustrated.

Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the ultrasound probe <NUM> has begun emitting a second acoustic energy field <NUM> that penetrates at least through the membrane <NUM>, the first material layer <NUM>, and partially into the second material layer <NUM>. In response to the second acoustic energy field <NUM>, the transport target <NUM> can be driven from the first material layer <NUM> to a deeper portion of the first material layer <NUM> or into the second material layer <NUM>.

It should be appreciated that there exist intermediate states between the state of the arrangement in <FIG> and that illustrated in <FIG>, where the second acoustic energy field <NUM> can penetrate throughout the first material layer <NUM>, but not into the second material layer <NUM>, or can penetrate into the second material layer <NUM> to a depth different than that illustrated. In similar intermediate states, the transport target <NUM> can penetrate throughout the first material layer <NUM>, but not into the second material layer <NUM>, or can penetrate into the second material layer <NUM> to a depth different than that illustrated.

Referring to <FIG>, the arrangement illustrated in <FIG>, and <FIG> is illustrated after the transport target <NUM> has been driven into the second material layer <NUM>. In the second material layer <NUM>, the transport target <NUM> can interact with constituents within the second material layer <NUM>. In certain aspects, a third acoustic energy field <NUM>, optionally referred to as a therapeutic energy field <NUM>, can be directed to a target volume <NUM> within the second material layer <NUM>. In certain aspects, the third acoustic energy field <NUM> is substituted for a therapeutic energy field <NUM> that can include a photon-based therapeutic energy field, which can be generated by a photon-based source as described elsewhere herein, or a radiofrequency ("RF") therapeutic energy field, which can be generated by an RF electrode. The target volume <NUM> can be located in the first material layer <NUM> or a subsequent material layer. The target volume <NUM> can be located in a portion of the second material layer <NUM> containing the transport target <NUM>.

The transport target <NUM> can be applied to the surface after the formation of the microchannels <NUM>. The microneedles <NUM> and the ultrasound probe <NUM> can be part of the same instrument or can be separate. In aspects where they are separate, a device containing the microneedles <NUM> can be used to form the microchannels <NUM>, the transport target <NUM> can be applied to the top membrane surface <NUM> prior to or subsequent to the formation of the microchannels <NUM>, and the ultrasound probe can be coupled to the transport target <NUM>, the top membrane surface <NUM>, and the microchannels <NUM>.

As will be described with respect to <FIG>, <FIG>, a delivery system <NUM> which is not part of the invention can include an ultrasound probe <NUM>, a standoff <NUM> including a transport target <NUM>, and one or more hollow microneedles <NUM> extending from a bottom standoff surface <NUM>. The delivery system <NUM> can include features described elsewhere herein. The standoff <NUM> can include a plurality of pores in the bottom standoff surface <NUM>, the plurality of pores each in fluid communication with the interior of a hollow microneedle <NUM>. The plurality of pores and the interiors of the hollow microneedles <NUM> can be in fluid communication with the transport target <NUM>. The plurality of pores can be of a size and shape that are sufficient to retain the transport target <NUM> within the standoff <NUM> when acoustic energy is not being applied. In certain aspects, the transport target <NUM> is retained in the standoff by virtue of a surface tension of the transport target <NUM>. In certain aspects, the standoff is a gel pack coupled to the ultrasound source <NUM>. In certain aspects, the standoff <NUM> can be rigid or flexible.

Referring to <FIG>, the delivery system <NUM> is positioned above the top membrane surface <NUM>. Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the delivery system <NUM> has been coupled to the top membrane surface <NUM> and the hollow microneedles <NUM> have punctured the membrane <NUM>, thereby traversing the membrane <NUM>, and the ultrasound probe <NUM> has begun emitting a first acoustic energy field <NUM>. The hollow microneedles <NUM> also produce microchannels <NUM> that extend over the full depth of the membrane <NUM>. The first acoustic energy field <NUM> can penetrate at least through the membrane <NUM> and at least partially into the first material layer <NUM>. In response to the first acoustic energy field <NUM>, the transport target <NUM> can be driven from the standoff <NUM> into the first material layer <NUM>.

It should be appreciated that there exist intermediate states between the state of the arrangement in <FIG> and that illustrated in <FIG>, where the delivery system <NUM> is positioned between the illustrated positions. There also exist intermediate states where the first acoustic energy field <NUM> penetrates only partially into the membrane <NUM>, or penetrates throughout the membrane <NUM>, but not into the first material layer <NUM>, or penetrates throughout the membrane <NUM> and partially into the first material layer <NUM> to a depth different than that illustrated. In similar intermediate states, the transport target <NUM> can penetrate only partially into the hollow microneedles <NUM>, or penetrates throughout the hollow microneedles <NUM>, but not into the first material layer <NUM>, or penetrates throughout the hollow microneedles <NUM> and partially into the first material layer <NUM> to a depth different than that illustrated.

Referring to <FIG>, the arrangement illustrated in <FIG>, and <FIG> is illustrated after the transport target <NUM> has been driven into the second material layer <NUM>. In the second material layer <NUM>, the transport target <NUM> can interact with constituents within the second material layer <NUM>. In certain aspects, a third acoustic energy field <NUM>, optionally referred to as a therapeutic acoustic energy field <NUM>, can be directed to a target volume <NUM> within the second material layer <NUM>. The target volume <NUM> can be located in a portion of the second material layer <NUM> containing the transport target <NUM>.

The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can be planar, focused, weakly focused, unfocused, or defocused. The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency in the range of about <NUM> to about <NUM>, including, but not limited to, a frequency in the range of about <NUM> to about <NUM>,, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or other combinations of the lower and upper limits of these ranges not explicitly recited. The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can be configured to avoid damaging the material in the membrane <NUM> or in the first material layer <NUM>.

The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can be pulsed or continuous wave. In the case of pulsed acoustic energy, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a pulse width ranging from <NUM> ns to <NUM> seconds, including but not limited to, a pulse width ranging from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM> seconds, <NUM> to <NUM>, from <NUM> to <NUM>, or from <NUM> to <NUM>.

In the case of pulsed acoustic energy, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM>, the pulses can be separated by a length of time ranging from <NUM> to <NUM>, including but not limited to, a length of time ranging from <NUM> to <NUM>.

The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a peak intensity ranging from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, including, but not limited to, a peak intensity ranging from <NUM> W/cm<NUM> to less than <NUM> W/cm<NUM>, from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, or other combinations of the lower and upper limits of these ranges not explicitly recited. The first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have an average intensity ranging from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, including but not limited to, an average intensity ranging from <NUM> W/cm<NUM> to <NUM> W/cm<NUM>, or from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>.

In certain applications, the acoustic energy produced by the systems and utilized by the methods described herein can be a high-frequency and high-intensity acoustic energy. For these applications, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency in the ranges disclosed above that are at least <NUM> and a peak intensity in the ranges disclosed above that are at least <NUM> W/cm<NUM>.

In certain applications, the acoustic energy produced by the systems and utilized by the methods described herein can be a low-frequency and low-intensity acoustic energy. For these applications, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency in the ranges disclosed above that are less than <NUM> and a peak intensity in the ranges disclosed above that are less than <NUM> W/cm<NUM>.

