Electrical stimulation of tissue

Abstract

A method for stimulating a nerve group, the method including placing at least one electrode in contact with the skin of a subject, applying an electrical signal to the subject through the at least one electrode, the electrical signal including a series of pulses, and continuously randomly varying at least one of the following signal parameters: (i) the duration of each of the pulses, (ii) the time interval between each pair of pulses, and (iii) the energy value of each of the pulses, while maintaining the number of pulses per second of the electrical signal above a predetermined minimum number of pulses per second and maintaining the energy value per pulse above a predetermined minimum energy value.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 898,602, filed September 11, 2019, the entire contents of which are incorporated herein by reference.

[0002] Some applications of the present invention relate generally to medical devices, and more particularly to devices and methods for electrical stimulation of tissue. [Background technology]

[0003] A chronic wound is one that does not heal in a predictable time and in the manner in which most wounds heal. A wound is considered chronic when the wound measurement does not decrease by about 10% per week or about 50% per month.

[0004] The wound healing process is a highly orchestrated series of mechanisms, involving numerous cellular and biological cascades. The cutaneous cell of injury mechanisms and currents have become topics of interest for their impact on chronic wounds.

[0005] Electrical stimulation therapy supports wound healing by affecting the electrochemical wound process. Intact skin has a transepithelial potential, with the skin surface containing a negative charge from chloride ions and the dermis maintaining a positive charge via sodium ions. Ulcers and wounds lead to intense electrical activity measured in the skin across the wound due to abnormalities in the transepithelial potential and possibly neural activity that may aid wound healing. Chronic wounds lose electrical current and therefore heal less quickly. Electrical stimulation therapy reintroduces electrical current and supports the healing process.

[0006] The foregoing examples of the related art and limitations associated therewith are intended to be illustrative and not exhaustive. Other limitations of the related art will become apparent to those skilled in the art upon reading this specification and studying the drawings. Summary of the Invention

[0007] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools, and methods that are meant to be exemplary and illustrative, not limiting in scope.

[0008] In accordance with some applications of the present invention, an apparatus and method for administering electrical stimulation therapy to a subject is disclosed.

[0009] Typically, an apparatus is provided that includes an electrical stimulator including at least one electrode configured to be placed in contact with the skin of a subject, a signal generator configured to provide an electrical signal for application to the subject through the at least one electrode, and a control processor. Optionally, although not necessarily, the signal generator is configured to provide the electrical signal in an automatic, non-user-controllable manner.

[0010] Thus, in one embodiment, an apparatus is provided comprising: an electrical stimulation device comprising at least one electrode configured to be placed in contact with the skin of a subject; a signal generator configured to provide an electrical signal for application to the subject through the at least one electrode, the electrical signal comprising a series of pulses; and a control processor configured to continuously and randomly vary at least one of the following signal parameters: (i) the duration of each of the pulses, (ii) the time interval between each pair of pulses, and (iii) the energy value of each of the pulses, while maintaining the number of pulses per second of the electrical signal above a predetermined minimum number of pulses per second and maintaining the energy value per pulse above a predetermined minimum energy value.

[0011] In one embodiment, a method for stimulating a nerve group is also provided, the method including: placing at least one electrode in contact with the skin of a subject; applying an electrical signal to the subject through the at least one electrode, the electrical signal including a series of pulses; and continuously randomly varying at least one of the following signal parameters: (i) the duration of each of the pulses, (ii) the time interval between each pair of pulses, and (iii) the energy value of each of the pulses, while maintaining the number of pulses per second of the electrical signal above a predetermined minimum number of pulses per second and maintaining the energy value per pulse above a predetermined minimum energy value.

[0012] In one embodiment, there is further provided a computer program product including a non-transitory computer-readable storage medium having program instructions embodied therein, the program instructions being executable by at least one hardware processor to operate a signal generator to provide an electrical signal including a series of pulses for application to a subject via at least one electrode in contact with the subject's skin, and to continuously and randomly vary at least one of the following signal parameters: (i) the duration of each of the pulses, (ii) the time interval between each pair of pulses, and (iii) the energy value of each of the pulses, while maintaining the number of pulses per second of the electrical signal above a predetermined, minimum number of pulses per second and maintaining the energy value per pulse above a predetermined minimum energy value.

[0013] In some embodiments, the duration of each of the pulses is within a predetermined range of durations.

[0014] Some embodiments include an equal number of positive and negative polarity pulses.

[0015] In some embodiments, the total charge delivered to the subject by the electrical signal is equal to zero.

[0016] In some embodiments, the predetermined minimum number of pulses per second is 100, the predetermined minimum energy value is 0.005 microjoules, and the duration is between 0.05 milliseconds and 0.25 milliseconds.

[0017] In some embodiments, the predetermined minimum number of pulses per second is 150, the predetermined minimum energy value is 1 microjoule, and the duration is between 0.5 milliseconds and 1 millisecond.

[0018] In some embodiments, the minimum number of pulses per second is 250, the minimum energy value is 0.5 microjoules, and the duration range is 0.25 milliseconds to 0.5 milliseconds.

[0019] In some embodiments, the predetermined minimum energy value is 2 microjoules and the duration is between 1 millisecond and 2.5 milliseconds.

[0020] In some embodiments, the predetermined minimum energy value is 10 microjoules and the duration is between 2.5 milliseconds and 10 milliseconds.

[0021] In some embodiments, all of the signal parameters are varied continuously and randomly.

[0022] In some embodiments, the series of pulses comprises individual pulses.

[0023] In some embodiments, the signal has a waveform selected from the group consisting of sinusoidal, square, and triangular.

[0024] In some embodiments, the pattern of signal parameters is repeated only once within a predetermined time duration, hi some embodiments, the predetermined time duration is 0.2 seconds.

[0025] The electrical signal generated by the signal generator and applied to the subject is characterized by a series of pulses (trains) or by a continuous waveform characterized by peaks. Typically, the pulses / peaks are characterized by at least one (e.g., at least two) parameters that are randomly varied by the control processor during application of the signal. Additionally, the control processor is configured to provide the signal such that a predetermined amount of energy is applied to the subject by the signal despite the varying pulse / peak parameters.

[0026] In some applications, the at least two pulse / peak parameters include a pulse / peak duration and a pulse / peak energy level, each of which is randomly varied by the control processor independently of one another (and independently of the amount of energy applied to the subject by the signal) during application of the signal. It should be noted that while the pulse / peak parameters are randomly varied independently of one another, a change in one parameter may affect one or more other parameters. For example, increasing the pulse / peak duration may increase the energy level applied by the pulse / peak. It should also be noted that additional pulse / peak parameters (e.g., volt / watt amplitude and frequency) may also be randomly varied by the control processor. Additionally or alternatively, if the electrical signal is a pulsed signal, the control processor is configured to randomly vary the interval between pulses so that pulses, particularly identical pulses, are applied at random intervals during application of the signal.

[0027] In some applications, the signal generator is configured to generate at least one waveform or pulse train. For example, the signal generator is configured to generate at least first and second waveforms or positive trains. The waveforms may include any known type of waveform, such as a sine wave, a square wave, a triangular wave, and / or a sawtooth wave, or any other type of waveform. The first and second waveforms or positive trains are each characterized by a series of minimum numbers of positive and negative pulses / peaks applied per second (typically the first and second waveforms or positive trains have different numbers of minimum pulses / peaks). Additionally, the pulses / peaks of each waveform are characterized by varying energy levels with minimum and maximum microjoule ranges and varying pulse / peak durations with minimum and maximum pulse / peak duration ranges. Additionally, the average energy applied by the waveforms or positive trains varies between the first and second waveforms or positive trains.

[0028] The control processor is configured to randomly intermix the series of pulses / peaks within each waveform or positive train and between waveforms or positive trains to provide a randomly intermixed series of pulses / peaks, such that the electrical signal applied to the subject through the at least one electrode includes pulses / peaks having varied and random energy levels and durations. In some applications, the pulses / peaks are additionally applied to the subject by at least one electrode of the electrical stimulator at random intervals.

