Skin treatment and pre-treatment technology based on micro-current

Abstract

A method includes applying one or more electrodes to a skin or skin surface of a subject, applying a voltage or current signal to the skin surface via one or more of the electrodes, and modulating the signal to maintain therapeutic efficacy, or such that a power output may be charge balanced, or both. The agent may be applied to the skin surface during a treatment period defined after application of the voltage or current signal. During the treatment period, skin permeability to one or more components of the agent is enhanced or increased in response to the modulated power output. An apparatus for performing the method is also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 311,900, filed on February 18, 2022, “Microcurrent-Based Skin Treatment and Pretreatment Techniques,” and U.S. Provisional Application Serial No. 63 / 336,573, filed on April 29, 2022, “Microcurrent-Based Skin Treatment and Pretreatment Techniques,” each of which is incorporated herein by reference in its entirety and for all purposes. Technical Field

[0003] The present application relates to skin treatment and pretreatment technologies based on electric current. More generally, the present application relates to microcurrent treatments adapted for enhanced transport to, from, and across selected layers of skin tissue. Applications include, but are not limited to, delivery of topical agents, skin treatments, and other beneficial products. Background Art

[0004] The skin covers the surface of the body, forming a physical, insulating barrier against the external environment and protecting the body from excessive heat, cold, dryness, moisture, solar radiation, dust and foreign matter, as well as insects and other invading organisms. The skin also helps maintain body temperature and forms an important part of the immune system, while regulating the passage of water, electrolytes and other substances, and providing a neural network adapted for touch, thermal sensitivity and other forms of physical sensation.

[0005] Skin is the main component of the integumentary system, which also includes hair, nails, and (in some animals) other features such as feathers, scales, and hooves. The outermost layer of the skin is the epidermis, which includes cells called keratinocytes, which form an environmental barrier and synthesize vitamin D. The epidermis also includes melanocytes, which produce melanin to protect from harmful UV radiation; Merkel cells, which provide sensitivity to touch; and Langerhans cells, a type of white blood cell or macrophage, which, as part of the immune system, protects the body from infection.

[0006] The epidermis surrounds the dermis. The structure of the dermis is provided by fibroblasts, which synthesize collagen and elastin to form an extracellular matrix, in which collagen fibers provide strength and toughness, and elastin threads or filaments provide elasticity and flexibility. Fibroblasts also produce proteoglycans, sticky proteins that provide hydration and lubrication, and regulate ion binding and molecular transport. The dermis also includes macrophages and mast cells, additional components of the immune system, as well as hair follicles, sweat glands and oil glands, nerve cells and a network of blood vessels.

[0007] The epidermis and dermis make up the epithelium. The subcutaneous tissue lies beneath the epithelium and includes fat (lipid) cells, elastin, and other subcutaneous tissue that connects the epithelium to underlying muscle, fascia, and other connective tissue such as the periosteum (covering the bone).

[0008] In addition to its protective barrier function, the skin includes a system of pores to help regulate the passage of fluids across the various skin layers and underlying tissues. However, little is known about the effects of electrical current on skin permeability, and there remains a significant need for improved technologies adapted to enhance the delivery of topical agents, therapeutic products, and other beneficial substances across selected skin layers. Summary of the invention

[0009] A method for skin treatment, comprising applying one or more electrodes to a subject's skin surface, applying a voltage or current signal to the skin surface via one or more of the electrodes, and modulating a power output to the skin surface via the voltage or current signal. A delay period may be defined after the modulated power output; for example, during which no further voltage or current signal is applied via the one or more electrodes. An agent may be applied to the skin surface after the signal or after the delay period, wherein the permeability of the skin to one or more components of the agent is enhanced or increased in response to the modulated power output.

[0010] In any of the various examples and embodiments described herein, the methods may be used for cosmetic skin treatments, as opposed to medical procedures as may be employed in other examples and embodiments, subject to applicable regulations. Also contemplated are apparatus for implementing the methods.

[0011] In some examples and embodiments, the method includes pre-treating the skin surface of the subject by applying a voltage or current signal surface via one or more electrodes; for example, wherein power is output to the skin surface and the voltage or current signal is modulated; for example, wherein the power output is selected to enhance or increase the permeability of the skin surface. Depending on the application, the method may also include treating the skin surface by applying an agent to the skin surface; for example, wherein when pre-treating the skin surface, in the absence of further voltage or current signals applied to the skin surface via one or more electrodes, in response to the modulated power output, the permeability of the skin to one or more components of the agent is enhanced or increased.

[0012] In any of these examples and embodiments, the method may include generating a voltage or current signal as a DC, pulsed DC, microcurrent, or pulsed microcurrent waveform. The power output to the skin may be charge balanced, or the polarity of the power output to the skin may alternate at periodic or non-periodic intervals.

[0013] In any of these examples and embodiments, the method may apply the agent to the skin surface before or during pre-treatment of the skin surface, or after pre-treatment of the skin surface; for example, wherein no further voltage or current signal is applied after application of the agent.

[0014] In any of these examples and embodiments, modulating the voltage or current signal may include adjusting the amplitude of the signal so that the power output is selected for user comfort or enhanced or increased efficacy in permeability, or both; for example, compared to the power output without modulating the voltage or current signal. The modulated power output may be selected for enhanced or increased permeability to include enhanced or increased adsorption, absorption, diffusion, or transmissibility of one or more components of the agent into or through one or more layers of the skin surface during the treatment period; for example, compared to the adsorption, absorption, diffusion, or transmissibility without applying the voltage or current signal to the skin surface.

[0015] In any of these examples and embodiments, one or more layers of the skin surface may include the stratum corneum, the outer epidermis, the lower epidermis, or the dermis, or wherein one or more layers of the skin surface include vasculature or fibroblasts. The treatment period may be extended by at least 1 to 2 hours or more after the application of the voltage or current signal, by at least 2 to 4 hours or more after the application of the voltage or current signal, by at least 4 to 8 hours or more after the application of the voltage or current signal, by at least 6 to 12 hours or more after the application of the voltage or current signal, by at least 12 to 24 hours or more after the application of the voltage or current signal, or by at least 24 hours or more after the application of the voltage or current signal.

[0016] In any of these examples and embodiments, the method may include defining a delay period after pre-treating the skin surface; for example, wherein no further voltage or current signal is applied to the skin surface via one or more electrodes during the delay period. The agent may be applied to the skin surface after the delay period, and / or the agent may be applied to the skin surface again or multiple times at a different time during or after the delay period, or multiple different agents may be applied to the skin surface; for example, at the same or different times during or after the delay period.

[0017] In any of these examples and embodiments, the delay period can be extended by at least 1 to 2 minutes after the voltage or current signal is applied, by at least 2 to 5 minutes after the voltage or current signal is applied, by at least 5 to 10 minutes after the voltage or current signal is applied, by at least 10 to 30 minutes after the voltage or current signal is applied, by at least 30 minutes to 1 hour after the voltage or current signal is applied, or by at least 1 hour after the voltage or current signal is applied, or more. For example, the delay period can be extended by at least 1 to 2 hours after the voltage or current signal is applied, by at least 2 to 4 hours after the voltage or current signal is applied, by at least 4 to 8 hours after the voltage or current signal is applied, by at least 6 to 12 hours after the voltage or current signal is applied, by at least 12 to 24 hours after the voltage or current signal is applied, or by at least 24 hours after the voltage or current signal is applied, or more.

[0018] In any of these examples and embodiments, the method may include modulating the power output to the skin surface based on a feedback signal responsive to a change in an applied voltage or current signal, and one or more of the voltage or current signals near one or more of the sensing electrodes; for example, wherein the change is based at least in part on the sensed voltage or current signal, and / or defining a response curve for the power output; for example, wherein the response curve modulates the power output between predetermined minimum and maximum power levels based on the feedback signal.

[0019] In any of these examples and embodiments, the method may include one or more of the following: defining a threshold for a change in the feedback signal, reducing the power output or lowering the response curve to a predetermined minimum power level or toward a predetermined minimum power level; for example, based on the change in the feedback signal reaching or exceeding the threshold, and / or increasing the power output or raising the response curve to a predetermined maximum power level or toward a predetermined maximum power level; for example, based on the change in the feedback signal not reaching or exceeding the threshold.

[0020] In any of these examples and embodiments, the method may include generating a waveform for applying a voltage or current signal to the skin surface, wherein the waveform includes an alternating sequence of positive and negative polarities. Modulating the power output may include controlling a pulse width, period, or amplitude of the waveform based on an impedance between two of the electrodes; for example, as determined by a feedback circuit.

[0021] In any of these examples and embodiments, the method of modulating the power output can be performed utilizing a three-terminal device having a first terminal coupled to a voltage sensor adjacent to one or more of the electrodes, a second terminal coupled to a feedback signal, and a gate adapted to control the power output.

[0022] In any of these examples and embodiments, the alternating sequence of positive and negative polarities may be symmetrical, non-periodic, or have a randomized or pseudo-random pulse width, pulse height, or period. The positive and negative components of the waveform may be charge balanced over a period of about 0.1-0.2 s or less, over a period of about 0.2-0.5 s or less, over a period of about 0.5-1.0 s or less, over a period of about 1.0-1.5 s or less, or over a period of about 1.4 s, or a combination thereof. The voltage or current signal applied to the skin surface may include a voltage or current pulse having an amplitude of about 100 μA or less, about 100-150 μA or less, about 150-200 μA or less, about 200-250 μA or less, or about 250 μA or less.

[0023] In any of these examples and embodiments, the voltage or current signal applied to the skin surface may include voltage or current pulses having individual pulse widths of between about 1-10 ms or less, between about 10-20 ms or less, between about 20-50 ms or less, between about 50-100 ms or less, or about 100 ms or less. The voltage or current signal applied to the skin surface may include alternating sequences of voltage or current pulses; for example, wherein the alternating sequences each include between two and six individual pulses or less, between five and ten individual pulses or less, between six and twelve individual pulses or less, between ten and twenty individual pulses or less, between twenty and fifty individual pulses or less, or fifty individual pulses or less.

[0024] In any of these examples and embodiments, applying a voltage or current signal and modulating the power output to the skin surface can be performed within a pre-treatment period selected to achieve enhanced or increased skin permeability when the agent is applied. The pre-treatment period can be selected for enhanced or increased adsorption, absorption, diffusion or transmissibility of one or more components of the agent into or through one or more of the skin surface layers during the treatment period; for example, compared to the adsorption, absorption, diffusion or transmissibility without applying a voltage or current signal to the skin surface. The range of the pre-treatment period can be between about 1 to 2 minutes or less, between about 2 to 3 minutes or less, between about 3 to 5 minutes or less, between about 5 to 10 minutes or less, or about 10 minutes or less.

[0025] In any of these examples and embodiments, one or more components of the agent for which permeability is enhanced or increased may include ions, or ions or polar molecules. One or more components of the agent for which permeability is enhanced or increased may also include non-ionic or non-polar molecules, or proteins, amino acids, genetic material, genetic markers, allantoin or caffeine.

[0026] In any of these examples and embodiments, the method may include applying a topical agent to the skin surface; for example, wherein the topical agent is applied prior to or simultaneously with the application of the voltage or current signal. The topical agent may include a conductive gel, serum, moisturizer, or base component of a skin treatment product, or wherein the topical agent forms a conductive path for the voltage or current signal between one or more of the electrodes and the skin surface.

[0027] In any of these examples and embodiments, the method may be applied to cosmetic skin treatments. The examples and embodiments may be performed in any order or combination. A non-transitory computer readable medium may also be provided with program code stored thereon, wherein the program code is executable on a computer processor or controller to perform a skin treatment method according to these examples and embodiments in any order or combination.

[0028] According to any one of these examples and embodiments or any combination thereof, the skin treatment system may include one or more electrodes configured or adapted to apply a voltage or current signal. As described herein, the voltage or current source may be configured or adapted to generate a voltage or current signal, and the control circuit may be configured or adapted to modulate the power output to the skin surface. For example, the one or more electrodes may include one or more electrode pairs having an elongated leaf-like structure, and / or the voltage or current signal may be applied to the electrodes in each pair with opposite polarities.

[0029] In various examples and embodiments, the method includes placing at least two electrodes adjacent to a skin area, providing a microcurrent pre-treatment to the skin area via a voltage or current waveform applied to the electrodes, and modulating the power output of the microcurrent pre-treatment to enhance or increase the permeability of the skin area to a selected therapeutic substance. The method may also include one or more of the following: removing the electrodes from the adjacent skin area, and / or applying the selected therapeutic substance to the skin area; for example, wherein after removing the electrodes, the permeability of the skin area to the selected therapeutic substance increases.

[0030] In any of these examples and embodiments, modulating the power output may include adjusting the power output between selected minimum and maximum power levels to enhance or increase the permeability of the skin surface to the selected therapeutic substance during the treatment phase; for example, compared to such skin surface without the application of microcurrent pre-treatment during the pre-treatment phase. The minimum and maximum power levels may be further selected to maintain user comfort compared to the application of microcurrent pre-treatment without modulating the power output.

[0031] In any of these examples and embodiments, the waveform may have a DC, pulsed DC, microcurrent, or charge-balanced microcurrent function form; for example, as defined within a period for modulating the power output. The period may range from at least 100 microseconds to at least 1 millisecond, at least 10 milliseconds, at least 100 milliseconds, at least one second, or at least two seconds, and the period may also range from less than two seconds or less than one second.

