SYSTEMS AND METHODS FOR TREATMENT OF TOPICAL CONDITIONS

Abstract

The present disclosure provides a variety of systems, techniques and machine readable programs for using plasmas and/or electric fields alone, or in combination with other therapies, to treat different tissue conditions as well as other conditions, such as tumors, bacterial infections and the like.

Claims

1. A method of treating a topical condition, comprising: a) providing an electrode adapted to be placed proximate an anatomical region of interest having a topical condition; and b) applying an electric field or plasma to the region of interest to treat the topical condition, wherein applying the electric field or plasma includes applying a pulsed voltage waveform to the electrode to generate a plasma proximate the electrode, the pulsed voltage waveform having pulses with durations between about 0.11 ns and 100 ns, and having a pulse repetition rate less than about 3,000 Hz.

2. The method of claim 1, wherein the power deposited by the plasma on the anatomical region of interest is between about 1.0 milliwatts per square centimeter and about 10.0 watts per square centimeter.

3. The method of claim 1, wherein the power deposited by the plasma on the anatomical region of interest is between about 10.0 milliwatts per square centimeter and about 1.0 watts per square centimeter.

4. The method of claim 1, wherein the anatomical region of interest is exposed to the plasma for between about five seconds and about fifteen minutes.

5. The method of claim 1, wherein the anatomical region of interest is exposed to the plasma for between about thirty seconds and about ten minutes.

6. The method of claim 1, wherein the anatomical region of interest is exposed to the plasma for between about three minutes and about seven minutes.

7. The method of claim 1, wherein the anatomical region of interest is not wetted with a beneficial agent during the treatment.

8. The method of claim 1, wherein the anatomical region of interest is wetted with a beneficial agent prior to applying plasma or an electric field to the region of interest.

9. The method of claim 8, wherein the beneficial agent is water.

10. The method of claim 8, wherein the beneficial agent includes at least one material selected from the group consisting of organic materials, gaseous materials, gelatinous materials, liquid materials amino acids, saline, deionized water, and phosphate buffered saline.

11. The method of claim 1, wherein the topical condition includes onychomycosis.

12. The method of claim 1, wherein the topical condition includes psoriasis.

13. The method of claim 1, wherein the topical condition includes an infection.

14. The method of claim 1, wherein the topical condition includes vitiligo.

15. The method of claim 1, wherein at least one of reactive oxygen species and reactive nitrogen species are delivered to the region of interest.

16. The method of claim 1, further comprising applying a sensitizing material to the region of interest prior to application of plasma to the region of interest.

17. The method of claim 1, further comprising applying a blocking material to tissue proximate the region of interest to protect the tissue from plasma.

18. The method of claim 1, wherein the electric field has a strength between about 3,000V/mm and 20,000 V/mm.

19. The method of claim 18, wherein the electric field does not result in substantial formation of plasma in the anatomical region of interest.

20. The method of claim 19, wherein the electric field results in no detectable plasma formation in or on the anatomical region of interest.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIG. 1 is a schematic showing an exemplary single, rigid plasma electrode, high voltage supply and treatment of a nail.

[0052] FIG. 2 is a schematic showing an exemplary multi-electrode device and how it may be used to treat multiple nails.

[0053] FIG. 3 is a schematic of an exemplary semi-flexible to flexible plasma electrode.

[0054] FIG. 4 is a schematic of an exemplary plasma-jet device and its application to a nail.

[0055] FIG. 5 is a schematic showing an exemplary treatment electrode employing a surface plasma.

[0056] FIG. 6 is a schematic showing an exemplary treatment electrode employing small holes to help initiate the plasma formation at lower voltages and/or less complex waveforms.

[0057] FIG. 7 is a schematic showing an exemplary flexible treatment electrode with an integrated spacer.

[0058] FIGS. 8a-8b illustrate side and top views of an assembly for testing formation of plasma in small gaps.

[0059] FIGS. 9a-9c present photographic evidence of plasma discharge formation.

[0060] FIG. 10 is a depiction of an exemplary plasma treatment device for treating onychomycosis and other infections.

DETAILED DESCRIPTION

[0061] Reference will now be made in detail to the present preferred embodiments of the disclosure, examples of which are illustrated in the accompanying drawings. The methods and corresponding steps of the disclosed embodiments will be described in conjunction with the detailed description of the exemplary systems.

[0062] By way of introduction, plasma, sometimes referred to as the fourth state of matter, typically includes partially and/or fully ionized gas molecules and can be produced and directed in a variety of ways and geometries. More specifically, a plasma can be thought of as a gas having molecules that can be partially or fully ionized and electrons that have kinetic energy sufficient to strip at least one electron from at least one of the gas molecules through collisions, such that the resulting plasma includes a mixture of positively charged ions in a sea of free electrons that may or may not also include neutral species mixed therewith. Plasmas can be used for a variety of purposes, including sterilization, blood coagulation, ozone generation, chemical processing, light sources, ion sources (for propulsion) and heat sources, among others. As a result of the relative simplicity of the construction of gas discharges as opposed to other emitters, such as solid state lasers, it is possible to create a variety of structures to provide a distributed energy source at an economical cost. Perhaps the best example of such arrays is the plasma television.

[0063] Plasma is most often generated in some region of gas when the electric field in this region exceeds a certain breakdown value. This breakdown value may depend on a number of factors including gas pressure, the type of gas, and the size of the region. In atmospheric pressure air, when the size of the plasma generation region exceeds several times the mean free path, the break down field is about 3,000 Volts per millimeter. In practice, the size of the region where this field needs to be exceeded to generate plasma is on the order of few micrometers. For smaller regions, it may not be possible to generate plasma within them unless the electric field is substantially larger. Thus, as long as the pores within the nail and the nail bed are larger than few micrometers (1-2 micrometers), it should be possible to generate plasma within these pores using electric fields in the range of about 3,000-20,000 Volts per millimeter in increments, for example, of one volt/mm (e.g., 3001 V/mm, 3002V/mm . . . ). However, larger (e.g., 20,000-50,000 V/mm) or smaller (e.g., 100V/mm-3,000V/mm) electric fields can be used, as desired, as the present disclosure can provide merely applying electric field irrespective of whether plasma is created as a result of the applied electric field. Since the electric field in the nail and the nail bed can be generated remotely, without necessarily direct contact with conducting electrode, plasma in the pores of the nail and the nail bed can also be generated remotely from any current conducting electrode.