[0029] The control processor is further configured to mix the series of positive and negative polarity pulses / peaks such that a pulse / peak with a positive polarity is followed by a pulse / peak with a negative polarity (and vice versa), thereby balancing the charges and reducing charge buildup, thereby ensuring safety of the device.

[0030] Optionally, but not necessarily, when the signal is a pulsed signal, the control processor is configured to mix the pulses so that there are random and varying intervals (time gaps) between the negative and positive pulses. During the time gaps between the negative and positive pulses, there is typically no current flow so that each pulse is an isolated electrical event. In other applications, there are uniform intervals between the pulses. Additionally, in some applications, the electrical signal is applied as a continuous signal with no intervals.

[0031] In some applications, the control processor is configured to mix the pulse / peak series so that the parameter patterns (e.g., combinations of pulse / peak energy levels and durations) of the pulse / peak series applied during a predetermined subset of the signal's duration are not repeated within the same subset, thereby further contributing to signal variation. For example, the parameter patterns are not repeated within a predetermined subset time frame of 0.2 seconds. However, despite the random combination of pulse / peak parameters, the signal applies a predetermined amount of energy to the subject.

[0032] In some applications, the electrical signal is applied to the subject for at least 10 minutes per day, typically two to three times per day, for 20 to 30 minute treatment therapy sessions. In some applications, at least one electrode is placed in contact with intact skin anywhere on the subject's body. In some applications, the electrical stimulation therapy is applied to a subject suffering from a chronic wound. Optionally, but not necessarily, if the subject suffers from a chronic wound, the electrodes are placed near the wound. Alternatively, if the subject suffers from a chronic wound, the electrodes are placed away from the wound, for example, more than 100 cm from the wound.

[0033] According to some applications of the present invention, the electrical stimulation therapy applied by the device assists in chronic wound healing and / or revascularization and oxygen perfusion within the body. Additionally or alternatively, the electrical stimulation therapy applied by the device according to some applications of the present invention encourages the growth and epithelialization of granulation tissue.

[0034] The inventors hypothesize that applying random and varying electrical signals having the characteristics described herein will promote enhanced wound healing, angiogenesis, and revascularization compared to other known electrotherapy stimulation procedures. The inventors hypothesize that applying the varied, mixed electrical signals characterized herein will prevent the body from adapting to the applied electrical stimulation, thereby achieving better wound healing and revascularization parameters. Additionally or alternatively, the inventors hypothesize that applying the varied, mixed electrical signals characterized herein will promote stimulation of different nerve groups at different depth levels, thereby achieving enhanced wound healing and revascularization parameters.

[0035] Additionally or alternatively, the inventors hypothesize that application of random and varying electrical signals as characterized herein plays a role in stimulating, particularly, unmyelinated Group C afferent fibers. According to some applications of the present invention, varying electrical signals applied to Group C afferent nerves signal the presence of injury to the CNS, thus activating the delivery of "repair" commands in efferent nerves, thereby achieving enhanced wound healing and revascularization parameters.

[0036] Thus, according to some applications of the present invention, there is provided an apparatus including: an electrical stimulation device including at least one electrode configured to be placed in contact with the skin of a subject; a signal generator configured to provide an electrical signal for application to the subject through the at least one electrode, the electrical signal being characterized by a series of pulses or peaks of a wave; and a control processor configured to (i) randomly vary at least one of the pulse or peak parameters during application of the signal; and (ii) provide the signal such that a predetermined amount of energy is applied to the subject by the signal independent of the randomly varied pulse or peak parameter.

[0037] In some applications, the control processor is configured to randomly vary at least two pulse / peak parameters.

[0038] In some applications, the control processor is configured to randomly vary multiple pulse / peak parameters.

[0039] In some applications, the control processor is configured to randomly vary multiple combinations of pulse / peak parameters.

[0040] In some applications, the control processor is configured to randomly vary the pulse / peak parameters independently of each other.

[0041] In some applications, the at least one pulse / peak parameter includes a pulse / peak duration range, and the control processor is configured to randomly vary the pulse / peak duration range during the signal.

[0042] In some applications, the pulse / peak duration includes at least two different pulse / peak durations, a first pulse / peak duration having a first minimum and maximum duration range and a second pulse / peak duration having a different second minimum and maximum duration range.

[0043] In some applications, one of the at least two pulse / peak parameters includes a pulse / peak energy range level, and the control processor is configured to randomly vary the pulse / peak energy range level during the signal.

[0044] In some applications, the varying energy level parameter includes at least two different energy levels, a first energy level having a first minimum and maximum microjoule range and a second energy level having a different second minimum and maximum microjoule range.

[0045] In some applications, the first energy level has a first average energy with a first average minimum and maximum microjoule range, and the second energy level has a second average energy with a second average minimum and maximum microjoule range.

[0046] In some applications, the parameter pattern of a series of pulses / peaks applied in a signal does not repeat within a predetermined subset of time periods within the signal.

[0047] In some applications, the parameter pattern is not repeated in a predetermined time window subset of 0.2 seconds.

[0048] In some applications, the varying energy level parameter includes at least two different energy levels, a first energy level having a first minimum and maximum microjoule range and a second energy level having a different second minimum and maximum microjoule range.

[0049] In some applications, the first energy level has a first average energy with a first average minimum and maximum microjoule range, and the second energy level has a second average energy with a second average minimum and maximum microjoule range.

[0050] In some applications, the control processor is configured to randomly vary the duration of the intervals between pulses such that a series of pulses are applied in the signal with random intervals between the pulses.

[0051] In some applications, the random interval includes at least two different interval durations.

[0052] In some applications, the predetermined amount of energy includes a maximum energy level of 15 volts.

[0053] In some applications, the signal generator is configured to provide the electrical signal as an automatic, non-user-controllable signal.

[0054] In some applications, the electrical signal is a stochastic AC signal.

[0055] In some applications, the at least one electrode includes at least two electrodes.

[0056] In some applications, at least one electrode is placed in contact with the subject's intact skin.

[0057] In some applications, at least one electrode is positioned in contact with the subject's skin near a wound in the skin.

[0058] For some applications, the at least one electrode includes at least two electrodes, the at least two electrodes configured to be placed on two opposing sides of a skin wound.

[0059] In some applications, at least one electrode is placed in contact with the subject's skin at a site suffering from impaired oxygenation.

[0060] In some applications, at least one electrode is positioned upstream of an afferent axon leading to the spinal cord.

[0061] In some applications, the peak comprises a varying waveform selected from the group consisting of a sinusoidal waveform, a square waveform, or a triangular waveform.

[0062] In some applications, the series of pulses / peaks includes a series of pulses / peaks where a positive pulse / peak is followed by a negative pulse / peak and a negative pulse / peak is followed by a positive pulse / peak.

[0063] Thus, according to some applications of the present invention, there is provided a method for stimulating a first nerve group at a first tissue depth, the method comprising: placing at least one electrode in contact with the skin of a subject; applying an electrical signal to the subject through the at least one electrode, the electrical signal being characterized by a series of pulses or peaks in a wave; randomly varying at least one parameter of the pulses / peaks; and applying a first predetermined amount of energy by applying the electrical signal to the subject independent of the randomly varying pulse / peak parameter, thereby stimulating the first nerve group at the first tissue depth.

[0064] For some applications, the method further includes applying a second predetermined amount of energy to the subject by application of the signal independent of the randomly varying pulse / peak parameters and stimulating a second nerve group at a second tissue depth, wherein the first tissue depth is different from the second tissue depth.

[0065] In some applications, the method further includes randomly selecting the first and second nerve groups to be stimulated.

[0066] In some applications, the method further includes randomly varying the interval between pulses.

[0067] In some applications, the method further includes controlling the application of the series of pulses / peaks such that a parameter pattern of the series of pulses / peaks applied during a time window subset of the electrical signal is not repeated during the same subset.

