Systems and methods for nail treatment
11278734 · 2022-03-22
Assignee
Inventors
Cpc classification
A61N2005/0626
HUMAN NECESSITIES
International classification
Abstract
Exemplary system and method are provided for affecting nail growth rate, which can use a light dosage and a wavelength of light to affect a growth rate of a nail of a subject. For example, it is possible to detect a presence of a nail using, e.g., a presence detector. The nail can be irradiated over a treatment time with a light having a wavelength and a power, e.g., using a narrowband light source. Further, using a controller, it is possible to control one or more of the power and the treatment time to irradiate the nail with a light dosage that is within a biphasic light dosage range bounded by a lesser light dosage and a greater light dosage. The wavelength of the light and the light dosage can be configured to affect a growth rate of the nail.
Claims
1. A method for affecting a growth rate of a nail of a digit of a subject, comprising: detecting, using a presence detector, a presence of the nail or the digit; irradiating, using a narrowband light source, the nail over a treatment time using a light; controlling, using a controller, at least one of (a) a power of the light or (b) the treatment time to irradiate the nail with a dosage of the light that is within a biphasic light dosage range, wherein a wavelength of the light and the dosage of the light are (i) configured to affect a growth rate of the nail, and (ii) provided in a range of 502 nm-980 nm; and recording, using the controller, at least one parameter related to the dosage of the light as electronic information.
2. The method of claim 1, wherein the wavelength of the light is at least one of 658 nm, 665 nm, 765 nm, 850 nm, or 855 nm.
3. The method of claim 2, wherein the biphasic light dosage range is bounded by (a) a lesser light dosage which is about 0.5 J/cm.sup.2, and (b) a greater light dosage that is about 100 J/cm.sup.2.
4. The method of claim 3, wherein the treatment time is between 60 seconds and 14400 seconds.
5. The method of claim 1, further comprising: estimating or determining a treatment irradiance for the nail based on (a) the presence of the nail or the digit at a known location, and (b) a power of the light; and controlling the dosage of the light based on the treatment irradiance.
6. The method of claim 1, further comprising: measuring, using a photodetector, a treatment irradiance for the nail; and controlling the dosage of the light based on the treatment irradiance.
7. The method of claim 1, wherein the narrowband light source comprises at least one of a light emitting diode, a light emitting capacitor, a laser, a flash lamp, or a filtered wideband light source.
8. The method of claim 1, wherein the method is configured to increase the growth rate of the nail or decrease the growth rate of the nail.
9. The method of claim 1, wherein the at least one parameter related to the dosage of the light comprises at least one of a start time of treatment, an end time of treatment, the power of the light, the treatment time of the light, or the dosage of the light.
10. The method of claim 9, further comprising verifying the dosage of the light for compliance using the electronic information.
11. The method of claim 1, further comprising controlling, using the controller, the dosage of the light based upon a dosing schedule.
12. The method of claim 1, wherein the presence detector comprises at least one of a pressure sensor, a camera, a time of flight (TOF) system, a LiDAR system, a capacitive proximity sensor, a photoelectric sensor, an optical sensor, an infrared sensors, or a switch.
13. The method of claim 1, wherein the wavelength of the light and the dosage of the light is provided in a range of 600 nm-850 nm.
14. The method of claim 1, further comprising: irradiating, using a further narrowband light source, the nail over using a further light; and controlling, using the controller, at least one of (a) a power of the further light or (b) the treatment time to irradiate the nail with a further dosage of the further light.
15. The method of claim 14, wherein a further wavelength of the further light and a further dosage of the further light are provided in a range of 700 nm-2000 nm.
16. The method of claim 14, wherein a further wavelength of the further light and a further dosage of the further light are provided in a range of 700 nm-2000 nm.