[0064] In accordance with the present disclosure, onychomycosis treatment methods and related systems and machine readable programs have been developed using atmospheric pressure plasmas and/or electric fields, alone or in combination with other therapies described herein. Atmospheric plasmas are typically considered to be those plasmas that can exist in a room environment at standard conditions or conditions that vary slightly therefrom (e.g. at standard temperature and pressure STP). The plasma can be a corona, dielectric barrier discharge, microdischarge; inductively coupled plasma, microwave induced plasma, or capacitively coupled radio frequency induced plasma. The plasma can also be induced as the result of a laser exposure. In one embodiment, plasma is created within the nail for a duration of at least one tenth of a second and no more than one hour, or any duration therebetween in increments of minutes, seconds, or tenths of seconds, as desired. Other embodiments are also presented.

[0065] The plasma produces reactive chemical species such as hydroxyl radicals (OH), nitrous oxide (NO.sub.2), nitric oxide (NO), ozone (O.sub.3), superoxide (O.sub.2.sup.) that kill the pathogens responsible for the onychomycosis. The plasma can also emit light of a variety of wavelengths, can generate heat, ions, and electrons. The combination of these species and energy emissions can react with or cause reactions within the tissue that can affect the local cellular makeup, inflammation or other cellular processes and thereby alleviate the symptoms of various conditions.

[0066] For purposes of illustration only, and not limitation, FIG. 1 shows a schematic of an exemplary treatment electrode and nail treatment method in accordance with the disclosure. A nail (fingernail or toenail), 1, has a conductive media, 2, placed upon it. The treatment electrode, 3, which can include a conductor that is encapsulated by a dielectric layer, is placed in contact with the conductive media, 2. The treatment electrode is connected to a high-voltage power supply and control system, 4, which is connected to an electrical ground, 5. FIG. 2 shows a schematic of an electrode structure that can treat multiple nails at one time. The electrode support structure, 1, has multiple treatment heads, 2, which are placed and sized appropriately to address individual nails, 3. The electrode support structure, 1, is connected to a high voltage power supply and control system, 4, which is connected to ground, 5. FIG. 3 shows a schematic of a flexible or semi-flexible treatment electrode. This flexible or semi-flexible treatment electrode, 1, can be bent to conform to the shape of the target nail structure (not shown). The treatment electrode, 1, is connected to a high voltage power supply and control system, 2, which is connected to an electrical ground, 3. FIG. 4 shows a schematic of a plasma jet device. The treatment electrode, 1, is connected to a gas supply, 2, which provides a stream of gaseous media that is excited into a plasma state when the high voltage power supply and control system, 3, is activated. The high voltage power supply and control system, 3, is connected to an electrical ground, 4. Note that in this case, no external conductive media is needed to be applied to the nail, 5, because the gas supply (which becomes a plasma, 6) provides this conductive function.

[0067] In accordance with the disclosed embodiments, the treatment electrode may include multiple materials and have multiple shapes and surface finishes. Some example materials include aluminum or other conductor and alumina (Al.sub.2O.sub.3) dielectric, copper or other conductor and silicon nitride dielectric, conductor and quartz dielectric, conductor with rubber or plastic dielectrics (such as a metal conductor with silicone or epoxy with or without glass reinforcement), and conductor with a foam dielectric (such as silicone, polyurethane, or polyethylene foam). The choice of the dielectric material is based on the dielectric breakdown strength, dielectric constant, and the intended duration of usage. Some material combinations may be more suitable for long-term usage (such as copper and quartz), whereas other material combinations may be more suitable for short-term or single time usage. In the case of a foam dielectric, the pores of the foam are designed such that a microdischarge may form in each of a plurality of pores. These microdischarges are sufficiently numerous such that no individual microdischarge has sufficient energy to cause damage, pain, erythema, or irritation. The dielectric layers have a minimum thickness of about 10 microns and are attached to the conductor, for example, by molding, laminating, bonding, brazing, welding, mechanical joining. Alternatively, the dielectric layer may be applied via a coating process, such as anodizing or thermal spraying or by an oxidation process. The shape of the conductor may be flat or curved, which will affect the distribution, location and intensity of the plasma created. If the treatment electrode is smaller than the affected tissue area, then the operator will have to sweep the electrode over the desired treatment area to generate the plasma where required. Alternately, the treatment electrode may have the same size or substantially the same size as the desired treatment area, in which case the operator can apply the electrode in contact with the desired treatment area and maintain its position for the duration of treatment. The connection of the treatment electrodes to the electrical support structure may be rigid or adjustable.

[0068] In order to prevent formation of powerful microdischarges that bridge the gap between the electrode surface and tissue (e.g., nail) and remain in one specific location on the tissue (e.g., nail) for a period longer than about 1 second, one or more of the following exemplary techniques can be used: [0069] Electrodes having non-uniform air (gas) gap and some portions of the electrode surface extending so as to be in or near contact with tissue (e.g., nail) can be used to create plasma on the electrode surface and guide this surface plasma toward the tissue (e.g., nail) localizing around the point of contact or near contact between the electrode and the tissue (e.g., nail). [0070] Scanning the electrode rapidly (manually or with a motor) across the tissue (e.g., nail) so as to treat areas that may not be sufficiently exposed to the plasma when the electrode is immobile. [0071] Use of high voltage waveforms that are similar to pulses having rise time and fall time in the range between 1 picosecond and 100 nanoseconds so as to form plasma where strong microdischarges do not have sufficient time to be created. [0072] Varying the electrode Z-position (that is, the gap between the electrode and the tissue (e.g., nail)) via vibration, oscillation or other motions (such as with a piezomotor or other oscillatory motor) such that plasma is formed between different portions of the electrode area and the tissue (e.g., nail), depending on the magnitude of the gap. [0073] Use of microdischarge electrodes having sub-millimeter sizes and applying them in stationary or scanning exposures.

[0074] As shown in FIG. 6, small openings or holes can be defined in the dielectric layer. These holes can change the nature of the plasma discharge. The characteristic dimension of the microdischarges is on the order of 100 to 200 microns (diameter). As shown in FIG. 5, when the hole diameter is significantly smaller than the microdischarge diameter, the amount of current that can be passed through the hole to the electrode can be significantly restricted permitting generation of non-thermal plasma possibly even without AC voltage waveform typical of a dielectric barrier discharge.