Acoustic energy utilized for the generation of inertial cavitation or acoustic streaming can have a pulse width ranging from nanoseconds to seconds. In an example of a set of parameters suitable for generating an inertial cavitation effect or acoustic streaming effect, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency ranging from <NUM> to <NUM>, and a peak intensity ranging from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>. As an example of a set of parameters suitable for generating an inertial cavitation effect or acoustic streaming, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency ranging from <NUM> to <NUM>, an average intensity ranging from <NUM> W/cm<NUM> to <NUM> kW/cm<NUM>, delivering a pressure ranging from <NUM> kPa to <NUM> MPa. As an example of a set of parameters suitable for generating an inertial cavitation effect, the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, or the third acoustic energy field <NUM> can have a frequency ranging from <NUM> to less than <NUM>, and a peak intensity ranging from <NUM> W/cm<NUM> to less than <NUM> W/cm<NUM>.

In certain applications, such as generating inertial cavitation in the microchannels <NUM> or microneedles <NUM>, the first acoustic energy field <NUM> can have a pulse width in a range from about <NUM> ns to about <NUM>. In these certain applications, the first acoustic energy field <NUM> can be pulsed and can have a pulse width in the range of about <NUM> to about <NUM> second, or in the range of about <NUM> seconds to about <NUM> seconds. In these certain applications, the first acoustic energy field <NUM> can have a peak intensity of greater than <NUM> W/cm<NUM> and less than or equal to about <NUM> kW/cm<NUM> at the top membrane surface <NUM>. The intensity of the first acoustic energy field <NUM> can be below a threshold value for creating a shock wave. A person having ordinary skill in the art will appreciate that this threshold value can vary based on material properties and the specific parameters of the ultrasound being used, and can determine this threshold value for specific materials and sets of parameters experimentally or computationally.

In certain applications, such as generating acoustic streaming providing acoustic streaming pressure to the microchannels <NUM>, the microneedles <NUM>, the first material layer <NUM>, or a combination thereof, the first acoustic energy field <NUM> can be pulsed and the pulses can have a pulse width in a range of about <NUM> to about <NUM>, including, but not limited to, a range of about <NUM> seconds to about <NUM> seconds. In these certain applications, the first acoustic energy field <NUM> can have a peak intensity in the range from about <NUM> W/cm<NUM> to about <NUM> kW/cm<NUM> at the top membrane surface <NUM>. Acoustic streaming can generate micro-channels having a transcellular route from the top membrane surface <NUM> to the first material layer <NUM>. In these certain applications, acoustic streaming generated by the first acoustic energy field <NUM> can create pressures ranging from about <NUM> kPa to about <NUM> MPa, including, but not limited to, pressures ranging from about <NUM> kPa to about <NUM> MPa and pressures ranging from about <NUM> MPa to about <NUM> MPa, in the microchannels <NUM>, the microneedles <NUM>, the first material layer <NUM>, or a combination thereof.

In certain applications, such as generating inertial cavitation and acoustic streaming to the microchannels <NUM>, the microneedles <NUM>, the first material layer <NUM>, or a combination thereof, the first acoustic energy <NUM> can provide two or more effects, such as inertial cavitation and acoustic streaming, simultaneously or alternating. In certain aspects, generating inertial cavitation and acoustic streaming can facilitate moving a larger medicant, such as a medicant with a molecular weight greater than <NUM> Da, through the membrane <NUM>.

In certain applications, the second acoustic energy <NUM> can be configured to generate inertial cavitation or acoustic streaming in the first material layer <NUM>, the second material layer <NUM>, or a combination thereof. In certain aspects, the second acoustic energy <NUM> can be configured to increase diffusion of the transport target <NUM> through the first material layer <NUM> and the second material layer <NUM>. In certain aspects, the second acoustic energy <NUM> can provide a pressure in a range from about <NUM> kPa to about <NUM> MPa to push the transport target <NUM> through the first material layer <NUM> and into the second material layer <NUM>.

It should be appreciated that the effects described herein are material-dependent, so the ultrasound energy necessary to generate inertial cavitation or acoustic streaming in one type of material might be different than the ultrasound energy necessary to generate inertial cavitation or acoustic streaming in a different type of material. It should also be appreciated that for a certain effect to be generated, the threshold for generating that effect must be exceeded. However, the thresholds for generating the effects described herein, such as inertial cavitation and subsequent acoustic streaming, in certain materials, such as tissues, are generally unknown.

With respect to inertial cavitation in tissue, aside from a single experimental study regarding the frequency-dependence of the threshold for inertial cavitation in canine skeletal muscle, a recent article by Church et al. states that "too little information on the experimental threshold for inertial cavitation in other tissues is available" to make conclusions regarding frequency-dependent trends. See, <NPL>). This observation is solely about the inertial cavitation threshold as it relates to frequency, and does not take into account the other spatial and temporal parameters aside from frequency. Accordingly, one of skill in the art should appreciate that the present invention is disclosed in terms of effects that have been shown to produce a specific result, i.e., transporting a medicant across the stratum corneum, and a set of general parameters that are suitable for achieving that result are set forth above. One of skill in the art should also appreciate that the presence of inertial cavitation can be identified by a characteristic broadband signal that is the result of the complex dynamics associated with inertial cavitation.

With respect to acoustic streaming, this effect can be generated by an effect including the aforementioned inertial cavitation or without the inertial cavitation. In instances without the inertial cavitation, acoustic streaming can be accomplished by introducing heat into a tissue, for example the stratum corneum, which expands the tissue, then applying a pressure to the medicant or a carrier containing the medicant to initiate acoustic streaming.

The inertial cavitation and acoustic streaming effects are described herein with respect to the discrete layers of the skin, but can penetrate to a greater depth beneath the skin surface to enhance the penetration of the medicant deeper into the skin or into subcutaneous tissue.

In certain aspects, the first acoustic energy <NUM> and the second acoustic energy <NUM> can be substantially the same. In certain aspects, the second acoustic energy <NUM> can have a frequency that concentrates the acoustic energy deeper and moves the transport target <NUM> into the second material layer <NUM>.

In certain aspects, the second acoustic energy <NUM> or third acoustic energy <NUM> can be configured to cause a thermal effect in the first material layer <NUM> or the second material layer <NUM>, which is non-destructive to the first material layer <NUM> or second material layer <NUM>. The thermal effect can elevate the temperature of the first material layer <NUM> or the second material layer <NUM>, which can enhance dispersion of the transport target <NUM> within the first material layer <NUM> or the second material layer <NUM>.

The first acoustic energy <NUM>, second acoustic energy <NUM>, or third acoustic energy <NUM> can be generated from one or more ultrasound sources.