[0032] In any of these examples and embodiments or any combination thereof, the method may be performed for cosmetic skin treatment. For example, the microcurrent pre-treatment may be applied for a period of at least 10 seconds, at least 30 seconds, at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, or less than 10 minutes, or less than 5 minutes. The selected therapeutic substance may include ions, ionic or polar molecules, non-ionic or non-polar molecules, proteins, amino acids, genetic material, genetic markers, allantoin, or caffeine.

[0033] In various examples and embodiments, the method for cosmetic skin treatment includes a pre-treatment phase; e.g., including deploying at least two electrodes adjacent to the skin surface; e.g., wherein an area of ​​the skin surface is located therebetween, and providing a microcurrent pre-treatment to the area of ​​the skin surface via an electrical waveform applied to the electrodes; e.g., wherein the electrical waveform includes one or more pulses of the same or opposite polarity. The pre-treatment phase may be followed by a treatment phase; e.g., including applying a treatment substance to the area of ​​the skin surface, wherein the permeability of the skin surface to the treatment substance is enhanced or increased in response to the microcurrent pre-treatment in the area between the electrodes, and no further electrical waveforms are applied during the treatment phase.

[0034] In any of these examples and embodiments, the electrical waveform may have a DC, pulsed DC, microcurrent, or charge-balanced microcurrent function form. The method may also include adjusting or modulating the power output of the electrical waveform in the pre-treatment phase; for example, wherein the power output is selected to enhance or increase the permeability of the skin surface to the treatment substance during the treatment phase, or to enhance or increase the user's comfort during the pre-treatment phase, or both, compared to the application of microcurrent pre-treatment without adjusting or modulating the power output in the pre-treatment phase.

[0035] Any of these examples and embodiments may include a delay phase defined between the pre-treatment phase and the treatment phase; for example, wherein the delay phase extends for a period of at least five minutes, at least ten minutes, at least thirty minutes, at least one hour, at least two hours, at least four hours, at least eight hours, at least twelve hours, or at least twenty-four hours. The treatment phase may extend for a period of at least 5 minutes, at least 10 minutes, at least 30 minutes, at least one hour, at least two hours, at least four hours, at least eight hours, at least 12 hours, at least 24 hours, or at least 48 hours; for example, during which the permeability of the skin surface to the therapeutic substance is enhanced or increased compared to the permeability of such skin surface without the pre-treatment phase.

[0036] In any of these examples and embodiments, a conductive gel or fluid may be applied to the skin surface prior to or during the pre-treatment phase. For example, the conductive gel or fluid may be selected to form a conductive path between the electrode and the skin surface, or to modulate the current density of the microcurrent pre-treatment along the area of ​​the skin surface between the electrodes, or both.

[0037] The method of cosmetic skin treatment may be performed in any order or combination according to any of these examples and embodiments. The device may be configured or adapted to perform the method of cosmetic skin treatment in any order or combination according to any of these examples and embodiments. A non-transitory computer readable medium may be provided with program code stored thereon, wherein the program code is executable on a computer processor or controller to perform the method of cosmetic skin treatment in any order or combination according to any of these examples and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is a cross-sectional view illustrating application of electrical current treatment to the skin surface.

[0039] Figure 2 is a block diagram of an apparatus for applying electrical current therapy to the surface of the skin.

[0040] Figure 3 is a block diagram of a method for applying electrical current therapy to the surface of the skin.

[0041] Figure 4 is a block diagram of a method for modulating power delivered by current therapy.

[0042] Figure 5 is an electronic schematic illustrating a circuit for modulating power.

[0043] Figure 6 is a block diagram illustrating a method for waveform modulation.

[0044] Fig. 7A Schematic diagram of a Franz Cell adapted to test the permeability of a skin sample.

[0045] Figure 7B is a schematic diagram of a Franz Cell system adapted for applying microcurrent treatment to a skin sample.

[0046] Fig. 8A , 8B 8C are schematic diagrams illustrating representative waveforms for application to the skin surface.

[0047] Fig. 9A and 9B is a bar graph illustrating transdermal permeability and retention of 1.0% allantoin reagent following selected current treatments.

[0048] Fig. 10A and 10B is a bar graph illustrating the transdermal penetration and retention of 0.1% allantoin serum following selected electrical current treatments.

[0049] Fig.11A , 11B 11C are bar graphs illustrating transdermal allantoin permeation, retention, and flux following selected current treatments.

[0050] Fig. 12A , 12B 12A and 12C are bar graphs illustrating transdermal allantoin permeation, retention, and flux following alternate current treatment.

[0051] Fig.13A , 13B 13 and 13C are bar graphs illustrating transdermal caffeine permeation, retention, and flux following selected current treatments.

[0052] Fig.14A , 14B 14 and 14C are bar graphs illustrating transdermal caffeine permeation, retention, and flux following alternating current treatment.

[0053] Fig.15A , 15B 15 and 15C are bar graphs illustrating transdermal allantoin permeation, retention, and flux for selected three and six minute current treatment durations.

[0054] Fig.16A , 16B 16C are bar graphs illustrating transdermal permeation, retention, and flux of 0.1% allantoin serum with selected electrical waveform pre-treatment durations of 3 minutes and 6 minutes.

[0055] Fig.17A and 17B are histograms illustrating expert assessment of skin radiance, texture, and firmness for the treated upper arm and upper thigh areas and for the appearance of cellulite on the upper thigh.

[0056] Fig.18 is a histogram illustrating the circumference measurements of the upper thigh area.

[0057] Fig.19A and 19B are histograms illustrating self-perceived assessments of skin radiance, texture, and firmness for the treated upper arm and upper thigh areas and the appearance of cellulite on the upper thighs.

[0058] Fig. 20A and 20B is a scatter plot illustrating tape strip assessment of allantoin recovery in the upper thigh.

[0059] The present application describes the disclosed technology with reference to the accompanying drawings and associated written descriptions, in which like numbers may represent similar structural and functional components. These examples and embodiments are merely representative and do not limit the practice of the invention as claimed. Those skilled in the art will recognize that equivalents may be substituted and changes may be made in form and detail while remaining within the scope of coverage as defined by the language of the appended claims. DETAILED DESCRIPTION

[0060] In addition to the barrier properties provided by the stratum corneum, epidermis, dermis, and other layers, the skin also includes sudoriferous (sweat) glands to help regulate temperature by secreting water, electrolytes, and (e.g., nitrogenous) waste products. Eccrine sweat glands open onto the skin surface via pores, while apocrine sweat glands open into hair follicles in selected areas of the skin. Sebaceous glands also open into hair follicles, secreting lipids and other natural oils (sebum) to lubricate the hair and adjacent skin surface.

[0061] Pores, hair follicles and associated glandular structures can also provide pathways for transdermal absorption and delivery and secretion. Skin is also permeable at the cellular level, and permeability depends on the structure of the corresponding layer. For example, when keratinocytes form in the lower layer of the epidermis, they have a relatively permeable phospholipid cell membrane. However, when keratinocytes migrate outwards toward the stratum corneum, they are converted into keratinocytes, which are flat, differentiated, anucleate (dead) cells, with a lasting, insoluble envelope made of cross-linked proteins, which is embedded in a lipid matrix and linked together by a protein complex called desmosomes. Fluid transport can also occur via extracellular matrix and associated interstitial fluids, which surround individual cells of cells, and support the transportation of salt, sugar, lipid, fatty acid, amino acid, protein, enzyme, hormone, neurotransmitter and other cell products including genetic material.

[0062] The present disclosure relates to the effects of electrical current (e.g., microcurrent) based skin treatments on skin transport processes, including both cellular and intercellular transport, as well as pores, follicles, and associated glandular structures. These techniques are not limited to the current treatment itself, but also cover the potential, enhanced permeability effects observed after a given treatment. Applications include, but are not limited to, enhanced delivery of topical agents, skin treatments, and other beneficial products to and across selected skin layers during treatment periods extending for minutes, hours, or up to days after electrical current treatment.

[0063] A range of suitable voltage and current signals can be generated to improve the delivery of topical agents via enhanced transmission, absorption, or absorption of the agent by, to, or through one or more layers of the skin surface. Suitable modulated waveforms are described, for example, in U.S. Publication No. 2021 / 0308452A1, “Modulated Waveform Treatment Device and Method,” and in U.S. Provisional Patent Application No. 63 / 256,106, filed on October 15, 2021, “Current Control System for Skin Treatment Device,” each of which is incorporated herein by reference in its entirety and for all purposes.

[0064] These techniques differ from iontophoresis, electromigration, electroosmosis, electroporation, and similar conventional methods, in which the transport of ions or polar agents can be enhanced by applying a parallel (e.g., DC) current signal. Instead, carefully modulated microcurrent stimulation is applied during the pre-treatment phase, with or without the use of a conductive gel or similar topical agent. Permeability is improved or enhanced after the pre-treatment phase for selected beneficial components of the therapeutic agent, which can be applied before, during, or after the pre-treatment phase. There is improved permeability in response to the power applied by the current stimulation during the pre-treatment phase, and the improved permeability is exhibited without further application of stimulation, even when the pre-treatment is performed before the agent is applied and the agent is applied after the pre-treatment is completed.

[0065] These microcurrent pre-treatment techniques are also distinguished from laser, needle and micromechanical methods in which small holes or orifices are physically formed in the skin surface rather than applying carefully modulated waveforms to enhance the skin's natural permeability process. In addition, in contrast to the use of chemical permeation enhancers (CPEs) and other chemical methods, no reactive chemicals, adsorption promoters or accelerators are required to disrupt the skin's natural barrier properties. Instead, skin permeability is enhanced through carefully modulated microcurrent pre-treatment, increasing the transdermal flux of selected components of a topical agent or skin treatment formulation without applying reactive chemical agents to the skin.

[0066] Figure 1 is a cross-sectional view illustrating the application of an electrical current therapy device 100 configured to deliver electrical stimulation S to the skin 10 or skin surface 11 of a subject by, for example, a user of the device 100, or by a skin therapist, therapist, or other person applying the device 100 to the skin 10 or skin surface 11.

[0067] like Figure 1 , a skin care device 100 includes one or more electrodes 120 adapted to apply an electrical current treatment S to a surface 12 of a subject's skin 10, such as in combination with a topical agent 20 as shown, or directly to the skin surface 12. The skin (or "epithelium") 10 extends from the skin surface 12 through an epidermal layer (or epidermis) 14 to a lower dermal layer (dermis) 16. Subcutaneous tissue (or hypodermis) 18 includes subcutaneous tissue beneath the epidermis 16.

[0068] The dermis 16 includes an upper papillary layer and a lower reticular layer, formed by looser and denser collagen fibers, respectively. The collagen fibers extend from the dermis 16 through the subcutaneous tissue 18, thereby forming a connective tissue (fascia) that attaches the skin (epithelium) 10 to the underlying muscle and other connective tissue. The subcutaneous tissue 18 also includes adipose tissue, such as in the form of adipocytes (fat cells) and intracellular or intercellular lipids formed between the collagen fibers. Circulation is provided by a network of small blood vessels or capillaries extending from the subcutaneous tissue 18 into the dermis 16.

[0069] Depending on the application, the electrical current stimulus S may be generated by one or more electrodes 120 deployed along the skin surface 12. A topical skin treatment 20 may be applied to the skin surface 12 to increase conductivity and provide nutrients and other beneficial agents to the skin 10.

[0070] like Figure 1 As shown in , the electrical stimulus S propagates through the skin surface 12 to the epidermis 14, and through the epidermis 14 to one or both of the dermis 16 and the subcutaneous tissue 18. Thus, the stimulus S can promote a series of beneficial responses in the epidermis, dermis (skin), and subcutaneous tissue.

[0071] The current treatment S can be applied as a steady-state (constant or alternating) voltage signal; for example, using a modulated waveform, such as a charge-balanced microcurrent waveform generated by two or more electrodes 120 spaced apart along the skin surface 12. Alternatively, the current treatment can be galvanic or polarized (non-charge-balanced). One or more of the electrodes 120 can be deployed on the skin surface 12 or adjacent to the skin surface 12 at a selected treatment location, such as on the face, arm, torso, or leg. Another electrode can be deployed adjacent to the first electrode, or coupled through the skin surface via the subject's hand or other body part.

[0072] The device 100 may be configured to generate a current or voltage signal to the electrodes 120, wherein the output characteristics are adapted to deliver a selected current or voltage to the resistive surface 12, and to accommodate changes in skin resistance (i.e., in the resistive load between the electrodes 120). The actual output performance is limited by the voltage used to supply the current, and in accordance with the resistive load according to Ohm's law:

[0073] V=I×R, (1).

[0074] Therefore, depending on the resistance of the load, the output power associated with a given current or voltage signal can vary. This relationship is defined by the following power equation:

[0075] P=I 2 × R, (2).

[0076] Where I is the current output, R is the resistance, and P is the electrical power delivered to the load (e.g., the user's skin). Alternatively,

[0077] P=I × V (3).

[0078] The resistance R may also vary depending on skin thickness, moisture level, and the presence (or absence) of facial and body hair, as well as the nature of any topical agent or skin treatment 20 applied.