[0075] In the case of pulsed operation, devices and associated methods are provided that provide pulsed voltages over time with very short duration. In accordance with one embodiment, the pulse duration can use any suitable voltage and be between about 0.010 seconds and about 0.10 seconds. In accordance with another embodiment, the pulse duration is between about 0.0010 seconds and about 0.010 seconds. In accordance with still another embodiment, the pulse duration is between about 0.00010 seconds and about 0.0010 seconds. In accordance with yet another embodiment, the pulse duration is between about 0.000010 seconds and about 0.00010 seconds. In accordance with another embodiment, the pulse duration is between about 0.0000010 seconds and about 0.000010 seconds. In accordance with still another embodiment, the pulse duration is between about 0.00000010 seconds and about 0.0000010 seconds. In accordance with a further embodiment, the pulse duration is between about 0.000000010 seconds and about 0.00000010 seconds. In accordance with still a further embodiment, the pulse duration is between about 0.0000000010 seconds and about 0.000000010 seconds. In accordance with yet a further embodiment, the pulse duration is between about 0.00000000010 seconds and about 0.0000000010 seconds. In accordance with another embodiment, a waveform is provided with a combination of pulses selected from the durations set forth above. Use of pulses of such short duration are believed to result in decreased streamer (microdischarge) formation on the basis that the pulse is too short for the plasma to organize itself in a manner in which it can form a streamer (microdischarge). It is also believed that use of such pulsing can result in a large amount of reactive ion species for treating the tissue (e.g., nail). Moreover, it is possible to not use a dielectric material between the electrode and tissue when using pulses of such short duration, since the power applied to the area being treated is controlled by microprocessor; although a dielectric layer can be included for safety reasons. As such, this technique of using pulses of such short duration differs from dielectric barrier discharge plasmas, which require a dielectric layer to operate. Moreover, using such short pulses also results in a more uniform plasma.

[0076] In accordance with further aspects, the disclosure provides systems and methods for generating surface plasmas and techniques for applying surface plasmas to a patient's tissue (e.g., nail).

[0077] For purposes of illustration, and not limitation, a further embodiment of a treatment device is provided in FIG. 5. The treatment device includes a handle (not shown) and a treatment electrode including a conductor 1 surrounded at least in part by an insulating material 2 defining an outer surface that may be placed in direct contact with a patient's tissue (e.g., nail) 3. The treatment device is used in this embodiment by applying a voltage to the conductor 1 such that a surface plasma is generated along the surface of the insulating material and between the surface of the insulating material 2 and patient's nail in areas where they are not in direct physical contact, and a gap is defined between the nail and the insulating material. The behavior of surface plasma is affected by a variety of variables, including the type and overall shape of insulating material 2 used, as well as the characteristics of surface of the insulating material 2.

[0078] If desired, the insulating material can be rigid or flexible. If flexible, insulating material 2 can be, for example, a silicone compound, synthetic rubber, polyurethane, or polyethylene. These can be applied to the conductor via lamination or the conductor can be plated or otherwise sprayed onto the base insulating material. If rigid, insulating material can be a moldable material, such as PTFE, PVDF, PC, PP and the like, and can be molded such as by injection molding. As will be appreciated, the texturing of the surface will have a surface finish that can be a result of the molding process or other processing. Thus, in one embodiment, such as where insulating material is injection molded, a mold having a surface finish in accordance with SPI/SPE A1, A2, A3, B1, B2, B3, C1, C2, C3, D1, D2 or D3 can be used. Moreover, if desired, the mold can have a first, rougher, surface finish in one region, and a second, smoother surface finish in another region.

[0079] Regardless as to how it is formed, the resulting surface of material 2 facing and/or contacting the tissue (e.g., nail) of the patient/user can be provided with a surface having a region with a mean surface roughness Ra between about 0.01-2000 microinches, 0.1-1000 microinches, 1-100 microinches, 5-50 microinches, 20-40 microinches, 100-200 microinches, 75-125 microinches, 1-4 microinches, 4-8 microinches, 8-12 microinches, 12-20 microinches, 20-30 microinches, 30-40 microinches, 40-50 microinches, 50-60 microinches, 70-80 microinches, 80-90 microinches, 90-100 microinches, or the like.

[0080] The surface of insulating material 2 that faces and/or contacts a user's/patient's tissue (e.g., nail) can be provided with one or more bumps, ridges or undulations 78 that are distinct and on a generally larger scale than the surface finish, having an average height of about 0.01 mm-5 mm, 0.1-0.5 mm, 0.5-1.0 mm, 1.0-1.5 mm, 1.5-2.0 mm, 2.0-2.5 mm, 2.5-3.0 mm, 3.0-3.5 mm, 3.5-4.0 mm, 4.0-4.5 mm, or 4.5-5.0 mm, among others. Distances between adjacent bumps, ridges or undulations for the foregoing examples can be between 0.01 mm-5 mm, 0.1-0.5 mm, 0.5-1.0 mm, 1.0-1.5 mm, 1.5-2.0 mm, 2.0-2.5 mm, 2.5-3.0 mm, 3.0-3.5 mm, 3.5-4.0 mm, 4.0-4.5 mm, or 4.5-5.0 mm, among others.

[0081] The material of the dielectric can also be provided with pores. These pores can serve as microcavities for a plasma microdischarge. These pores may be connected to one another or be separate and distinct. Such pores could be regular, as in a capillary array, or irregular in distribution. The shape of the pores may be spherical, cylindrical, or other. The pores have a characteristic dimension of 0.000 to 0.100 mm, 0.100 to 0.5 mm, 0.5 to 1.0 mm, 1.0-1.5 mm, 1.5-2.0 mm, 2.0-2.5 mm, 2.5-3.0 mm, 3.0-3.5 mm, 3.5-4.0 mm, 4.0-4.5 mm, or 4.5-5.0 mm, among others.

[0082] If desired, insulating material can be a semiconductor material. Concentration of charge carriers (consisting of valence and conduction electrons) in semiconductors can be modulated in a variety of ways including changes in temperature, incident light and electric field inside the material. The semiconducting material properties at different locations can also be controlled through incorporation of impurities that create either excess of conduction or excess of valence electrons. Modulating charge carrier density within the semiconducting material permits to exercise control over current being delivered into the plasma. Charge carrier density within the semiconductor may also change its electron emission capabilities and the manner in which insulating material acts as an electron emitter. Furthermore, charge carrier density within the semiconducting material may result in changes of surface breakdown enabling control over surface plasma discharge on semiconductor surface.