17. A system for affecting a growth rate of a nail of a digit of a subject, the system comprising: a presence detector configured to detect a presence of the nail or the digit; a narrowband light source configured to irradiate the nail over a treatment time using a light; and a controller configured to control at least one of (a) a power of the light or (b) the treatment time to irradiate the nail with a dosage of the light that is within a biphasic light dosage range, wherein a wavelength of the light and the dosage of the light are (ii) configured to affect a growth rate of the nail and (ii) provided in a range of 502 nm-980 nm, and wherein the controller is configured to record at least one parameter related to the dosage of the light as electronic information.
18. The system of claim 17, wherein the wavelength of the light is at least one of 658 nm, 665 nm, 765 nm, 850 nm, or 855 nm.
19. The system of claim 18, wherein the biphasic light dosage range is bounded by (a) a lesser light dosage which is about 0.5 J/cm.sup.2, and (b) a greater light dosage that is about 100 J/cm.sup.2.
20. The system of claim 19, wherein the treatment time is between 60 seconds and 14400 seconds.
21. The system of claim 18, wherein the at least one parameter related to the dosage of the light comprises at least one of a start time of treatment, an end time of treatment, the power of the light, the treatment time of the light, or the dosage of the light.
22. The system of claim 21, wherein the controller is configured to verify the dosage of the light for compliance using the electronic information.
23. The system of claim 17, wherein the controller is configured to: estimate or determining a treatment irradiance for the nail based on (a) the presence of the nail or the digit at a known location, and (b) a power of the light; and control the dosage of the light based on the treatment irradiance.
24. The system of claim 17, comprising: a photodetector configured to measure a treatment irradiance for the nail; and wherein the controller is configured to control the dosage of the light based on the treatment irradiance.
25. The system of claim 17, wherein the narrowband light source comprises at least one of a light emitting diode, a light emitting capacitor, a laser, a flash lamp, or a filtered wideband light source.
26. The system of claim 17, wherein the system is configured to increase the growth rate of the nail or decrease the growth rate of the nail.
27. The system of claim 17, wherein the controller is configured to control the dosage of the light based on a dosing schedule.
28. The system of claim 17, wherein the presence detector comprises at least one of a pressure sensor, a camera, a time of flight (TOF) system, a LiDAR system, a capacitive proximity sensor, a photoelectric sensor, an optical sensor, an infrared sensors, or a switch.
29. The system of claim 17, wherein the wavelength of the light and the dosage of the light is provided in a range of 600 nm-850 nm.
30. The system of claim 17, further comprising: a further narrowband light source irradiating the nail over using a further light, wherein the controller is further configured to control at least one of (a) a power of the further light or (b) the treatment time to irradiate the nail with a further dosage of the further light.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) Further objects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying Figures showing illustrative embodiments of the present disclosure, in which:
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(11) Throughout the drawings, the same reference numerals and characters, unless otherwise stated, are used to denote like features, elements, components or portions of the illustrated embodiments. Moreover, while the present disclosure will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments and is not limited by the particular embodiments illustrated in the figures and the appended claims.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
(12) Exemplary Definitions
(13) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of any conflict, the exemplary definitions provided in the present disclosure, as applicable, would be controlling.
(14) A “subject” is a vertebrate, including any member of the class mammalia, including humans, domestic and farm animals, and zoo, sports or pet animals, such as mouse, rabbit, pig, sheep, goat, cattle and higher primates. It will be appreciated that a “subject” may also be referred to as a patient.
(15) As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
(16) The exemplary ranges described herein are understood to be shorthand for all of the values within the range. For example, and in no way limiting, an exemplary range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (as well as any fractions thereof unless the context clearly dictates otherwise).
(17) As used herein, the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
(18) In the present disclosure, the terms “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
(19) Other definitions appear in context throughout the present disclosure.
(20) Exemplary Embodiments of Present Disclosure
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(22) Once the nail is detected, the nail can be irradiated with a narrowband light 214. In one exemplary embodiment, narrowband light can be approximated as representing only a single center wavelength. In practice, narrowband light can include mostly (e.g., greater than 50%, greater than 75%, or greater than 90%) light from a narrow wavelength band (e.g., less than lnm, less than 10 nm, less than 100 nm, or less than 500 nm).