In certain aspects, the delivery system <NUM> can be configured to create an intensity gain from the delivery system <NUM> to the target volume <NUM> of at least about <NUM>, including, but not limited to, an intensity gain of at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. In aspects having a focused or a strongly focused ultrasound, the delivery system <NUM> can be configured to create an intensity gain from the delivery system <NUM> to the target volume <NUM> of at least about <NUM>, including, but not limited to, an intensity gain of at least about <NUM>, or at least about <NUM>, or a gain ranging from <NUM> to <NUM>,<NUM>. In aspects having a weakly focused ultrasound, the delivery system <NUM> can be configured to create an intensity gain from the delivery system <NUM> to the target volume <NUM> of at least about <NUM> or a gain ranging from <NUM> to <NUM>.

In certain aspects with pulsed ultrasound, a first pulse can be ultrasound having a first type of focus, a second pulse can be ultrasound having a second type of focus, a third pulse can be ultrasound having the first type of focus or a third type of focus, and so on. Any of a variety of combinations of focused, defocused, or unfocused energy can be used for any of the various pulses.

In certain aspects, the first acoustic energy <NUM>, second acoustic energy <NUM>, or third acoustic energy <NUM> can create a thermal effect, a mechanical effect, or a combination thereof in the target volume <NUM>. A mechanical effect is a non-thermal effect within a medium that is created by acoustic energy. A mechanical effect can be one of, for example, acoustic resonance, acoustic streaming, disruptive acoustic pressure, shock waves, inertial cavitation, and non-inertial cavitation.

The thermal effect can elevate the temperature by about <NUM> to about <NUM>, including but not limited to, elevating the temperature by about <NUM> to about <NUM> or by about <NUM> to about <NUM>.

Referring to <FIG>, a variation on the delivery system <NUM> which is not part of the invention is a roller delivery system <NUM>. The roller delivery system <NUM> can take a variety of shapes that are suitable for rolling along a surface, but is illustrated as a cylinder <NUM> comprising a plurality of microneedles <NUM> projecting from an outer cylinder surface <NUM>. The roller delivery system <NUM> can be coupled to a top membrane surface <NUM> and can be moved along a direction <NUM> by a user or another means of impulsion, including but not limited to, robotic means of impulsion, automatic means of impulsion, and the like. A layer of coupling medium <NUM> including a transport target <NUM> can be positioned atop the top membrane surface <NUM>. When moving along the top membrane surface <NUM>, the microneedles <NUM> can puncture the membrane <NUM>, thereby producing microchannels <NUM> in the membrane. The microchannels <NUM> can extend over the full depth of the membrane <NUM>.

In one aspect, the roller delivery system <NUM> can be configured to direct a first acoustic energy field <NUM> into an area including a microchannel <NUM>, thereby driving the transport target <NUM> into or through the microchannel <NUM>. The transport target <NUM> can be directed into the first material layer <NUM> by the first acoustic energy field <NUM>. The transport target <NUM> can then diffuse deeper into the first material layer <NUM> or into the second material layer <NUM>, or can be driven deeper into the first material layer <NUM> or into the second material layer <NUM> by a subsequent acoustic energy field (not pictured). In some aspects, the ultrasound <NUM> can include multiple transducers <NUM> or transduction elements that are fired in a time fashion to continue directing the first acoustic energy field <NUM> into the microchannel <NUM> even as the roller delivery system <NUM> moves along the direction <NUM> and away from the microchannel <NUM>.

The roller delivery system <NUM> can include a position sensor <NUM> for sensing the position of the roller delivery system <NUM> as it moves in the direction <NUM>. The roller delivery system <NUM> can include an orientation sensor <NUM> for sensing the relative orientation of the microneedles <NUM> in relation to the ultrasound source <NUM>. The roller delivery system <NUM> can include one or more of the features described elsewhere for the delivery system <NUM>.

Referring to <FIG>, the roller delivery system <NUM> can be configured to direct a therapeutic energy field <NUM>, such as an acoustic energy field, into a target volume <NUM>. The target volume <NUM> can be located beneath a microchannel <NUM>. To achieve this, the control module <NUM> can be programmed with the distance between microneedles <NUM>, which is the distance between the microchannels <NUM> that they create in the membrane. The control module <NUM> can then direct the ultrasound source <NUM> to direct the therapeutic energy field <NUM> to the target volume <NUM> in a pulsed manner after the roller delivery system <NUM> has moved the distance between the microchannels <NUM>. Alternatively, or in combination, the control module <NUM> can be programmed to receive from the orientation sensor <NUM> the relative orientation of the microneedles <NUM> relative to the ultrasound source <NUM>, and can be programmed to direct the ultrasound source <NUM> to direct the therapeutic energy field <NUM> to the target volume <NUM> in a pulsed manner when the orientation sensor <NUM> indicates that a microneedle is located beneath the ultrasound source <NUM>.

Referring to <FIG>, the roller delivery system <NUM> can include an ultrasound source <NUM> that is not contained within the cylinder <NUM>. In this aspect, the ultrasound source <NUM> can direct a first acoustic energy field <NUM>, a second acoustic energy field <NUM>, or other acoustic energy field described herein into the microchannel <NUM>, the membrane <NUM>, the first material layer <NUM>, the second material layer <NUM>, or a combination thereof.

In some aspects, the cylinder <NUM> and the ultrasound source <NUM> are contained within the same device. In some aspects, the cylinder <NUM> and the ultrasound source <NUM> are contained in different devices.

The roller delivery system <NUM> can further include one or more of the aspects disclosed in <CIT>.

As will be discussed with respect to <FIG>, <FIG>, a delivery system <NUM> which is not part of the invention can be in the form of a photon-emitting delivery system <NUM>. The photon-emitting delivery system <NUM> can include a photon probe <NUM> including a photon source <NUM> and features of the delivery system <NUM> described elsewhere herein, in particular, features described with respect to <FIG>, <FIG>. In some aspects, the photon-emitting delivery system <NUM> can include can include the photon probe <NUM>, the photon source <NUM>, a standoff <NUM> including a transport target <NUM>, and one or more hollow microneedles <NUM> extending from the bottom standoff surface <NUM>.

Referring to <FIG>, the photon-emitting delivery system <NUM> is positioned above the top membrane surface <NUM>. Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the photon-emitting delivery system <NUM> has been coupled to the top membrane surface <NUM> and the hollow microneedles <NUM> have punctured the membrane <NUM>, thereby creating microchannels <NUM> in the membrane <NUM>, and the photon probe <NUM> has begun emitting a first photon-based energy field <NUM>. The first photon-based energy field <NUM> can be directed into the standoff <NUM> and is configured to move the transport target <NUM> through the hollow microneedles <NUM> and into the first material layer <NUM>. In some aspect, the first photon-based energy field <NUM> can be configured to initiate a photoacoustic effect within the standoff to generate pressure that causes the transport target <NUM> to move through the hollow microneedles <NUM> and into the first material layer <NUM>. Without wishing to be bound by any particular theory, it is believed that the photoacoustic effect can create a rapid thermalization via absorption of the first photon-based energy field <NUM>, which can initiate an expansion of the transport target <NUM> in the location where the first photon-based energy field <NUM> is delivered, thereby producing an acoustic wave.

In certain aspects, the standoff <NUM> can be configured as an acoustic amplifier, which can amplify the Q factor of the photoacoustic energy generated by the first photon-based energy field <NUM> from <NUM> times to <NUM> times.