[0068] In some applications, disposing at least one electrode includes disposing at least two electrodes.

[0069] For some applications, placing at least one electrode includes placing at least two electrodes on opposite sides of the wound in the skin.

[0070] For some applications, placing at least one electrode includes placing an electrode proximate a wound in the skin.

[0071] For some applications, placing the at least one electrode includes placing the electrode at least 5 cm from the outermost edge of the wound.

[0072] For some applications, the method further includes promoting healing of a skin wound of the subject by applying an electrical signal.

[0073] For some applications, the method further includes reducing pain in the subject by applying an electrical signal.

[0074] For some applications, the method further includes enhancing revascularization of the subject by applying an electrical signal.

[0075] For some applications, the method further includes increasing granulation in the subject's skin by applying an electrical signal.

[0076] For some applications, the method further includes increasing oxygen perfusion of the subject by applying an electrical signal.

[0077] For some applications, the method further includes reducing the healing time of a skin wound.

[0078] In some applications, applying the electrical signal includes applying the electrical signal for 10 to 30 minutes, 1 to 3 times within a 24-hour period.

[0079] For some applications, the method further includes generating the electrical signal in an automatic, non-user-controllable manner.

[0080] Thus, according to some applications of the present invention, there is provided a computer program product including a non-transitory computer-readable storage medium having program code embodied therein, the program code being executable by at least one hardware processor to generate, via at least one electrode in contact with the skin of a subject, an automatic, non-user-controllable electrical signal characterized by a series of pulses or peaks of waves applied with randomly varying pulse / peak parameters, and to apply a first predetermined amount of energy to the subject and stimulate a first nerve group at a first tissue depth by applying the signal independent of the randomly varying pulse / peak parameters.

[0081] For some applications, the computer program product further includes applying pulses at random intervals.

[0082] Thus, according to some applications of the present invention, a first series of wave pulses or peaks includes a series of at least 250 positive current pulses / peaks and at least 250 negative current pulses / peaks per second having (i) an energy level of 0.5 to 13 microjoules, (ii) a pulse / peak duration of 0.25 milliseconds to 0.5 milliseconds, and (iii) an average energy of 1 to 4 microjoules; a signal generator configured to generate an electrical signal characterized by a second series of wave pulses or peaks, the second series including at least 100 positive current pulses / peaks and at least 100 negative current pulses / peaks per second; a control processor electrically coupled to the signal generator and configured to mix the series of pulses / peaks of the first and second series of wave pulses or peaks; and an electrical stimulator including at least one electrode configured to be placed in contact with the skin of the subject and to apply the mixed pulses / peaks to the subject with random intervals between the pulses / peaks.

[0083] In some applications, the signal generator is further configured to generate a third series of wave pulses or peaks, the third series including at least 150 positive current pulses / peaks per second and at least 150 negative current pulses / peaks / second, having (i) an energy level of 1 to 20 microjoules, (ii) a pulse / peak duration of 0.5 milliseconds to 1 millisecond, and (iii) an average energy of 2 to 10 microjoules, and the control processor is configured to mix the first, second, and third series of wave pulses or peaks.

[0084] In some applications, the signal generator is further configured to generate a fourth series of wave pulses or peaks including a series of at least 30 positive current pulses / peaks per second and at least 30 negative current pulses / peaks / second having (i) an energy level of 2 to 40 microjoules, (ii) a pulse / peak duration of 1 millisecond to 2.5 milliseconds, and (iii) an average energy of 4 to 20 microjoules, and the control processor is configured to mix the series of pulses / peaks of the first, second, third, and fourth series of wave pulses or peaks.

[0085] In some applications, the signal generator is further configured to generate a fifth series of wave pulses or peaks, the fifth series including at least 0.5 positive current pulses / peaks per second and at least 0.5 negative current pulses / peaks per second, having (i) an energy level of 10 to 250 microjoules, (ii) a pulse / peak duration of 2.5 milliseconds to 10 milliseconds, and (iii) an average energy of 20 to 200 microjoules, and the control processor is configured to mix the first, second, third, fourth, and fifth series of wave pulses or peaks.

[0086] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed descriptions. [Brief explanation of the drawings]

[0087] Exemplary embodiments are illustrated in the referenced figures. Dimensions of components and features shown in the figures have generally been chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are as follows:

[0088] [Figure 1] 1 is a schematic diagram of an apparatus for applying electrical stimulation therapy, comprising electrodes positioned on a subject's skin near a wound, according to some applications of the present invention. FIG. [Figure 2] 1 is a schematic diagram of an apparatus for applying electrical stimulation therapy, comprising electrodes positioned on a subject's skin remote from a wound, in accordance with some applications of the present invention. FIG. [Figure 3] 1 is a flowchart illustrating a method for treating a subject by application of electrical stimulation therapy, according to some applications of the present invention. [Figure 4-13] 1 is an example of a chronic wound in a subject before, during, and after treatment of the subject according to some applications of the present invention. [Figure 14] 1 is a schematic diagram of an apparatus for applying electrical stimulation therapy for use with various items used by a subject to improve oxygen prefusion in the subject, according to some applications of the present invention; FIG. DETAILED DESCRIPTION OF THE INVENTION

[0089] In some aspects of the invention, a device is provided for applying electrical stimulation therapy to a subject. Optionally, but not necessarily, the electrical stimulation applied in accordance with some applications of the invention accelerates and improves wound healing, enhances revascularization, promotes blood flow, and improves circulation and oxygen levels in tissue.

[0090] According to some embodiments of the present invention, the electrical stimulation applied to the subject comprises a pulsed current or waveform electrical signal characterized by wave peaks whose pulse / peak operating parameters (e.g., energy level, number of pulses / peaks per second, waveform, pulse / peak pattern, and / or pulse / peak duration) vary randomly and continuously over the course of the pulse / peak, thereby providing the subject with a randomly varying electrical signal that delivers a predetermined total amount of electrical energy (despite the varying pulse / peak parameters). Typically, a predetermined amount of positive energy is delivered to the subject, but the total charge applied to the subject during a treatment session is substantially zero.

[0091] According to some embodiments of the present invention, electrical stimulation is applied by a device comprising an electrical stimulator having at least one electrode (e.g., two electrodes) configured to be placed in contact with the subject's skin. The device further comprises a signal generator configured to provide an electrical signal through the at least one electrode. Optionally, but not necessarily, the signal generator is configured to provide the electrical signal in an automatic, non-user-controllable manner. In some applications, the signal generator comprises a power source and is configured to generate at least one series of pulses / waveforms. Typically, the signal generator generates first and second series of pulses / waveforms. The waveforms may be any known type of waveform, e.g., sine wave, square wave, triangular wave, and / or sawtooth wave, or combinations thereof. The device further comprises a control processor configured to randomly vary the pulses / peaks to provide the subject with a randomly varying electrical signal. Typically, the current applied according to some applications of the present invention is characterized by randomly varying pulse / peak parameters, such as the number of pulses / peaks per second, duration, and pulse / peak energy level.

[0092] Additionally, the pulses / peaks are typically applied as a train of positive and negative pulses / peaks, with a positive pulse / peak followed by a negative pulse / peak (or vice versa).

[0093] Optionally, but not necessarily, in the case of pulsed current, there are random and varying intervals (time gaps) between the negative and positive pulses. During the time gaps between the negative and positive pulses / peaks, there is no current flow so that each pulse is an isolated electrical event.