(23) Certain wavelengths stimulate DNA and RNA synthesis, as discussed in Karu and Kolyakov's 2005 document entitled “Exact Action Spectra for Cellular Responses Relevant to Phototherapy” published in Photomedicine and Laser Surgery and incorporated herein by reference in its entirety. The Karu and Kolyakov document indicates that light having center wavelengths of approximately 660 nm and 850 nm correspond to critical active regions for stimulated RNA and DNA synthesis. This indication can be supported in the use and success of photobiomodulation and phototherapy at these wavelengths. Examples of effective photobiomodulation are provided in Zein, Selting and Hamblin 2018 review entitled “Review of Light Parameters and Photobiomodulation Efficacy: Dive into Complexity” published in the Journal of Biomedical Optics and incorporated herein by reference in its entirety. For example, wounds, ulcers, and bone were found to be effectively treated with photobiomodulation by narrowband light centered at wavelengths including: 830 nm, 670 nm, 632 nm, and 670 nm.
(24) A dosage of the narrowband light can be controlled in procedure 216 in order to affect (e.g., increase) a growth rate of the nail. According to certain exemplary embodiments of the present disclosure, the light dosage can be controlled by modulating an optical power of the narrowband light. For example, in some exemplary variants and/or versions, pulse width modulation (PWM) can be used to control optical power of a narrow band light source (e.g., a light emitting diode [LED]). In certain exemplary variants and/or versions, the control of the dosage in procedure 216 can be a closed loop and the optical power of the narrowband light can be actively measured, for example, using a photodetector. Examples of photodetectors can include, e.g., photodiodes, photoresistors, phototransistors, active-pixel sensors (e.g., a charge coupled device [CCD] and a capacity metal-oxide semiconductor [CMOS] sensors), and/or photovoltaic cells. In other exemplary variants and/or versions, the control of the dosage in procedure 216 can be an open loop. In this exemplary case, it can be advantageous for the control in procedure 216 be calibrated based upon a representative measured optical power of the narrowband light at the known nail location prior to treatment. Controlling power of the narrowband light can control a treatment irradiance (for example, measured in W/cm.sup.2). The treatment irradiance can be the irradiance of the narrowband light as applied to the nail.
(25) According to particular exemplary embodiments of the present disclosure, the dosage can be controlled in procedure 216 by controlling a treatment time over which the nail undergoes irradiation. The dosage can be measured according total energy delivered over total treated area or using an accumulated fluence (e.g., the treatment irradiance integrated over the treatment time). The accumulated fluence can be measured in Fern′. Controlling the treatment time, therefore, controls the light dosage as measured by accumulated fluence.
(26) While it is certainly beneficial to alter a nail growth rate and the scientific research indicates the promise of photobiomodulation, it is believed that no commercial systems are available. Effective photobiomodulation of the nail matrix stimulates and increases nail growth, increasing a rate of growth of aged, diseased, or normal nails. The effectiveness of photobiomodulation of nails can be largely dependent on light dosage. The light dosage can determine whether the growth rate of a nail is stimulated or inhibited. Additionally, as discussed herein below, a proper light dosage during photobiomodulation has proven difficult in a research setting in the past.