In certain aspects, the photon-emitting delivery system <NUM> can be configured in the same fashion as the delivery system <NUM> described with respect to <FIG>, <FIG>, and the first photon-based energy field can be configured to drive the transport target <NUM> through the microchannels <NUM> and into the first material layer <NUM>.

Referring to <FIG>, the photon-emitting delivery system <NUM> can optionally include the ultrasound probe <NUM> and can function in the fashion described above for <FIG> with respect to the delivery system <NUM>.

Referring to <FIG>, the photon-emitting delivery system can optionally deliver a therapeutic energy field <NUM> to a target volume <NUM> in the second material layer <NUM> as described elsewhere herein. The therapeutic energy field <NUM> that can include an acoustic therapeutic energy field, which can be generated by the ultrasound source <NUM>, a photon-based therapeutic energy field, which can be generated by a photon source <NUM>, or an RF therapeutic energy field, which can be generated by an RF electrode.

It should be appreciated that there exist intermediate states between the state of the arrangement in <FIG> and that illustrated in <FIG>, between the state of the arrangement in <FIG> and that illustrated in <FIG>, and between the state of the arrangement in <FIG> and that illustrated in <FIG>, as described elsewhere herein.

As will be described with respect to <FIG>, <FIG>, and <FIG>, a delivery system <NUM> according to the invention is in the form of a remote microchannel generating delivery system <NUM>. The delivery system <NUM> includes an ultrasound probe <NUM> and a remote microchannel probe <NUM>. The remote-microchannel probe <NUM> can include a photon source <NUM> configured to ablate the membrane <NUM> and optionally the first material layer <NUM> or second material layer <NUM> in a spatially-controlled fashion to generate microchannels <NUM> therein.

Referring to <FIG>, the delivery system <NUM> is illustrated positioned above the top membrane surface <NUM>. A layer of coupling medium <NUM> is positioned atop the top membrane surface <NUM>. The coupling medium <NUM> includes a transport target <NUM>. In some aspects, the transport target <NUM> can be dispersed or dissolved in the coupling medium <NUM>. In some aspects, the coupling medium <NUM> itself can be the transport target <NUM>. The remote microchannel probe <NUM> has begun emitting a second photon-based energy field <NUM> into the membrane <NUM> and partially into the first material layer <NUM>.

Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the remote microchannel probe <NUM> has generated microchannels <NUM> in the membrane <NUM>.

Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the ultrasound probe <NUM> has begun emitting a first ultrasound energy field <NUM>. The microchannels <NUM> extend over the full depth of the membrane <NUM>. The first acoustic energy field <NUM> can penetrate at least through the membrane <NUM> and at least partially into the first material layer <NUM>. In response to the first acoustic energy field <NUM>, the transport target <NUM> can be driven from above the top membrane surface <NUM>, into or through the microchannels <NUM>, and into the first material layer <NUM>.

Referring to <FIG>, the arrangement illustrated in <FIG> is illustrated after the transport target <NUM> has been driven into the second material layer and a therapeutic energy field <NUM> has been directed to a target volume <NUM> within the second material layer <NUM>. The operation illustrated in <FIG> can function substantially the same as that described above with respect to <FIG>.

It should be appreciated that there exist intermediate states between the state of the arrangement in <FIG> and that illustrated in <FIG>, between the state of the arrangement in <FIG> and that illustrated in <FIG>, between the state of the arrangement in <FIG> and that illustrated in <FIG>,, and between the state of the arrangement in <FIG> and that illustrated in <FIG>, as described elsewhere herein.

Referring to <FIG>, multiple devices, including a microchannel device <NUM> comprising a microchannel creation means <NUM>, a first ultrasound device <NUM>, a second ultrasound device <NUM>, and a third ultrasound device <NUM>, can be configured individually or as a part of a single system to independently or cooperatively provide delivery of a transport target <NUM>. The microchannel device <NUM> comprising the microchannel creation means <NUM> is configured to create a microchannel <NUM> through the membrane <NUM>. The microchannel creation means <NUM> can be one of a variety of the systems or methods described herein as being capable of producing a microchannel <NUM>. For example, the microchannel creation means <NUM> can employ one or more acoustic energy fields, such as those described elsewhere herein. The microchannel creation means <NUM> can also include one or more microneedles. The microchannel creation means <NUM> can include a second photon-based energy field <NUM> configured to generate microchannels <NUM> in the membrane <NUM>.

The microchannel device <NUM>, the first ultrasound device <NUM>, the second ultrasound device <NUM>, and the third ultrasound device <NUM> can move from right to left across the illustrated top membrane surface <NUM>, either collectively or independently. A coupling medium <NUM> can be applied to the top membrane surface <NUM> before or after the microchannel creation means <NUM> has created a microchannel <NUM>. If the microchannel device <NUM>, the first ultrasound device <NUM>, the second ultrasound device <NUM>, and the third ultrasound device <NUM> are operating in series, then the coupling medium <NUM> is typically applied to the top membrane surface <NUM> after the microchannel creation means <NUM> has created the microchannel <NUM> to avoid loss of the transport target <NUM> or contamination of the transport target <NUM> by the microchannel creation means <NUM>. The microchannel device <NUM>, the first ultrasound device <NUM>, the second ultrasound device <NUM>, and the third ultrasound device <NUM> can be controlled by a control module <NUM>, either collectively or independently. In certain aspects, the microchannel device <NUM>, the first ultrasound device <NUM>, the second ultrasound device <NUM>, and the third ultrasound device <NUM> can each be housed in individual cylinders or spheres that are configured to roll across the top membrane surface <NUM>.

The first ultrasound device <NUM> can be configured to direct a fourth acoustic energy field <NUM> into the top membrane surface <NUM>. The fourth acoustic energy field <NUM> can be configured to drive the transport target <NUM> through the microchannel <NUM>. In certain aspect, the fourth acoustic energy field <NUM> can have the properties of the first acoustic energy field <NUM>, as described herein.

The second ultrasound device <NUM> can be configured to direct a fifth acoustic energy field <NUM> into the top membrane surface <NUM>. The fifth acoustic energy field <NUM> can be configured to drive the transport target <NUM> through the first material layer <NUM> and optionally through the second material layer <NUM>. In certain aspects, the fifth acoustic energy field <NUM> can have the properties of the second acoustic energy field <NUM>, as described herein.

The third ultrasound device <NUM> can be configured to direct a sixth acoustic energy field <NUM> into the top membrane surface <NUM>. The sixth acoustic energy field <NUM> can be configured to interact with the transport target <NUM> or with tissue containing or proximate to the transport target <NUM>. In certain aspect, the sixth ultrasound acoustic energy field <NUM> can have the properties of the third acoustic energy field <NUM>, as described herein.

In addition to the first acoustic energy field <NUM>, the second acoustic energy field <NUM>, the third acoustic energy field <NUM>, the fourth acoustic energy field <NUM>, the fifth acoustic energy field <NUM>, or the sixth acoustic energy field <NUM>, the methods described herein can utilize additional acoustic energy fields configured to provide one or more effects described herein.