[0094] Reference is now made to FIG. 1, which is a schematic diagram of an apparatus 20 for applying electrical stimulation therapy to a subject, according to some applications of the present invention. The apparatus 20 typically includes a signal generator 8, an electrical stimulator including electrodes 2 and 4 configured to be placed in contact with the subject's skin, and a control processor 9. When the apparatus 20 is operated, an electrical current is generated by the signal generator 8 and delivered to the subject through the electrodes 2 and 4. The current typically has a therapeutic signal waveform including a train of pulses / peaks. The apparatus 20 may further include an amplifier (not shown) and / or a power supply (not shown), etc. The control processor 9 may be an analog signal processor or a digital signal processor. For example, the electrical signal generator 8 is a digital signal generator operated by at least one hardware processor to generate a signal output from a preamplifier. For example, the amplifier may be a current-limited digital voltage amplifier, such as an electronic device that increases the power of the signal from the electrical signal generator. For example, the power source may be an alkaline battery, a lead-acid battery, a rechargeable lithium-ion battery, a nickel-metal hydride battery, etc.

[0095] The signal generator 8 typically generates an electrical signal to provide therapy to the subject to improve oxygen perfusion within the subject to promote healing of the chronic wound 6. The electrical signal is sent to electrodes 2 and 4, which are placed in contact with the subject's skin, to deliver a therapeutic signal waveform current anywhere on the subject's body. The electrodes 2 and 4 are typically configured to be placed in contact with the subject's intact skin. In some applications, as shown in FIG. 1 , the device 20 includes two electrodes 2 and 4 placed in contact with the subject's skin. It should be noted that the device 20 may include more than two electrodes. The device 20 typically further includes a signal generator 8 and a control processor 9.

[0096] Optionally, signal generator 8 provides an automatic, non-user-controllable electrical signal for application to the subject through at least one electrode 2 and / or 4 (optionally through electrical lead 5). The electrical signal applied by signal generator 8 is typically characterized by a series of pulses / peaks having at least two pulse / peak parameters (e.g., pulse / peak duration and pulse / peak energy level) that are randomly varied during application of the signal. According to some applications of the invention, control processor 9 is configured to (i) randomly vary each of the pulse / peak parameters during application of the electrical signal, and (ii) provide the electrical signal such that a predetermined total amount of energy is applied to the subject by the signal regardless of and independent of the varied pulse / peak parameters. Typically, the pulse / peak parameters are continuously and randomly varied throughout the duration of the signal. The pulse / peak parameters typically vary independently of each other.

[0097] Electrodes 2 and 4 are shown in Figure 1 as being positioned near wound 6, and specifically on opposite sides of wound 6, by way of example and not limitation. It should be noted that, according to some applications of the present invention, electrodes 2 and 4 may be placed anywhere on the subject's skin or on an article worn by the subject (as described elsewhere herein).

[0098] In some applications, the control processor 9 is configured to mix pulse / peak sequences so that the parameter patterns (e.g., combinations of pulse / peak energy levels and durations) of the sequences applied during a predetermined subset of signal durations are not repeated within the same subset, thereby further contributing to signal variation. For example, the parameter patterns are not repeated within a predetermined subset time frame of 0.2 seconds. However, despite the random combination of pulse / peak parameters, application of the signal applies a predetermined amount of energy to the subject. For example, the predetermined amount of energy includes a maximum potential level of 15 volts.

[0099] In some applications, the signal generator 8 is configured to generate at least one waveform or pulse train. For example, the signal generator 8 is configured to generate at least first and second waveforms or pulse trains. The first and second waveforms (or positive trains) are each characterized by a series of minimum numbers of positive and negative pulses / peaks applied per second (typically the first and second waveforms having different numbers of minimum pulses / peaks). Additionally, the pulses / peaks of each waveform are characterized by varying energy levels with minimum and maximum microjoule ranges and varying pulse / peak durations with minimum and maximum pulse / peak duration ranges. Additionally, the average energy applied by the waveforms varies between the first and second waveforms.

[0100] For example, the first waveform (or positive train) is characterized by a train of at least 250 positive current pulses / peaks and at least 250 negative current pulses / peaks per second, with energy levels in the range of 0.5-13 microjoules, pulse / peak durations of 0.25-0.5 milliseconds, and average energies of 1-4 microjoules. The second waveform is characterized by a train of at least 100 positive current pulses / peaks and at least 100 negative current pulses / peaks per second, with energy levels in the range of 0.005-7 microjoules, pulse / peak durations of 0.05-0.25 milliseconds, and average energies of 0.02-1 microjoules.

[0101] In some applications, the signal generator is configured to generate additional waveforms (or plus trains) characterized by having pulses / peaks with varying energy levels, minimum and maximum pulse / peak duration ranges, varying pulse / peak durations, and average energy levels, with different numbers of minimum pulses / peaks and minimum and maximum microjoule ranges.

[0102] For example, the signal generator generates a third waveform (or positive train) characterized by a train of at least 150 positive current pulses / peaks and at least 150 negative current pulses / peaks per second, with energy levels in the range of 1 to 20 microjoules, pulse / peak durations of 0.5 milliseconds to 1 millisecond, and average energies of 2 to 10 microjoules.

[0103] Additionally or alternatively, the signal generator generates a fourth waveform (or positive train) characterized by a train of at least 30 positive current pulses / peaks and at least 30 negative current pulses / peaks per second, with energy levels in the range of 2 to 40 microjoules, pulse / peak durations of 1 millisecond to 2.5 milliseconds, and average energies of 4 to 20 microjoules.

[0104] Additionally or alternatively, the signal generator generates a fifth waveform (or positive train) characterized by a train of at least 0.5 positive current pulses / peaks and at least 0.5 negative current pulses / peaks per second, with an energy level in the range of 10 to 250 microjoules, a pulse / peak duration of 2.5 milliseconds to 10 milliseconds, and an average energy of 20 to 200 microjoules.

[0105] Typically, the control processor 9 is configured to randomly intermix the series of pulses / peaks within each waveform (or positive train) and between waveforms (or positive trains) to provide a randomly intermixed series of pulses / peaks, such that the electrical signal applied to the subject through the at least one electrode includes pulses / peaks having varied and random energy levels and durations. Additionally, pulses may be applied to the subject by the at least one electrode of the electrical stimulator at random intervals.

[0106] Typically, the signal applies a predetermined amount of energy to the subject despite various combinations of randomly applied electrical signals and pulse / peak parameters. Additionally, the control processor is configured to mix the series of pulses / peaks such that the parameter patterns (e.g., pulse / peak energy levels and durations) of the series of pulses / peaks applied during a predetermined time-frame subset of the signal are not repeated within the same subset, further contributing to variations in the signal.

[0107] Reference is now made to Figure 2, which is a schematic diagram of an apparatus 20 for applying electrical stimulation therapy, including electrodes 2 and 4 positioned on a subject's skin 10 remote from a wound 6, in accordance with some applications of the present invention. As described with reference to Figure 1, a signal generator 8 is electrically connected to two or more electrical leads 5. For example, electrical lead 5 is electrically connected to two electrodes 2 and 4 that are electrically connected to the patient's skin 10.

[0108] In some applications, electrodes 2 and 4 are positioned at least 5 centimeters from the anatomical location of wound 6, measured along the surface of the skin between the nearest edge of the wound and the nearest electrode. For example, treatment of a leg wound is performed using electrodes connected to the thigh 45 centimeters from the wound. For example, treatment of a thigh wound is performed using electrodes connected to a wristband 110 centimeters from the skin surface. For example, treatment of a calf wound is performed using electrodes connected to the thigh 20 centimeters from the wound. Electrodes 2 and 4 can be positioned anywhere on the body at a distance from wound 6. For example, electrodes can be positioned on a wrist strap device, a waist belt, a watch, an upper arm strap device, a head strap device, eyeglasses, clothing, clothing accessories, etc. For example, in a wrist or upper arm strap device, the electrodes are positioned on the strap with exposed electrical contacts, such as electrodes, on the surface of the strap closest to the skin, and an electrical signal generator is embedded within the strap. For example, in eyeglasses, electrodes are positioned on the arm, with the electrodes placed on the skin-contacting surface above the ear, and the electrical signal generator is within the frame. For example, in a hat, the electrodes may be located on the interior hat band, with electrical contacts exposed at the temples, and the electrical signal generator may be located within the hat frame. As another example, signal generator 8 and electrodes 2 and 4 may be incorporated into exercise equipment such as a handle, an electronic device such as a television controller, a household appliance such as a broom handle, a mop handle, etc.