[0083] It will be further appreciated that insulating material 2 can have a variety of different dielectric breakdown strengths, such as rubber (450-700 V/mil), Teflon (1500 V/mil), glass (2000-3000 V/mil), alumina (300-500 V/mil), polyimide (12000-18000 V/mil), PVDF (1700 V/mil), PVC, polyurethane, UHMW polyethylene, etc. By comparison, air has a dielectric breakdown strength of approximately 20 V/mil. The choice of the dielectric thickness is determined by the magnitude of the applied voltage, the gap between the dielectric and the tissue (or the profile of the dielectric, in the case of a surface discharge), the thickness of the nail plate, and the local surface profile of the tissue (which includes tissue surface roughness and topographical variations due to swelling, scarring, or gross curvature of the body). In such cases, a typical thickness of approximately 0.010 to 4 mm for the dielectric layer is suitable to account for the variations in the applied voltage, electrode-tissue separation, tissue surface profile, etc. Generally, the smaller the gap, the smaller the dielectric thickness that is required.

[0084] The minimum gap between the dielectric and the tissue (e.g., nail) can be determined according to the Paschen curve, which shows the relationship between the breakdown voltage of a gas as a function of its pressure times the characteristic distance. In some embodiments, the characteristic distance is the air gap between the dielectric and the tissue. For atmospheric pressures, the Paschen curve provides that minimum voltages of approximately 400 to 6000 volts are useful to generate a breakdown for gaps of approximately 0.01 to 1 mm, respectively. In order to form a plasma over a large area as opposed to a single microdischarge, significantly higher voltages are useful for generating plasma while overcoming the variations induced by the tissue surface roughness, tissue impedance variations, and local topographical variation of the tissue. Such voltages range, for example, from about 500 to about 1000 volts, about 1000-about 10000 volts, and about 10000-about 50000 volts.

[0085] In further accordance with the disclosure, additional features are provided to facilitate the use of plasma treatment devices by lightly trained or untrained operators. In order to maintain the same intensity of the dose of the plasma to the tissue (e.g., nail), it is useful to apply the plasma treatment electrode in close proximity to the tissue (for cases where the curved electrode is not used) in a reliable and repeatable fashion. Alternatively, a spacer made from a non-conductive material can be used to set the distance between the plasma treatment electrode and the tissue, as shown in FIG. 7, for example. The spacer/spacing means can be provided around the periphery of the treatment electrode, in which case it can also surround or encapsulate the local gas. By surrounding the local gas, the structure can facilitate concentration of the heat and reactive species in the desired treatment area. Such a border can also incorporate an ozone-absorbing material, such as carbon black, to absorb the ozone that is commonly generated by the dielectric barrier discharge. In some embodiments, a line, group of lines, a polygon or polygons, a post or a plurality of posts, such as in the form of an array, or other geometries at or around the central portion of the treatment area can be included in the electrode insulating material to prevent the tissue from rising up inside the region defined by the spacer, which would adversely affect the maintenance of a constant gap between the treatment electrode and the body. Alternately, the spacer itself can be mounted on a spring or other resilient member that provides a defined preload contact force between the plasma treatment electrode and the tissue. When combined with an overload protection interlock (such as a contact or proximity switch or sensor) to prevent operation if the spring is fully compressed, this mechanism can be used to prevent the tissue from coming too close to the plasma treatment electrode.

[0086] In another embodiment, when microdischarges are employed to generate the plasma in close proximity to the tissue to be treated (e.g., nail), the size of the microcavities is preferably small enough such that the spacing between the tissue and the plasma treatment electrodes can be controlled without additional spacing means, springs, or other mechanisms, as desired.

[0087] In accordance with some embodiments, the electrical output is delivered by a power supply and affects the nature of the plasma that is emitted. Thermal and non-thermal plasmas may be used. If desired, the power supply can be connected to a control system that provides control means (e.g., a controller) that controls turning the device on an off, and may be used to control the dose (or intensity) of the plasma, which can in turn be controlled by adjusting the gas flow rate, applied voltage and hence applied current, and the like. In order to maintain user safety, a variety of controls are preferably employed. At the point of application to the tissue, a temperature sensor (thermocouple or infrared sensor, for example) is employed to ensure that the gas temperature does not exceed the threshold for causing pain and erythema. Also, the electrode can contain a fuse or fast circuit breaker to ensure that the current does not increase dramatically as a result of electrode damage, which can cause significant pain to the patient. This fuse or circuit breaker can also be mounted within the power supply.

[0088] If desired, the controller can control a second set of conductors proximate the plasma emitters to provide a magnetic field proximate the plasma to help influence the direction of flow of the plasma as well as its density, particularly the density of free electrons within a given volume containing the tissue to be treated. Electromagnets and/or permanent magnets can be used, for example, to apply a dipole magnetic field across the tissue, thus providing magnetic field lines that are substantially oblique to the nail, thus influencing the motion of reactive species across the tissue being treated.

[0089] The electrodes that are used to generate the plasma are optionally configured to deliver the electrical energy simultaneously or sequentially. In this manner, the entire plasma emitter may be excited at one time or sequentially in lines, or sub-regions may be excited sequentially (or at the same time or substantially the same time, if desired). The control system further provides the means (by way of software or hard-wired) to excite the electrodes in the desired sequence. For sequential excitation, the electrodes or sets of electrodes are individually addressable by the control system. For sequential excitation, the control system provides the means to vary the intensity and duration of the exposure to the plasma. This variation is applied spatially, allowing the user to deliver different plasma exposure doses to different regions of the target nail or nails.

[0090] The gas delivery from a gas supply, if provided, can be controlled by a valve or set of valves. In one embodiment, the operator opens the valve to provide continuous gas flow. In an alternate embodiment, the valve or series of valves is electrically controlled via the control system.

[0091] In an alternate embodiment, there is no gas container structure. The electrodes are then used to excite the surrounding ambient air to generate the plasma. When the emitter is applied to the nail, a spacing means/spacer is used to ensure that sufficient air is available to generate the plasma that is to be directed at the nail. The spacing means can be a number of cavities, microcavities, microchannels, or other depressions having negative skewness. Alternatively, the spacing means can have positive skewness, such as posts, pillars, raised lines, or other structures that extend above the main surface of the device. The spacing means also provides isolation of the electrodes from the nail.

[0092] In order to treat the desired nail section with the plasma the following exemplary method can be used:

[0093] 1. Apply a polarizable material to the target area of the nail surface. The polarizable material may be water, gel, or some other conductor.

[0094] 2. Apply the plasma emitter/electrode to the polarizable material on the target area of the nail such that the emission surface(s) are aimed towards the desired treatment area. Depending on the duration of treatment, the plasma emitter may be held in place via hand pressure, gravity, or a securing means, such as an adhesive, hook and loop fastener (e.g., from Velcro, Inc.), latch, springs, or elastic straps.

[0095] 3. Once the plasma emitter is in place, the user activates the device using a control means. Once activated, the emitter delivers plasma to the target nail and/or creates plasma within the target nail (as required).

