Electrical stimulation of tissue

Abstract

A method for stimulating a group of nerves, 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, wherein the electrical signal comprises a series of pulses; and continuously and randomly changing at least one of the following signal parameters: (i) the duration of each pulse, (ii) the time interval between each pair of pulses, and (iii) the energy value of each pulse, 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 of each pulse above a predetermined minimum energy value.

Description

[0001] Cross-reference to related applications

[0002] 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. Technical Field

[0003] Some applications of this invention generally relate to medical devices, and more specifically to apparatus and methods for electrically stimulating tissues. Background Technology

[0004] A chronic wound is a wound that does not heal in the manner most wounds heal within a predictable timeframe. A wound is considered chronic when wound measurements do not decrease by approximately 10% per week or by approximately 50% per month.

[0005] The wound healing process is a highly coordinated series of mechanisms involving numerous cells and biological cascades. The electrical activity of skin batteries and injury mechanisms has become a topic of interest due to its impact on chronic wounds.

[0006] Electrical stimulation therapy aids wound healing by influencing electrochemical wound processes. Intact skin possesses a transepithelial potential, with the skin surface containing a negative charge from chloride ions, while the dermis maintains a positive charge via sodium ions. Ulcers and wounds cause abnormalities in the transepithelial potential, and strong electrical activity is measured across the skin across the wound, likely due to neural activity that may promote wound healing. Chronic wounds lose electrical current, thus slowing the healing process. Electrical stimulation therapy reintroduces electrical current and assists the healing process.

[0007] The foregoing examples and related limitations of the related art are intended to be illustrative rather than exclusive. Further limitations of the related art will become apparent to those skilled in the art upon reading the specification and studying the accompanying drawings. Summary of the Invention

[0008] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods intended to be exemplary and illustrative rather than limiting.

[0009] According to some applications of the present invention, apparatus and methods for applying electrical stimulation therapy to a subject are disclosed.

[0010] Typically, an apparatus is provided comprising: 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 via the at least one electrode; and a control processor. Optionally, but not necessarily, the signal generator is configured to provide the electrical signal in an automatic, non-user-controlled manner.

[0011] Therefore, in one embodiment, an apparatus is provided comprising: 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 via the at least one electrode, wherein the electrical signal comprises a series of pulses; and a control processor configured to continuously and randomly change at least one of the following signal parameters: (i) the duration of each pulse, (ii) the time interval between each pair of pulses, and (iii) the energy value of each pulse, 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 of each pulse above a predetermined minimum energy value.

[0012] In one embodiment, a method for stimulating a group of nerves is also provided, 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, wherein the electrical signal comprises a series of pulses; and continuously and randomly changing at least one of the following signal parameters: (i) the duration of each pulse, (ii) the time interval between each pair of pulses, and (iii) the energy value of each pulse, 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 of each pulse above a predetermined minimum energy value.

[0013] In one embodiment, a computer program product is further provided, the computer program product including a non-transitory computer-readable storage medium having program instructions embedded therein, the program instructions being executable by at least one hardware processor to: operate a signal generator to provide an electrical signal for application to a subject via at least one electrode in contact with the subject's skin, wherein the electrical signal comprises a series of pulses; and continuously and randomly change at least one of the following signal parameters: (i) the duration of each pulse, (ii) the time interval between each pair of pulses, and (iii) the energy value of each pulse, 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 of each pulse above a predetermined minimum energy value.

[0014] In some embodiments, the duration of each pulse is within a predetermined duration range.

[0015] In some embodiments, the electrical signal includes an equal number of positive and negative pulses.

[0016] In some embodiments, the total charge delivered to the subject by the electrical signal is equal to zero.

[0017] 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 0.05ms and 0.25ms.

[0018] 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 0.5ms and 1ms.

[0019] In some embodiments, the minimum number of pulses per second is 250, the minimum energy value is 0.5 microjoules, and the duration ranges from 0.25ms to 0.5ms.

[0020] In some embodiments, the predetermined minimum energy value is 2 microjoules, and the duration is between 1 ms and 2.5 ms.

[0021] In some embodiments, the predetermined minimum energy value is 10 microjoules, and the duration is between 2.5 ms and 10 ms.

[0022] In some embodiments, all signal parameters change continuously and randomly.

[0023] In some embodiments, the series of pulses includes discrete pulses.

[0024] In some embodiments, the signal has a waveform selected from the group consisting of: sine wave, square wave, and triangle wave.

[0025] In some embodiments, the pattern of the signal parameters is repeated no more than once within a predetermined duration. In some embodiments, the predetermined duration is 0.2 seconds.

[0026] An electrical signal generated by a signal generator and applied to a subject is characterized by a series of pulses (pulse trains) or 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 changed by a control processor during signal application. Furthermore, the control processor is configured to provide a signal such that a predetermined energy dose is applied to the subject via the signal despite the variation in the pulse / peak parameters.

[0027] For some applications, at least two pulse / peak parameters, including pulse / peak duration and pulse / peak energy level, vary randomly from each other (and independently of the energy dose applied to the subject by the signal) during the signal application period via a control processor. Note that while the pulse / peak parameters vary randomly independently of each other, a change in one parameter may affect one or more other parameters. For example, increasing the pulse / peak duration may increase the applied energy level of the pulse / peak. It should also be noted that additional pulse / peak parameters (e.g., volt / watt amplitude and frequency) may also be randomly changed by the control processor. Additionally or alternatively, in the case where the electrical signal is a pulse signal, the control processor is configured to randomly vary the interval between pulses, such that pulses, particularly identical pulses, are applied at random intervals during the signal application period.

[0028] For 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 pulse trains. The waveforms can include any known type of waveform, such as sine waves, square waves, triangle waves, and / or sawtooth waves, or any other type of waveform. The first and second waveforms or pulse trains are each characterized by a minimum number of positive and negative pulses / peaks applied per second (typically, the first and second waveforms or pulse trains have different numbers of minimum pulses / peaks). Furthermore, the pulses / peaks of each waveform are characterized by different energy levels with minimum and maximum microjoule ranges, and different pulse / peak durations with minimum and maximum pulse / peak duration ranges. Additionally, the average energy applied by the waveforms or pulse trains varies between the first and second waveforms or pulse trains.

[0029] The control processor is configured to randomly mix a series of pulses / peaks within each of the waveforms or pulse trains and between the waveforms or pulse trains to provide a randomly mixed series of pulses / peaks such that the electrical signal applied to the subject through at least one electrode includes pulses / peaks with varying and random energy levels and durations. For some applications, the pulses / peaks are additionally applied to the subject through at least one electrode of the electrical stimulator at random intervals.

[0030] The control processor is also configured to mix a series of positive and negative pulses / peaks, such that a positive pulse / peak is followed by a negative pulse / peak (and vice versa), thereby ensuring the safety of the device by balancing the charge and reducing the accumulation of charge.

[0031] Optionally, but not necessarily, when the signal is a pulse signal, the control processor is configured to mix pulses, such that there are random and varying intervals (time gaps) between negative and positive pulses. During the time gaps between negative and positive pulses, there is typically no current flow, so each pulse is an isolated electrical event. For other applications, there are uniform intervals between pulses. Furthermore, for some applications, the electrical signal is applied as a continuous signal without intervals.

[0032] For some applications, the control processor is configured to mix a series of pulses / peaks such that the parameter patterns (e.g., combinations of pulse / peak energy levels and durations) of a series of pulses / peaks applied during a predetermined subset of the signal duration do not repeat within the same subset, thereby further promoting signal variation. For example, the parameter patterns do not repeat within a predetermined subset of time frames of 0.2 seconds. However, although the pulse / peak parameters are randomly combined, a predetermined energy dose is applied to the subject via the signal.