Referring to <FIG>, this disclosure provides a method (not claimed) <NUM> for transporting a transport target across a membrane. At process block <NUM>, the method <NUM> can include contacting a top surface of the membrane with the transport target. At process block <NUM>, the method <NUM> can include creating a microchannel in the membrane. At process block <NUM>, the method <NUM> can include directing an acoustic energy field or a photon-based energy field to the transport target, thereby driving the transport target through the microchannel.

Referring to <FIG>, this disclosure provides a method (not claimed) <NUM> for transporting a transport target across a membrane. At process block <NUM>, the method <NUM> can include creating a microchannel in the membrane. At process block <NUM>, the method <NUM> can include contacting a top surface of the membrane with the transport target. At process block <NUM>, the method <NUM> can include directing an acoustic energy field or a photon-based energy field to the transport target, thereby driving the transport target through the microchannel.

Referring to <FIG>, this disclosure provides a method (not claimed) <NUM> for transporting a transport target across a membrane. At process block <NUM>, the method <NUM> can include contacting a top surface of the membrane with the transport target. At process block <NUM>, the method <NUM> can include inserting a hollow microneedle in the membrane. At process block <NUM>, the method can include directing an acoustic energy field or a photon-based energy field to the transport target, thereby driving the transport target through the microneedle.

Referring to <FIG>, this disclosure provides a method (not claimed) <NUM> for transporting a transport target across a membrane. At process block <NUM>, the method <NUM> can include inserting a hollow microneedle in the membrane. At process block <NUM>, the method <NUM> can include contacting a top surface of the membrane with the transport target. At process block <NUM>, the method can include directing an acoustic energy field or a photon-based energy field to the transport target, thereby driving the transport target through the microneedle.

A person having ordinary skill in the art will appreciate that in some aspects, the properties of the transport target can help determine whether the transport target is applied to the surface prior to or subsequent to the generation of microchannels and/or the insertion of microneedles. For example, if the means of generating the microchannels involves.

In certain aspects, the membrane <NUM> can be a stratum corneum layer of skin, the top membrane surface <NUM> can be a surface of skin, the first material layer <NUM> can be an epidermis layer of skin, and the second material layer <NUM> can be a dermis layer of skin. When the transport target <NUM> has been delivered to the dermis layer of skin, the transport target <NUM> can interact with the tissue therein or enter the blood stream via capillaries.

The transport target <NUM> can be mixed into or can be a component of a carrier. The carrier can be biocompatible. Examples of a biocompatible carrier include, but are not limited to, glycerin, liposomes, nanoparticles, microbubbles, and the like. In certain aspects, the carrier can enhance and/or lower the threshold for inertial cavitation.

The transport target <NUM> can be a medicant.

In certain aspect, the methods described herein can achieve transport of greater than <NUM>µL per minute of the transport target <NUM> across the membrane <NUM>, including, but not limited to, greater than <NUM>µL per minute, greater than <NUM>µL per minute, greater than <NUM>µL per minute, greater than <NUM>µL per minute, greater than <NUM>µL per minute, or greater than <NUM>µL per minute of transport target <NUM> across the membrane <NUM>.

The medicant can be mixed into or be a component of an acoustic coupling medium. In some embodiments, an acoustic coupling medium, such as an acoustic coupling gel or an acoustic coupling cream, can comprise the medicant. In some embodiments, a medicant is administered to a skin surface above the ROI. In some applications, the medicant can be the acoustic coupling medium. In some applications, the medicant can be a combination of medicants, such as combinations of those described herein.

A medicant can comprise an anesthetic. In some aspects, the anesthetic can comprise lidocaine, benzocaine, prilocaine, tetracaine, novocain, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, tetracaine, or any combination thereof. The anesthetic an eliminate or reduce the pain generated by the application of ultrasound energy to the skin, for example, the creation of the micro-channels in the skin by ultrasound energy. The anesthetic can constrict blood flow, which can eliminate or reduce blood flowing that emerges to the skin surface by way of damage from the application of ultrasound energy to the skin, for example, blood flowing up a micro-channel generated by ultrasound energy and onto the skin surface. Further, the use of an anesthetic, such as lidocaine, in the acoustic coupling medium substantially eliminates skin irritation from the application of ultrasound energy, such as the ultrasound-induced creation of micro-channels penetrating the skin surface.

A medicant can comprise a drug, a vaccine, a nutraceatical, or an active ingredient. A medicant can comprise blood or a blood component, an allergenic, a somatic cell, a recombinant therapeutic protein, or other living cells that are used as therapeutics to treat diseases or as actives to produce a cosmetic or a medical effect. A medicant can comprise a biologic, such as for example a recombinant DNA therapy, synthetic growth hormone, monoclonal antibodies, or receptor constructs. A medicant can comprise stem cells.

A medicant can comprise adsorbent chemicals, such as zeolites, and other hemostatic agents are used in sealing severe injuries quickly. A medicant can comprise thrombin and/or fibrin glue, which can be used surgically to treat bleeding and to thrombose aneurysms. A medicant can comprise Desmopressin, which can be used to improve platelet function by activating arginine vasopressin receptor 1A. A medicant can comprise a coagulation factor concentrates, which can be used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. A medicant can comprise a Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma, which can be used as coagulation factor products. A medicant can comprise recombinant activated human factor VII, which can be used in the treatment of major bleeding. A medicant can comprise tranexamic acid and/or aminocaproic acid, which can inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. A medicant can comprise platelet-rich plasma (PRP), mesenchymal stem cells, or growth factors. For example, PRP is typically a fraction of blood that has been centrifuged. The PRP is then used for stimulating healing of the injury. The PRP typically contains thrombocytes (platelets) and cytokines (growth factors). The PRP may also contain thrombin and may contain fibenogen, which when combined can form fibrin glue.

In addition, a medicant can comprise a steroid, such as, for example, like the glucocorticoid cortisol. A medicant can comprise an active compound, such as, for example, alpha lipoic Acid, DMAE, vitamin C ester, tocotrienols, and/or phospholipids. A medicant can comprise a pharmaceutical compound such as for example, cortisone, Etanercept, Abatacept, Adalimumab, or Infliximab. A medicant can comprise Botox. A medicant can comprise lignin peroxidase, which can be derived from fungus and can be used for skin lightening applications. A medicant can comprise hydrogen peroxide, which can be used for skin lighting applications.

The medicant can comprise an anti-inflammatory agent, such as, for example, a non-steroidal anti-inflammatory drug (NSAID), such as aspirin, celecoxib (Celebrex), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), ibuprofen (Motrin), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (Amigesic), sulindac (Clinoril), or tolmetin (Tolectin).

Still further, a medicant can comprise an active ingredient which provides a cosmetic and/or therapeutic effect to the area of application on the skin. Such active ingredients can include skin lightening agents, anti-acne agents, emollients, non-steroidal anti-inflammatory agents, topical anesthetics, artificial tanning agents, antiseptics, anti-microbial and anti-fungal actives, skin soothing agents, sunscreen agents, skin barrier repair agents, anti-wrinkle agents, anti-skin atrophy actives, lipids, sebum inhibitors, sebum inhibitors, skin sensates, protease inhibitors, skin tightening agents, anti-itch agents, hair growth inhibitors, desquamation enzyme enhancers, anti-glycation agents, compounds which stimulate collagen production, and mixtures thereof.