[0109] Reference is now made to FIG. 3, which is a flowchart illustrating a method for treating a subject by application of electrical stimulation therapy, according to some applications of the present invention. At least one electrode is positioned in contact with the subject's skin so that electrical stimulation is applied to the subject, typically through the electrode (202). Typically, the electrical stimulation is applied to the subject as an electrical signal characterized by a train of pulses / peaks having pulse / peak parameters such as pulse / peak duration and pulse / peak energy level (204). The pulse / peak parameters are randomly varied independently of each other throughout the duration of the signal application, resulting in an electrical signal characterized by randomly varying pulse / peak parameters (206). In some applications, the train of pulses / peaks is intermixed so that the parameter pattern (e.g., combination of pulse / peak energy level and duration) of the train of pulses / peaks applied during a predetermined subset of the signal's duration is not repeated within the same subset, thereby further contributing to the variation in the signal. For example, the parameter pattern is not repeated within a predetermined subset time frame of 0.2 seconds. However, despite the random combination of pulse / peak parameters, application of the signal results in a predetermined amount of energy being applied to the subject 208. For example, the predetermined amount of energy includes a maximum energy level of 15 volts.

[0110] In some applications, electrical stimulation therapy (i.e., electrical signals) is applied to a subject for at least 10 minutes per day, typically 20-30 minutes, two to three times per day. In some applications, electrical stimulation therapy is applied to a subject suffering from a chronic wound. In some such applications, electrodes are positioned in contact with the skin near the wound. Additionally or alternatively, electrodes are positioned in contact with the skin away from the wound.

[0111] In some applications, the electrical stimulation therapy (i.e., electrical signal) application protocol, e.g., duration of treatment, frequency of treatment, and time intervals between treatments, can vary according to, for example, the characteristics of the wound and tissue being treated. For example, in some applications, the electrical stimulation therapy (i.e., electrical signal) is applied to the subject for at least 10 minutes per day, typically 20-30 minutes, two to three times per day. In some applications, the electrical stimulation therapy is applied to subjects suffering from chronic wounds. In some such applications, electrodes are positioned in contact with the skin near the wound. Additionally or alternatively, electrodes are positioned in contact with the skin away from the wound.

[0112] According to some applications of the present invention, the electrical stimulation therapy applied by the device assists in chronic wound healing and / or revascularization and oxygen perfusion within the body. Additionally or alternatively, the electrical stimulation therapy applied by the device according to some applications of the present invention encourages the growth and epithelialization of granulation tissue.

[0113] Conventional theory states that wound healing causes a short circuit in this electrophysiological process, i.e., a lower resistance, allowing current to flow back from the subcutaneous skin layer to the outer surface of the wound, generating an electric field that attracts tissue repair cells. Therefore, current scientific theory defines this process as a local process, such as a paracrine signaling process. In chronic wounds, this process is disrupted, slowing or halting healing and preventing wound healing. According to this theory, electrical stimulation for wound healing generates an artificial electric field that stimulates wound healing.

[0114] Furthermore, with regard to chronic wounds, the inventors hypothesize that wounds require a healthy level of tissue oxygenation to promote the granulation and epithelialization necessary for healing. However, in the case of chronic wounds, the occurrence of a wound not only causes nerve damage (e.g., damage to neuronal dendrites and axons) but also oxygen deficiency in the wound. Over time, this nerve damage causes impaired signal transduction, resulting in impaired wound healing. Electrical stimulation breaks this cycle by reinitiating appropriate signal transduction, leading to the resumption of the healing process. For example, electrical signals initiate signal stimulation healing by signaling messages reporting nerve division up the nervous system. Delivering electrical signals anywhere in a subject's body signals the subject's brain to treat the physical wound, especially in the case of chronic wounds.

[0115] It is further hypothesized by the inventors that applying random and varying electrical signals having the characteristics described herein will promote enhanced wound healing and revascularization compared to other known electrotherapy stimulation procedures. The inventors hypothesize that applying the varied, mixed electrical signals characterized herein will prevent the body from adapting to the applied electrical stimulation, thereby achieving better wound healing and revascularization parameters. Additionally or alternatively, it is hypothesized by the inventors that applying the varied, mixed electrical signals characterized herein will promote stimulation of different nerve groups at different depth levels, thereby achieving enhanced wound healing and revascularization parameters.

[0116] Experimental data The experiments described below were carried out by the inventors in accordance with the application of the present invention and using the devices and techniques described herein. The experiments presented below with reference to Examples 1 and 2 demonstrate that the application of electrical signals according to the devices and techniques described herein can be used to accelerate and improve wound healing and improve tissue oxygenation.

[0117] Example 1 In one set of experiments, the effects of the devices and techniques described herein on chronic wound healing were investigated.

[0118] Method in Example 1 A series of protocols are described below that can be used separately or in combination as needed, depending on the application of the present invention. It should be understood that the numerical values are provided by way of example and not limitation. Typically, but not necessarily, each value shown is an example selected from a range of values within 10% of the shown value. Similarly, while certain steps are described with a high level of specificity, those skilled in the art will understand that other steps can be performed, mutatis mutandis.

[0119] According to some applications of the present invention, the following methods have been applied: Acquisition of subject population IRB approval (Clalit Health Services, Tel Aviv, Israel) was received to conduct a retrospective analysis of patients treated with the devices and techniques described herein.

[0120] The subject population included subjects (N=29) who presented with a total of 34 diabetic foot or venous leg ulcers. To be included in the study, patients had to have wounds that had been present for at least 3 months and had not improved for at least 30 days prior to enrollment, as assessed by a physician. Patients enrolled in the study were instructed on the proper use of the device and were instructed to use it for 30 minutes, three times daily, per session. A total of 34 wounds were presented by 29 patients. Eighteen of the wounds were in male subjects, and 16 of the wounds were in female subjects. Twenty-two wounds were diabetic foot ulcers and 12 wounds were venous leg ulcers. The mean age of enrolled subjects was 77.2 years. The mean duration of wounds at presentation was 7.5 months. The mean wound size at presentation was 4.08 cm. 2 (range 0.15-21.02).

[0121] The information for the 29 subjects (and 34 wounds) is shown in Table A below. [Table 1]

[0122] This study was conducted as an open-label, non-randomized phase 1 trial.

[0123] Subjects were followed until wound closure, or if the wound did not completely close, subjects were treated for 16 weeks. Subjects were followed weekly throughout the treatment period, at which time photographs were taken. Wound measurements were performed using Image J software (NIH).

[0124] stimulation therapy The device according to some applications of the present invention is a computerized electrotherapy system based on specially designed software that generates electrical signals characterized by randomly varying pulse / peak parameters.

[0125] The device is intended for home use. It is a self-contained unit with two electrodes that are placed around the wound. The device is operated for 30 minutes, three times a day.

[0126] At the start of treatment, the software automatically calibrates the treatment amplitude to be achieved during the treatment session. Each treatment session lasts 30 minutes, and the device generates a balanced, low-intensity current (maximum current density; 0.32 mA / cm rms) with net zero DC, as described elsewhere herein.

[0127] Results obtained in Example 1 Reference is again made to Table A, which shows the overall results of the study described in Example 1.

[0128] As shown in Table A, at 4 weeks, wound size improved by an average of 36.20% compared to the time of enrollment. Five of the 34 wounds were completely healed at 4 weeks (14.70%). Age, gender, wound type, and wound duration had no statistical effect on the results.

[0129] At 12 weeks, there was an average 74.92% improvement in wound size compared to baseline. Compared to the improvement at week 4, there was an additional 56.80% improvement in wound size. An additional 12 wounds were completely healed (35.30%) between weeks 4 and 12. In total, 17 wounds were completely healed (50%) by week 12.

[0130] At 16 weeks, three additional wounds had completely closed. The mean size of the remaining wounds was 1.82 cm. 2 That's a 55% decrease from the start.