[0033] For some applications, electrical signals are applied to the subject for at least 10 minutes of treatment per day, typically 2-3 times daily for 20-30 minutes each time. For some applications, at least one electrode is placed in full skin contact anywhere on the subject's body. For some applications, electrical stimulation therapy is applied to subjects with chronic wounds. Optionally, but not necessarily, if the subject has a chronic wound, the electrode is placed near the wound. Alternatively, if the subject has a chronic wound, the electrode is placed at a distance from the wound, for example, more than 100 cm away.

[0034] According to some applications of the invention, electrical stimulation therapy applied by the device can aid in chronic wound healing and / or vascular remodeling and intravascular oxygen perfusion. Additionally or alternatively, electrical stimulation therapy applied by the device according to some applications of the invention can promote granulation tissue growth and epithelial formation.

[0035] The inventors hypothesize that, compared to other known electrotherapy stimulation procedures, the application of random and varying electrical signals with the characteristics described herein promotes enhanced wound healing, angiogenesis, and revascularization. The inventors hypothesize that the application of the varied mixed electrical signals characterized herein prevents the body from adapting to the applied electrical stimulation, thereby achieving better wound healing and revascularization parameters. Additionally or alternatively, the inventors hypothesize that the application of the varied mixed electrical signals characterized herein promotes stimulation of different neural groups at different depth levels, thereby achieving enhanced wound healing and revascularization parameters.

[0036] Additionally or alternatively, the inventors hypothesize that the application of random and varying electrical signals, as characterized herein, is particularly effective in stimulating unmyelinated Group C afferent fibers. According to some applications of the invention, the varying electrical signals applied to Group C afferent fibers signal the presence of damage in the central nervous system (CNS), thus activating the delivery of “repair” commands in the efferent nerves, thereby achieving enhanced wound healing and vascular remodeling parameters.

[0037] Therefore, according to some applications of the present invention, an apparatus is provided comprising: 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 via 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 change at least one parameter of the pulse or peak parameter during signal application, and (ii) provide a signal such that a predetermined energy dose is applied to the subject via the signal, independent of the randomly changing pulse or peak parameter.

[0038] For some applications, the control processor is configured to randomly change at least two pulse / peak parameters.

[0039] For some applications, the control processor is configured to randomly change multiple pulse / peak parameters.

[0040] For some applications, the control processor is configured to randomly change multiple combinations of pulse / peak parameters.

[0041] For some applications, the control processors are configured to randomly change the pulse / peak parameters independently of each other.

[0042] For some applications, at least one pulse / peak parameter includes a pulse / peak duration range, and the control processor is configured to randomly change the pulse / peak duration range during the signal.

[0043] For 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.

[0044] For some applications, at least one of the two pulse / peak parameters includes the pulse / peak energy range level / energy level range, and the control processor is configured to randomly change the pulse / peak energy range level during the signal.

[0045] For some applications, the varying energy level parameters include 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.

[0046] For 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.

[0047] For some applications, a series of pulse / peak parameter patterns applied during a signal may not repeat within a predetermined time frame subset of the signal.

[0048] For some applications, the parameter pattern does not repeat within the 0.2-second predetermined time frame subset.

[0049] For some applications, the varying energy level parameters include at least two distinct energy levels: a first energy level with a first minimum and maximum microjoule range and a second energy level with a different second minimum and maximum microjoule range.

[0050] For 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.

[0051] For some applications, the control processor is configured to randomly change the duration of the interval between pulses, so that a series of pulses are applied during the signal at random intervals between pulses.

[0052] For some applications, random intervals include at least two different interval durations.

[0053] For some applications, the predetermined energy dose includes a maximum energy level of 15 volts.

[0054] For some applications, the signal generator is configured to provide electrical signals as automatic, non-user-controllable signals.

[0055] For some applications, the electrical signal is a random AC signal.

[0056] For some applications, at least one electrode comprises at least two electrodes.

[0057] In some applications, at least one electrode is placed in full contact with the subject's skin.

[0058] In some applications, at least one electrode is placed near a wound in the skin in contact with the subject's skin.

[0059] For some applications, at least one electrode includes at least two electrodes, and the at least two electrodes are configured to be placed on two opposite sides of a wound in the skin.

[0060] In some applications, at least one electrode is placed in contact with the subject's skin at a location where oxygenation is impaired.

[0061] For some applications, at least one electrode is placed upstream of the afferent axons leading to the spinal cord.

[0062] For some applications, peak values ​​include varying waveforms selected from a group consisting of: sine waves, square waves, or triangle waves.

[0063] For some applications, a series of pulses / peaks includes a series of pulses / peaks in which a positive pulse / peak is followed by a negative pulse / peak and vice versa.

[0064] Therefore, according to some applications of the present invention, a method for stimulating a first group of nerves at a first tissue depth is provided, 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 of a wave; randomly changing at least one parameter of the pulse / peak; and applying a first predetermined dose of energy to the subject by applying the electrical signal, independent of the randomly changing pulse / peak parameter, thereby stimulating the first group of nerves at a first tissue depth.

[0065] For some applications, the method may include applying a second predetermined dose of energy to the subject by means of an applied signal, independent of randomly varying pulse / peak parameters, and stimulating a second group of nerves at a second tissue depth, the first tissue depth being different from the second tissue depth.

[0066] For some applications, the method also includes randomly selecting a first group of nerves and a second group of nerves to be stimulated.

[0067] For some applications, the method also includes randomly changing the interval between pulses.

[0068] For some applications, the method also includes controlling the application of a series of pulses / peaks such that the parameter patterns of the series of pulses / peaks applied during a subset of time frames of the electrical signal do not repeat during the same subset.

[0069] For some applications, placing at least one electrode includes placing at least two electrodes.

[0070] For some applications, placing at least one electrode involves placing at least two electrodes on opposite sides of the wound in the skin.

[0071] For some applications, placing at least one electrode involves placing the electrode in the skin near the wound.

[0072] For some applications, placing at least one electrode involves placing the electrode at least 5 cm from the outermost edge of the wound.

[0073] For some applications, the method also includes promoting wound healing in the subject's skin by applying electrical signals.

[0074] In some applications, the method also includes relieving pain in the subject by applying electrical signals.

[0075] For some applications, the method also includes increasing vascular remodeling in subjects by applying electrical signals.

[0076] For some applications, the method also includes increasing granulation tissue in the subject's skin by applying electrical signals.

[0077] For some applications, the method also includes increasing oxygen perfusion in the subject by applying an electrical signal.

[0078] For some applications, the method also includes reducing the healing time of wounds in the skin.

[0079] For some applications, applying an electrical signal involves applying the signal 1-3 times within 24 hours, each time lasting 10-30 minutes.

[0080] For some applications, the method also includes generating electrical signals in an automatic, non-user-controlled manner.

[0081] Therefore, according to some applications of the present invention, a computer program product is provided, comprising a non-transitory computer-readable storage medium having embedded program code therein, the program code being executable by at least one hardware processor to: generate an automatic non-user-controllable electrical signal via at least one electrode in contact with the skin of a subject, the automatic non-user-controllable electrical signal being characterized by a series of pulses or peaks of a wave applied with randomly varying pulse / peak parameters; apply a first predetermined dose of energy to the subject by means of an application signal, independent of the randomly varying pulse / peak parameters; and stimulate a first group of nerves at a first tissue depth.

[0082] For some applications, computer program products also include applying pulses at random intervals.