Other examples of such active ingredients can include any of panthenol, tocopheryl nicotinate, benzoyl peroxide, <NUM>-hydroxy benzoic acid, flavonoids (e.g., flavanone, chalcone), farnesol, phytantriol, glycolic acid, lactic acid, <NUM>-hydroxy benzoic acid, acetyl salicylic acid, <NUM>-hydroxybutanoic acid, <NUM>-hydroxypentanoic acid, <NUM>-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate), azelaic acid, arachidonic acid, tetracycline, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, <NUM>,<NUM>,<NUM>'-trichloro-<NUM>'-hydroxy diphenyl ether, <NUM>,<NUM>,<NUM>'-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline, and mixtures thereof.

A medicant can be a natural or synthetic compound or a combination of compounds, or a drug, or a biologic, as described herein, or is known to one skilled in the art, or is developed in the future.

A medicant can be diluted with an appropriate solvent for delivery. For example, a medicant can be diluted or mixed with a solvent to lower viscosity to improve transfer of the medicant. For example, a medicant can be diluted or mixed with a solvent that is a vehicle for transfer of the medicant, such as, for example, mixing a medicant with a formulation of polyethylene glycol (PEG). In some applications, the medicant can be mixed with a solvent to improve a tissue effect, such as uptake into the tissue, such as, for example, mixing a medicant with dimethyl sulfoxide (DMSO). In some applications, the medicant can be mixed with a solvent, which can restrict or inhibit an ultrasound energy effect. For example, a medicant can be mixed with ethanol (EtOH), which inhibits the thermal effect of ablation. In some applications, the medicant can be mixed with a solvent, which can amplify an ultrasound energy effect. For example, a medicant can be mixed with a contrast agent, which can be configured to promote higher attenuation and/or cavitation at lower acoustic pressures.

A medicant can be in a non-liquid state. In some applications, a medicant can be a gel or a solid, which by using a thermal effect, can melt into a liquid state suitable for delivery. For example, a medicant can be mixed into a thermally responsive hydrogel, which is configured to transform into an injectable state upon receiving a suitable amount of thermal energy emitted from a transducer.

In some aspects, a medicant can be administered to a skin surface above the ROI. The medicant can be mixed into or be a component of an acoustic coupling medium. In some applications, the medicant can be the acoustic coupling medium. In some aspects, the acoustic coupling medium can comprise a preservative and/or a preservative enhancer, such as, for example, water-soluble or solubilizable preservatives including Germall <NUM>, methyl, ethyl, propyl and butyl esters of hydroxybenzoic acid, benzyl alcohol, sodium metabisulfite, imidazolidinyl urea, EDTA and its salts, Bronopol (<NUM>-bromo-<NUM>-nitropropane- -<NUM>,<NUM>-diol) and phenoxypropanol; antifoaming agents; binders; biological additives; bulking agents; coloring agents; perfumes, essential oils, and other natural extracts.

In general, the microneedles <NUM> described herein can be solid or hollow. The microneedle <NUM> can have a length ranging from <NUM> to <NUM>. The microneedles <NUM> can be arranged in an array having a microneedle concentration ranging from <NUM> microneedles per cm<NUM> to <NUM> microneedles per cm<NUM>. The microneedle can have a diameter of <NUM> gauge or smaller (i.e. a higher gauge value), including but not limited to, <NUM> gauge or smaller, <NUM> gauge or smaller, or a diameter in the range of <NUM> gauge to <NUM> gauge. The microneedle <NUM> can have a substantially consistent diameter along their length or can have a diameter that varies along their length. In certain aspects, the microneedle <NUM> can have a diameter that tapers to form a point at a tip of the microneedle <NUM>. In some aspects, the microneedle can have a diameter, length, or both sufficiently small to prevent pain for being registered in a patient or to prevent bleeding within a patient upon insertion into the patient's skin.

In certain aspects, the ultrasound energy fields described herein can be coupled into the microneedles <NUM>. This can cause a vibration in the microneedles <NUM> that can be sensed by a patient if the ultrasound energy field has a low enough frequency. This can also cause a thermal effect in the microneedles <NUM> if the ultrasound energy field is configured to produce a thermal effect. These effects can relieve pain or assist in healing.

In certain aspects, the delivery system <NUM> can be configured as a transdermal patch. For example, the delivery system <NUM> can be configured for off-the-shelf operation, where the delivery system <NUM> include the medicant in appropriate dosage within the standoff <NUM> and a suitable portable power supply, such as battery power, to power the delivery system <NUM>. After removing any packaging for the delivery system <NUM>, the delivery system <NUM> can be applied to a location by a patient or a user. In certain aspects, the delivery system <NUM> can include an adhesive material on the bottom surface of the standoff <NUM> or a patch that extends over the delivery system <NUM> to facilitate retention of coupling between the delivery system <NUM> and the skin surface.

In certain aspects, the delivery system <NUM> can have an on-off switch or a separate on-off device that allows a patient or user to turn the delivery system <NUM> on (and subsequently off) when the delivery system <NUM> is properly located on the skin surface. The delivery system <NUM> can utilize at least one ultrasound energy effect to move the medicant from the standoff <NUM> to below the skin surface.

A delivery system <NUM> as described herein can have significant advantages over a traditional transdermal patch. For example, the delivery system <NUM> can deliver medicants having a higher molecular weight, for example, medicants having a molecular weight of at least about <NUM> Da or at least about <NUM> Da. As another example, the delivery system <NUM> does not rely on mechanical diffusion, so lower doses of the medicant can be deployed because more of the medicant reaches areas beneath the skin surface. As yet another example, the delivery system <NUM> is not limited to deploying medicants having an affinity for both lipophilic and hydrophilic phases or medicants that are non-ionic. In certain aspects, the delivery system <NUM> can include a solar panel, which can optionally be no bigger than the area of a patch covering the delivery system <NUM>, to supplement power to the delivery system <NUM>.

In certain aspects, the microneedles <NUM> can be retracted inside the delivery system <NUM>. Once the delivery system <NUM> has been positioned, the microneedles <NUM> can be extended to puncture the membrane <NUM>. Once the membrane <NUM> has been punctured, the microneedles <NUM> can optionally be retracted again.

The membrane <NUM> can have a thickness ranging from <NUM> to <NUM>, including but not limited to, a thickness ranging from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, or other combinations of the lower and upper limits of these ranges not explicitly recited.

In certain aspects, the microchannels <NUM> can have a diameter ranging from <NUM> to <NUM>. The microchannels <NUM> can have a depth ranging from <NUM> to <NUM>.

The photon source <NUM> can be a laser, a light-emitting diode ("LED"), an intense pulsed light source, or a combination thereof. In certain aspect, the photon source <NUM> can be an Er:YAG laser emitting light at <NUM>, a CO<NUM> laser emitting light at <NUM>, a nanosecond Q-switched laser, a picosecond laser, a femtosecond laser, or other light source that a person having ordinary skill in the art would identify as capable of initiating a photoacoustic effect or generating microchannels in the membrane <NUM>.