(27) In order to better control light dosing over time, according to certain exemplary embodiments of the present disclosure, it is possible to track (i.e., log or record) the use and/or light dosage over a period of time. It is understood that compliance of a subject to a treatment regimen can be an issue in many areas of healthcare, veterinary medicine and aesthetics. For example, subjects responsible for treating themselves outside of a clinical or spa setting commonly may fail to adhere to treatment regimens, thereby possibly limiting the potential effects of treatment. As effects from photobiomodulation may be very sensitive to light dosage amount (as described in detail below), a negative impact from non-compliance by a subject user of a device intended to affect nail growth rate can counteract any (and possibly all) of the desired results. In order to ensure a careful delivery of therapeutic or cosmetic light dosage, in some exemplary embodiments of the present disclosure, one or more parameters can be provided, saved, documented, etc., e.g., to a log file in procedure 218 after a light dosage has been applied to the nail. In some exemplary cases, the one or more parameters can be related to light dosage. For example, exemplary light dosage parameters can include start time of treatment, end time of treatment, treatment time (e.g., duration), the power of the light, and/or the light dosage. Recording, saving, storing and/or documenting information related to treatment (e.g., light dosage parameters) can facilitate a subsequent verification of light dosage by a review of the log file, any electronic file and/or any storage electronic facility which retains such information. In some exemplary cases, the log file may be reviewed by the user of the device or a medical professional. Alternatively, the log file, the electronic file and/or the storage electronic facility can be reviewed automatically (e.g., by a controller within the device) to ensure that over time (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, etc.), an actual amount of delivered light dosage is compliant with a prescribed dosage and within a therapeutic range, as intended and/or desired according to the treatment plan. Ensuring that light dosage is delivered in a manner consistent with treatment is important, at least according to various exemplary embodiments of the present disclosure, at least because of a nature of dose response for photobiomodulation.
(28) Photobiomodulation, which is at times referred to as low level light (or laser) therapy (LLLT), can act according to a biphasic (i.e., hormesis) dose-response relationship. Hormesis dose-responses can be understood as following the Arndt-Scholz rule of pharmacology: “For every substance, small doses stimulate, moderate doses inhibit, and large doses kill.” Thus, e.g., hormesis dose-response can be modeled using an Arndt-Schulz curve.
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(30) A controller 322 receives input (e.g., data, signals, etc.) from the presence detector 314, and can control the narrowband light source 316. The controller 322 can control the narrowband light source 316 in order to, e.g., accurately deliver a light dosage to the nail 310. In some exemplary embodiments, the light dosage can be controlled according to a treatment irradiance, typically measured in units of W/cm.sup.2. Treatment irradiance is a function of the power of the light source 316 and/or the distance between the light source 316 and the nail 310. In some exemplary cases, output from the light source can be modeled according to Lambert's Sine Law;
(31) and, the light can be said to be Lambertian. In some exemplary variants and/or versions, the controller 322 can comprise a pulse width modulator (PWM) and/or similar electronic power regulator, to the power of the light 318 emitted by the narrowband light source 316. In some further exemplary embodiments, the light dosage can be measured in accumulated fluence, typically measured in units of J/cm.sup.2. Accumulated fluence can be estimated by, e.g., integrating the treatment irradiance over a treatment time. Therefore, in some exemplary variants and/or versions, the controller 322 can control the light dosage by controlling the treatment time.
(32) According to certain exemplary embodiments of the present disclosure, the controller 322 can control the light dosage based upon the treatment irradiance delivered to the nail 310. In some exemplary variants and/or versions, the controller 322 can additionally include an estimating system that can be configured to estimate the treatment irradiance. The estimating system—according to various exemplary embodiments of the present disclosure—can estimate the treatment irradiance based upon the presence of the nail 310, the distance 320 between the nail and the light source, and the power of the light 318. In some further exemplary variants and/or versions, the system 300 can also include a photodetector 324 that can be configured to measure the power of the light 318 and the treatment irradiance.