[0131] Six additional wounds were completely healed by week 20 (17.65).

[0132] Twenty-three of the 34 wounds closed completely within 140 days. The mean time to complete healing in this group was 79 days. In the diabetic foot ulcer group, there were 14 men and 9 women. In the venous leg ulcer group, there were 4 men and 7 women. There was no difference in the effect of gender on the study results.

[0133] No adverse events or safety issues related to the device were reported during the study.

[0134] Chart I below depicts the total wound area measured over time in response to treatment using devices and methods according to several applications of the present invention. [ka]

[0135] Example 2 In one set of experiments, the effects of the devices and techniques described herein on chronic wound healing and tissue oxygenation were investigated.

[0136] Method in Example 2 Acquisition of subject population This study included eight patients (2F; 6M), all elderly (74.5 ± 5.8 years old), with poor arterial circulation (TcPO2 = 29.1 mmHg ± 9.6), except for one (37 years old; TcPO2 = 64 mmHg). All had non-healing ulcers on their lower extremities (2 post-traumatic, 1 pressure ulcer, 1 third-degree burn, 2 venous, and 2 diabetic). The mean surface area was 12.5 cm2 ± 9.8 cm, and the mean PushTool score was 11.5 ± 2.6 points.

[0137] stimulation therapy Low-intensity electrical current in the microampere range was applied to healthy, intact skin near the wound edge for 30 minutes, three times daily. All ulcers were treated with dressings made according to best practices. Varying electrical signals were applied as described herein.

[0138] Results obtained in Example 2 The rate of wound surface reduction and improvement in granulation and epithelialization were evaluated (measured by the Push Tool 3.0 system). Results: Three patients achieved complete wound closure by 40 days. Two patients were withdrawn from the study due to hospitalization for other reasons. One patient discontinued treatment because she was tired of the procedure. Two patients are still undergoing treatment. In all cases except one (virtually unchanged), statistically significant reductions in wound surface and PT values were observed (-49% and -4 pt, respectively, P<0.05). The mean treatment time was 35.1±17.5 days. After treatment, TcPO2 increased from 29.1mmHg±9 to 49.5mmHg±6.7.

[0139] Reference is now made to Figures 4A-13D, which are examples of chronic wounds in subjects (selected from Table A) before, during, and after treatment of the subjects according to some applications of the present invention. As described with reference to Example 1 and listed in Table A, subjects suffering from diabetic foot ulcers or venous leg ulcers were treated according to applications of the present invention to heal the wounds.

[0140] Figures 4A-4D are images of a venous leg ulcer in an 84-year-old female subject who had the wound for 12 months before initiating treatment with some applications of the present invention. Figures 4A-D show the wound before and during follow-up treatment.

[0141] Figure 4A shows the wound at time 0 before application of any treatment.

[0142] FIG. 4B shows partial healing of the wound 5 weeks after the start of treatment with some applications of the present invention.

[0143] FIG. 4C shows additional partial healing of the wound 7 weeks after the start of treatment with some applications of the present invention.

[0144] Figure 4D shows complete closure of the wound 11 weeks from the start of treatment with some applications of the present invention. Figure 4D shows complete closure of the wound from 4.8 cm2 to 0.0 cm2.

[0145] Figures 5A-5D are images of a diabetic foot ulcer in a 68-year-old female subject who had the wound for three months before beginning treatment with some applications of the present invention. Figures 5A-D show the wound before and during follow-up treatment.

[0146] Figure 5A shows the wound at time 0 before application of any treatment.

[0147] FIG. 5B shows partial healing of the wound 4 weeks after the start of treatment with some applications of the present invention.

[0148] FIG. 5C shows additional partial healing of the wound 8 weeks from the start of treatment with some applications of the present invention.

[0149] Figure 5D shows complete closure of the wound 20 weeks from the start of treatment with some applications of the present invention. Figure 5D shows complete closure of the wound from 1.05 cm2 to 0.0 cm2.

[0150] 6A-6D are images of a venous leg ulcer in an 89-year-old female subject who had the wound for four months before beginning treatment with some applications of the present invention. Figures 6A-D show the wound before and during follow-up treatment.

[0151] Figure 6A shows the wound at time 0 before application of any treatment.

[0152] FIG. 6B shows partial healing of the wound two weeks after the start of treatment with some applications of the present invention.

[0153] FIG. 6C shows additional partial healing of the wound 8 weeks after the start of treatment with some applications of the present invention.

[0154] Figure 6D shows complete closure of the wound 15 weeks from the start of treatment with some applications of the present invention. Figure 6D shows complete closure of the wound from 21.22 cm2 to 0.0 cm2.

[0155] 7A-7D are images of a venous leg ulcer in a 92-year-old female subject who had suffered from the wound for 17 months before initiating treatment with some applications of the present invention. Figures 7A-D show the wound before and during follow-up treatment.

[0156] Figure 7A shows the wound at time 0 before application of any treatment.

[0157] FIG. 7B shows partial healing of the wound 3 weeks after the start of treatment with some applications of the present invention.

[0158] FIG. 7C shows additional partial healing of the wound 8 weeks after the start of treatment with some applications of the present invention.

[0159] Figure 7D shows complete closure of the wound 10 weeks from the start of treatment with some applications of the present invention. Figure 7D shows complete closure of the wound from 14.67 cm2 to 0.0 cm2.

[0160] 8A-8D are images of a diabetic foot ulcer in a 77-year-old female subject who had the wound for 12 months before initiating treatment with some applications of the present invention. Figures 8A-D show the wound before and during follow-up treatment.

[0161] FIG. 8A shows a wound prior to the start of a treatment session, according to some applications of the present invention.

[0162] FIG. 8B shows partial healing of the wound after a previous treatment session according to some applications of the present invention, and before resuming treatment according to some applications of the present invention.

[0163] FIG. 8C shows partial healing of the wound 6 weeks after resumption of treatment with some applications of the present invention.

[0164] Figure 8D shows complete closure of the wound 9 weeks after resumption of treatment with some applications of the present invention. Figure 8D shows complete closure of the wound from 1.23 cm2 to 0.0 cm2.

[0165] Figures 9A-9D are images of an additional diabetic foot ulcer in the 77-year-old female subject from Figures 8A-D, who had suffered from the wound for 12 months before initiating treatment with some applications of the present invention. Figures 9A-D show the wound before and during follow-up treatment.

[0166] FIG. 9A shows a wound prior to the start of a treatment session, according to some applications of the present invention.

[0167] FIG. 9B shows partial healing of the wound after a previous treatment session according to some applications of the present invention, and before resuming treatment according to some applications of the present invention.

[0168] FIG. 9C shows partial healing of the wound 6 weeks after resumption of treatment with some applications of the present invention.

[0169] Figure 9D shows complete closure of the wound 9 weeks after resumption of treatment with some applications of the present invention. Figure 9D shows complete closure of the wound from 0.47 cm to 0.0 cm.

[0170] 10A-10D are images of a diabetic foot ulcer in a 92-year-old female subject who had the wound for three months before beginning treatment with some applications of the present invention. Figures 10A-D show the wound before and during follow-up treatment.

[0171] FIG. 10A shows the wound at time 0 before application of any treatment.

[0172] FIG. 10B shows partial healing of the wound three weeks after the start of treatment with some applications of the present invention.

[0173] FIG. 10C shows additional partial healing of the wound 12 weeks from the start of treatment with some applications of the present invention.

[0174] Figure 10D shows complete closure of the wound 16 weeks from the start of treatment with some applications of the present invention. Figure 10D shows complete closure of the wound from 6.14 cm2 to 0.0 cm2.

[0175] 11A-11D are images of a diabetic foot ulcer in an 86-year-old male subject who had the wound for 12 months before initiating treatment with some applications of the present invention. Figures 11A-D show the wound before and during follow-up treatment.

[0176] FIG. 11A shows the wound at time 0 before application of any treatment.