[0096] 4. Upon completion of the treatment, the user deactivates the device using a control means. The control means alternatively provides an automatic shutoff once the desired dose has been delivered.

[0097] 5. The user then removes the plasma emitter from the target treatment area.

[0098] In an alternate embodiment, a flexible electrode is applied directly to the nail. In this case, a conductive gel is optionally applied prior to application of the flexible electrode. Such conductive gel may be integrated into an adhesive patch thereby enabling simultaneous application of the electrode and the gel.

[0099] In an alternate method to treat the target nail with plasma, sensitizing and/or blocking materials can be used to provide differential dosing for different sections of the nail. Such sensitizing materials can include water-based creams, ointments, lotions, sprays, gels, or other fluids. They can also include hydrophilic materials, such as glycerin, which can be used to attract water and water-based materials. These fluids are preferably applied topically.

[0100] The sensitizing materials can act in a variety of ways. These ways include promoting the generation of higher concentrations of specific reactive species, promoting emission of particular light wavelengths, modulating the electric field strength and direction, or other. For example, fluids such as hydrogen peroxide, saline, antioxidants such as N-acetyl cysteine (NAC) and others can react with the plasma to generate a variety of reactive species. Other suitable fluids are described, for example, in International Patent Application No. PCT/US2011/046382, filed Aug. 3, 2011 which is incorporated by reference herein in its entirety for any purpose whatsoever. These fluids may also become highly acidic, continue to penetrate the nails post-treatment, and thereby enhance the pathogen killing efficacy. Moreover, the sensitizing material can include organic materials, as well as being in a gaseous, gelatinous or liquid state. The sensitizing material may likewise include an amino acid such as Cysteine. In certain embodiments, the sensitizing material is dissolved in a liquid. Suitable liquids include saline, deionized water, phosphate buffered saline, or a combination thereof. The amount of organic material in the sensitizing material may vary. In certain embodiments, the organic material in the is at a concentration of at least about 2.5 mM. In other embodiments, the organic material in the sensitizing material is at a concentration of at least about 5 mM. In still other embodiments, the organic material in the sensitizing material, or composition, is at a concentration of at least about to mM.

[0101] The blocking materials can include anhydrous (such as oil-based) creams, ointments, gels, or other fluids. They can also include hydrophobic materials which are used to repel water and water-based materials. An exemplary illustrative method can have the following steps:

[0102] 1. Apply the plasma sensitizing and/or blocking materials to the desired treatment region (or protection region) of the nail. In the case of sensitizing materials, it may be necessary to wait for a certain period of time (an incubation period) for the sensitizing materials to be absorbed by the target regions of the nail.

[0103] 2. Apply the plasma emitter to the target area of the nail such that the emission surface is aimed towards the desired treatment area. Depending on the duration of treatment, the plasma emitter may be held in place via hand pressure, gravity, or a securing means, such as an adhesive, Velcro, latches, springs, or elastic straps.

[0104] 3. Once the plasma emitter is in place, the user activates the device using a control means. Once activated, the emitter delivers plasma to the target nail.

[0105] 4. Upon completion of the treatment, the user deactivates the device using a control means. The control means alternatively provides an automatic shutoff once the desired dose has been delivered.

[0106] 5. The user then removes the plasma emitter from the target treatment area.

[0107] In still another embodiment, heat, ultraviolet light, and/or infrared radiation can be applied in concert with the plasma in order to further accelerate the killing of pathogens. In another embodiment, topical and/or systemic drugs can be used in synergistic combination with the plasma treatment in order to further increase the effectiveness and speed of killing the pathogens. If thermal plasma or heat enhancements such as infrared radiation are employed, it may be desirable to cool the tissue surrounding the nail for greater patient comfort. The tissue may be cooled by flowing or spraying water or cryogen at it.

[0108] In accordance with a further aspect, a plasma sensitizer can also be used. In one aspect, the sensitizer can act as a conductive fluid to direct the plasma in a desired direction, such as toward the nail. In another aspect, the sensitizer can additionally or alternatively provide chemicals that react with the plasma, thereby enabling other reactions with the nail to occur. This can result in faster reactions at the nail. Suitable materials to be used as sensitizers can include, for example, water, saline, deionized water, or any fluid containing organic compounds, as well as materials including antioxidants.

[0109] In another embodiment, a layer containing an exposure indicator is applied to the plasma treatment electrode. By using the exposure indicator, the user will obtain direct feedback about the amount and level of exposure applied to the body. The exposure indicator can contain one or more compounds that react to the exposure from plasma such that the exposure can be detected and/or metered upon removal from the tissue. The indicator may change color or otherwise provide a visual indication of exposure. This change may occur immediately or after exposure to a developer or other chemical. An example of an exposure indicator is a photosensitive material that responds to the light emitted by the plasma. Another example of an exposure indicator is a material that changes color upon exposure to different pH levels or other chemical species, such as litmus paper. A combination of different materials may be employed to indicate different exposure levels. Such materials can be provided in sheet form, and can be replaced with each subsequent use of the treatment device if the device is otherwise intended to or capable of being reusable.

[0110] In some alternative embodiments, the exposure level is monitored automatically using optical sensors, electronic sensors, or a combination thereof. The optical sensors, for example, can detect visible, ultraviolet, or infrared emissions from the plasma. The electrical sensors can detect current flow or electrical field variation and the like as generated by the plasma emission. The information from these sensors can then be delivered to the power supply and control system to enable closed loop control of the exposure dose and intensity. Such closed loop control may be desirable to account for patient-specific anatomical or disease variations that affect the plasma intensity, for example. The gas delivery from the gas supply can be controlled by a valve or set of valves. In one embodiment, the operator opens the valve to provide continuous gas flow. In an alternate embodiment, the valve or series of valves is electrically controlled via the control system.

[0111] In another alternate embodiment, the power supply and control system are connected to the electrode by a high-voltage cable. This cable preferably has sufficient length to enable targeting any single portion of the body or multiple areas of the body. The electrode dimensions and weight are set so to enable comfortable hand gripping while a plastic or other insulating material shields the operator from any high-voltage exposure. Alternately, the electrode may be curved (i.e. to match or nearly match the curvature of the desired treatment) and/or flexible (as shown in FIG. 7). A treatment electrode can have a variety of shapes, including squares, circles, rectangles, and the like that enable it to conform to the desired treatment area while maintaining the desired gap or surface discharge configuration as appropriate. The shape may be standardized for all patients or custom-made based on casting, molding, optical scanning or other measurement methods to create an electrode that more precisely conforms to the anatomy of the specific patient to be treated. Alternately, the electrode, power supply and control system can be integrated into a single handheld unit. This unit optionally contains batteries and/or a cable port to connect to a wall outlet.