[0079] More generally, for real-time modulation of pulsed microcurrent, pulsed DC, and DC current therapy, as well as other time-varying modulated power applications, a complex impedance Z should be used; that is, a complex combination of resistance R and reactance with an inductive component X L and the capacitance component X C Both of these:

[0080] Z 2 =R 2 +(X L –X C ) 2 (4).

[0081] The inductive and capacitive components of the reactance can vary as a function of frequency, and the current and voltage can be out of phase.

[0082] In some cases, changes in skin resistance R or impedance Z can be significant and can occur in a relatively short period of time; for example, depending on the speed at which the device 100 is moved across the skin 10, the treatment area of ​​the skin surface 12 and the pressure applied at the electrodes 120, the dryness, moisture level and thickness of the skin 10, and other operating parameters. The changes may cause rapid voltage, current and power transients, which are associated with tingling or pins and needles and (in some cases) potential user discomfort. There may also be a tradeoff between user comfort and treatment efficacy based on the applied current level.

[0083] The control circuit can be adapted to help address these issues by regulating the applied current I and voltage V so as to maintain a substantially constant power output P selected to maintain therapeutic efficacy and user comfort while reducing transients. A feedback loop can be included to adapt the power regulation technique for a range of devices 100 adapted for pulse modulated current balanced microcurrent skin treatment, or adapted for modulated DC, pulsed DC (unipolar or bipolar) or current treatments, as described herein.

[0084] Equipment Application

[0085] Figure 2is a block diagram of a representative skin treatment device 100 having a housing 110 with one or more electrodes or transmitters 120. For example, according to Figure 1 In the device 100 shown in FIG. 1 , electrodes 120 are adapted to provide electrical stimulation S to the skin 10 of a subject.

[0086] like Figure 2 As shown in , the microcurrent device 100 also includes a power supply (P / S) 130, a current or voltage source (IV) 140 electrically connected to one or more of the electrodes 120, and a microprocessor (μP)-based controller 150 having a memory 155 and an external communication interface (I / F) 160.

[0087] A power source 130 may be provided in the form of a rechargeable capacitor or battery system, such as a wireless charger 135 with adapted inductive charging, or another wired or wireless charger port (P) 135. A microprocessor controller 150 is provided in data communication with a memory 155, which provides storage for control code 156 and operational data 158. A communication interface (I / F) 160 may be adapted for both data and control communications with the controller 150, such as using a hardwired communication port or a wireless communication device (D) 165. One or more sensors 170 may also be included, such as configured to determine skin and environmental or operational conditions, such as resistivity, surface temperature, hydration, ambient temperature, humidity, etc.

[0088] Depending on the embodiment, the device 100 may include a plurality of at least two electrodes 120 adapted to apply a current signal to a skin surface of a subject, and a voltage or current source (or waveform generator) 140 configured to generate a current signal for application via the at least two electrodes, wherein power is output to the surface of the skin 10. In operation of the device 100, the power supply 130 provides power to the voltage or current source 140 as well as the microprocessor controller 150, the memory 155, and the interface 160.

[0089] The controller 150 is configured to regulate the potential (V) or current (I) signal generated by the source 140, for example by executing control code 156 stored in the memory 155. Control parameters and other operational data 158 can be used to modulate the signal provided to each selected electrode or emitter 120 so as to deliver the desired microcurrent pulse waveform (e.g., using voltage and current feedback from the electrodes 120 and sensor data from the sensors 170).

[0090] In certain applications, the controller / microprocessor 150 can use the monitoring circuit to modulate the power output to the surface of the skin 10 to generate a feedback signal in response to changes in the current signal (or the power output to the surface of the skin 100) so as to maintain the comfort level of the subject based on the power output. The control circuit 150 may include a level controller configured to modulate the current within a predefined range (e.g., a predefined comfort range) based on the feedback signal. The level controller can be coupled to a current control device configured to modulate the current, such as a gate of a three-terminal current control device coupled between the monitoring circuit and one or more of the electrodes. Thus, the level control can define a response curve of the current control device within a predefined range.

[0091] The control circuit 150 may be configured to modulate or adjust the current signal to an adjusted lower or minimum value within a predefined comfort range in response to a predefined change in the current signal or a change in the power output to the surface of the skin 10. The change may be associated with a reduction in the comfort level or the possibility of discomfort. Thereafter, the control circuit 150 may be responsive to a detection based on an average of voltage samples at one or more of the electrodes 120, adjacent to one or more of the electrodes 120, or across one or more of the electrodes 120 sensed or detected by the monitoring circuit, and after modulating to an adjusted lower current signal value, such that the current signal or the power output to the skin surface at that time is no longer associated with the possibility of discomfort, in which case the control circuit 150 may be configured to modulate the current to an adjusted, higher or maximum current value within the predefined comfort range, if such a value is available within the comfort range.

[0092] Application Methods

[0093] Figure 3 300 is a block diagram of a method for enhancing permeability of one or more components of a topical agent applied to a skin surface. The method may include activating (turning on) a device having one or more electrodes on or adjacent to a skin surface (step 310), applying a voltage or current signal to the skin surface via one or more of the electrodes (step 320), and modulating a power output to the skin surface (step 330); for example, such that the power output provides charge-balanced pulsed DC, modulated DC, or otherwise modulated power output adapted to enhance user comfort while maintaining therapeutic efficacy. As described herein, the power may be modulated to reduce the power output (step 340), or increase the power output (345) to maintain therapeutic efficacy while reducing transients.

[0094] Depending on the application, the method may also include defining a delay period (step 350) after applying the voltage or current signal (step 320); for example, during which no further voltage or current is applied to the skin surface via one or more electrodes. The method may include applying the agent to the skin surface (step 360), either directly after applying the signal or after the delay period (step 350). Applying the agent during the treatment period (step 370), wherein the permeability of the skin to one or more components of the agent is enhanced or increased in response to the modulated power output (step 330). The treatment can be completed at any suitable time (step 380); for example, by removing the agent. However, it is noted that for components that have penetrated one or more layers of the skin surface or have not been removed, enhanced permeability may still be exhibited after the treatment period.

[0095] In any of these examples, the enhanced or increased permeability can be expressed as enhanced or increased adsorption, absorption, diffusion or transmissibility of one or more components of the agent into or through one or more layers of the skin surface to which the voltage or current signal is applied. The enhanced or increased effect can extend during all or any portion of the treatment period compared to the adsorption, absorption, diffusion or transmissibility that would be expressed in the absence of (no) applied voltage or current signal.

[0096] The layers of the skin surface may include any one or more of the stratum corneum, the outer epidermis, the lower epidermis and / or the dermis. The one or more layers of the skin surface may also include vascular systems or fibroblasts.

[0097] In any of these examples, modulating the power output to the skin surface (step 330) can be based on a feedback signal responsive to a change in the applied voltage or current signal. The change can be based at least in part on the voltage or current signal; for example, as sensed near one or more of the electrodes. The power can be adjusted to modulate the transient, for example, by defining a response curve for the power output, wherein the response curve defines the power output between predetermined minimum and maximum power levels based on the feedback signal.

[0098] Depending on the application, a threshold may be defined for the change in the feedback signal; and based on the change in the feedback signal meeting or exceeding the threshold, the power output may be reduced (step 340); for example, by reducing the response curve to or toward a predetermined minimum power level. Alternatively, based on the change in the feedback signal not meeting or exceeding the threshold, the power output may be increased (step 345); for example, by reducing the response curve to or toward a predetermined maximum power level. In a specific example, the power output modulated to the skin surface (step 330) may be implemented using a three-terminal device having a first terminal coupled to a voltage sensor adjacent to one or more of the electrodes, a second terminal coupled to the feedback signal, and a gate adapted to control the power output.

[0099] A waveform may be defined for applying a voltage or current signal to the skin surface (step 320), wherein modulating the power output (step 330) comprises modulating the waveform such that the power output is charge balanced, modulated DC or pulsed DC, and maintains user comfort and therapeutic efficacy (or both). The waveform may include an alternating sequence of positive and negative polarities; for example, wherein the positive and negative polarities of the alternating sequence are charge balanced, or a series of pulses having the same polarity. The alternating sequence of positive and negative polarities may be symmetrical, or the waveform may include pulses of positive and negative polarities having randomized or pseudo-random pulse widths or pulse heights, or both.

[0100] The positive and negative components of the waveform may be modulated (step 330) so that the voltage or current waveform is charge balanced over a period of about 0.1-0.2 s or less, about 0.2-0.5 s or less, about 0.5-1.0 s or less, about 1.0-1.5 s or less, or about 1.4 s. Alternatively, the period may be longer, about 0.1-0.2 s or more, about 0.2-0.5 s or more, about 0.5-1.0 s or more, about 1.0 s-1.5 s or more, or greater than 1.5 s.

[0101] The voltage or current signal applied to the skin surface (step 320) may include a voltage or current pulse having an amplitude of up to about 100 μA, about 100-150 μA or less, about 150-200 μA or less, about 200-250 μA or less, or up to about 375 μA. Other suitable amplitude ranges are up to about 100 μA or more, about 100-150 μA or more, about 150-200 μA or more, about 200-250 μA or more, or greater than about 375 μA.

[0102] The voltage or current signal applied to the skin surface (step 320) may be formed of or include voltage or current pulses having individual pulse widths of about 1-10 ms or less, about 10-20 ms or less, about 20-50 ms or less, about 50-100 ms or less, or about 100 ms or less. Alternatively, other suitable pulse widths may be about 1-10 ms or more, about 10-20 ms or more, about 20-50 ms or more, about 50-100 ms or more, or greater than about 100 ms.

[0103] The voltage or current signal applied to the skin surface (step 320) may include an alternating sequence of voltage or current pulses, wherein the alternating sequences each include between two and six individual pulses or less, between five and ten individual pulses or less, between six and twelve individual pulses or less, between ten and twenty individual pulses or less, between twenty and fifty individual pulses or less, or fifty individual pulses or less. Alternatively, other suitable alternating sequences may include two to six pulses or more, five to ten pulses or more, six to twelve pulses or more, ten to twenty pulses or more, twenty to fifty pulses or more, or more than fifty pulses.

[0104] Applying a voltage or current signal (step 320) and modulating the power output to the skin surface (step 330) can be performed within a predetermined time period (or "pre-treatment" period) before applying the agent (step 360) and after any delay period (step 350). For one or more components of the agent, the pre-treatment period can be selected to achieve enhanced or increased permeability of the skin after the delay period. For example, the pre-treatment period can be selected for enhanced or increased adsorption, absorption, diffusion or transmissibility of one or more components of the agent into or through one or more layers of the skin surface during the treatment period, compared to the adsorption, absorption, diffusion or transmissibility without applying a voltage or current signal to the skin surface.

[0105] Suitable pretreatment periods include, but are not limited to, about 1 to 2 minutes or less, about 2 to 3 minutes or less, about 3 to 5 minutes or less, about 5 to 10 minutes or less, or about 10 minutes or less. Other suitable pretreatment periods include, but are not limited to, about 1 to 2 minutes or more, about 2 to 3 minutes or more, about 3 to 5 minutes or more, about 5 to 10 minutes or more, or greater than about 10 minutes.

[0106] The components of the agent for which permeability is enhanced or increased when applied to the skin surface (step 360) and during the treatment period (step 370) can include ions and ionic or polar molecules. Alternatively, the components that exhibit enhanced or increased permeability can include non-ionic and / or non-polar molecules. Additional suitable components include, but are not limited to, proteins, amino acids, genetic material, genetic markers, allantoin, and caffeine.

[0107] The treatment period (step 370) can be extended 1 to 2 hours or longer after the voltage or current signal is applied to the skin surface, 2 to 4 hours or longer after the application, 4 to 8 hours or longer after the application, 6 to 12 hours or longer after the application, 12 to 24 hours or longer after the application, or 24 hours or longer after the application. Other suitable delay periods can start within 1 to 2 hours or less after the voltage or current signal is applied to the skin surface, 2 to 4 hours or less after the application, 4 to 8 hours or less after the application, 6 to 12 hours or less after the application, 12 to 24 hours or less after the application, or 24 hours or less after the application.

[0108] The delay period (step 350) can be extended by 1 to 2 hours or longer after applying the voltage or current signal, by 2 to 4 hours or longer after applying, by 4 to 8 hours or longer after applying, by 6 to 12 hours or longer after applying, by 12 to 24 hours or longer after applying, or by 24 hours or longer after applying. Other suitable delay periods can be extended by 1 to 2 hours or shorter after applying the voltage or current signal, by 2 to 4 hours or shorter after applying, by 4 to 8 hours or shorter after applying, by 6 to 12 hours or shorter after applying, by 12 to 24 hours or shorter after applying, or by 24 hours or shorter after applying.

[0109] A topical agent may also be applied to the skin surface; for example, before or after activating the device (step 310), or while applying a voltage or current signal (step 320) and modulating the power output (step 330), or with an agent (step 360), so that the topical agent may be applied before, while, or during a delay period. For example, the topical agent may include a conductive gel, a serum, a moisturizer, or a matrix. The topical agent may also include allantoin, caffeine, collagen, a moisturizer, or other skin treatment products.