[0177] FIG. 11B shows partial healing of the wound 4 weeks after the start of treatment with some applications of the present invention.

[0178] FIG. 11C shows additional partial healing of the wound 12 weeks from the start of treatment with some applications of the present invention.

[0179] Figure 11D shows further complete wound closure 20 weeks from the start of treatment with some applications of the present invention. Figure 11D shows wound closure from 6.07 cm to 0.96 cm (84% closure).

[0180] 12A-12D are images of two diabetic foot ulcers in a 74-year-old female subject who had suffered from the wounds for 12 months prior to the initiation of treatment with some applications of the present invention. Figures 12A-D show the wounds before and during follow-up treatment.

[0181] FIG. 12A shows the wound at time 0 before application of any treatment.

[0182] FIG. 12B shows partial healing of the wound 5 weeks after the start of treatment with some applications of the present invention.

[0183] FIG. 12C shows complete closure of one of the wounds (indicated by the arrow) and partial healing of one additional of the wounds 10 weeks from the start of treatment with some applications of the present invention.

[0184] Figure 12D shows complete closure of both wounds (indicated by arrows) 18 weeks from the start of treatment with some applications of the present invention. Figure 12D shows complete closure of both wounds, from 1.35 cm to 0.0 cm and from 1.01 cm to 0.0 cm.

[0185] 13A-13D are images of a diabetic foot ulcer in a 63-year-old male subject who had the wound for 6 months before beginning treatment with some applications of the present invention. Figures 13A-D show the wound before and during follow-up treatment.

[0186] Figure 13A shows the wound at time 0 before application of any treatment.

[0187] FIG. 13B shows partial healing of the wound two weeks after the start of treatment with some applications of the present invention.

[0188] FIG. 13C shows additional partial healing of the wound 5 weeks after the start of treatment with some applications of the present invention.

[0189] Figure 13D shows complete closure of the wound 10 weeks from the start of treatment with some applications of the present invention. Figure 13D shows complete closure of the wound from 1.05 cm2 to 0.0 cm2.

[0190] Reference is now made to FIG. 14 , which is a schematic diagram of a device for applying electrical stimulation therapy for use with various articles used by a subject to improve oxygen prefusion in the subject, according to some applications of the present invention. The following are examples of possible placements of electrodes away from the wound on an electrode assembly article, such as a wearable and / or grippable article. For example, electrodes are placed distal to the wound within a wearable article, such as clothing, clothing accessories, shoes, or a wristband. FIG. 14 shows a schematic diagram of an article including electrodes and an electrical signal generator for wound treatment. A headwear article 700, such as a hat or cap, may have an electrode assembly integrated into the headband of the headwear article 700, such as electrodes 704 and 708 on the inner surface of the headband of the headwear article 700, adjacent to the skin at the subject's temples. The assembly is embedded in the headwear article 700 structure and includes electrical leads 706 electrically connected at one end of each electrical lead 706 to both electrodes 704 and 708 and to an electrical signal generator 702 electrically connected at the other end of the electrical lead 706. A fixation element, such as a headband, on the headwear article 700 keeps the electrodes 704 and 708 firmly connected to the subject's skin. An advantage of incorporating the electrical signal generator 702 and electrode assembly into the headwear article 700 is that the patient can be treated while performing other tasks, such as walking.

[0191] The eyeglass frame 710 may have an electrode assembly integrated into the arms of the eyeglass frame 710, such as electrodes 714 and 716 on the inner surface of the end of each arm adjacent the skin behind the subject's ear. The assembly is embedded in the eyeglass frame 710 structure and includes electrical leads 718 electrically connected to both electrodes 714 and 716 at one end of each electrical lead 718 and to an electrical signal generator 712 electrically connected at the other end of the electrical lead 718. The electrical signal generator 712 may be embedded in one arm of the eyeglass frame 710. A fixation element, such as an arm of the eyeglass frame 710, keeps the electrodes 714 and 716 firmly connected to the subject's skin. An advantage of incorporating the electrical signal generator 712 and electrode assembly into the eyeglass frame 710 is that the patient may be treated while performing other tasks, such as reading.

[0192] The watch 720 may have an electrode assembly integrated into the wristband of the watch 720, such as electrodes 724 and 726 on the inner surface of the wrist adjacent to the skin of the subject's wrist. The assembly is embedded in the wristband and includes electrical leads electrically connected to both electrodes 724 and 726 at one end of each lead and to an electrical signal generator 722 electrically connected at the other end of the lead. The electrical signal generator 722 may be embedded within the wristband or the watch itself. A fixation element, such as the wristband of the watch 720, keeps the electrodes 724 and 726 firmly connected to the subject's skin. An advantage of incorporating the electrical signal generator 722 and electrode assembly into the watch 720 is that the patient may be treated while performing other tasks.

[0193] The garment 730 may have an electrode assembly integrated into the sleeve of the garment 730, such as electrodes 734 and 736 on the inside of the sleeve adjacent the skin of the subject's upper arm. The assembly is embedded in the sleeve and includes electrical leads electrically connected to both electrodes 734 and 736 at one end of each lead and to an electrical signal generator 732 electrically connected at the other end of the lead. The electrical signal generator 732 may be embedded into the sleeve of the garment 730. A fixation element, such as the sleeve of the garment 730, keeps the electrodes 734 and 736 firmly connected to the subject's skin. An advantage of incorporating the electrical signal generator 732 and electrode assembly into the garment 730 is that the patient may be treated while performing other tasks.

[0194] Barbell 740 may have an electrode assembly incorporated into the bars of barbell 740, such as electrodes 744 and 746 on the exterior surface of the bar adjacent to the skin of the subject's hands holding the bar. The assembly includes electrical leads embedded in the bar and electrically connected to both electrodes 744 and 746 at one end of each lead and to an electrical signal generator 742 electrically connected at the other end of the lead. Electrical signal generator 742 may be embedded within the bars or weights of barbell 740. An immobilization element, such as the subject's hands, keeps electrodes 744 and 746 firmly connected to the subject's skin. An advantage of incorporating the electrical signal generator and electrode assembly into barbell 740 is that the patient may engage in fitness training while being treated.

[0195] Broom 750 may have an electrode assembly incorporated into the handle of broom 750, such as electrodes 754 and 756 on the exterior surface of the handle adjacent to the skin of the subject's hand holding the handle. The assembly is embedded in the handle and includes electrical leads electrically connected to both electrodes 754 and 756 at one end of each lead and to an electrical signal generator 752 electrically connected at the other end of the leads. Electrical signal generator 752 may be embedded within the handle of broom 750. An immobilization element, such as the subject's hand, keeps electrodes 754 and 756 firmly connected to the subject's skin. An advantage of incorporating electrical signal generator 752 and electrode assembly into broom 750 is that the patient may be treated while performing other tasks, such as cleaning.

[0196] Optionally, the electrode assembly is disposed in a medical bandage, adhesive bandage, or the like. For example, the electrode is a patch electrode connected to the patient's skin with an adhesive, and the electrical signal generator is integrated into the patch. In this example, the fixation element is the adhesive of the patch. For example, the electrical signal generator and electrode are integrated into an elastic bandage such as used for sports injuries. The elastic bandage is applied to the patient's joint so that the electrode on one end of the adhesive bandage touches the skin. The adhesive bandage is the fixation element including the electrical signal generator and leads. Similarly, the electrical signal generator, leads, and electrodes can be incorporated into straps, belts, medical bandages, springs, elastic cords, elastic webbing, elastic bandages, adhesive bandages, adhesive patches, or the like. Optionally, these articles are incorporated into wearable articles such as clothing, underwear, clothing accessories, or the like.