[0112] In still another embodiment, heat, ultraviolet light, visible light, and/or infrared radiation can be applied in concert with or in alternating fashion with the plasma in order to further accelerate the killing of pathogens, alleviation of inflammation, and/or activation of other cellular processes and chemistry. In another embodiment, topical and/or systemic drugs can be used in synergistic combination with the plasma treatment in order to further increase the effectiveness and speed of killing and/or other reactions. In another embodiment, the electrode itself is heated and thereby provide conductive heating of the tissue, which can combine with the non-thermal plasma to enhance the effectiveness and speed of killing and/or other reactions.

[0113] If thermal plasma or heat enhancements such as infrared radiation are employed, it may be desirable to cool the tissue surrounding the treatment area for greater patient comfort. The tissue may be cooled by flowing or spraying water or cryogen at it. Alternatively, when the electrode is in contact with the tissue being treated, it can be cooled and thereby provide conductive cooling to the local tissue region being treated. In another embodiment, after-care creams, gels, or other materials may be applied to the treated tissue to help alleviate or repair pain, irritation, erythema, or other unwanted effects, such as cellular or DNA damage. For example, anti-oxidants may be used to help reduce post-treatment levels of reactive oxygen species and promote DNA repair.

[0114] In accordance with a further aspect, a plasma sensitizer can also be used. In one aspect, the sensitizer can act as a conductive fluid to direct the plasma in a desired direction, such as toward the tissue (e.g., nail). In another aspect, the sensitizer can additionally or alternatively provide chemicals that react with the plasma, thereby enabling other reactions with the tissue to occur. This can result in faster reactions at the tissue. Suitable materials to be used as sensitizers can include, for example, water, saline, deionized water, or any fluid containing organic compounds, as well as materials including antioxidants. The plasma sensitizing fluid can also be delivered to the tissue as part of the device construction. The device can contain a spray, sponge or vapor (aerosolized fluid) jet that has the sensitizing fluid and controllably releases said fluid as desired by the user or automatically upon contact by the electrode to the tissue. Finally, a moistened fabric may be placed between the electrode and the tissue. In this case, the discharge will occur within the cloth and excessive streamer formation will also be avoided.

[0115] In order to deliver higher power levels to the body, it is desirable to provide a grounding (dispersive) pad proximately located to the plasma emitter. Such pads are commonly used in conjunction with electrosurgical devices. As the current transmission increases, there is a higher risk of burning the tissue. The risk of creating tissue burns depends on the amount of current divided by the area over which it is distributed, which is also known as the current density. Nominally, the current density at the ground pad is defined by the area of the pad. However, there are some additional considerations:

[0116] 1. The entire ground pad is preferably securely attached to the body of the patient. A partial attachment or removal of the ground pad can cause the current density to increase.

[0117] 2. The ground pad preferably has sufficiently low resistance to avoid generation of heat within the pad. Such a resistance can range, for example, from about 0.1 to about 5000 ohms.

[0118] 3. The ground pad preferably radiates any heat generated within the pad and/or can provide active cooling to minimize the risk of burning.

[0119] In order to ensure that the ground pad is attached securely to the patient, prior to treatment, remote monitoring of the pad attachment can be employed as follows. First, two or more pads or pad sections can be attached to the body in close proximity to one another. These pads can have matching connectors and a cable or cables that run back to the power supply and control system. Prior to and during treatment, the power supply and control system can send a small amount of current via one of the conductive pathways to one of the ground pads. It then measures the return current that is conducted by the second ground pad to determine the overall impedance of the system. If the measured impedance deviates from the nominal value, then the power supply and control system prevents the treatment from starting and/or interrupts the treatment. An indicator means (visual, audible, etc.) is provided on the power supply and control system to inform the operator that the grounding pad(s) are not fully attached to the body.

[0120] Optionally, the grounding pad(s) may be integrated with the plasma emitter. Such a construction may provide advantages in ease of application to the body, convenience, and/or lower cost. The grounding pad can be provided within the plasma emitter, for example, by providing a grounding conductor that is mounted around the periphery or other non-treatment areas of the plasma emitter. This grounding conductor is optionally mounted to the tissue via a conductive tissue adhesive or gel. This conductor can be connected to the power supply through a separate connector. As in the previous discussion, it is possible to monitor the connection (and thereby the overall current density) of the patch by sending a small current to the grounding pad(s) and measuring the return current to determine the overall impedance.

[0121] The plasma emitter can be connected to the power supply by a variety of techniques. For example, short wires having an external connector may be laminated, glued, soldered, or crimped onto the conductive layer of the flexible plasma emitter. Alternatively, a variety of connectors may be mounted (via soldering, lamination, or gluing) on the conductor of the plasma emitter. These can include, for example, snap connectors, surface mount connectors, pin holes, crimp or clamps connectors, among others. Finally, the conductor of the flexible plasma emitter can be formed into one half of a connector, such as a conductive tab or pin. The plasma emitter can be attached to the treatment area through a variety of fasteners/attachment techniques, including hook and loop fastener, straps, and tissue adhesives. The tissue adhesives may be single-use or multi-use, such as in the case of hydrogels.

EXAMPLES

[0122] The following summarizes in vitro work performed by Applicant evidencing that the disclosed systems and techniques are useful for killing the fungus responsible for onychomycosis in clinically-infected nail samples, including work done with a microsecond and a nanosecond power supply.

[0123] Applicant recently demonstrated the ability of cold atmospheric pressure plasma to kill T. rubrum, the fungus most frequently associated with onychomycosis, in vitro in a simulated nail model.

[0124] 0.70.7 cm sections of 317.5 micron thick shim stock were cut and double washed in ethanol for 10 minutes. Next, 1 ml of stock T. rubrum was homogenized with 4 ml of sterile SDM (Sabouraud Dextrose media). The sterile shim stock was placed in 5 ml solution of T. rubrum and inoculated for 2 hours. After removing the shim stock from solution, it was plasma treated for varying time and frequency settings: 1.5 or 3 kHz, 30 seconds or 3 minutes. The treated shim stock was then placed on an SDA (agar) plate to grow overnight. Experience has suggested that direct treatment of microbes on agar can lead to modification of the agar itself (making it acidic), potentially confounding the results. Hence, the shim stock was inoculated and treated separately prior to placement on fresh agar. Resulting sterilization of the shim stock was determined by visual observation of growth or no growth as shown in Table 1. We note that in these experiments, the shim stock was still moist/wet with solution prior to treatment with plasma. When the shim stock was allowed to dry after inoculation, the resulting inhibition of fungal growth was less significant (2-3 day delay, results not shown). Applicant believes that the plasma treatment in the presence of fluids such as water creates a local acidic environment that can enhance killing efficacy.