[0110] During or before applying the voltage or current signal, a conductive gel or conductive fluid may also be applied to the skin surface. For example, the conductive gel or conductive fluid forms a conductive path for the voltage or current signal between one or more electrodes and the skin surface.

[0111] Suitable skin treatment methods may include any or all of these steps and techniques performed in any order or combination, with or without additional treatment steps, as described herein and known in the art. The skin treatment system may also be provided with one or more electrodes adapted to apply a voltage or current signal to the skin surface accordingly. For example, the system may include a voltage source or current source adapted to generate a voltage or current signal, and a control circuit adapted to modulate the power output to the skin surface. A non-transitory computer readable medium may be provided with program code stored thereon, wherein the program code is executable on a computer processor or controller to perform such a method or operate such a system.

[0112] Power modulation

[0113] Figure 4 is a diagram for example using Figure 2 The device 200 or according to Figure 3 300 is a block diagram of a representative method or process 400 for modulating power delivered by current therapy. Figure 4 In a specific example, method 400 includes one or more steps of determining operating data (step 410), defining stimulation (step 420), generating a waveform (step 430), modulating the waveform (step 440), and applying stimulation to the user's skin based on the modulated waveform (step 450).

[0114] Depending on the application, method 400 may also include monitoring feedback (step 460), and adjusting the modulation waveform (step 470); for example, to reduce the difference between the defined stimulus and the applied stimulus. These steps may be performed in any order or combination, with or without additional procedures. For example, monitoring feedback (step 460) may also include monitoring sensor data, for example, to determine skin conditions (step 480) and environmental conditions (step 485).

[0115] Determining operational data (step 410) may be performed as a startup or start operation of method 400, such as by reading operational data from a memory. The operational data may include a set of operational parameters for performing the steps of method 400, or data for generating such a set of parameters. For example, the operational data may include stimulation data or parameters from which a desired stimulation may be selected or defined (step 420), and waveform data or parameters from which a desired voltage or current waveform may be generated (step 430).

[0116] The waveform data may also include a selected set of pulse parameters for modulating the waveform (step 440) so that the desired stimulation can be delivered or applied to the subject's skin (step 450). The pulse parameters may be selected to characterize one or more pulse widths of the "on" and "off" portions of the cycle, as well as the pulse period, frequency, and amplitude.

[0117] The applied waveform may be unipolar or bipolar; for example as defined based on the sign of the amplitude parameter, or by defining the absolute (non-negative) amplitude using a separate polarity parameter to determine the sign. The pulse modulation may be randomized by assigning selected parameters to successive pulses in a random or pseudo-random sequence, or by including a random or pseudo-random component in the modulating pulse parameters themselves, so as to generate a non-repeating or non-periodic modulated pulse train.

[0118] For example, pulse width, period, frequency, amplitude, or other modulated pulse parameters may be non-periodic or non-repeating over a given set of pulses, such that the modulation parameter does not repeat at all, or does not repeat in any identifiable pattern or sequence, within a given subset or set. Non-periodic or non-repeating pulse parameters may be modulated over a set of continuous pulses defining a treatment cycle having one or more treatment phases, or over a subset of continuous pulses defining one or more phases.

[0119] The applied stimulation (step 450) may be monitored (step 460) by measuring the applied voltage or current flowing through the electrodes or other transmitters. Feedback parameters may be used to adjust the modulation waveform (step 470), such as by applying hardware or software based gain parameters to reduce any differences between the defined stimulation (at step 420) and the stimulation actually applied (at step 450). Feedback monitoring (step 460) may also include receiving sensor data for determining skin and environmental conditions, such as resistivity, surface temperature, hydration, ambient temperature, humidity, etc. (steps 480 and 485).

[0120] The operational data (step 410) may also include historical log data of previous operations of a suitable microcurrent device 300 according to the method 400. For example, log data may be recorded to characterize previously defined stimulations (step 420), and to record parameters used for waveform generation (step 430) and modulation (step 440). Additional log data may provide a record of stimulations actually delivered or applied in previous treatments (step 450), as well as electrode or transmitter and sensor feedback (step 460), and additional parameters used to adjust the modulated waveform (step 470), to determine resistivity and other skin conditions (step 480), and to describe relevant environmental conditions (step 485).

[0121] Waveform modulation (step 440) can apply a variety of different pulse modification techniques. For example, in the radio frequency (RF) range, amplitude modulation (AM) and frequency modulation (FM) are commonly used. In these techniques, the modulating waveform is typically a sinusoidal carrier generated at a specific carrier frequency, such as in the kilohertz (kHz), megahertz (MHz), or gigahertz (GHz) range.

[0122] In amplitude modulation (AM), the amplitude of a carrier wave can be varied in response to an analog (e.g., voice frequency) signal. The modulated carrier signal is demodulated at the receiver, separating the modulation frequency that carries the information from the carrier wave. For analog modulation in the voice frequency range of approximately 1-10 kHz, typical carrier frequencies extend from tens of kilohertz (kHz) to tens of megahertz (MHz) and above.

[0123] In frequency modulation (FM) techniques, the instantaneous frequency (not amplitude) of a carrier wave is varied. For voice range applications, FM carrier frequencies traditionally extend from about 10 megahertz (10 MHz) and above into the gigahertz (GHz) range. Frequency shift keying (FSK) can also be applied across both lower and higher frequency ranges, for example to encode digital signals by shifting the carrier frequency between a selected set of discrete adjacent frequencies.

[0124] In skin treatment applications, stimulation is not limited to narrowband carriers and can also be defined (step 420) in terms of a pulse waveform (step 430), to which programmed randomized pulse waveform modulation (PRPWM) can be applied (step 440) in order to deliver the desired stimulation to the subject's skin (step 450). Programmed randomized pulse waveform modulation can also be adapted to provide charge and power balance and incorporate a higher level understanding of the underlying biological mechanisms of the body, including the effects of randomized pulse width modulation on the body's steady-state response. Pulsed DC or modulated DC therapy can also be applied, either with unipolarity or using bipolarity, with the modulation signal switching at periodic or non-periodic intervals.

[0125] Power Regulation

[0126] Figure 5 is an electronic schematic diagram illustrating a representative power modulation circuit 500; for example, for regulating the Figure 2 The power output of the skin treatment device 100, or according to Figure 3 The method 300 is adjusted. Figure 4 As shown in FIG. 5 , the control circuit 500 is divided into a front-end (hardware) section 510 and a back-end (software) section 550 .

[0127] The front end section 510 of the control circuit 500 includes a sequence of operational amplifiers (op amps) 520, 525 coupled to a first electrode 120A (electrode A), and a current control device 530 coupled to a second electrode 120B (electrode B). The electrodes 120A, 120B are adapted to provide current stimulation to the subject's skin 10. The power output is regulated using a feedback circuit 535 to modulate power transients and improve user comfort while maintaining therapeutic efficacy.

[0128] The back-end section 550 of the control circuit 500 includes a programmable microprocessor or microcontroller (MCU) 560, a signal generator 570, and a level control 575 and a voltage monitor or feedback circuit 535. The front-end section 510 includes a sequence of operational amplifiers (op amps) 520, 525 coupled to a first electrode 120A (electrode A), and a current control device 530 coupled to a second electrode 120B (electrode B). The electrodes 120A, 120B are adapted to provide current stimulation to the skin 10 of the subject, which is modulated by the control circuit 500 to reduce power transients and increase user comfort while maintaining therapeutic efficacy, as described herein.

[0129] The front end section 510 of the control circuit 500 operates continuously in an analog configuration. The back end section 550 operates sequentially in a digital configuration based on the digital sampling rate of the signal generator 570, which is coupled to the electrode A via operational amplifiers 520, 525 to control feedback and determine gain using a series of resistors R1, R2, R3. As described above, the signal itself can be generated as a modulated waveform or current signal for applying microcurrent therapy.

[0130] The level control 575 is via a resistor R G coupled to the current control device 530, generating a gate voltage V GS The feedback circuit 535 is connected between the (second) operational amplifier 525 and the current control device 530, wherein the current limiting resistor (ILIMIT) R L The MCU 560 in the control circuit 500 may be adapted to measure the cross Figure 5 Medium current limiting resistor R LA voltage drop across a voltage level (e.g., a fixed value resistor). A software routine encoded into (or used for the operation of) the MCU 560 may be adapted to convert the voltage reading into a current level, such as a microampere (μA) or milliampere (mA) reading, or other suitable scale, using Ohm's law. These readings are then digitized and fed into a moving average filter at short-term and long-term average rates, which contains a moving average of the corresponding samples (e.g., the last nine and thirty samples, respectively, or at other suitable sampling rates, such as the last two to ten samples and the last ten to fifty samples, or more or less). See FIG. 7 .

[0131] In order to maintain a more constant power control while preventing or avoiding the skin sensation associated with discomfort due to transients, the control circuit 500 is adapted to provide a power control parameter or signal to the current control device 530; for example, ranging from a minimum value (MIN) to a maximum value (MAX), as described above. In operation of the circuit 500, the parameter value or level can be shifted up or down based on voltage monitoring (or other feedback signals) from the circuit 535.

[0132] Although the control circuit 500 itself may not measure power directly, power has a mathematical relationship defined by the skin resistance (or impedance) and the amount of current applied. Although the impedance of the skin 10 can be determined independently of the operation of the control circuit 500, the front-end section 510 actively regulates the power applied to the skin 10. The hardware power regulation is further enhanced by the software-controlled back-end section 550; for example, by measuring voltage and / or skin current via the feedback circuit 535, and providing a gate voltage V to the control device 530. GS The level of power applied to the skin 10 is conditionally controlled based on the feedback signal.

[0133] By manipulating the gate input voltage V of the current control device 530 GS To complete the output shift. For example, according to Figure 4 , if the gate voltage V GS is set at –V3, the current level output by device 530 will be lower than the gate voltage V GS This shift in the control parameter value corresponds to a shift in the current and power level between the minimum (MIN) and maximum (MAX) curves, as Figure 3 A and 3B. In other words, by manipulating the gate voltage V at device 530 GS , power levels can be established and shifted to reduce transient effects and increase the dynamic range of the current output.

[0134] To address transients, one or more of the following features may also be included in the constant power modulation circuit 500 or elsewhere on the device and coupled in data communication with the MCU 560 , for example via the feedback circuit 535 .

[0135] An accelerometer or velocity sensor / detector 580 may also be employed as part of the feedback circuit 535. When a user moves the device too quickly, poor electrode contact may occur, causing a hyperpolarization event. In this case (e.g., when a preselected velocity or acceleration value is reached or exceeded), the power modulation circuit 500 may be adapted to alert the user and reduce (reduce) the power output until the movement returns to the normal recommended range of velocity and / or acceleration.

[0136] The pressure sensor 540 may be adapted to sense appropriate contact between one or more of the electrodes 120A, 120B and the surface of the skin 10, for example based on a predefined range of forces or loads on the electrode surfaces. In the event of inappropriate contact (force or load outside the predefined range), the system may alert the user and / or reduce (decrease) power output until the recommended pressure (force or load within the predefined range) is reestablished.

[0137] Additional feedback to the power modulation circuit 500 may be accomplished with a skin sensor 545 to help prevent or reduce hyperpolarization events. In these examples, the skin sensor may also be adapted to measure skin temperature, roughness, resistivity, or other operating parameters associated with the skin surface 10, and used to modulate the feedback voltage according to a predefined function relating the measured skin parameter to load or impedance or skin sensitivity.

[0138] Waveform Modulation

[0139] Figure 6 6 is a block diagram of a method or process 600 for waveform modulation. For example, the method 600 may be used to operate a device 100 having one or more electrodes or transmitters 120, such as Figure 2 and is adapted according to Figure 3 and Figure 4 Any of the above can be used to apply pulsed electrical stimulation to the subject's skin. Similarly, method 500 can also be adapted, for example, according to Figure 5 The circuit 500 shown modulates a waveform for microcurrent-based skin treatment.

[0140] exist Figure 6In the example of , method 600 includes generating a waveform (step 610), modulating the waveform (step 620), and applying a pulse modulated stimulus (step 660). These steps can be performed in any order or combination, with or without additional processes. For example, method 400 may also include monitoring a combination of sensor and electrical feedback (step 670), and adjusting the modulated waveform based on the feedback (step 680); for example, to match a predefined and applied stimulus according to method 300 or method 400.

[0141] Generating a waveform (step 610) includes, for example, using Figure 5 The voltage or current generator shown in provides an electrical signal. The waveform can be sinusoidal or non-sinusoidal, such as a square wave, rectangular wave, sawtooth, or triangular waveform, or other periodic or non-periodic function, or a modulated DC waveform can be used. The waveform can also be generated with positive or negative polarity or bipolar form, and can be referenced to ground or superimposed on a DC signal with a positive or negative offset.

[0142] Waveform modulation (step 620) encompasses a range of modulation techniques, including pulse frequency modulation (PFM; step 630), pulse width modulation (PWM; step 635), pulse amplitude modulation (PAM; step 640), and combinations thereof. In a specific example, when the stimulus is applied to the subject's skin, random or pseudo-random pulse width modulation (RPW) 650 (step 660) may be applied to enhance the biological response and reduce the tendency for homeostasis.