[0083] Therefore, according to some applications of the present invention, an apparatus is provided comprising: a signal generator configured to generate an electrical signal characterized by: a first series of pulses or peaks of a wave comprising a series of at least 250 positive current pulses / peaks per second and at least 250 negative current pulses / peaks per second, having (i) an energy level of 0.5-13 microjoules, (ii) a pulse / peak duration of 0.25 ms-0.5 ms and (iii) an average energy of 1-4 microjoules; and a second series of pulses or peaks of a wave comprising a series of at least 100 positive current pulses / peaks per second and at least 10... 0 negative current pulses / peaks having (i) an energy level of 0.005–7 microjoules, (ii) a pulse / peak duration of 0.05 ms–0.25 ms, and (iii) an average energy of 0.02–1 microjoules; a control processor electrically coupled to a signal generator and configured to mix a first series of pulses or peaks and a second series of pulses or peaks; and an electrical stimulator comprising at least one electrode configured to be placed in contact with the subject’s skin to apply mixed pulses / peaks to the subject at random intervals between pulses / peaks.

[0084] For some applications, the signal generator is further configured to generate a third series of pulses or peaks of a wave, comprising a series of at least 150 positive current pulses / peaks and at least 150 negative current pulses / peaks per second, having (i) an energy level of 1-20 microjoules, (ii) a pulse / peak duration of 0.5ms-1ms and (iii) an average energy of 2-10 microjoules; and the control processor is configured to mix a series of pulses / peaks of the first series of pulses or peaks, the second series of pulses or peaks and the third series of pulses or peaks of the wave.

[0085] For some applications, the signal generator is further configured to generate a fourth series of pulses or peaks of a wave, comprising a series of at least 30 positive current pulses / peaks and at least 30 negative current pulses / peaks per second, having (i) an energy level of 2-40 microjoules, (ii) a pulse / peak duration of 1 ms-2.5 ms and (iii) an average energy of 4-20 microjoules; and the control processor is configured to mix a series of pulses / peaks of the first series of pulses or peaks, the second series of pulses or peaks, the third series of pulses or peaks and the fourth series of pulses or peaks of the wave.

[0086] For some applications, the signal generator is further configured to generate a fifth series of pulses or peaks of a wave, comprising a series of at least 0.5 positive current pulses / peaks and at least 0.5 negative current pulses / peaks per second, having (i) an energy level of 10-250 microjoules, (ii) a pulse / peak duration of 2.5 ms-10 ms and (iii) an average energy of 20-200 microjoules; and the control processor is configured to mix a series of pulses / peaks of the first series, second series, third series, fourth series and fifth series of pulses or peaks of the wave.

[0087] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent from reference to the accompanying drawings and from studying the following detailed description. Attached Figure Description

[0088] Exemplary embodiments are shown in the reference figures. The dimensions of the components and features shown in the figures are generally chosen for ease of presentation and clarity, and are not necessarily shown to scale. These figures are listed below.

[0089] Figure 1 This is a schematic diagram of a device for applying electrical stimulation therapy according to some applications of the present invention, the device comprising electrodes placed on the skin of a subject near a wound;

[0090] Figure 2 This is a schematic diagram of a device for applying electrical stimulation therapy according to some applications of the present invention, the device comprising electrodes placed on the skin of a subject away from a wound;

[0091] Figure 3 This is a flowchart illustrating a method for treating a subject by applying electrical stimulation therapy according to some applications of the present invention; and

[0092] Figures 4A-4D , Figures 5A-5D , Figures 6A-6D , Figures 7A-7D , Figures 8A-8D , Figures 9A-9D , Figures 10A-10D , Figures 11A-11D , Figures 12A-12D and Figures 13A-13D Examples of the application of the present invention to chronic wounds of subjects before, during, and after treatment; and

[0093] Figure 14 This is a schematic diagram of the configuration of a device for applying electrical stimulation therapy according to some applications of the present invention, which is used in conjunction with various items used by the subject to improve the subject's oxygen prefusion. Detailed Implementation

[0094] In some aspects of the invention, an apparatus is provided for applying electrical stimulation therapy to a subject. Optionally, but not necessarily, electrical stimulation applied according to some applications of the invention accelerates and improves wound healing, increases revascularization, promotes blood flow, and improves circulation and oxygen levels in tissues.

[0095] According to some aspects of the invention, the electrical stimulation applied to the subject comprises an electrical signal of pulsed current or a waveform characterized by peaks, wherein the operating parameters of the pulses / peaks (e.g., energy level, number of pulses / peaks per second, waveform, pulse / peak pattern, and / or pulse / peak duration) vary randomly and continuously during the pulse / peak process. Thus, a randomly varying electrical signal is provided to the subject, through which a total predetermined dose of electrical energy is delivered (although the pulse / peak parameters differ). Typically, a predetermined positive dose of energy is delivered to the subject; however, the total charge applied to the subject during the treatment session is practically zero.

[0096] According to some aspects of the invention, electrical stimulation is applied by a device including an electrical stimulator having at least one electrode (e.g., two electrodes) configured to be placed in contact with the skin of a subject. The device also includes 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 and non-user-controllable manner. For some applications, the signal generator includes 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 can be any known type of waveform, such as sine waves, square waves, triangle waves, and / or sawtooth waves or combinations thereof. The device also includes a control processor configured to randomly vary the pulses / peaks to provide a randomly varying electrical signal to the subject. Typically, the current applied according to some applications of the invention is characterized by randomly varying pulse / peak parameters, such as the number of pulses / peaks per second, the duration, and the pulse / peak energy level.

[0097] In addition, pulses / peaks are usually applied as a series of positive and negative pulses / peaks, where a positive pulse / peak is followed by a negative pulse / peak (or vice versa).

[0098] Optionally, but not necessarily, in the case of pulsed current, there is a random and varying interval (time gap) between the negative and positive pulses. No current flows during the time interval between the negative pulse / peak and the positive pulse / peak, thus each pulse is an isolated electrical event.

[0099] Now for reference Figure 1 This figure is a schematic diagram of an apparatus 20 for applying electrical stimulation therapy to a subject according to some applications of the present invention. Apparatus 20 typically includes a signal generator 8, an electrical stimulator including electrodes 2 and 4, and a control processor 9, the electrodes 2 and 4 being configured to contact the subject's skin. When apparatus 20 is operated, an electric current is generated by the signal generator 8 and reaches the subject through electrodes 2 and 4. The current is typically a therapeutic signal waveform comprising a series of pulses / peaks. Apparatus 20 may also include an amplifier (not shown) and / or a power supply (not shown) and / or the like. 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 is a current-limiting digital voltage amplifier, such as an electronic device that increases the signal power from the electrical signal generator. For example, the power supply is an alkaline battery, a lead-acid battery, a rechargeable lithium-ion battery, a nickel-metal hydride battery, and / or the like.

[0100] Signal generator 8 typically generates an electrical signal to provide treatment to the subject, improving oxygen perfusion and promoting healing of chronic wound 6. The electrical signal is delivered to electrodes 2 and 4, positioned in contact with the subject's skin, to deliver a therapeutic signal waveform current anywhere on the subject's body. Electrodes 2 and 4 are typically configured to be in contact with the subject's intact skin. For some applications, such as... Figure 1 As shown, device 20 includes two electrodes 2 and 4, which are positioned to contact the subject's skin. Note that device 20 may include more than two electrodes. Device 20 typically also includes a signal generator 8 and a control processor 9.

[0101] Optionally, the signal generator 8 provides an automated, non-user-controllable electrical signal for application to a subject via at least one electrode 2 and / or 4 (optionally via electrical lead 5). The electrical signal applied by the 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), which vary randomly during signal application. According to some applications of the invention, the control processor 9 is configured to (i) randomly change each of the pulse / peak parameters during signal application and (ii) provide an electrical signal such that a predetermined total dose energy is applied to the subject by the signal, independent of and unrelated to the varying pulse / peak parameters. Typically, the pulse / peak parameters vary continuously and randomly during the signal duration. The pulse / peak parameters typically vary independently of each other.