The systems and methods described herein can be employed in numerous clinical applications. For example, a treatment for scars can include a medicant directed by acoustic energy through micro-channels to a scar location. A second acoustic energy can be directed to the scar location and be configured to interact with the medicant to remodel and/or modify the scar tissue and eventually replace the scar tissue via remodeling. The treatment can also include directing therapeutic acoustic energy into the scar tissue. In some applications, the therapeutic acoustic energy can be configured to ablate a portion of the scar tissue, thereby removing a portion of the scar tissue. In some applications, the therapeutic acoustic energy can be configured to create a lesion in or near the scar tissue, thereby facilitating skin tightening above the lesion. In some applications, the therapeutic acoustic energy can be configured to remodel and/or increase an amount of collagen around the scar tissue, thereby replacing portions of the scar tissue with newly formed collagen.

In another example, the systems and methods described herein can be used in the treatment of hyperpigmentation. A medicant can be a skin lightening agent, which can be an active ingredient that improves hyperpigmentation. Without being bound by theory, use of skin lightening agents can effectively stimulate the epidermis, particularly the melanocyte region, where the melanin is generated. The combined use of the skin lightening agent and ultrasound energy can provide synergistic skin lightening benefit. A medicant comprise a skin lightening agent, such as, for example, ascorbic acid compounds, vitamin B3 compounds, azelaic acid, butyl hydroxyanisole, gallic acid and its derivatives, glycyrrhizinic acid, hydroquinone, kojic acid, arbutin, mulberry extract, and mixtures thereof. Use of combinations of skin lightening agents can be advantageous as they may provide skin lightening benefit through different mechanisms.

In one aspect, a combination of ascorbic acid compounds and vitamin B3 compounds can be used. Examples of ascorbic acid compounds can include L-ascorbic acid, ascorbic acid salt, and derivatives thereof. Examples of ascorbic acid salts include sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine salts. Examples of ascorbic acid derivatives include for example, esters of ascorbic acid, and ester salts of ascorbic acid. Examples of ascorbic acid compounds include <NUM>-O-D-glucopyranosyl-L-ascorbic acid, which is an ester of ascorbic acid and glucose and usually referred to as L-ascorbic acid <NUM>-glucoside or ascorbyl glucoside, and its metal salts, and L-ascorbic acid phosphate ester salts such as sodium ascorbyl phosphate, potassium ascorbyl phosphate, magnesium ascorbyl phosphate, and calcium ascorbyl phosphate. In addition, medicant can comprise lignin peroxidase, which can be derived from fungus used for skin lightening applications. In another example, medicant can comprise hydrogen peroxide, which can be used for skin lighting applications.

In an exemplary application, a coupling agent can comprise a medicant, which comprises a skin lighting agent. Ultrasound energy can direct the lightening agent into the epidermis and into contact with melanin. The lightening agent can remove excess melanin. Additional ultrasound energy can be directed to the epidermis to provide a cavitation effect to break up the excess melanin pigment. In some examples, additional ultrasound energy can be directed to the epidermis to provide a thermal effect, which can be configured to increase the effectiveness of the skin lightening agent. In one example, the skin lightening agent can be hydrogen peroxide and the ultrasound energy can increase the temperature of the hydrogen peroxide by at least <NUM> and to about <NUM>, which increases the effectiveness of the skin lightening agent.

In another example of a clinical application, the systems and methods described herein can be used in the treatment of hypopigmentation. In an exemplary application, a coupling agent can comprise a medicant, which can comprise a corticosteroid. Ultrasound energy can direct the corticosteroid into the epidermis at the light colored areas of the skin. A second ultrasound energy can be directed to the treatment location and be configured to interact with the corticosteroid to provide a synergistic treatment to increase pigment concentration at the treatment location. A second energy, such as, a photon-based energy from a laser can be directed to the treatment location to further increase the pigment concentration in the treatment location. A third energy, such as, ultrasound energy can be directed to the treatment location to disperse the generated pigment and provide an even coloring pattern at the treatment location.

In another example, large molecule medicants can be delivered using the systems and methods described herein. A large molecule can be greater than <NUM> Da. A large molecule can be a medicinal product manufactured in or extracted from biological sources. Examples of large molecule include vaccines, blood or blood components, allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein and living cells. In one example, a large molecule comprises stem cells. An energy effect is provided by an acoustic energy field, which is configured to drive the large molecule through the micro-channels and into subcutaneous tissue. The energy effect can be acoustic streaming and/or cavitation. In some applications, the energy effect is a thermal effect, which can be configured to lower the viscosity of a large molecule for improved transfer through the micro-channels.

In another example, chemotherapy drugs can be delivered using the systems and methods described herein. Some of the advantages, of using such systems and methods, include concentrating the chemotherapy drug to the tumor site (as opposed to exposing the whole body to the drug), lower doses may be required (due to the site specific treatment), and greater effectiveness of the drug.

In some applications, a chemotherapy drug can be a large molecule. In some applications, the systems and methods, described herein, can deliver anti-body drug conjugates, which target cancer stem cells to destroy a tumor. In some applications, a chemotherapy drug is a liposome encapsulated chemotherapy drug, which can be delivered through the micro-channels to a treatment site by an acoustic energy field, and then a second acoustic energy field can be delivered to melt the liposome and release the chemotherapy drug. In some applications, an acoustic energy field can be delivered, which is configured to provide micro-bubbles (cavitation) to a tumor in a treatment site without generating heat, which can lead to reduction or elimination of the tumor. These micro-bubbles can increase microvessel permeability of drugs, enhance drug penetration through the interstitial space, and increase tumor cell uptake of the drugs, thus enhancing the antitumor effectiveness of the drugs.

In some applications of chemotherapy, a drug-loaded nanoemulsion can be driven through the micro-channels to a tumor site via an acoustic energy field. A second acoustic energy field can be delivered to the tumor site and can be configured to trigger drug release from nanodroplets, which can be created by micro-bubbles. A third acoustic energy field can be delivered to the tumor site and can be configured to produce an energy effect, for example, a thermal effect and/or cavitation, which enhances uptake of the drug by the tumor.

In another example, photodynamic therapy can be delivered using the systems and methods described herein. As known to one skilled in the art, photodynamic therapy is a medical treatment that utilizes a medicant, which comprises a photosensitizing agent and a photon-emission source to activate the administered medicant. In some applications, the medicant comprising a photosensitizing agent is delivered through the micro-channels into tissue via an acoustic energy field. After the medicant has been delivered, a second acoustic energy field can be delivered to enhance permeability and/or uptake of the medicant by the tissue. After the medicant has been delivered, a photon energy field at a specific wavelength is delivered from the photon-emission source to the tissue, which activates the medicant. The photon-emission source can include, but are not limited to: laser, LED or intense pulsed light. The optimal photon-emission source is determined by the ideal wavelength for activation of the medicant and the location of the target tissue. The photon energy field is directly applied to the target tissue for a specific amount of time. The medicant can be Levulan, which is used for the treatment of skin cancer. The medicant can be Metvix, which is used for the treatment of skin cancer. The medicant can be Photofin, which is used for the treatment of bladder cancer, lung cancer and esophagus cancer. The medicant can be aminolevulinic acid, which has been used in the treatment of various skin conditions, such as, for example, acne, rosacea, sun damage, enlarged sebaceous glands, wrinkles, warts, hidradenitis suppurativa, and psoriasis.