(33) In the various exemplary variants and versions, the controller 322 can be configured to document, store, save and otherwise provide one or more treatment related parameters or variables electronically, e.g., to a log file, electronic storage file, etc. Such exemplary files—in some exemplary cases—can be located within a non-volatile memory located within the system 300, the controller 322, external storage device, etc. . . . . Exemplary non-volatile memories can include solid state drives (SSD), flash drives (e.g., NAND flash), hard drives (HDD), and read-only memory (ROM) (e.g., electrically erasable programmable ROM [EEPROM]). In some cases, the exemplary files can be stored locally or remotely, and, e.g., the communication with such exemplary file(s) (e.g., reading, writing, analyzing, etc.) can be performed over one or more networks. Exemplary networks include local area networks (LAN), wide area networks (WAN), closed areas networks (CAN), and wireless networks (e.g., WiFi). In the exemplary cases where the exemplary file(s) is/are located remotely and accessed via one or more networks, the controller 322 can comprise a network interface (not shown). Exemplary network interfaces can include a network interface controller (NIC), a wireless network interface controller (WNIC), cellular network portable transceivers (e.g., 4g-LTE wireless broadband modem), a modem, and/or an integrated service digital network (ISDN) terminal adapter (TA). In some exemplary cases, such one or more parameters being documented, stored, saved, reviewed, analyzed, etc. e.g., in the exemplary file can include parameters related to light dosage, for example, a start time of treatment, an end time of treatment, the treatment time, the power of the light, and/or the light dosage. In certain exemplary embodiments of the present disclosure, the controller 322 can be further configured to review the exemplary (e.g., log, electronic, etc.) file to verify light dosage compliance to a treatment regimen. For example, in an exemplary case, the controller 322 can estimate a total light dosage delivered by the system 300 from the exemplary file over a given or predetermined time period (e.g., 1 day, 1 week, 2 weeks, etc.), and can be configured to determine if this light dosage is within limits of a prescribed or predetermined light dosage regimen.
(34) A diagram of a system 400 for treatment of nails according to another exemplary embodiment of the present disclosure is shown in
(35) The exemplary system 400 is shown without a cover in
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(37) As described in detail herein above, wavelength selection and light dosage can determine changes in nail growth rate. The biphasic dose-response for photobiomodulation facilitates stimulating effects or inhibitory effects to be realized by varying dose. An optimum stimulating light dosage can be sought and/or obtained for the exemplary embodiments of the present disclosure which are configured to increase nail growth rate. For example, in one exemplary embodiment, a maximum inhibiting light dosage can be sought for the exemplary embodiments configured to suppress nail growth rate. A limiting characteristic for the maximum inhibiting light dosage can be typically heat. Increasing treatment irradiance can ultimately heat the nail bed and limb resulting in discomfort and in extreme cases, thermal disruption.
(38) A table below enumerates exemplary narrowband wavelengths for nail treatment according to certain exemplary embodiments of the present disclosure:
(39) TABLE-US-00001 Representative Treatment Wavelength List of Narrowband Wavelength Range Light Nom. Center (nm) (nm) Wavelengths (nm) 665 600-700 600, 610, 620, 635, 640, 643, 650, 660, and 680 765 700-800 720, 730, 740, 765, and 770 850 800-900 810, 820, 830, 850, 855, 856, 870, 875, 880, 885, 890, and 900
(40) A table below enumerates exemplary light dosages, according to certain exemplary embodiments of the present disclosure:
(41) TABLE-US-00002 Nom. Min. Nom. Max. Min. Nom. Max. Min. Nom. Max. Wavelength Irradiance Irradiance Irradiance Fluence Fluence Fluence Time Time Time (nm) (W/cm.sup.2) (W/cm.sup.2) (W/cm.sup.2) (J/cm.sup.2) (J/cm.sup.2) (J/cm.sup.2) (S) (S) (S) 665 0.0005 0.008 5 0.5 5 50 60 600 14400 765 0.0005 0.008 10 0.5 5 100 60 600 14400 850 0.001 0.008 10 1 5 100 60 600 14400
(42) It can certainly be appreciated that, for example, additional exemplary embodiments can be provided that can include wavelengths not described in detail above, including, e.g.: 265-275 nm, 275 nm, 278 nm, 280 nm, 285 nm, 295 nm, 310 nm, 325 nm, 340 nm, 355 nm, 357 nm, 365 nm, 365-375 nm, 367 nm, 368 nm, 370 nm, 375 nm, 377 nm, 378 nm, 380 nm, 370-385 nm, 380-390 nm, 382 nm, 383 nm, 385 nm, 388 nm, 390 nm, 395 nm, 400 nm, 402 nm, 403 nm, 405 nm, 410 nm, 415 nm, 420 nm, 425 nm, 430 nm, 447 nm, 450 nm, 460 nm, 470 nm, 502 nm, 520 nm, 525 nm, 527 nm, 562 nm, 570 nm, 590 nm, 595 nm, 597 nm, 905 nm, 920 nm, 935 nm, 940 nm, 945 nm, 950 nm, 980 nm, 1020 nm, 4050 nm, 4060 nm, 1200 nm, 1300 nm, 1450 nm, 1550 nm, 1650 nm, and 1720 nm.