[0197] The two or more electrodes of the described article are connected by a substrate of the article, such as the substrate of the electrode assembly. The substrate may be a 1x10 inch (1x10 cm) thick substrate, such as a rigid substrate of cotton, linen, or the like. -7 Nm 2 The substrate may have a stiffness greater than 10x10, such as the stiffness of a patch electrode with two or more electrode elements, an elastic bandage, etc. -7 Nm 2 Optionally, the substrate may have a stiffness greater than 100x10, such as the stiffness of a headband, a wrist strap for a watch, a headband for a hat, etc.-7 Nm 2 Optionally, the substrate may have a stiffness greater than 1x10, such as the stiffness of a barbell bar, broom handle, etc. -4 Nm 2 Optionally, the substrate may have a stiffness greater than 1x10 -9 Nm 2 Optionally, the substrate may have a stiffness greater than 1x10 -9 Nm 2 ~1x10 9 Nm 2 The stiffness may be

[0198] Some applications of the present invention may be systems, devices, methods, and / or computer program products. The computer program product may include a computer-readable storage medium (or media) having computer-readable program instructions thereon for causing a processor to perform aspects of the present invention.

[0199] A computer-readable storage medium may be a tangible device capable of retaining and storing instructions for use by an instruction execution device. A computer-readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing. A non-exhaustive list of more specific examples of computer-readable storage media includes: portable computer diskettes, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), static random access memory (SRAM), portable compact disk read-only memory (CD-ROM), digital versatile disks (DVD), memory sticks, floppy disks, mechanically encoded devices such as punch cards or grooved ridge structures on which instructions are recorded, and any suitable combination of the foregoing. As used herein, a computer-readable storage medium should not be interpreted as a transitory signal, such as an electric wave or other freely propagating electromagnetic wave, an electromagnetic wave propagating through a waveguide or other transmission medium (e.g., a light pulse passing through a fiber optic cable), or an electrical signal transmitted over a wire.

[0200] The computer-readable program instructions described herein can be downloaded from a computer-readable storage medium to each computing / processing device or to an external computer or external storage device via a network, such as the Internet, a local area network, a wide area network, and / or a wireless network. The network may include copper transmission cables, optical fiber transmissions, wireless transmissions, routers, firewalls, switches, gateway computers, and / or edge servers. A network adapter card or network interface in each computing / processing device receives the computer-readable program instructions from the network and forwards the computer-readable program instructions for storage in a computer-readable storage medium in the respective computing / processing device.

[0201] The computer-readable program instructions for carrying out the operations of the present invention may be either assembler instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, state-setting data, or source or object code written in any combination of one or more programming languages, including object-oriented programming languages such as Java, Smalltalk, C++, and traditional procedural programming languages such as the "C" programming language, or similar programming languages. The computer-readable program instructions may be executed entirely on the user's computer, partly on the user's computer, as a standalone software package, partly on the user's computer and partly on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (e.g., via the Internet using an Internet Service Provider). In some embodiments, electronic circuitry including, for example, a programmable logic circuit, a field programmable gate array (FPGA), or a programmable logic array (PLA) can execute computer-readable program instructions by utilizing state information of the computer-readable program instructions to personalize the electronic circuitry to perform aspects of the present invention.

[0202] Aspects of the present invention are described herein with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer-readable program instructions.

[0203] These computer-readable program instructions may be provided to a processor of a general-purpose computer, special-purpose computer, or other programmable data processing apparatus, such that the instructions, when executed by the processor of the computer or other programmable data processing apparatus, cause the machine to generate means for implementing the functions / acts specified in one or more blocks of the flowcharts and / or block diagrams. These computer-readable program instructions may also be stored within a computer-readable storage medium that can instruct a computer, programmable data processing apparatus, and / or other device to function in a particular manner, such that the computer-readable storage medium having instructions stored therein comprises an article of manufacture containing instructions that implement an aspect of the function / acts specified in a block or blocks of the flowcharts and / or block diagrams.

[0204] The computer-readable program instructions may also be loaded into a computer, other programmable data processing apparatus, or other device and cause the computer, other programmable apparatus, or other device to perform a series of operational steps to generate a computer-implemented process, such that the instructions executing on the computer, other programmable apparatus, or other device implement the function / act specified in a block or blocks of the flowcharts and / or block diagrams.

[0205] The flowcharts and block diagrams in the figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present invention. In this regard, each block in the flowcharts or block diagrams may represent a module, segment, or portion of instructions, including one or more executable instructions for implementing a specified logical function. In some alternative implementations, the functions noted in the blocks may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending on the functionality involved. It should also be noted that each block of the block diagrams and / or flowchart diagrams, and combinations of blocks in the block diagrams and / or flowchart diagrams, can be implemented by a special-purpose hardware-based system that performs the specified functions or operations or executes a combination of dedicated hardware and computer instructions.

[0206] The description of various embodiments of the present invention has been presented for illustrative purposes, but is not intended to be exhaustive or limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terms used herein have been selected to best explain the principles of the embodiments, practical applications, or technical improvements to technology found in the market, or to enable persons other than those skilled in the art to understand the embodiments disclosed herein.

[0207] Those skilled in the art will appreciate that the present invention is not limited to what has been particularly shown and described above, but rather the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as variations and modifications thereof that would occur to those skilled in the art upon reading the foregoing description and that are not in the prior art.

Claims

1. 1. An apparatus comprising: an electrical stimulation device comprising at least one electrode configured to be placed in contact with the subject's skin; a signal generator configured to provide an electrical signal for application to the subject through the at least one electrode, the electrical signal comprising a series of pulses; (i) an energy value of each of said pulses; and (ii) the duration of each of said pulses being within a predetermined duration range; and a control processor configured to continuously, randomly, and independently vary signal parameters including:

2. 10. The apparatus of claim 1, wherein the electrical signal includes an equal number of positive and negative polarity pulses, and wherein a total charge delivered to the subject by the electrical signal equals zero.

3. The apparatus of any one of claims 1 to 2, wherein the signal has a waveform selected from the group consisting of sinusoidal, square, and triangular.

4. 4. The apparatus of claim 1, wherein the control processor is configured to repeat the pattern of signal parameters only once within a predetermined time duration, the predetermined time duration being 0.2 seconds.

5. 5. The apparatus of claim 1, wherein the signal generator is configured to provide the electrical signal by generating a first series of pulses and one or more second series of pulses, and the control processor is configured to intermix the first and one or more second series of pulses with random spacing between pulses.

6. 6. The apparatus of claim 5, wherein the first train of pulses comprises at least 250 positive pulses and at least 250 negative pulses per second, the pulses having (i) an energy level of 0.5 to 13 microjoules, (ii) a pulse duration of 0.25 milliseconds to 0.5 milliseconds, and (iii) an average energy of 1 to 4 microjoules.

7. 7. The apparatus of claim 5, wherein at least one of the one or more second series of pulses comprises at least 100 positive pulses and at least 100 negative pulses per second, the pulses having (i) an energy level of 0.005 to 7 microjoules, (ii) a pulse duration of 0.05 milliseconds to 0.25 milliseconds, and (iii) an average energy of 0.02 to 1 microjoules.

8. 8. The apparatus of claim 5, wherein at least one of the one or more second series of pulses comprises at least 150 positive pulses and at least 150 negative pulses per second, the pulses having (i) an energy level of 1 to 20 microjoules, (ii) a pulse duration of 0.5 milliseconds to 1 millisecond, and (iii) an average energy of 2 to 10 microjoules.

9. 9. The apparatus of claim 5, wherein at least one of the one or more second series of pulses comprises at least 30 positive pulses and at least 30 negative pulses per second, the pulses having (i) an energy level of 2 to 40 microjoules, (ii) a pulse duration of 1 millisecond to 2.5 milliseconds, and (iii) an average energy of 4 to 20 microjoules.

10. 10. The apparatus of claim 5, wherein at least one of the one or more second series of pulses comprises at least 0.5 positive pulses and at least 0.5 negative pulses per second, the pulses having (i) an energy level of 10 to 250 microjoules, (ii) a pulse duration of 2.5 milliseconds to 10 milliseconds, and (iii) an average energy of 20 to 200 microjoules.

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