[0143] The frequency of the pulse waveform may be varied independently of the pulse width and amplitude, or in combination, in pulse frequency modulation (PFM) 630. The change in frequency is reflected by varying the period between successive pulses, and may be performed according to an analog or digital modulation signal, such as by frequency shift keying (FSK), where the pulse-to-pulse frequency varies among a selected set of discrete digital frequency changes.

[0144] Pulse Width Modulation (PWM; step 635) is a technique for selectively distributing power over individual pulses in a pulse waveform or carrier wave according to a desired (e.g., analog or digital) modulation function. The average value of the power delivered is determined from the time integral of the modulated voltage and current waveforms, while the instantaneous power is determined by the corresponding amplitude at a particular time. Since the pulse width is also reflected in the length or duration of the signal, pulse width modulation can also be described as pulse duration modulation (PDM).

[0145] In pulse amplitude modulation (PAM) 640, the amplitude of the pulse waveform (or carrier) may vary from pulse to pulse independently of or in combination with one or more of pulse width, pulse period, and carrier frequency. Pulse amplitude modulation (PAM) may also be applied as an analog or digital modulation technique, such as by amplitude shift keying (ASK), in which the pulses are modulated according to a selected set of discrete amplitudes, each of which is assigned a different digital value.

[0146] In randomized pulse width modulation (RPW; step 650), the width of individual waveform pulses is modulated according to a randomized or pseudo-random scheme. As described below, the pulse width and duty cycle of a waveform may be randomized independently of the pulse frequency and amplitude, or the techniques may be combined.

[0147] The modulated waveform may be applied in the form of a voltage or current (step 660), such as delivered to the subject's skin via one or more electrodes or transmitters 120, such as Figure 2 Feedback from the electrodes 120 and the one or more sensors 170 may also be monitored (step 670) to determine the difference between the defined stimulation and the stimulation actually applied.

[0148] The pulse width of the modulation (step 680) can be adjusted based on the feedback to match the applied stimulation to the desired effect. For example, the amplitude of a given voltage stimulus can be adjusted based on the resistivity of the skin to deliver the desired current stimulus. Alternatively, any combination of pulse width, frequency, and amplitude of the applied stimulation can be adjusted based on temperature, hydration level, and other skin and environmental conditions, or based on the presence or absence of a topical therapy between the treatment electrode (or other transmitter) and the skin surface.

[0149] As described above, randomized pulse width modulation (RPW) 650 may also encompass any combination of pulse frequency modulation (PWM) 635, pulse width modulation (PFM) 630, and pulse amplitude modulation (PAM) 640. For example, a set of individual "on" and "off" pulse widths may be defined within a particular range and then randomly ordered using a machine-based pseudo-random number generator (PRNG) or a hardware-based ("true") random number generator (HRNG) for successive pulses applied to a waveform.

[0150] Alternatively, the pulse width can be defined using a randomized or pseudo-random component and applied sequentially to successive pulses, with or without an additional sequential randomization step. Similar randomization techniques can also be used to modulate pulse amplitude, pulse period, and frequency, thereby generating a modulated waveform having any suitable combination of constant, deterministic, and random or pseudo-random pulse amplitude, frequency, and width.

[0151] For example, if the total pulse period ("on" plus "off") is fixed, the pulse width can nominally be modulated independently of the instantaneous (pulse-to-pulse) carrier frequency, although the changing pulse width will still be reflected in the Fourier transform. If the total period ("on" plus "off") is not fixed, both the pulse width and the instantaneous carrier frequency will change from pulse to pulse. Similarly, although the pulse amplitude can nominally be modulated independently of the pulse width and the instantaneous carrier frequency (based on the pulse-to-pulse period), the frequency of any amplitude modulation will be reflected as sidebands in the Fourier transform. All of these randomized modulations of the applied stimulus can enhance the skin's response and provide additional benefits for skin treatment, as described in various examples herein.

[0152] test

[0153] Fig. 7A is a schematic diagram of a Franz cell (or cell system) 700 adapted to test the permeability of a skin sample 710. Fig. 7A As shown in FIG. 7 , system 700 includes a Franz Cell 710 adapted to support a skin sample 720 (eg, human or mammalian skin) to which a reagent or donor compound 730 is applied.

[0154] Voltage can be applied to or across the sample 720 via electrodes 740 in contact with the skin sample 730 and conductive leads 750 disposed in the sampling port 760. Suitable materials for the electrodes 740 and leads 750 include platinum, silver, copper, and other conductive metals in the form of porous meshes, wafers, plates, or wires. A heater 770 can be provided to maintain the temperature of the Franz cell 710, the sample 720, and the donor compound 730 during operation of the system 700.

[0155] Figure 7B is a schematic diagram of a Franz Cell system 700 adapted for applying microcurrent treatment to a skin sample 710. In this example, a current unit or waveform generator 780 may be provided to apply a microcurrent waveform to a skin sample 720; for example, via a negative polarity platinum wire 755 connected to a porous mesh or wafer electrode 740 on the skin surface, with the opposite polarity (+) defined by a platinum lead or wire electrode 755. Different metals, such as copper or silver, or other suitable conductors may also be used. The polarity may also be reversed, or the lead 750 may be used to define the ground potential of the Franz Cell 710.

[0156] Fig. 8A , 8B 8 and 8C are schematic diagrams illustrating representative waveforms 810, 820, 830 for application to a skin surface. Fig. 8AA conventional DC or current waveform is illustrated which is not charge balanced.

[0157] Figure 8B A charge-balanced waveform 820 is illustrated having a sequence of positive polarity pulses (or positive phases) 830 and a sequence of opposite (negative) polarity pulses (or negative phases) 835; for example, a programmed random pulse modulated electrical waveform (PRPWMEW) with variations in the number and / or width of individual pulses in each phase 830, 835. The pulse height or pulse width may vary in a random or pseudo-random manner, while the integrated pulse height may be selected or controlled to have the same or substantially similar value for each of the opposite polarity sequences or phases 830 and 835. As a result, the waveform is charge-balanced over the entire cycle time, including both the positive and negative sequences.

[0158] Figure 8C A charge-balanced symmetrical waveform 840 is illustrated having a sequence of positive pulses 850 and a sequence of opposite (negative) pulses 855; for example, a charge-balanced symmetrical electrical waveform (CSW) having charge-balanced positive phases 850 and negative phases 855. The pulses are symmetrical, having the same pulse height, pulse width, and number of pulses in each sequence. The pulse periods may also be symmetrical, or they may vary. Suitable amplitudes range from about 100 μA or less to about 375 μA or more; that is, in the microcurrent range, typically an order of magnitude or more lower than other more conventional techniques that apply currents in the milliampere (mA) range or higher.

[0159] First round of testing

[0160] Fig. 9A is a bar graph illustrating the transdermal permeability of a 1.0% allantoin agent following selected current treatments. Fig. 9B is a bar graph illustrating allantoin retention in the epidermis and dermis after application of the agent.

[0161] Fig. 9A and 9B and thereafter using the codes GEWF (current electrical waveform), TNFEWF (CSW electrical waveform), PRPWMEWF (programmed random pulse width modulation electrical waveform), and PBS / 1.0% allantoin (phosphate buffered saline containing 1.0% allantoin). Fig. 9A As shown in Figure 1, all three waveforms produced allantoin permeation levels at 6 and 24 hours. In this particular example, when applied as an electrical waveform during the pre-treatment phase, the transdermal permeation of allantoin increased five-fold with the three selected waveforms: current, CSW, and PRPWM. The delivered dose is in any unit, such as μg / cm 2 , or other suitable, appropriate or convenient metric as known in the art.

[0162] exist Fig. 9A and 9B In the specific example of using the New Body Serum (NBS) v1.18 and Body Sculpting Gel (BSG) formulas, Fig. 7A and 7B Representative marker components from NBS and BSG reagent ingredients were tracked in the Franz cell test of . Suitable BSG components for enhanced transport, adsorption, absorption, permeability, flux and retention in various skin layers include, but are not limited to, kelp extract, chrysanthemum extract and cocoa extract (e.g., 0.1% caffeine).

[0163] Table 1 illustrates a range of these and other beneficial skin treatment components - which are suitable for enhanced skin permeability after microcurrent pre-treatment, representing other topical agents, serums, gels and treatments described herein - as well as similar or related organic and inorganic compounds, proteins, amino acids, genetic materials and genetic markers as known in the art. Additional test components, parameters and study design procedures are described in Tables 1-6 and in Figure 7A-7B and 8A-8C, with Figure 9A-16C The results in .

[0164] More specifically, Table 1 illustrates representative NBS v1.18 and BSG formulation ingredients, quantified using standard INCI (International Nomenclature of Cosmetic Ingredients) (EU), including tracking markers from NBS and BSG reagents used in Franz cell experiments. The tracking marker components in these reagent formulations are suitable for use in a wide range of Franz cell tests and include allantoin (in the NBS reagent), also known as 5-ureidohydantoin or oxalyl diurea.

[0165] Table 1 Representative topical agent components

[0166]

[0167]

[0168] Allantoin has been shown to exhibit anti-irritant and antioxidant functions and is also known for keratolytic effects (e.g., exfoliation) and is used as an active ingredient in skin creams. Caffeine (BSG) is another suitable marker, also known as trimethylxanthine, an antioxidant and anti-inflammatory active substance understood to stimulate vasodilation and induce fatty acid oxidation.

[0169] The first round of testing was performed on the three electrical waveforms using allantoin in either PBS (phosphate buffered saline) or NBS reagent. The goal was to compare the three electrical waveforms for their ability to deliver one or more components in the NBS v1.18 reagent. Delivery was tracked via allantoin measurements, which were used as skin penetration tracking markers.

[0170] The study was conducted in two phases or parts. Round 1a (Round 1: Phase 1a) evaluated the penetration of 1.0% allantoin (an active substance) in PBS using a galvanic electrical waveform (GEWF), a charge-balanced symmetric electrical waveform (CSW), and a programmed random pulse width modulated electrical waveform (PRPWMEWF) in the Franz Cell model. Details of the testing process included the collection and processing of the receptor wells (Table 2A), as well as the epidermal and dermal residence protocols to evaluate the penetration of the tracking markers (Table 2B).

[0171] Table 2A Recipient Well Collection and Processing

[0172]

[0173] The samples and treatments included 1.0% allantoin in PBS without electrical stimulation. The skin samples were also pre-treated with GEWF (galvanic electrical waveform) in PBS for 36 minutes (36 m), followed by treatment with a PBS topical agent or agent containing 1.0% allantoin. Pre-treatment was also applied with a charge-balanced symmetrical electrical waveform (CSW) in PBS for 36 minutes, followed by treatment with a PBS agent containing 1.0% allantoin, or treated with a programmed random pulse width modulated electrical waveform (PRPWMEWF) in PBS for 36 m, followed by application of a PBS agent with 1.0% allantoin.

[0174] The delivered microcurrent dose ranged up to 375 microamperes (μA) within a 12 minute cycle, repeated for three cycles. Receptor fluid collection was measured at time t=0 (before and immediately after topical sample treatment), at the end of waveform cycle 1 (t=12 min), at the end of waveform cycle 3 (t=36 m); and at 1 hour (1 h), 6 hours, and 24 hour intervals after pre-treatment with the electrical waveform and treatment with the selected topical agent.

[0175] Table 2B Protocol for evaluating epidermal and dermal retention of tracking markers

[0176]

[0177]

[0178] like Fig. 9BAs shown in Figure 2, at 24 hours, all three electrical waveforms, GEWF, TNFEWF, and PRPWMEWF, produced epidermal and dermal retention of allantoin. In this particular example, GEWF (current electrical waveform) treatment induced slightly more retention in the skin epidermis and dermis compared to CSW (charge-balanced symmetric electrical waveform) and PRPWMEWF (programmed random pulse width modulated electrical waveform).

[0179] Fig. 10A is a bar graph illustrating the transdermal permeability of 0.1% allantoin serum following a selected treatment (eg, New Body Serum v1.18, available from NuSkin Enterprises, Inc. of Provo, Utah). Fig. 10B is a bar graph illustrating allantoin retention in the epidermis and dermis after serum application.

[0180] Round 1b (Round 1: Phase 1b) testing included evaluation of NBS v1.18 reagent using GEWF (Geo-Electro-Waveform), CSW (Charge-Balanced Symmetrical Electro-Waveform), and PRPWMEWF (Programmed Random Pulse-Width Modulated Electro-Waveform) in the Franz Cell model as described herein. Samples and treatments included NBS v1.18 reagent containing 0.1% allantoin without electrical stimulation.

[0181] The skin was also pretreated with GEWF (galvanic electrical waveform) for 36 minutes in PBS followed by treatment with NSB v1.18 reagent containing 0.1% allantoin, CSW (charge-balanced symmetric electrical waveform) for 36 minutes in PBS followed by treatment with NBS v1.18 reagent containing 0.1% allantoin, and PRPWMEWF (programmed random pulse width modulated electrical waveform) for 36 minutes in PBS followed by treatment with NBS v1.18 reagent containing 0.1% allantoin.

[0182] Microcurrent doses ranged up to 375 μA per cycle (12 m) over three cycles (36 m). Receptor fluid collections were performed at time t=0 (before and immediately after topical sample treatment), at the end of waveform cycle 1 (12 m), at the end of waveform cycle 3 (36 m), and at intervals of 1 hour, 6 hours, and 24 hours after pre-treatment with the electrical waveform and treatment with the topical agent.