[0102] Electrodes 2 and 4 in Figure 1 The electrodes are shown, by way of illustration and not limitation, as positioned near wound 6, specifically on the opposite side of wound 6. Note that, according to some applications of the invention, electrodes 2 and 4 can be placed anywhere on the subject's skin or on items worn by the subject (as described elsewhere herein).

[0103] For some applications, the control processor 9 is configured to blend a series of pulses / peaks such that the parameter patterns (e.g., combinations of energy levels and pulse / peak durations) of a series of pulses / peaks applied during a predetermined subset of the signal duration do not repeat within the same subset, thereby further facilitating signal variation. For example, the parameter patterns do not repeat within a predetermined subset of time frames of 0.2 seconds. However, although the pulse / peak parameters are randomly combined, a predetermined dose of energy is applied to the subject by applying the signal. For example, the predetermined dose of energy includes a maximum potential level of 15 volts.

[0104] For some applications, signal generator 8 is configured to generate at least one waveform or a pulse train. For example, signal generator 8 is configured to generate at least first and second waveforms or pulse trains. The first and second waveforms (or pulse trains) are each characterized by a series of minimum numbers of positive pulses / peaks and negative pulses / peaks applied per second (typically, the first and second waveforms have different numbers of minimum pulses / peaks). Furthermore, the pulses / peaks of each waveform are characterized by different energy levels having minimum and maximum microjoule ranges, and different pulse / peak durations having minimum and maximum pulse / peak duration ranges. Additionally, the average energy applied by the waveform varies between the first and second waveforms.

[0105] For example, the first waveform (or pulse train) is characterized by a series of at least 250 positive current pulses / peaks and at least 250 negative current pulses / peaks per second, having energy levels in the range of 0.5-13 microjoules, pulse / peak durations of 0.25 ms-0.5 ms, and average energy of 1-4 microjoules. The second waveform is characterized by a series of at least 100 positive current pulses / peaks and at least 100 negative current pulses / peaks per second, having energy levels in the range of 0.005-7 microjoules, pulse / peak durations of 0.05 ms-0.25 ms, and average energy of 0.02-1 microjoules.

[0106] For some applications, the signal generator is configured to generate additional waveforms (or pulse trains) characterized by having different numbers of minimum pulses / peaks, and the pulses / peaks having different energy levels with minimum and maximum microjoule ranges, different pulse / peak durations with minimum and maximum pulse / peak duration ranges, and an average energy level.

[0107] For example, a signal generator generates a third waveform (or pulse train) characterized by a series of at least 150 positive current pulses / peaks and at least 150 negative current pulses / peaks per second, having an energy level in the range of 1-20 microjoules, a pulse / peak duration of 0.5ms-1ms, and an average energy of 2-10 microjoules.

[0108] Additionally or alternatively, the signal generator generates a fourth waveform (or pulse train), characterized by a series of at least 30 positive current pulses / peaks and at least 30 negative current pulses / peaks per second, having an energy level in the range of 2-40 microjoules, a pulse / peak duration of 1ms-2.5ms, and an average energy of 4-20 microjoules.

[0109] Further, or alternatively, the signal generator generates a fifth waveform (or pulse train), characterized by a series of at least 0.5 positive current pulses / peaks and at least 0.5 negative current pulses / peaks per second, having an energy level of 10-250 microjoules, a pulse / peak duration of 2.5ms-10ms, and an average energy of 20-200 microjoules.

[0110] Typically, the control processor 9 is configured to randomly mix a series of pulses / peaks within and between each waveform (or pulse train) to provide a randomly mixed series of pulses / peaks, such that the electrical signal applied to the subject through at least one electrode includes pulses / peaks with varying and random energy levels and durations. Additionally, pulses can be applied to the subject by at least one electrode of the electrical stimulator at random intervals.

[0111] Typically, a predetermined dose of energy is applied to the subject via a signal, despite various combinations of randomly applied electrical signals and pulse / peak parameters. Furthermore, the control processor is configured to blend a series of pulses / peaks such that the parameter patterns (e.g., pulse / peak energy levels and durations) of a series of pulses / peaks applied during a predetermined subset of time frames of the signal do not repeat within the same subset, further facilitating signal variation.

[0112] Now for reference Figure 2 This is a schematic diagram of a device 20 for applying electrical stimulation therapy according to some applications of the present invention, the device comprising electrodes 2 and 4 placed on the skin 10 of a subject located away from the wound 6. See reference... Figure 1 The signal generator 8 is electrically connected to two or more electrical leads 5. For example, the electrical leads 5 are electrically connected to two electrodes 2 and 4, which are electrically connected to the patient's skin 10.

[0113] For some applications, electrodes 2 and 4 are positioned at least 5 cm from the anatomical location of wound 6, as measured along the skin surface from the nearest edge of the wound to the nearest electrode. For example, treatment of a foot wound is performed using an electrode attached to the thigh 45 cm from the wound. For example, treatment of a thigh wound is performed using an electrode attached to a wristband 110 cm from the wound along the skin surface. For example, treatment of a calf wound is performed using an electrode attached to the thigh 20 cm from the wound. Electrodes 2 and 4 can be placed at a distance from wound 6, such as anywhere on the body. For example, electrodes can be placed on wristband devices, belts, watches, upper armband devices, headband devices, eyeglasses, clothing articles, clothing accessories, and / or similar items. For example, in a wrist or upper armband device, electrodes are placed in the band with exposed electrical contacts, such as electrodes, on the side of the band closest to the skin, and an electrical signal generator is embedded within the band. For example, in eyeglasses, electrodes are placed on the arm, positioned on either side of the skin above the ear, and an electrical signal generator is within the frame. For example, in a hat, electrodes are placed in the inner hood strap, electrical contacts are exposed at the temples, and an electrical signal generator is inside the hat frame. As another example, the signal generator 8, along with electrodes 2 and 4, can be incorporated into exercise equipment (such as handles), electronic devices (such as television controllers), household appliances (such as broom handles, mop handles), and / or the like.

[0114] Now for reference Figure 3 This is a flowchart illustrating a method for treating a subject by applying electrical stimulation therapy according to some applications of the invention. Typically, at least one electrode is positioned in contact with the subject's skin (202), such that electrical stimulation is applied to the subject through the electrode. Typically, the electrical stimulation is applied to the subject as an electrical signal (204), characterized by a pulse / peak sequence having pulse / peak parameters such as pulse / peak duration and pulse / peak energy level. The pulse / peak parameters vary randomly and independently throughout the entire duration of signal application to generate an electrical signal characterized by randomly varying pulse / peak parameters (206). For some applications, a series of pulses / peaks are mixed such that the parameter patterns (e.g., combinations of energy levels and pulse / peak durations) of a series of pulses / peaks applied during a predetermined subset of the signal duration do not repeat within the same subset, thereby further promoting signal variation. For example, the parameter patterns do not repeat within a predetermined subset of time frames of 0.2 seconds. However, although the pulse / peak parameters are randomly combined, a predetermined dose of energy is applied to the subject by applying the signal (208). For example, the predetermined dose of energy includes a maximum energy level of 15 volts.

[0115] For some applications, electrical stimulation therapy (i.e., electrical signals) is applied to the subject for at least 10 minutes daily, and typically 2-3 times daily for 20-30 minutes. For some applications, electrical stimulation therapy is applied to subjects with chronic wounds. For some such applications, the electrodes are positioned to contact the skin near the wound. Additionally or alternatively, the electrodes are positioned to contact the skin away from the wound.

[0116] For some applications, the protocol for applying electrical stimulation therapy (i.e., electrical signals), such as the duration of treatment, the frequency of treatment, and the time interval between treatments, can vary, for example, depending on the characteristics of the wound and tissue being treated. For instance, in some applications, electrical stimulation therapy (i.e., electrical signals) is applied to the subject for at least 10 minutes daily, and typically 2-3 times daily for 20-30 minutes. In some applications, electrical stimulation therapy is applied to subjects with chronic wounds. In some such applications, the electrodes are positioned to contact the skin near the wound. Additionally or alternatively, the electrodes are positioned to contact the skin away from the wound.