(43) In another additional exemplary embodiment for treatment of onychomycosis, an additional narrowband light source 520 can emit a supplementary narrowband light (see, e.g.,
(44) In another additional exemplary embodiment of the present disclosure, the biphasic light dose response can be used to intentionally produce an inhibitory response in nail growth rate. In such exemplary case, a light dosage controlled above a threshold at which inhibitory effects result.
(45) In another a further exemplary embodiment of the present disclosure, treatment and light dosage can be controlled according to a dosing schedule. The dosing schedule is prescribed to induce a desired effect on the nail growth rate. For example, the dosing schedule in certain exemplary versions facilitates a user to be treated only once a day for a certain number of hours, days, etc. The dosing schedule can be controlled by the controller and can prevent and/or modify operation of the device at times outside the schedule, for example to prevent or reduce overdosage. In other exemplary variants and/or versions, the dosing schedule can be provided as regiment for treatment (e.g., directions for use) and the user is responsible for facilitating treatment according to the dosing schedule. Exemplary dosing schedules can include a frequency (e.g., four times a day, three times a day, twice a day, once a day, once every two days, once every three days, once every four days, etc.) and a duration (e.g., within a range of ten seconds to two hours).
(46) In some exemplary cases, an electronic (e.g., log) file can be maintained in which parameters or variables related to light dosage are documented, stored, analyzed, recorded, etc. Actual light dosages delivered, according to the electronic file, may then be compared with the prescribed light dosage schedule in order to ensure that a proper amount of light is being delivered. As described above, in many exemplary cases, precise delivery of a light dosage can result in a desired nail growth change, where a little higher dosage (or a little lower dosage) can result in no or little change in nail growth or even a change in nail growth rate that is the opposite of the desired nail growth change (e.g., decreasing nail growth rate instead of increasing nail growth rate).
(47) The exemplary device 400 described herein and shown in
(48) TABLE-US-00003 Wavelength of light 660 nm and 850 nm Delivered light dosage range Within a range of 2.1 J/cm.sup.2 and 16 J/cm.sup.2 Exposure time 10 minutes Maximum light intensity No greater than 30 mW/cm.sup.2
(49) The treatment was self-administered by the subjects. Nail growth rate was determined by examining photographs of the treated toenails. The toenails were marked and the mark was used in the photographs to gauge growth.
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(51) The foregoing merely illustrates the principles of the disclosure. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements, and procedures which, although not explicitly shown or described herein, embody the principles of the disclosure and can be thus within the spirit and scope of the disclosure. Various different exemplary embodiments can be used together with one another, as well as interchangeably therewith, as should be understood by those having ordinary skill in the art. In addition, certain terms used in the present disclosure, including the specification, drawings and claims thereof, can be used synonymously in certain instances, including, but not limited to, for example, data and information. It should be understood that, while these words, and/or other words that can be synonymous to one another, can be used synonymously herein, that there can be instances when such words can be intended to not be used synonymously. Further, to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above, it is explicitly incorporated herein in its entirety. All publications referenced are incorporated herein by reference in their entireties.