[0183] like Fig. 10AAs shown in , all three waveforms produced similar levels of transdermal permeation of the NBS v1.18 agent at 6 hours and 24 hours. At 24 hours after electrical pre-treatment, the transdermal permeation of the NBS v1.18 agent using the three waveforms GEWF, TNFEWF, and PRPWMEWF increased 5-fold when compared to the NBS v1.18 agent in which the skin was not stimulated with microcurrent electrical pre-treatment.

[0184] like Fig. 10B As shown in , at 24 hours, the charge-balanced symmetric electrical waveform (TNFEWF) produced higher epidermal and dermal retention of the NBS v1.18 agent compared to GS and PRPWM waveform electrical pretreatment.

[0185] Second round of testing

[0186] The second round of the "Tioga" study was also performed in two parts or phases. Round 2a (Round 2: Phase 2a) treatment methods included evaluation of the TNFEWF (CSW) electrical waveform to stimulate the delivery of PBS and NBS v1.18 agents. Table 3 summarizes the electrical pretreatment (Ept), including PBS (phosphate buffered saline) samples used as a dosing agent for Ept-36E (electrical pretreatment using 36 minutes of microcurrent waveform application).

[0187] Fig.11A is a bar graph illustrating transdermal allantoin permeation following selected current treatments. Fig. 11B is a bar graph illustrating allantoin retention in the epidermis and dermis following selected treatments. Fig. 11C is a bar graph showing the allantoin flux after the selected treatment. Flus is in arbitrary units, e.g., μg / cm 2 / hr, or other suitable, appropriate or convenient measure as known in the art.

[0188] Fig.11A and 11B The data in FIG. 1 were generated by testing the delivered dose through skin samples in a number of different conditions (e.g., in the arm area), which are ordered from left to right in the histogram as #3, #4, #5, #6, #9, #10, and #11 (Test # or "Arm #"). Fig.11A As shown in Figure 1, Test #3 and Test #4 data (see legend for conditions) are consistent with data from Round 1 of the same experimental treatment design. After electrical pretreatment with PBS, a more than five-fold (>5×) increase in allantoin permeation was seen compared to non-electrical pretreatment skin samples with PBS.

[0189] Table 3 Electrical pretreatment (Ept)

[0190]

[0191]

[0192] Test #5 and Test #6 data show >5× skin delivery of NBS reagent containing 0.1% allantoin after electrical pretreatment with PBS compared to samples with no electrical waveform pretreatment using NBS reagent containing 0.1% allantoin. Test #9 and Test #11 data show >5× delivery of allantoin after electrical pretreatment using conductive gel containing 1.0% allantoin compared to samples with no electrical waveform pretreatment using conductive gel containing 1.0% allantoin (Test #10). Note that Test #5, #6, #9, #10, and #11 data have lower doses of allantoin.

[0193] like Fig. 11B As shown in , the test #3 and test #4 data are consistent with the data from round 1 for the same treatment design. After electrical pretreatment, more than five times the penetration of allantoin was seen in both the epidermis and dermis compared to the non-electrically stimulated samples with PBS. Test #5 showed greater than two times (>2×) skin delivery of the NBS reagent containing 0.1% allantoin in the electro-pretreated epidermal samples compared to the non-electrically stimulated NBS samples containing 0.1% allantoin (test #6). There was not necessarily a significant difference in the retention of allantoin in the dermis.

[0194] Test #9 and Test #11 data show >5× skin allantoin delivery for electrically treated conductive gel in both the epidermis and dermis compared to the no-electrical stimulation sample (Test #10) utilizing conductive gel. Note that since the concentration of allantoin in these samples was 0.1%, the overall skin penetration may be lower with the NBS reagent.

[0195] like Fig. 11C As shown in , for the same treatment design, Test #3 and Test #4 data were consistent with the data from Round 1. After electrical pretreatment, more than five-fold increase in allantoin penetration was seen in both the epidermis and dermis compared to non-electrical pre-treated samples with PBS.

[0196] Test #5 showed that the skin delivery of NBS agent containing 0.1% allantoin was increased more than two-fold in the electrotreated epidermal samples compared to the non-electrostimulated samples using NBS agent containing 0.1% allantoin (Test #6). There was not necessarily a significant difference in allantoin retention in the dermis.

[0197] Test #9 and Test #11 data show that skin allantoin delivery was increased by >5X in the electrical pre-treated samples with the conductive gel agent compared to the non-electrically stimulated samples (Test #10) with the conductive gel containing 0.1% allantoin in both the epidermis and dermis.

[0198] Note that due to the 0.1% allantoin concentration in these samples, the overall skin penetration may be lower. Due to the 0.1% allantoin concentration in these samples, the overall skin penetration using the NBS samples may also be lower.

[0199] Fig. 12A is a bar graph illustrating transdermal allantoin permeation following alternating current treatment.

[0200] Fig. 12B is a bar graph illustrating allantoin retention in the epidermis and dermis after alternating treatments.

[0201] Fig. 12C is a bar graph illustrating allantoin flux after alternation treatment.

[0202] Fig. 12A The graph shows the TNEWF (CSW) waveform electrical pre-treatment, which uses a charged Franz Cell for stimulation delivery and transdermal penetration of conductive gel and NBS agent at 24h after electrical pre-treatment. At 24h, TNEWF (CSW) waveform pre-treatment resulted in a five-fold increase in transdermal penetration with conductive gel and NBS agent compared to the non-pulsed control sample (no pre-treatment). The conductive gel data allow for the same efficacy of delivering allantoin from either conductive gel or NBS serum.

[0203] Fig. 12B The TNEWF (CSW) electrical pre-treatment waveform using a charged Franz Cell for stimulus delivery is illustrated, where the retention of the conductive gel and NBS agent in the epidermis and dermis is significantly increased at 24 hours after treatment. Allantoin in the conductive gel can be more retained in the epidermis than allantoin in the NBS agent, while retention of the conductive gel and NBS treatment materials in the dermis is not necessarily significantly different.

[0204] Fig. 12C Illustration of TNEWF (CSW) waveform electrical pre-treatment using charged Franz Cells for stimulus delivery, where conductive gel and NBS reagent fluxes were significantly increased as assessed by accumulation of allantoin at 0.5 h to 24 h.

[0205] Round 2b (Round 2: Phase 2b) included a caffeine assessment. Fig.13A is a bar graph illustrating transdermal caffeine penetration following selected current treatments. Fig. 13Bis a bar graph illustrating caffeine retention in the epidermis and dermis following selected treatments. Fig. 13C is a bar graph illustrating caffeine flux following selected treatments.

[0206] like Fig.13A As shown in the Figures, Test #1 and Test #2 data are consistent with data from the first round for the same experimental treatment design. After electrical pre-treatment with PBS, a more than five-fold increase in the penetration of allantoin was seen compared to the non-electrical waveform pre-treated samples with PBS using caffeine as a tracking marker. The data shown in Test #7 show that after electrical pre-treatment, the skin delivery of the conductive gel containing 0.1% allantoin was increased by >5× compared to the non-electrical waveform pre-treated samples with the conductive gel containing 0.1% allantoin (Test #8). Note that Arms 7, 8, and 12 had lower doses of allantoin.

[0207] like Fig. 13B As shown in , the test #1 and test #2 data are consistent with the data from the first round for the same treatment design. After electrical pre-treatment, more than five times the penetration of allantoin was seen in both the epidermis and dermis compared to the non-electrically stimulated samples using PBS. Test #7 showed slightly higher skin delivery in the dermis for the electrically pre-treated samples using a conductive gel containing 0.1% caffeine compared to test #8 for non-electrically treated samples using a conductive gel containing 0.1% caffeine. There is not necessarily a significant difference in caffeine retention in the epidermis and dermis between test #8 for non-electrically pre-treated samples using a conductive gel containing 0.1% caffeine and test #12 using a conductive gel followed by an electrical pre-treatment of a BSG agent containing 0.1% caffeine. Note that since the caffeine concentration in these samples is 0.1%, the overall skin penetration may be lower when using a conductive gel and BSG agent.

[0208] like Fig. 13C As shown in , Test #1 and Test #2 data are consistent with data from the first round for the same treatment design. After electrical pretreatment, more than five-fold increase in allantoin penetration was seen in both the epidermis and dermis compared to non-electrical waveform pre-treated samples with PBS.

[0209] Test #7 showed >2× caffeine flux in the electrically treated epidermis for the conductive gel containing 0.1% caffeine compared to the non-electrically stimulated sample (Test #8) using the conductive gel containing 0.1% caffeine. There was not necessarily a significant difference in caffeine flux between Test #8 using the non-electrically pre-treated sample with the conductive gel containing 0.1% caffeine and Test #12 using the conductive gel followed by the BSG reagent containing 0.1% caffeine for electrical pre-treatment. Note that since the caffeine concentration in these samples was 0.1%, the total caffeine flux may be lower with the conductive gel and NBS reagent.

[0210] Fig.14A is a bar graph illustrating transdermal caffeine penetration following alternating current treatment. Fig. 14B is a bar graph illustrating caffeine retention in the epidermis and dermis after alternating treatments.

[0211] Fig. 14C is a bar graph illustrating caffeine flux after alternation treatment.

[0212] Fig.14A It is shown that pre-treatment with the TNEWF(CSW) waveform in a charged Franz cell stimulated delivery, with a 5-fold increase in transdermal permeation of the conductive gel at 24 h, as assessed using caffeine as a tracking marker, compared to the BSG agent and non-electrically treated control samples after such treatment. There was minimal stimulation of BSG agent permeation when pre-treated with the TNEWF(CSW) waveform.

[0213] Fig. 14B The figure shows that TNEWF (CSW) waveform pretreatment in the charged Franz cell stimulated a significant increase in conductive gel retention in the dermis at 24h after treatment. There was not necessarily a significant difference between the electrically pretreated samples and the non-electrically pretreated samples for conductive gel retention in the dermis. Compared to the samples without electrical waveform pretreatment and conductive gel, the retention in the epidermis for the electrically treated samples with conductive gel was two times less, and similar in the dermis.

[0214] Fig. 14C It is shown that the TNEWF (CSW) waveform in the charged Franz cell stimulated a significant increase in conductive gel retention in the dermis at 24h after treatment. There was not necessarily a significant difference between the electrically pre-treated and non-electrically treated samples for conductive gel retention in the dermis. The electrically pre-treated samples with conductive gel had two times less retention in the epidermis and similar in the dermis compared to the samples without electrical waveform pre-treatment and conductive gel.

[0215] Table 4 Electrical properties of the topical agents studied: pH and conductivity

[0216]

[0217] Table 4 illustrates the electrical properties of representative studied topical agents, including the pH and conductivity of the topical agent used in the "Tioga" study. The conductivity is given in microsiemens / cm (μS / cm or simply "μS"). Topical agents can have different pHs and different conductivities, but can perform equally well or substantially similarly in their ability to penetrate the skin when pre-treated with a selected electrical waveform as described herein.

[0218] Conclusions from the first and second rounds of testing include the following:

[0219] PBS, followed by electrical pre-treatment and administration with PBS containing allantoin / caffeine, which is consistent with data from round 1 for the same treatment design. After pulsed microcurrent pre-treatment, more than five-fold increase in allantoin / caffeine penetration was seen compared to the non-pulsed microcurrent samples treated with PBS.

[0220] TNEWF (CSW) waveform charged (pulsed) Franz cell testing resulted in increased delivery and penetration of conductive gel and NBS reagent as assessed by allantoin labeling.

[0221] The TNEWF (CSW) electrical waveform Franz cell test also resulted in a two-fold increase in the delivery and penetration of the conductive gel compared to the BSG agent as assessed by the caffeine marker.

[0222] The BSG agent permeated better in the electrically pretreated samples compared to the treated topical control samples without electrical pretreatment.

[0223] Charged topical agents (applications in Franz cells with electrical waveform pretreatment) were typically delivered up to five times more effectively than uncharged topical agents (applications in Franz cells without electrical waveform pretreatment).

[0224] The data demonstrate that the charged pre-treatment induces changes in skin properties resulting in substantial or significantly increased penetration of the applied topical agent into the skin compared to topical application alone without pre-treatment.

[0225] The third round of testing

[0226] The third round of testing included evaluation of 1.0 wt% allantoin in PBS using the TNFEWF (CSW) electrical waveform. Pretreatment using the CSW electrical waveform included varying the current (e.g., up to 375 μA, up to 250 μA, or up to 125 μA), varying the pretreatment time period (e.g., up to 3 minutes or up to 6 minutes), wherein allantoin was 1.0 wt% in PBS.

[0227] Table 5 summarizes the third round of treatment methods and experimental design. For the non-electric pre-treatment samples, the number of Franzcell replicas (multiple Franz cells) per sample was n=3, and for the pulsed electrical pre-treatment samples, n=6. The number of Franzcell replicas can also vary. The current flow (I) is given in microamperes (μA), and the pulse time (PT) is given in minutes (min), where zero indicates no current and no pulse time. In each case, the next step includes extracting the sample (extract), and post-pulse treatment / administration with phosphate buffered saline (PBS) containing 1.0% allantoin. The assessment time is 0.5, 1.0, 6 and 24 hours (hr) later, and the allantoin is measured.