In another example, injuries to muscles can be treated using the systems and methods described herein. For treating an injury to a muscle, ligament, or tendon, a medicant can comprise platelet-rich plasma (PRP), mesenchymal stem cells, or growth factors. For example, PRP is typically a fraction of blood that has been centrifuged. The PRP is then used for stimulating healing of the injury. The PRP typically contains thrombocytes (platelets) and cytokines (growth factors). The PRP may also contain thrombin and may contain fibenogen, which when combined can form fibrin glue. The medicant can be directed through a micro-channels to the injury, such as, for example a tear in the tissue. An acoustic energy field can then be directed to the injury to activate the medicant and/or disperse the medicant. The acoustic energy field can create a thermal effect to heat the injury location which can initiate interaction of the medicant with the tissue at the injury location and/or increase blood perfusion in the injury location. The acoustic energy field can ablate a portion of tissue in the injury location, which can peak inflammation and increase the speed of the healing process. The acoustic energy field can be directed to the injury location and weld together the tear using both an ablative thermal effect and various mechanical effects.

In an example, acne can be treated using the systems and methods described herein. A medicant can comprise any one or more of cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate), azelaic acid, arachidonic acid, tetracycline, ibuprofen, naproxen, ketoprofen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, <NUM>,<NUM>,<NUM>'-trichloro-<NUM>'-hydroxy diphenyl ether, <NUM>,<NUM>,<NUM>'-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline. The medicant is directed through the micro-channels to a ROI comprising a sebaceous gland. The medicant interacts with bacteria in the sebaceous gland to reduce or eliminate the bacteria responsible for acne. An acoustic energy field can provide a mechanical effect to disperse the medicant into one or more sebaceous gland. An acoustic energy field can provide a thermal effect to accelerate the reaction of the medicant to eliminate or reduce the amount of bacteria in the sebaceous gland. An acoustic energy field can provide a thermal effect to injure or destroy at least a portion of the sebaceous gland. A photon based energy field can be directed to the medicant in the ROI to initiate a photodymanic effect to activate the medicant. A photon based energy field can be directed to the medicant in the ROI to reduce photosensitivity of the tissue in the ROI from sunlight.

As used herein, pulse width is the time from the start of the pulse to the end of the pulse measured at a -<NUM> dB or -<NUM> dB power point.

As used herein, "acoustic streaming" refers to a force of acoustic energy which displaces a material through a tissue environment.

Several water baths were each covered by a membrane <NUM> with the membrane <NUM> contacting the water within the water bath. A first water bath was covered by a <NUM> thick silicon rubber membrane <NUM> having microchannels with a diameter of <NUM>. Second and third water baths were covered by a <NUM> thick silicon rubber membrane <NUM> having microchannels with a diameter of <NUM> microns. A fourth water bath was covered by a <NUM> thick high-attenuation FR-<NUM> membrane <NUM> having microchannels with a diameter of <NUM> microns. Fifth and sixth water baths were covered by an approximately <NUM> thick ex vivo pig skin membrane <NUM> having microchannels with a diameter of <NUM>-<NUM> microns. Dyed glycerin solutions having viscosities of <NUM>-<NUM> centipoise served as the transport target <NUM> and were applied to the surface of each membrane <NUM>. Without application of ultrasound, no glycerin solution passed through the microchannels.

Referring to <FIG>, for each of the first and second water baths, a <NUM> diameter transducer was coupled to the glycerin and an ultrasound energy field having a frequency of <NUM>, a peak power of <NUM> kW, a pulse width of <NUM>, and a pulse repetition rate of <NUM> was focused to a depth just beneath the membrane. The peak intensity was about <NUM> kW /cm<NUM>. The acoustic pressure was estimated to be about <NUM> MPa. The glycerin was driven through the microchannel, across the membrane <NUM>, and into the water.

Referring to <FIG>, for the third water bath, a <NUM> diameter transducer was coupled to the glycerin and an ultrasound energy field having a frequency of <NUM>, a peak power of <NUM> kW, a pulse width of <NUM>, and a pulse repetition rate of <NUM> was focused to a depth just beneath the membrane. The peak intensity was about <NUM> kW /cm<NUM>. The acoustic pressure was estimated to be about <NUM> MPa. The glycerin was driven through the microchannel, across the membrane <NUM>, and into the water.

Referring to <FIG>, for the fourth water bath, a <NUM> diameter transducer was coupled to the glycerin and an ultrasound energy field having a frequency of <NUM>, a peak power of <NUM> kW, a pulse width of <NUM>, and a pulse repetition rate of <NUM> was focused to a depth just beneath the membrane. The peak intensity was about <NUM> kW/cm<NUM>. The acoustic pressure was estimated to be about <NUM> MPa. The glycerin was driven through the microchannel, across the membrane <NUM>, and into the water.

For the fifth water bath, a <NUM> diameter transducer was coupled to the glycerin and an ultrasound energy field having the same properties as described above with respect to the examples shown in <FIG> was focused to a depth just beneath the membrane. For the sixth water bath, a <NUM> diameter transducer was coupled to the glycerin and an ultrasound energy field having the same properties as described above with respect to the examples shown in <FIG> was focused to a depth just beneath the membrane. In both cases, the glycerin was driven through the microchannel, across the membrane, and into the water.

Measured linear streaming velocities for the above-referenced examples ranged from <NUM>/s to <NUM>/s. As should be appreciated, in <FIG>, <FIG>, drops that are spaced further apart are indicative of a greater linear streaming velocity.

Additional membrane parameters and ultrasound parameters were also deployed in the same general experimental setup as described above. Linear streaming velocities were measured up to <NUM>/s.

Claim 1:
A system for delivering a transport target (<NUM>) across a membrane (<NUM>) from a top membrane surface (<NUM>) to a first material layer (<NUM>) that is adjacent to the membrane (<NUM>) and opposite the top membrane surface (<NUM>), the membrane (<NUM>) is semi-permeable or impermeable to the transport target (<NUM>), the system comprising a probe housing and a standoff (<NUM>),
the standoff (<NUM>) comprising the transport target (<NUM>), the standoff (<NUM>) adapted to be positioned between the probe housing and the top membrane surface (<NUM>), the standoff (<NUM>) including a bottom standoff surface configured to engage the top membrane surface (<NUM>) and including one or more pores;
the probe housing comprising:
a) a microchannel probe (<NUM>) configured to create a microchannel in the membrane (<NUM>); and
b) an ultrasound energy source configured to deliver an acoustic energy field to the transport target (<NUM>), thereby driving the transport target (<NUM>) from the standoff (<NUM>),
through the one or more pores, through the microchannel, and into the first material layer (<NUM>); and
a power supply (<NUM>) configured to power the ultrasound energy source; and
a control module (<NUM>) configured to control the ultrasound energy source.