TABLE-US-00001 TABLE I Growth No Growth 2 Days Post Treatment Control 1.5 kHz, 30 seconds 1.5 kHz, 3 minutes 3 kHz, 30 seconds 3 kHz, 3 minutes 9 Days Post Treatment Control 1.5 kHz, 30 seconds 1.5 kHz, 3 minutes 3 kHz, 30 seconds 3 kHz, 3 minutes Table 1: Results of in vitro testing of plasma treatment of T. rubrum.

[0125] In onychomycosis, however, T. rubrum and other organisms can often infect the nail bed or infect sections within the nail plate. Like earthworms tunneling through dirt, these fungi can consume the keratin within the nail plate, leaving microscopic pockets within the nail plate. Accordingly, Applicant conducted tests to demonstrate whether atmospheric pressure plasma could be generated within microscopic air gaps of a similar size to those found within nail plates.

[0126] FIGS. 8a-b respectively illustrate side and top views of an experimental assembly to test generation of plasma within small gaps ranging in size from 12 to 50 microns. The gaps were created using shim stock and glass slides, which were then embedded in gel (to avoid generation of plasma along the periphery). The mesh was connected to ground and used as a transparent electrode to enable visualization of plasma formation within the gap. As shown in FIG. 8, two glass slides were epoxied together, separated by two pieces of shim stock having thicknesses of 50, 25 and 12.5 microns. In each case, a high voltage electrode was brought into contact with one side of the glass slides and a mesh was placed on the other side and connected to ground. The entire construction was then embedded in a gel. The mesh was used to enable visualization of the plasma through the glass slide.

[0127] FIG. 9 presents photographic evidence of plasma discharge formation within the small gaps at varying thicknesses from about 12.5 to about 50 microns. Applicant notes that the discharge is likely non-uniform due to small differences in the gaps, surface effects or other variations that could cause local concentrations of electric field. These non-uniformities can be easily overcome through appropriate design of the electrodes and power supplies. As shown in FIG. 2, plasma was successfully generated within each of the gaps, evidencing that plasmas can by analogy be generated in nail structures that are infected with T. rubrum and/or other organisms.

[0128] Finally, clinically-infected nail plates were harvested from human volunteers. Control samples were taken, sliced into 50 micron thick slices with a cryotome and cultured, confirming infection throughout the nail plate with T. rubrum. The remaining samples were treated with a pulsed dielectric barrier discharge at a frequency of approximately 200-300 Hz and a voltage of 20 kV for a duration of 5 minutes. The nail plates were treated three times for this duration. The first time, the nail plate was treated face up and then face down. The third time, the nail plate was embedded in a gel in order to enable generation of plasma within gaps in the nail plate. In all cases, the nail clippings were treated in their dry state.

[0129] Upon completion of the treatment, the samples were frozen and then sliced into 50 micron thick slices with a cryotome. The slices were then placed on agar and incubated as before. Table 2 below shows the number of days that elapsed until growth was seen on each slice. As shown, nearly all slices in the control sample grew by day 2, whereas the treated samples took an average of 7 days to grow. It is known that vegetative T. rubrum populations will double on average every 4.5 hours. Accordingly, this delay in growth represents approximately 4-5 log reduction in the fungal population.

TABLE-US-00002 TABLE 2 Days of Delayed Growth* 5 minute treatments Control #1 #2 #3 #4 Slice 0-50 3 11 X 3 X (microns) 50-100 3 X 11 3 X 100-150 3 10 7 3 X 150-200 2 5 X 3 4 200-250 2 X 5 4 4 250-300 2 X 5 4 X 300-350 2 5 4 5 X 350-400 2 10 3 5 5 400-450 2 X 3 5 5 450-500 2 X 3 5 5 500-550 2 X X 4 4 550-600 2 X X 3 4 600-650 2 7 X 2 4 650-700 2 X X 3 4 700-750 2 X 11 2 4 750-800 2 X X 2 800-850 2 X 5 2 850-900 2 X 4 2 900-950 2 6 3 2 950-1000 2 6 3 2 Average 2.2 7.5 5.2 3.6 3.5 Adj. Average 2.2 11.4 8.3 3.6 6.2 Table 2: Days to observable growth for-control (untreated) and plasma-treated nail clippings (clinically infected with T. rubrum. The experiment was monitored for 13 days. The X denotes that no growth was observed after 13 days. The average growth is computed for all samples. The adjusted average growth is calculated based on the assumption that all remaining samples grew on Day 14.

[0130] For reference, this fungus is estimated to double in population every 4.5 hours. So, if nothing grew after about 7-8 days, this corresponds to at least 6 log reduction.

[0131] Exemplary Plasma Treatment System Overview

[0132] Applicant has developed a technology to deliver atmospheric DBD plasma to toenails with a convenient disposable electrode. The Plasma Pin device is applied to the tissue (e.g., nail) and connected to a high voltage power supply and control system, as shown in FIG. 10. This power supply generates the electric field characteristics within the patch that are necessary to initiate the formation of non-thermal DBD plasma proximate to the nail and within the nail. The control system has settings to enable the user to vary the intensity of the plasma as desired. Upon activation, plasma forms as a result of the electric field generated between the pin and the nail plate or nail bed below the contact point. It forms along the surface of the dielectric (silicone in this embodiment) and travels down towards the nail plate. Based on laboratory studies, Applicant believes that the plasma also forms within air pockets that may be within the nail plate or nail bed.

[0133] In the resulting non-thermal plasma, the plasma serves as a conductor, but at relatively low current is much lower (<1 milliamp) and, as described above, this non-thermal plasma can be operated in a regime where no damage to tissue (e.g., nail) is observed even over treatment times as long as 20 minutes. Moreover, this current is distributed over a large area (e.g., about 27 sq. mm). By virtue of this moderate local current density, it is expected that the intensity and severity of any side effects will be moderate to the extent that they occur.