[0228] Table 5 The third round of pretreatment methods and experimental design (TNFEW)

[0229]

[0230] Fig.15A is a bar graph illustrating transdermal allantoin penetration at various microcurrent levels for selected electrical waveform pre-treatment durations of three and six minutes. Fig. 15B is a bar graph illustrating allantoin retention in the epidermis and dermis for treatment duration and current level. Fig. 15C is a bar graph illustrating allantoin flux versus treatment duration and current level.

[0231] The treatment was performed by applying the waveform for 3 and 6 minute periods at microcurrent levels of 375 μA, 250 μA and 125 μA, respectively, in the order from (i) to (vi) in the figure. For each time interval, the corresponding histograms are arranged from left to right.

[0232] like Fig.15A As shown in , at all current levels, the transdermal permeation of allantoin increased at six minutes compared to three minutes pre-treatment. In general, at comparable treatment times (e.g., up to 3 minutes or 6 minutes, or more or less, respectively), higher current levels (e.g., up to 375 μA or more) and higher / longer pre-treatment times (up to 6 minutes or more) tend to stimulate greater permeation than lower current levels.

[0233] Fig. 15B It is shown that selected pre-treatment current levels (e.g., up to 375 μA) appear to stimulate increased epidermal retention of selected components of the topical agent. Lower microcurrent levels (e.g., up to 250 μA or up to 125 μA) can stimulate higher retention in the dermis. For all microcurrent levels, a six-minute pre-treatment can stimulate higher skin retention than a three-minute pre-treatment. This is not to say that the effects can persist with pre-treatment time and across skin layers, thereby reflecting changes in the corresponding skin structure (e.g., skin cells migrate upward as they age, and other related structural changes).

[0234] Fig. 15C It is shown that for all current levels, at an initial time point of 30 minutes to 1 hour after pre-treatment, the allantoin flux through the selected layer of the skin sample increases, and at a later time point of 1-6 hours, there may be substantially no flux; for example, because all of the agent has been delivered. In some applications, the agent may be applied again to increase the gradient of the selected component concentration across the selected skin layer for further enhanced delivery.

[0235] The third round of testing summary includes the following:

[0236] At all current levels, transdermal penetration of allantoin was increased with six-minute pretreatment compared to three-minute pretreatment. Higher currents (e.g., 375 μA or greater) and longer pretreatment periods (up to 6 minutes or more) can stimulate greater skin penetration of selected components of a topical agent than lower current levels (e.g., less than 375 μA) at comparable treatment times of 6 minutes and 3 minutes, respectively.

[0237] A current level of about 375 μA stimulated increased epidermal retention. Lower microcurrent treatment levels (e.g., about 250 μA or about 125 μA) stimulated higher retention in the dermis. Across all microcurrent treatments, a six-minute pretreatment stimulated higher skin retention than a three-minute pretreatment.

[0238] At all current levels, allantoin flux increases at initial time points of 30 minutes to 1 hour after treatment, and there may be little or essentially no flux at later time points of 1-6 hours.

[0239] Fourth round of testing

[0240] The fourth round of testing included an evaluation of an NBS agent containing 0.1 wt% allantoin using a TNFEWF (CSW) electrical waveform. Using an NBS agent containing 0.1 wt% allantoin, pretreatment was applied using different CSW electrical waveform current levels (e.g., up to 375 μA, up to 250 μA, or up to 125 μA) and different pretreatment times (e.g., up to 3 minutes or more, or up to 6 minutes or more).

[0241] Table 6 summarizes the fourth round of treatments and experimental design, similar to Table 5 (above) for round 3. In round 4, a New Body Serum (NBS) sample containing 0.1% allantoin was used. The sample was left on (not extracted) and there was no pulse treatment or dosing.

[0242] Fig.16A is a bar graph illustrating transdermal permeation for 0.1% allantoin serum for no pulse (no waveform) and selected electrical waveform pre-treatment durations of three and six minutes at various current levels. Fig. 16B is a bar graph illustrating allantoin retention for 0.1% allantoin serum using selected treatments. Fig. 16C is a bar graph illustrating allantoin flux for 0.1% allantoin essence using selected treatments. The treatments are ordered sequentially from (i) to (vi), respectively, and the histogram dates are ordered accordingly, starting with (0) for no pulse.

[0243] like Fig.16A As shown in , at all current levels, transdermal permeation of allantoin for six minutes of pretreatment was increased compared to three minutes of pretreatment. Higher current levels (e.g., up to 375 μA or more) at higher times (e.g., up to 6 minutes or more) appear to stimulate greater permeation than lower current levels at comparable treatment times (e.g., up to 6 minutes or up to 3 minutes, respectively).

[0244] Table 6 Treatment methods and experimental design for the fourth round (TNFEW)

[0245]

[0246]

[0247] like Fig. 16BAs shown in Figure 1, a current level of approximately 375 μA and a pretreatment time of six minutes appear to stimulate increased epidermal and dermal retention of allantoin compared to a three-minute pretreatment. At a current level of approximately 250 μA, a three-minute pretreatment appears to stimulate allantoin retention in the epidermis, and a six-minute pretreatment appears to stimulate additional allantoin retention in the dermis. At a current level of approximately 125 μA, both 3-minute and 6-minute electrical waveform pretreatments appear to stimulate comparable allantoin retention.

[0248] like Fig. 16C As shown in , six-minute pretreatment induced higher allantoin flux compared to three-minute electrical pretreatment at all current levels (eg, up to 375 μA, up to 250 μA, and up to 125 μA) from 0.5 hour to 24 hours after pretreatment.

[0249] The fourth round of summary includes the following contents:

[0250] Higher currents and longer pretreatment times appear to be better in stimulating transdermal penetration, skin retention, and allantoin flux.

[0251] A current level of approximately 375 μA and a six-minute pretreatment stimulated better NBS agent (allantoin 1.0 wt%) transdermal penetration, skin retention, and allantoin flux compared to a three-minute pretreatment.

[0252] Clinical evaluation

[0253] Clinical evaluations have been performed on low-level microcurrents (substantially less than 1 milliamp; e.g., ≤ 0.5 mA) of short duration (substantially less than ten minutes; e.g., ≤ 5 minutes) and associated treatment systems, which are applicable in enhancing allantoin penetration and improving the appearance, radiance, texture, and firmness of skin cellulite. The evaluation data are included in Figures 17A-20B middle.

[0254] One objective of the trial was to evaluate the effectiveness of a treatment system that uses short-duration, low-level microcurrent to enhance the appearance, radiance, texture, and firmness of skin cellulite. Another objective was to evaluate a treatment system that uses short-duration, low-level microcurrent to enhance the penetration of active ingredients in a topical body serum by tracking allantoin penetration in the skin.

[0255] Low levels of DC microcurrent can be used to enable electrically driven drug delivery in skin wounds and ulcers (see S. Zhao, A. S. Mehta, and M. Zhao, "Biomedical applications of electrical stimulation" (Cell. Mol. Life Sci., January 23, 2020), which is incorporated herein by reference in its entirety and for all purposes). However, it is not clear from the literature whether systems including very low levels of DC microcurrent of short duration can improve the penetration of topical actives through the skin and also improve skin appearance, such as properties of cellulite, radiance, texture, and firmness.

[0256] Thirty-one female subjects participated in a 12-week single-site study. The study involved treatment of either the left upper arm and left upper thigh or the right upper arm and right upper thigh, randomized for each subject, using a microcurrent device and a topical body serum, followed by a moisturizing body lotion applied after the device treatment. The topical body serum contained an ingredient, allantoin, which has anti-inflammatory, cell renewal, collagen stimulating and hydrating properties. The post-device treatment moisturizing body lotion contained active ingredients including Camellia sinensis extract (or green tea extract) with anti-lipogenic properties and sodium hyaluronate, palmitoyl hexapeptide-12, as active ingredients for moisturizing and barrier function enhancing activities.

[0257] Subjects treated (randomly selected) target areas on the upper arms and upper thighs with a microcurrent device set at a low microcurrent dose of 375 microamperes (μA) and a topical body serum for 5 minutes once daily, three days per week (once every other day), followed by application of a post-device treatment moisturizing body lotion twice daily over a 12-week period. During clinic visits at baseline, post-application, week 1, week 2, week 4, week 8, and week 12, each subject's upper arms were assessed for texture, firmness, and radiance using an expert rating and subject self-perception using a five-point ordinal scale, and the upper thighs were assessed for cellulite texture, firmness, and radiance.

[0258] During each follow-up visit, cellulite was further assessed by measuring the circumference of the upper thigh. At the end of the study completion at 12 weeks, 20 tape strips were removed from the treated upper thigh areas of 5 subjects selected based on visible improvements in skin attributes, and 5 control strips were obtained from untreated areas of the upper thigh. Tape strips from treated and control (untreated) areas were evaluated for penetration of allantoin from the topical body serum using a liquid chromatography-mass spectrometry (LC-MS) system.

[0259] The 12-week study was performed in 31 female subjects using a system including a non-invasive negative DC microcurrent device utilizing a topical body serum containing allantoin as an active ingredient followed by treatment with a post-device moisturizing lotion. Concordant areas on the upper thighs and upper arms were visually assessed using a five-point ordinal scale by an expert grader as well as subject self-assessment for improvements in skin cellulite, radiance, texture, and firmness at baseline, post-application, and 1, 2, 4, 8, and 12 weeks post-application.

[0260] In addition, the circumference of each subject's upper thigh was measured during each follow-up as an indicator of weight loss and improved firmness (see MH Gold, K. A. Khatri, K. Hails, RA Weiss, and N. Fournier, "Reduction in high circumference and improvement in appearance of cellulite" (J. of Cosmetic and Laser Therapy, February 13, 2011), which is incorporated herein by reference in its entirety and for all purposes. At the end of the study, twenty tape strips were collected from the treated upper thigh area and the untreated upper thigh area from five randomly selected subjects. Five tape strips from both the treated and untreated areas of the upper thigh were evaluated for the accumulation of allantoin using LC-MS spectroscopy.

[0261] Expert grader analysis and subject self-perception assessments also showed significant improvements in cellulite appearance, radiance, texture, and firmness at 12 weeks following treatment when compared to baseline. Further, the amount of allantoin recovered by the tape stripping method increased above background skin allantoin levels in the early tape strips (1 to 5), but tended to decrease as the tape strips were removed from deeper epidermal tissue. The low level DC microcurrent of the short duration treatment system was shown to enhance the skin appearance benefits of topically applied body serums containing allantoin.

[0262] Fig.17A and 17B is a histogram illustrating the expert grader assessment of skin radiance, texture and firmness for the treated upper arm and upper thigh areas. For the upper thigh, the appearance of cellulite is also included.

[0263] Expert Grader results are shown on a vertical scale as relative (percent) improvement from a defined baseline (e.g., pre-treatment) for post-treatment and at Weeks 1, 2, 4, 8, and 12 of the trial. Expert Grader evaluations were performed after application of microcurrent treatment, after application of low-level microcurrent treatment with a topical body serum, and a "post-device" treatment lotion.

[0264] The figures show the effect of 1, 2, 4, 8 and 12 weeks on the upper arm area ( Fig.17A ) and upper thigh area ( Fig. 17B )'s skin radiance, texture and firmness from baseline are shown as histogram data arranged from left to right accordingly. The appearance of cellulite in the upper thighs was also improved from baseline after application at the first to twelfth week of treatment ( Fig. 17B ). The percentages in the highlighted text ("*") indicate statistical significance relative to baseline, with statistical significance at Weeks 8 and 12 for the upper arm data ( Fig.17A ) and for the corresponding upper thigh data ( Fig. 17B ) showed statistical significance.

[0265] Comfort and tolerability results were also considered.There were no skin discomforts reported by any of the study subjects using the microcurrent therapy device as well as the topical body gel.

[0266] Fig.18 is a histogram illustrating circumference measurements of the upper thigh area. Relative (percent) improvements are shown on the vertical scale for measurements taken at the first, second, fourth, eighth, and twelfth weeks of the trial. The percentages in the highlighted text ("*") indicate statistical significance relative to baseline at weeks 2, 4, 8, and 12. The measurement of thigh circumference shows an improvement of approximately 4% relative to baseline after 12 weeks of treatment.

[0267] Fig.19A and 19B is a histogram illustrating the self-perceived assessment of skin radiance, texture and firmness on the treated upper arms and upper thighs. For the upper thighs, the appearance of cellulite is also included.

[0268] The self-perceived assessment results are shown on a vertical scale as relative (percent) improvement from a defined baseline (e.g., pre-treatment) for post-application and at study weeks 1, 2, 4, 8, and 12. The subjects' self-perceived assessments generally matched the expert grader assessments, indicating significant improvements in skin radiance, texture, and firmness in the treated upper arm area from baseline and up to 12 weeks of treatment ( Fig.19A ), and significant improvements in the appearance of cellulite, skin radiance, texture and firmness in the upper thighs ( Fig.19B ). The percentages in the tests in bold or highlighted (red) indicate the results for the upper arm at weeks 1, 2, 3, 4, 8, and 12 ( Fig.19A ) and for the upper thigh at weeks 4, 8, and 12 ( Fig.19B ) with respect to baseline.