[0117] According to some applications of the invention, electrical stimulation therapy applied by the device aids in chronic wound healing and / or vascular remodeling and intravascular oxygen perfusion. Additionally or alternatively, according to some applications of the invention, electrical stimulation therapy applied by the device promotes granulation tissue growth and epithelial formation.

[0118] Established theories state that wound healing causes a short circuit in this electrophysiological process, such as a decrease in resistance, allowing current to flow from the subcutaneous skin layer back to the outer surface of the wound. This current generates an electric field, which attracts tissue repair cells. Therefore, current scientific theory defines this process as a local process, such as paracrine signaling. In chronic wounds, this process is interrupted, and healing either slows down or stops, thus preventing wound healing. According to this theory, electrical stimulation used for wound healing generates an artificial electric field that stimulates wound healing.

[0119] Further concerning chronic wounds, the inventors hypothesize that wounds require healthy levels of tissue oxygenation to promote the formation of granulation tissue and epithelium necessary for healing. However, in the case of chronic wounds, the occurrence of the wound leads to wound hypoxia and nerve damage (e.g., damage to the dendrites and axons of neurons). Over time, this nerve damage results in impaired signaling, thus hindering wound healing. Electrical stimulation breaks this cycle by restarting appropriate transduction leading, thereby resuming the healing process. For example, electrical signals initiate the stimulation of healing by sending a message to the nervous system reporting neural disintegration. Delivering electrical signals anywhere in the subject's body signals the subject's brain to treat wounds on the body, especially in the case of chronic wounds.

[0120] The inventors further hypothesize that, compared to other known electrotherapy stimulation procedures, the application of random and varied electrical signals with the characteristics described herein contributes to enhanced wound healing and vascular remodeling. The inventors hypothesize that the application of the varied mixed electrical signals characterized herein prevents the body from adapting to the applied electrical stimulation, thereby achieving better wound healing and vascular remodeling parameters. Additionally or alternatively, the inventors hypothesize that the application of the varied mixed electrical signals characterized herein contributes to the stimulation of different neural groups at different depth levels, thereby achieving enhanced wound healing and vascular remodeling parameters.

[0121] Experimental data

[0122] The experiments described below were conducted by the inventors using the invention and the apparatus and techniques described herein. The experiments presented below with reference to Examples 1-2 demonstrate that applying electrical signals according to the apparatus and techniques described herein can accelerate and improve wound healing, as well as improve tissue oxygenation.

[0123] Example 1

[0124] In a series of experiments, the effects of the device and technique described in this article on chronic wound healing were tested.

[0125] The method in Example 1

[0126] The following describes a series of schemes that, according to the application of the invention, can be used individually or in combination as appropriate. It should be understood that the numerical values ​​are provided illustratively rather than limitingly. Typically, but not necessarily, each value shown is an example selected from a range of values ​​within 10% of the values ​​shown. Similarly, although some steps are described with high specificity, those skilled in the art will understand that other steps can be performed by analogy.

[0127] According to some applications of the present invention, the following method is applied:

[0128] Obtaining the subject population

[0129] IRB approval was received (Clalitheath services in Tel Aviv, Israel) to conduct a retrospective analysis of patients treated with the device and technology described herein.

[0130] The study population included a total of 34 participants (N=29) with diabetic foot ulcers or venous leg ulcers. To be included in the study, patients' wounds had to have been present for at least 3 months and show no improvement for at least 30 days prior to enrollment, as assessed by a physician. Participants were instructed on proper use of the device and were directed to use it three times daily for 30 minutes each time. The 29 patients had a total of 34 wounds. Male participants had 18 wounds, and female participants had 16 wounds. 22 wounds were diabetic foot ulcers, and 12 were venous leg ulcers. The mean age of the participants was 77.2 years. The mean duration of the wounds at presentation was 7.5 months. The mean size of the wounds at presentation was 4.08 cm. 2 (Range 0.15-21.02).

[0131] Information on 29 subjects (and 34 wounds) is shown in Table A below:

[0132] Table A:

[0133]

[0134]

[0135] * Not fully healed within 140 days

[0136] Complete healing within 4 weeks

[0137] This study was conducted as an open, non-randomized phase 1 study.

[0138] Subjects were followed until the wound closed, or for 16 weeks if the wound did not close completely. Subjects were followed up weekly during the treatment period, and photographs were taken during this time. Wound measurements were performed using ImageJ software (NIH).

[0139] Stimulation therapy

[0140] The apparatus for 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.

[0141] This device is designed for home use. It is a stand-alone unit with two electrodes placed around the wound. The device is to be used three times a day for thirty minutes each time.

[0142] At the start of treatment, the software automatically calibrates the therapeutic amplitude to be achieved during the treatment session. Each treatment session lasts 30 minutes, during which the device generates a balanced low-intensity current (maximum current density: 0.32 mA / cm²r·ms), net zero DC, as described elsewhere in this document.

[0143] The result obtained in Example 1

[0144] Referring again to Table A, it presents the overall results of the study described in Example 1.

[0145] As shown in Table A, the average wound size improved by 36.20% at 4 weeks compared to the time of inclusion. Five of the 34 wounds healed completely within 4 weeks (14.70%). Age, sex, wound type, and wound duration had no statistically significant impact on the results.

[0146] Compared to baseline, wound size improved by an average of 74.92% at week 12. Wound size further improved by 56.80% compared to the improvement at week 4. Between week 4 and week 12, another 12 wounds (35.30%) had completely healed. By week 12, a total of 17 wounds (50%) had completely healed.

[0147] By week 16, three more wounds had completely closed. The remaining wounds had an average size of 1.82 cm. 2 This is a 55% reduction compared to the beginning.

[0148] By week 20, the other 6 wounds had completely healed (17.65).

[0149] Of the 34 wounds, 23 closed completely within 140 days. The mean time for complete healing in this group was 79 days. There were 14 men and 9 women in the diabetic foot ulcer group. In the venous leg ulcer group, there were 4 men and 7 women. There was no difference in the outcome due to gender.

[0150] No adverse events or safety issues were reported with the equipment during the study.

[0151] Chart I below represents the total wound area measured over time in response to treatment using devices and methods according to some applications of the present invention:

[0152] Chart I

[0153]

[0154] Example 2

[0155] In a series of experiments, the effects of the device and technique described herein on chronic wound healing and tissue oxygenation were tested.

[0156] Method in Example 2

[0157] Obtaining the subject population

[0158] This study included 8 patients (2 women and 6 men), all elderly (74.5 ± 5.8 years) with poor arterial circulation (TcPO2 = 29.1 mmHg ± 9.6), except for one patient (37 years old; TcPO2 = 64 mmHg). All patients had unhealed lower extremity ulcers (2 cases of post-traumatic ulcers; 1 case of pressure ulcer; 1 case of third-degree burn; 2 cases of venous ulcers; 2 cases of diabetes). The mean surface area was 12.5 cm² ± 9.8 mmHg, and the mean pushing tool area was 11.5 ± 2.6 pt.

[0159] Stimulation therapy

[0160] A low-intensity current in the microampere range is applied three times daily for 30 minutes each time, with electrodes placed on healthy, intact skin near the wound edges. All ulcers are treated using dressings made according to best practices. Varying electrical signals are applied as described herein.