[0134] As to treatment steps for applying the plasma to a subject, it is contemplated that the following steps can be used: [0135] 1. Clean the target treatment site (e.g., nail) for treatment with isopropyl alcohol and allow to dry. [0136] 2. Connect the plasma emitter device to its power supply. [0137] 3. Connect a Grounding Pad (if provided) to the Ground wire of the Power Supply. [0138] 4. Apply the Grounding Pad to skin next to the tissue (e.g., toenail) to be treated. [0139] 5. Apply Dry Treatment: [0140] Verify connections from plasma emitter device and ground pad to control system. [0141] Set controls for frequency and amplitude to desired levels for Dry Treatment according to Table 3 below [0142] Verify trigger is set to External [0143] Turn system on. [0144] Set timer to desired duration for Treatment Dry according to Table 3 [0145] Position plasma emitter device in contact with the infected nail platelight hand pressure is sufficient. [0146] Flip trigger switch to Internal and activate timer. [0147] Starting in one of the proximal corners of the nail plate, scan the plasma emitter device in a serpentine path over the entire nail plate. Repeat scanning until treatment duration is complete. [0148] Once treatment has been completed, flip trigger switch to External [0149] 6. Apply a Wet treatment by moistening the site (e.g., toenail site) with water. [0150] 7. Repeat step 5 for Treatment Wet using the parameters listed in Table 3. Subjects will be asked to undergo treatment until it is no longer tolerable (due to pain, for example) or up to a maximum treatment time of 10 minutes. Moisten the target toenail as needed (5-10 times during the treatment). [0151] 8. Disconnect and remove and store Ground Pad (one for each patient) after the wet treatment. [0152] 9. The patient can then be sent home with e.g., anti-fungal cream and instructions for usage in order to help prevent potential new infections from surrounding tinea pedis if present.

TABLE-US-00003 TABLE 3 Dry Nail Wet Nail Frequency Amplitude Duration Duration Group Setting Setting (min.) (min.) 1 10 10 2.5 2.5 (5 subjects) (1 kHz) (20 kV) 2 10 10 5 5 (5 subjects) (1 kHz) (20 kV) 3 10 10 10 10 (5 subjects) (1 kHz) (20 kV)

[0153] It will be appreciated that the dry and wet treatments can be applied exclusively from the other, or in any desired succession. It will be further appreciated that an electric field alone and/or in combination with plasma can be applied to treat the onychomycosis. Applicant performed in vitro testing on nail clippings using wet and dry techniques to gage their relative efficacy. Two nail control clippings were set aside and then three 3 samples each were treated for 5 minutes per sample using the a power supply at two different pulse repetition frequencies (approx. 400, 800 Hz) and using the same applied voltage (20 kV). All of these treatments were done dry (i.e., without adding additional water). Then the experiment was repeated (3 samples each, 2 frequencies) with wet nail samples. As is evident from the below table, after eight days, there was no fungal growth observed on any of the wet samples post treatment. The dry samples showed some growth on the lower frequency treatment, but not on the higher frequency. These results are summarized in Table 4 below:

TABLE-US-00004 TABLE 4 Total = 8 Days Dry Wet Control 1 2 2 Control 2 3 2 20 kV, 400 Hz 3 20 kV, 400 Hz 3 20 kV, 400 Hz 4 20 kV, 800 Hz 20 kV, 800 Hz 20 kV, 800 Hz

[0154] Entries in the above table denoting --- indicate no detected growth after eight days. In order to address various issues and advance the art, the entirety of this application (including the Cover Page, Title, Headings, Field, Background, Summary, Brief Description of the Drawings, Detailed Description, Claims, Abstract, Figures, Appendices and/or otherwise) shows by way of illustration various embodiments in which the claimed inventions may be practiced. The advantages and features of the application are of a representative sample of embodiments only, and are not exhaustive and/or exclusive. They are presented only to assist in understanding and teach the claimed principles. It should be understood that they are not representative of all disclosed embodiments. As such, certain aspects of the disclosure have not been discussed herein. That alternate embodiments may not have been presented for a specific portion of the invention or that further undescribed alternate embodiments may be available for a portion is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those undescribed embodiments incorporate the same principles of the invention and others are equivalent. Thus, it is to be understood that other embodiments may be utilized and functional, logical, organizational, structural and/or topological modifications may be made without departing from the scope and/or spirit of the disclosure. As such, all examples and/or embodiments are deemed to be non-limiting throughout this disclosure. Also, no inference should be drawn regarding those embodiments discussed herein relative to those not discussed herein other than it is as such for purposes of reducing space and repetition. For instance, it is to be understood that the logical and/or topological structure of any combination of any program components (a component collection), other components and/or any present feature sets as described in the figures and/or throughout are not limited to a fixed operating order and/or arrangement, but rather, any disclosed order is exemplary and all equivalents, regardless of order, are contemplated by the disclosure. Furthermore, it is to be understood that such features are not limited to serial execution, but rather, any number of threads, processes, services, servers, and/or the like that may execute asynchronously, concurrently, in parallel, simultaneously, synchronously, and/or the like are contemplated by the disclosure. As such, some of these features may be mutually contradictory, in that they cannot be simultaneously present in a single embodiment. Similarly, some features are applicable to one aspect of the invention, and inapplicable to others. In addition, the disclosure includes other inventions not presently claimed. Applicant reserves all rights in those presently unclaimed inventions including the right to claim such inventions, file additional applications, continuations, continuations in part, divisions, and/or the like thereof. As such, it should be understood that advantages, embodiments, examples, functional, features, logical, organizational, structural, topological, and/or other aspects of the disclosure are not to be considered limitations on the disclosure as defined by the claims or limitations on equivalents to the claims. It is to be understood that, depending on the particular needs and/or characteristics of a MOE individual and/or enterprise user, database configuration and/or relational model, data type, data transmission and/or network framework, syntax structure, and/or the like, various embodiments of the MOE may be implemented that enable a great deal of flexibility and customization.

[0155] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0156] Descriptions herein of circuitry and method steps and computer programs represent conceptual embodiments of illustrative circuitry and software embodying the principles of the disclosed embodiments. Thus the functions of the various elements shown and described herein may be provided through the use of dedicated hardware as well as hardware capable of executing software in association with appropriate software as set forth herein.

[0157] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicant thus regard any means which can provide those functionalities as equivalent to those shown herein.

[0158] Similarly, it will be appreciated that the system and process flows described herein represent various processes which may be substantially represented in computer-readable media and so executed by a computer or processor, whether or not such computer or processor is explicitly shown. Moreover, the various processes can be understood as representing not only processing and/or other functions but, alternatively, as blocks of program code that carry out such processing or functions.

[0159] The methods, systems, computer programs and mobile devices of the present disclosure, as described above and shown in the drawings, among other things, provide for improved magnetic resonance methods, systems and machine readable programs for carrying out the same. It will be apparent to those skilled in the art that various modifications and variations can be made in the devices, methods, software programs and mobile devices of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure include modifications and variations that are within the scope of the subject disclosure and equivalents.