[0269] Fig. 20A and 20B is a scatter plot illustrating tape stripping assessment of allantoin recovery for the upper thigh. The results include representative, anonymous, arbitrarily labeled samples (S2 and S4) compared to corresponding controls. Allantoin recovery levels are presented in arbitrary units on the vertical axis, with the tape strip index presented on the horizontal axis.

[0270] Fig. 20A and 20B The representative subjects in are selected from a group of five people, showing the successful recovery of allantoin using the tape strip sampling method. In the early epidermal tape strips (strips one to five), the amount of allantoin recovered from the skin area treated with low-level microcurrent increases to exceed the background allantoin level (control; lower point). As expected, starting from the removal of the tape strip from the deeper epidermal tissue, the level tends to decline. These levels (upper points) are recorded by samples of samples S2 and S4.

[0271] In general, clinical trial data demonstrate that a system for short duration (as little as 5 minutes) low-level microcurrent treatment with a topical body serum and post-device treatment with a body lotion on the skin enhances skin penetration of the topical agent, as demonstrated by accumulation of allantoin (the active substance in the selected body serum topical agent). From application, expert grading and self-perception assessments showed substantial or significant improvements over baseline in several skin attributes over weeks 1 to 12 of clinical evaluation. Additionally, at week 12, an improvement of 4.0% over the defined baseline in thigh circumference was observed, which is consistent with improved skin firmness and weight loss effects, and consistent with an overall improvement in the appearance of cellulite. Further, all subjects tolerated the system well for low-level microcurrent treatment with the selected topical agent, with no adverse events reported during the 12-week trial treatment period.

[0272] The present disclosure has been made with respect to representative examples and embodiments. Each and every exemplary embodiment of the present invention disclosed herein may be used alone or in combination with any other embodiment or example described or illustrated herein, and each may incorporate additional modifications, changes, equivalents, and substitutes that fall within the scope of the present disclosure, as read and understood by a person of ordinary skill, and without departing from the practice of the present invention as claimed. These various examples and embodiments are provided by way of illustration and should not be construed to limit the scope of the present invention, nor should they be construed to limit the scope of coverage as defined by the plain language of the claims.

Claims

1. A method, include: pre-treating a skin surface of the subject by applying a voltage or current signal surface via one or more electrodes, wherein power is output to the skin surface, and modulating the voltage or current signal, wherein the power output is selected to enhance or increase permeability of the skin surface; as well as treating the skin surface by applying an agent to the skin surface; Wherein, in the absence of further voltage or current signals applied to the skin surface via one or more electrodes, skin permeability to one or more components of the agent is enhanced or increased in response to the modulated power output while pre-treating the skin surface. 2 . The method of claim 1 , further comprising generating the voltage or current signal as a DC, pulsed DC, microcurrent, or pulsed microcurrent waveform.

3. The method according to claim 2, in: The power output to the skin is charge balanced; and / or Wherein the polarity of power output to the skin alternates at periodic or non-periodic intervals.

4. A method according to any one of claims 1 to 3, wherein a reagent is applied to the skin surface before or during pre-treatment of the skin surface, or after pre-treatment of the skin surface, wherein no further voltage or current signal is applied after application of the reagent.

5. A method according to any one of claims 1-4, wherein modulating the voltage or current signal includes adjusting the amplitude of the signal so that the power output is selected for enhanced or increased efficacy in user comfort or transparency, or both, compared to the power output without modulating the voltage or current signal.

6. A method according to any one of claims 1 to 5, wherein the modulated power output is selected for enhanced or increased permeability to include enhanced or increased adsorption, absorption, diffusion or transmittance of one or more components of the agent into or through one or more layers of the skin surface during a treatment period compared to the adsorption, absorption, diffusion or transmittance without applying the voltage or current signal to the skin surface.

7. The method of claim 6, wherein the one or more layers of the skin surface include the stratum corneum, the outer epidermis, the lower epidermis or the dermis, or wherein the one or more layers of the skin surface include vasculature or fibroblasts, preferably in: The treatment period is extended by at least 1 to 2 hours or more after application of the voltage or current signal, by at least 2 to 4 hours or more after application of the voltage or current signal, by at least 4 to 8 hours or more after application of the voltage or current signal, by at least 6 to 12 hours or more after application of the voltage or current signal, by at least 12 to 24 hours or more after application of the voltage or current signal, or by at least 24 hours or more after application of the voltage or current signal.

8. The method according to any one of claims 1 to 7, further comprising defining a delay period after pre-treating the skin surface, wherein during the delay period, no further voltage or current signal is applied to the skin surface via the one or more electrodes, preferably, in: After the delay period, the agent is applied to the skin surface; The agent is reapplied to the skin surface or applied multiple times to the skin surface at different times during or after the delay period; and / or At the same or different times during or after the delay period, a plurality of different agents are applied to the skin surface.

9. The method according to claim 8, in: The delay period is extended by at least 1 to 2 minutes after the application of the voltage or current signal, by at least 2 to 5 minutes after the application of the voltage or current signal, by at least 5 to 10 minutes after the application of the voltage or current signal, by at least 10 to 30 minutes after the application of the voltage or current signal, by at least 30 minutes to 1 hour after the application of the voltage or current signal, or by at least 1 hour after the application of the voltage or current signal, or more; or The delay period is extended by at least 1 to 2 hours after applying the voltage or current signal, by at least 2 to 4 hours after applying the voltage or current signal, by at least 4 to 8 hours after applying the voltage or current signal, by at least 6 to 12 hours after applying the voltage or current signal, by at least 12 to 24 hours after applying the voltage or current signal, or by at least 24 hours after applying the voltage or current signal, or more.

10. The method of any one of claims 1-9, further comprising modulating the power output to the skin surface based on a feedback signal responsive to a change in the applied voltage or current signal; sensing a voltage or current signal in the vicinity of one or more of the electrodes, wherein the change is based at least in part on the sensed voltage or current signal; and / or A response curve for the power output is defined, wherein the response curve modulates the power output between predetermined minimum and maximum power levels based on the feedback signal.

11. The method according to claim 10, further comprising: include: defining a threshold for a change in the feedback signal; and reducing the power output or lowering the response curve to or toward a predetermined minimum power level based on a change in the feedback signal reaching or exceeding the threshold; and / or Based on the change in the feedback signal not reaching or exceeding the threshold, the power output is increased or the response curve is increased to or toward a predetermined maximum power level.

12. The method according to any one of claims 1 to 11, further comprising generating a waveform for applying the voltage or current signal to the skin surface, wherein the waveform comprises an alternating sequence of positive and negative polarities, preferably in: Modulating the power output includes controlling the pulse width, period, or amplitude of the waveform based on the impedance between the two electrodes as determined by the feedback circuit; and / or Modulating the power output is performed using a three terminal device having a first terminal coupled to a voltage sensor adjacent one or more of the electrodes, a second terminal coupled to a feedback signal, and a gate adapted to control the power output.

13. The method according to claim 12, in: The alternating sequence of positive and negative polarity is symmetrical, non-periodic, and / or has a randomized or pseudo-random pulse width, pulse height or period; and / or The positive and negative components of the waveform are charge balanced over a period of about 0.1-0.2 s or less, over a period of about 0.2-0.5 s or less, over a period of about 0.5-1.0 s or less, over a period of about 1.0-1.5 s or less, or over a period of about 1.4 s, or a combination thereof.

14. The method according to any one of claims 1 to 13, wherein the voltage or current signal applied to the skin surface include: A voltage or current pulse having an amplitude of about 100 μA or less, about 100-150 μA or less, about 150-200 μA or less, about 200-250 μA or less, or about 250 μA or less; and / or Voltage or current pulses having individual pulse widths of between about 1-10 ms or less, between about 10-20 ms or less, between about 20-50 ms or less, between about 50-100 ms or less, or about 100 ms or less.

15. A method according to any one of claims 1 to 14, wherein the voltage or current signal applied to the skin surface comprises an alternating sequence of voltage or current pulses, each of the alternating sequences comprising between two and six individual pulses or less, between five and ten individual pulses or less, between six and twelve individual pulses or less, between ten and twenty individual pulses or less, between twenty and fifty individual pulses or less, or fifty individual pulses or less.

16. The method according to any one of claims 1 to 15, wherein applying the voltage or current signal to the skin surface and modulating the power output to the skin is performed during a pre-treatment period, the pre-treatment period being selected to achieve enhanced or increased permeability of the skin when the agent is applied, preferably, in: The pre-treatment period is selected for enhanced or increased adsorption, absorption, diffusion or deliverability of one or more components of the agent into or through one or more layers of the skin surface during the treatment period as compared to said adsorption, absorption, diffusion or deliverability without application of a voltage or current signal to the skin surface; and further preferably, wherein: The pretreatment period is between about 1 to 2 minutes or less, between about 2 to 3 minutes or less, between about 3 to 5 minutes or less, between about 5 to 10 minutes or less, or about 10 minutes or less.

17. The method of any one of claims 1 to 16, wherein one or more components of the agent for which permeability is enhanced or increased comprises ions or ionic or polar molecules, non-ionic or non-polar molecules, proteins, amino acids, genetic material, genetic markers, allantoin or caffeine, or any subset or combination thereof.

18. The method according to any one of claims 1 to 17, further comprising applying a topical agent to the skin surface, wherein the topical agent is applied before applying the voltage or current signal, or is applied while applying the voltage or current signal, preferably, wherein the topical agent comprises a base component of a conductive gel, serum, moisturizer or skin treatment product, or wherein the topical agent forms a conductive path for the voltage or current signal between one or more of the electrodes and the skin surface.

19. A method for use in a cosmetic skin treatment method according to any one of claims 1 to 18.

20. A non-transitory computer readable medium having program code stored thereon, the program code executable on a computer processor or controller to perform the method for cosmetic skin treatment according to any one of claims 1-18.

21. A skin treatment system, include: a voltage or current source adapted to generate a voltage or current signal; one or more electrodes adapted to apply the voltage or current signal to a skin surface of the subject, wherein power is output to the skin surface during the pre-treatment phase; and a control circuit adapted to modulate a power output to the skin surface during a pre-treatment phase, wherein the power output is selected to enhance or increase permeability of the skin surface to one or more components of an agent applied to the skin surface during a treatment phase; There is enhanced permeability of the skin surface in response to the modulated power output in the pre-treatment phase, wherein no further voltage or current signal is applied to the skin surface via the one or more electrodes in the treatment phase.

22. The skin treatment system of claim 21, wherein the voltage or current signal comprises a microcurrent signal selected for cosmetic treatment of the skin surface.

23. A skin treatment system according to claim 21 or 22, wherein the one or more electrodes include one or more electrode pairs having elongated leaf-like structures, and / or wherein the voltage or current signal is applied to the electrodes in each pair with opposite polarities.

24. A skin treatment system according to any one of claims 21-23, wherein the control circuit is adapted to modulate the power output between minimum and maximum power levels, and the minimum and maximum power levels are selected to enhance or increase the permeability of the skin surface to one or more components of the agent during the treatment phase compared to such a skin surface without applying a voltage or current signal to the skin surface during the pre-treatment phase.

25. The skin treatment system of claim 24, wherein the minimum and maximum power levels are selected to maintain user comfort compared to application of the voltage or current signal without modulating the power output during the pre-treatment phase.

26. A skin treatment system according to any one of claims 21-25, wherein the waveform has a DC, pulsed DC, microcurrent or charge balanced microcurrent functional form, preferably as defined over a period of time for modulating a power output of at least 100 microseconds, at least 1 millisecond, at least 10 milliseconds, at least 100 milliseconds, at least 1 second, at least 2 seconds, less than 2 seconds or less than 1 second.

27. A skin treatment system according to any one of claims 21-26, wherein the agent comprises an ion, an ionic or polar molecule, a non-ionic or non-polar molecule, a protein, an amino acid, a genetic material, a genetic marker, allantoin or caffeine or any combination or subset thereof, preferably in: The microcurrent pre-treatment is applied for a period of at least 10 seconds, at least 30 seconds, at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, less than 10 minutes, or less than 5 minutes.

28. The skin treatment system according to any one of claims 21-27, further comprising a delay phase defined between the pre-treatment phase and the treatment phase, wherein the delay phase extends for a period of at least five minutes, at least ten minutes, at least thirty minutes, at least one hour, at least two hours, at least four hours, at least eight hours, at least twelve hours or at least twenty-four hours.

29. A skin treatment system according to any one of claims 21-28, wherein the treatment phase extends for a period of at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours or at least 48 hours, during which the permeability of the skin surface to the therapeutic substance is increased or enhanced compared to the permeability of such skin surface in the absence of the pre-treatment phase.

30. A skin treatment system according to any one of claims 21 to 29, wherein the agent comprises a conductive gel or fluid applied to the skin surface before or during a pre-treatment phase, preferably: wherein the conductive gel or fluid is selected to form a conductive path between one or more of the electrodes and the skin surface; and / or The conductive gel or fluid is selected to modulate the current density of a voltage or current signal applied to the skin surface area between the electrodes.

31. A non-transitory computer readable medium having program code stored thereon, the program code being executable on a computer processor or controller to control the skin treatment system according to any one of claims 21 to 29.

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