[0161] The result obtained in Example 2

[0162] The percentage reduction in wound surface area and the improvement in granulation tissue and epithelial formation were assessed (measured using the PushTool 3.0 system). Results: Complete wound closure was achieved in 3 patients over a period of up to 40 days. Two patients were discharged due to hospitalization for other reasons. One patient discontinued treatment due to dissatisfaction with the procedure. Two patients are still receiving treatment. In all cases, except one (with little change), we observed statistically significant reductions in wound surface area and PT values ​​(-49% and -4pt, respectively, P<0.05). The mean treatment time was 35.1 ± 17.5 days. Post-treatment TcPO2 increased from 29.1 mmHg ± 9. to 49.5 mmHg ± 6.7.

[0163] Now for reference Figures 4A-13D These are examples of applications of the invention in treating chronic wounds in subjects (selected from Table A) before, during, and after treatment. Subjects with diabetic foot ulcers or venous leg ulcers are treated according to the invention to achieve wound healing, as described in Example 1 and listed in Table A.

[0164] Figures 4A-4D The images are of a venous leg ulcer in an 84-year-old female subject who had a wound that had persisted for 12 months prior to the start of treatment, according to some applications of the present invention. Figures 4A-4D The image shows the wound before treatment and during subsequent treatment.

[0165] Figure 4A The wound at time 0 before treatment was applied is shown.

[0166] Figure 4B The invention demonstrates partial healing of the wound five weeks after the start of treatment in some applications.

[0167] Figure 4C The invention demonstrates additional healing of the wound from 7 weeks after the start of treatment in some applications.

[0168] Figure 4D The invention demonstrates complete wound closure 11 weeks after the start of treatment in some applications. Figure 4D The wound was shown to have completely closed from 4.8 cm² to 0.0 cm².

[0169] Figures 5A-5D Images of diabetic foot ulcers in a 68-year-old female subject who had a wound that had persisted for 3 months prior to the start of treatment, according to some applications of the present invention. Figures 5A-5D The image shows the wound before treatment and during subsequent treatment.

[0170] Figure 5A The image shows the wound at time 0 before treatment was applied.

[0171] Figure 5B The invention demonstrates partial healing of the wound as of 4 weeks from the start of treatment in some applications.

[0172] Figure 5C The invention demonstrates additional healing of the wound from 8 weeks after the start of treatment in some applications.

[0173] Figure 5D The invention demonstrates complete wound closure 20 weeks after the start of treatment in some applications. Figure 5D The wound was shown to be completely closed, ranging from 1.05 cm² to 0.0 cm².

[0174] Figures 6A-6D The images are of a venous leg ulcer in an 89-year-old female subject who had a wound that had persisted for 4 months prior to the start of treatment, according to some applications of the present invention. Figures 6A-6D The image shows the wound before treatment and during subsequent treatment.

[0175] Figure 6A The wound at time 0 before treatment was applied is shown.

[0176] Figure 6B The invention demonstrates partial healing of the wound from 2 weeks after the start of treatment in some applications.

[0177] Figure 6C The invention demonstrates additional healing of the wound from 8 weeks after the start of treatment in some applications.

[0178] Figure 6D The invention demonstrates complete wound closure 15 weeks after the start of treatment in some applications. Figure 6D The wound was shown to have completely closed from 21.22 cm² to 0.0 cm².

[0179] Figures 7A-7D The image shows a venous leg ulcer in a 92-year-old female subject who had suffered from a wound that had persisted for 17 months prior to the commencement of treatment according to some applications of the present invention. Figures 7A-7D The image shows the wound before treatment and during subsequent treatment.

[0180] Figure 7A The wound at time 0 before treatment was applied is shown.

[0181] Figure 7B The invention demonstrates partial healing of the wound as of 3 weeks from the start of treatment in some applications.

[0182] Figure 7C The invention demonstrates additional healing of the wound from 8 weeks after the start of treatment in some applications.

[0183] Figure 7D The invention demonstrates complete wound closure 10 weeks after the start of treatment in some applications. Figure 7D The wound was shown to have completely closed from 14.67 cm² to 0.0 cm².

[0184] Figures 8A-8D The images are of a 77-year-old female subject with diabetic foot ulcers who had a wound that had persisted for 12 months prior to the start of treatment, according to some applications of the present invention. Figures 8A-8D The image shows the wound before treatment and during subsequent treatment.

[0185] Figure 8A The image shows a wound before the start of a treatment procedure, according to some applications of the present invention.

[0186] Figure 8B The invention demonstrates partial healing of wounds after previous treatment steps and before treatment is restarted, according to some applications of the invention.

[0187] Figure 8C The invention demonstrates partial healing of the wound 6 weeks after the resumption of treatment, according to some applications of the invention.

[0188] Figure 8D The invention demonstrates complete wound closure nine weeks after the resumption of treatment, according to some applications of the invention. Figure 8D The wound was shown to have completely closed from 1.23 cm² to 0.0 cm².

[0189] Figures 9A-9D According to some applications of the present invention, the patient had a wound that had persisted for 12 months prior to the start of treatment. Figures 8A-8D Images of additional diabetic foot ulcers in a 77-year-old female subject. Figures 9A-9D The image shows the wound before treatment and during subsequent treatment.

[0190] Figure 9A The image shows a wound before the start of a treatment procedure, according to some applications of the present invention.

[0191] Figure 9B The invention demonstrates partial healing of wounds after previous treatment steps and before treatment is restarted, according to some applications of the invention.

[0192] Figure 9C The invention demonstrates partial healing of the wound 6 weeks after the resumption of treatment, according to some applications of the invention.

[0193] Figure 9D The invention demonstrates complete wound closure nine weeks after restarting treatment in some applications. Figure 9D The wound was shown to have completely closed from 0.47 cm² to 0.0 cm².

[0194] Figures 10A-10D The images are of bedsores in a 92-year-old female subject who had a wound that had persisted for 3 months prior to the start of treatment, according to some applications of the present invention. Figures 10A-10D It shows the wound before and during subsequent treatment.

[0195] Figure 10A The wound at time 0 before treatment was applied is shown.

[0196] Figure 10B The invention demonstrates partial healing of the wound as of 3 weeks from the start of treatment in some applications.

[0197] Figure 10C The invention demonstrates additional healing of the wound 12 weeks after the start of treatment in some applications.

[0198] Figure 10D The invention demonstrates complete wound closure 16 weeks after the start of treatment in some applications. Figure 10D The wound was shown to have completely closed from 6.14 cm² to 0.0 cm².

[0199] Figures 11A-11D The images are of a diabetic foot ulcer in an 86-year-old male subject who had a wound that had persisted for 12 months prior to the start of treatment, according to some applications of the present invention. Figures 11A-11D It shows the wound before and during subsequent treatment.

[0200] Figure 11A The image shows the wound at time 0 before treatment was applied.

[0201] Figure 11B The invention demonstrates partial healing of the wound as of 4 weeks from the start of treatment in some applications.

[0202] Figure 11C The invention demonstrates additional healing of the wound 12 weeks after the start of treatment in some applications.

[0203] Figure 11D The invention demonstrates further wound closure 20 weeks after the start of treatment in some applications. Figure 11D The wound closure rate was shown to be from 6.07 cm² to 0.96 cm² (84% closure).

[0204] Figures 12A-12D These are images of two diabetic foot ulcers in a 74-year-old female subject who had a wound that had persisted for 12 months prior to the start of treatment, according to some applications of the present invention. Figure 12A -- Figure 12D It shows the wound before and during subsequent treatment.

[0205] Figure 12A The image shows the wound at time 0 before treatment was applied.

[0206] Figure 12B The invention demonstrates partial healing of the wound five weeks after the start of treatment in some applications.

[0207] Figure 12C The illustration shows the complete closure of one wound (indicated by arrows) and additional healing of another wound 10 weeks after the start of treatment, according to some applications of the invention.

[0208] Figure 12D The image shows complete closure of two wounds 18 weeks after the start of treatment, according to some applications of the invention (indicated by arrows). Figure 12D The complete closure of two wounds, measuring 1.35 cm² to 0.0 cm² and 1.01 cm² to 0.0 cm², is shown.

[0209] Figures 13A-13D The images are of a 63-year-old male subject with diabetic foot ulcers who had a wound that had persisted for 6 months prior to the start of treatment, according to some applications of the present invention. Figures 13A-12D It shows the wound before and during subsequent treatment.

[0210] Figure 13A The image shows the wound at time 0 before treatment was applied.

[0211] Figure 13B The invention demonstrates partial healing of the wound from 2 weeks after the start of treatment in some applications.

[0212] Figure 13C The invention demonstrates additional healing of the wound starting 5 weeks after the start of treatment in some applications.

[0213] Figure 13D The invention demonstrates complete wound closure 10 weeks after the start of treatment in some applications. Figure 13D The wound was shown to be completely closed, ranging from 1.05 cm² to 0.0 cm².

[0214] Now for reference Figure 14 This is a schematic diagram of the configuration of a device for applying electrical stimulation therapy according to some applications of the invention, which is used with various items used by the subject to improve oxygen perfusion in the subject. Below are examples of possible electrode placements on electrode assembly articles (e.g., wearable and / or grippable articles) away from the wound. For example, electrodes are placed in wearable articles away from the wound, such as clothing, clothing accessories, shoes, wristbands, and the like. Figure 14 A schematic diagram of an article including electrodes and an electrical signal generator for wound treatment is shown. A headwear article 700 (e.g., a brimmed hat, a brimless hat, or the like) may have an electrode assembly incorporated 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, close to the skin of the subject's temples. The assembly includes electrical leads 706 and an electrical signal generator 702. The electrical leads 706 are embedded in the structure of the headwear article 700 and are electrically connected at one end to the two electrodes 704 and 708, while the electrical signal generator 702 is electrically connected at the other end of the electrical leads 706. Fixing elements (e.g., the headband of the headwear article 700) securely attach the electrodes 704 and 708 to the subject's skin. The advantage of incorporating the electrical signal generator 702 and the electrode assembly into the headwear article 700 is that treatment can be administered to the patient while performing other tasks, such as walking.

[0215] The eyeglass frame 710 may have an electrode assembly incorporated 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 to the skin behind the subject's ear. This assembly includes electrical leads 718 and an electrical signal generator 712. The electrical leads 718 are embedded in the structure of the eyeglass frame 710 and are electrically connected at one end to the two electrodes 714 and 716, while the electrical signal generator 712 is electrically connected at the other end of the electrical leads 718. The electrical signal generator 712 may be embedded in one arm of the eyeglass frame 710. Fixation elements, such as those in the arms of the eyeglass frame 710, securely connect the electrodes 714 and 716 to the subject's skin. The advantage of incorporating the electrical signal generator 712 and the electrode assembly into the eyeglass frame 710 is that treatment can be administered to the patient while performing other tasks, such as reading.

[0216] The watch 720 may have an electrode assembly incorporated into its wristband, such as electrodes 724 and 726 adjacent to the subject's wrist skin on the inner surface of the wristband. This assembly includes an electrical lead signal generator 722, which is embedded in the wristband and electrically connected at one end of each lead to the two electrodes 724 and 726, with the signal generator 722 electrically connected at the other end of the lead. The signal generator 722 may be embedded in the wristband or the watch itself. Fixing elements (such as the wristband of the watch 720) securely connect the electrodes 724 and 726 to the subject's skin. The advantage of incorporating the signal generator 722 and the electrode assembly into the watch 720 is that treatment can be administered to the patient while performing other tasks.

[0217] The T-shirt 730 may have an electrode assembly incorporated into the arm of the T-shirt 730, such as electrodes 734 and 736 on the inner surface of the arm adjacent to the skin of the subject's upper arm. This assembly includes electrical leads and an electrical signal generator 732. The electrical leads are embedded in the arm and electrically connected at one end of each lead to the two electrodes 734 and 736, and the electrical signal generator 732 is electrically connected at the other end of the leads. The electrical signal generator 732 may be embedded in the arm of the T-shirt 730. Fixation elements (such as the arm of the T-shirt 730) securely connect the electrodes 734 and 736 to the subject's skin. The advantage of incorporating the electrical signal generator 732 and the electrode assembly into the T-shirt 730 is that treatment of the patient can be performed while performing other tasks.

[0218] The barbell 740 may have an electrode assembly incorporated into the bar of the barbell 740, such as electrodes 744 and 746 located on the outer surface of the bar adjacent to the skin of the subject's hand gripping the bar. This assembly includes electrical leads and an electrical signal generator 742, the leads being embedded in the bar and electrically connected at one end of each lead to the two electrodes 744 and 746, with the electrical signal generator 742 electrically connected at the other end of the lead. The electrical signal generator 742 may be embedded in the bar of the barbell 740 or a weight. Fixing elements (e.g., the subject's hand) securely connect the electrodes 744 and 746 to the subject's skin. The advantage of incorporating the electrical signal generator and electrode assembly into the barbell 740 is that the patient can perform fitness training while receiving treatment.

[0219] The broom 750 may have an electrode assembly incorporated into the handle of the broom 750, such as electrodes 754 and 756 located on the outer surface of the handle adjacent to the skin of a subject's hand holding the handle. This assembly includes electrical leads and an electrical signal generator 752, the leads being embedded in the handle and electrically connected at one end of each lead to the two electrodes 754 and 756, the electrical signal generator 752 being electrically connected at the other end of the leads. The electrical signal generator 752 may be embedded in the handle of the broom 750. A retaining element (e.g., the subject's hand) securely connects the electrodes 754 and 756 to the subject's skin. The advantage of incorporating the electrical signal generator 752 and the electrode assembly into the broom 750 is that treatment can be administered to the patient while performing other tasks (e.g., cleaning).

[0220] Optionally, the electrode assembly is placed in a medical bandage, adhesive bandage, or the like. For example, the electrode is a patch electrode adhered to the patient's skin, and an electrical signal generator is integrated into the patch. In this example, the fixing element is the adhesive of the patch. For example, the electrical signal generator and electrode are integrated into an elastic bandage, such as an elastic bandage for sports injuries, and the elastic bandage is applied to the patient's joint so that the electrode at one end of the adhesive bandage contacts the patient's skin, and the adhesive bandage is a fixing element containing 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, and the like. Optionally, these articles are incorporated into wearable articles, such as clothing, underwear, clothing accessories, and the like.

[0221] The two or more electrodes described herein are connected via a substrate of an article, such as the substrate of an electrode assembly. The substrate may have a surface area greater than 1 x 10⁻⁶. -7 Nm 2 The stiffness, such as that of cotton, linen, and the like. The substrate can have a stiffness greater than 10 × 10. - 7 Nm 2The stiffness, for example, that of a patch electrode comprising two or more electrode elements, an elastic bandage, and the like. Optionally, the substrate may have a stiffness greater than 100x10. -7 Nm 2 The stiffness, such as that of a headband, watch strap, hat band, and the like. Optionally, the substrate may have a stiffness greater than 1 x 10⁻⁶. -4 Nm 2 The stiffness, such as that of a barbell bar, broom handle, and the like. Optionally, the substrate can have a stiffness greater than 1x10. -9 Nm 2 The stiffness of the substrate can be, optionally, between 1x10. -9 Nm 2 and 1x10 9 Nm 2 The stiffness between them.

[0222] Some applications of this invention may be systems, apparatus, methods, and / or computer program products. Computer program products may include computer-readable storage media (or mediums) having computer-readable program instructions thereon for causing a processor to perform aspects of the invention.

[0223] Computer-readable storage media can be tangible devices capable of retaining and storing instructions for use by an instruction execution device. Computer-readable storage media can be, for example, but not limited to, electronic storage devices, magnetic storage devices, optical storage devices, electromagnetic storage devices, semiconductor storage devices, or any suitable combination of the foregoing. A non-exhaustive list of more specific examples of computer-readable storage media includes the following: portable computer floppy disks, 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 optical disc read-only memory (CD-ROM), digital versatile disk (DVD), memory sticks, floppy disks, mechanical encoding devices (e.g., punched cards or raised structures in recesses on which instructions are recorded), and any suitable combination of the foregoing. As used herein, computer-readable storage media should not be construed as transient signals themselves, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through waveguides or other transmission media (e.g., light pulses through fiber optic cables), or electrical signals transmitted through wires.

[0224] The computer-readable program instructions described herein can be downloaded from a computer-readable storage medium to a suitable computing / processing device, or downloaded via a network (e.g., the Internet, a local area network, a wide area network, and / or a wireless network) to an external computer or external storage device. This network may include copper transmission cables, optical fiber transmission, wireless transmission, 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 them to a computer-readable storage medium within the suitable computing / processing device.

[0225] Computer-readable program instructions for performing the operations of this invention may be assembly instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, state setting data, or source code or object code written in any combination of one or more programming languages, including object-oriented programming languages ​​such as Java, Smalltalk, C++, or similar languages, and conventional procedural programming languages ​​such as the "C" programming language or similar languages. The computer-readable program instructions may be executed entirely on the user's computer, partially on the user's computer, as a standalone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In the latter case, 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 may be connected to an external computer (e.g., via the Internet provided by an Internet service provider). In some embodiments, electronic circuitry including, for example, programmable logic circuitry, a field-programmable gate array (FPGA), or a programmable logic array (PLA) may execute computer-readable program instructions by personalizing the electronic circuitry with state information from the computer-readable program instructions to perform various aspects of the invention.

[0226] This document describes aspects of the invention with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the invention. It should 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 using computer-readable program instructions.

[0227] These computer-readable program instructions may be provided to a processor of a general-purpose computer, a special-purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions / actions specified in the flowchart and / or one or more block diagram blocks. These computer-readable program instructions may also be stored in a computer-readable storage medium that can direct a computer, programmable data processing apparatus, and / or other device to operate in a particular manner, such that the computer-readable storage medium storing the instructions includes an article of manufacture comprising instructions for implementing aspects of the functions / actions specified in the flowchart and / or one or more block diagram blocks.

[0228] Computer-readable program instructions may also be loaded onto a computer, other programmable data processing apparatus or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer-implemented process, such that the instructions, which execute on the computer, other programmable apparatus or other device, implement the functions / actions specified in the flowchart and / or one or more block diagram blocks.

[0229] The flowcharts and block diagrams in the accompanying drawings 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 a flowchart or block diagram may represent a portion of a module, segment, or instruction, comprising one or more executable instructions for implementing one or more specific logical functions. In some alternative implementations, the functions marked in the blocks may not appear in the order indicated in the drawings. For example, two blocks shown consecutively may actually be executed substantially simultaneously, or these blocks may sometimes be executed in reverse order, depending on the functions involved. It should also be noted that each block illustrated in the block diagrams and / or flowcharts, and combinations of blocks illustrated in the block diagrams and / or flowcharts, may be implemented by a dedicated hardware-based system that performs a specific function or action or executes a combination of dedicated hardware and computer instructions.

[0230] Various embodiments of the invention have been described for illustrative purposes, but are not intended to be exhaustive or limiting. 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 terminology used herein has been chosen to best explain the principles of the embodiments, practical applications of techniques found in the market, or improvements to the technology, or to enable others skilled in the art to understand the embodiments disclosed herein.

[0231] Those skilled in the art will understand that this invention is not limited to what has been specifically shown and described above. Rather, the scope of this invention includes combinations and sub-combinations of the various features described above, as well as variations and modifications thereof that are not part of the prior art and will come to the attention of those skilled in the art upon reading the foregoing description.

Claims

1. An apparatus, the apparatus comprising: An electrical stimulator, 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 via the at least one electrode, wherein the electrical signal comprises a plurality of series of pulses; as well as A control processor is configured to continuously, randomly, and independently change the energy value of each pulse and at least one of the following signal parameters: (i) The duration of each pulse, and (ii) The time interval between each pair of pulses, The plurality of pulses in a series include: At least one first series of pulses, comprising at least 250 positive pulses and at least 250 negative pulses per second, the pulses having (i) an energy level of 0.5-13 microjoules, (ii) a pulse duration between 0.25 ms and 0.5 ms and (iii) an average energy of 1-4 microjoules; and At least one second series of pulses, comprising at least 100 positive pulses and at least 100 negative pulses per second, the pulses having (i) an energy level of 0.005-7 microjoules, (ii) a pulse duration between 0.05 ms and 0.25 ms and (iii) an average energy of 0.02-1 microjoules.

2. The apparatus according to claim 1, wherein the electrical signal comprises an equal number of positive and negative pulses.

3. The apparatus according to any one of claims 1-2, wherein the total charge delivered to the subject by the electrical signal is equal to zero.

4. The apparatus of claim 1, wherein the control processor is configured to continuously and randomly change all of the signal parameters.

5. The apparatus of claim 1, wherein the series of pulses comprises discrete pulses.

6. The apparatus of claim 1, wherein the signal has a waveform selected from the group consisting of a sine wave, a square wave, and a triangular wave.

7. The apparatus of claim 1, wherein the control processor is configured to repeat the pattern of the signal parameters no more than once within a predetermined duration.

8. The apparatus of claim 7, wherein the predetermined duration is 0.2 seconds.

9. The apparatus according to claim 1, wherein the electrical signal is a random AC signal.

10. The apparatus of claim 1, wherein the at least one electrode comprises at least two electrodes.

11. The device of claim 1, wherein the at least one electrode is positioned to contact the subject's intact skin.

12. The apparatus of claim 1, wherein the at least one electrode is positioned near a wound in the skin in contact with the skin of the subject.

13. The device of claim 1, wherein the at least one electrode comprises at least two electrodes, and wherein the at least two electrodes are configured to be placed on two opposite sides of a wound in the skin.

14. The apparatus of claim 1, wherein the at least one electrode is positioned to contact the subject's skin at a location suffering from oxygenation impairment.

15. The device of claim 1, wherein the at least one electrode is positioned upstream of an afferent axon leading to the spinal cord.

16. The apparatus of claim 1, wherein the control processor is configured to mix the first series of pulses and one or more of the second series of pulses at random intervals between the pulses.

17. The apparatus of claim 1, wherein the plurality of series pulses further comprises at least one third series pulse, the at least one third series pulse comprising at least 150 positive pulses and at least 150 negative pulses per second, the pulses having (i) an energy level of 1-20 microjoules, (ii) a pulse duration between 0.5 ms and 1 ms and (iii) an average energy of 2-10 microjoules.

18. The apparatus of claim 1, wherein the plurality of series pulses further comprises at least one third series pulse, the at least one third series pulse comprising at least 30 positive pulses and at least 30 negative pulses per second, the pulses having (i) an energy level of 2-40 microjoules, (ii) a pulse duration between 1 ms and 2.5 ms and (iii) an average energy of 4-20 microjoules.

19. The apparatus of claim 1, wherein the plurality of series pulses further comprises at least one third series pulse, the at least one third series pulse comprising at least 0.5 positive pulses and at least 0.5 negative pulses per second, the pulses having (i) an energy level of 10-250 microjoules, (ii) a pulse duration between 2.5 ms and 10 ms and (iii) an average energy of 20-200 microjoules.

20. A computer program product comprising a non-transitory computer-readable storage medium having program instructions embedded therein, the program instructions being executable by at least one hardware processor to: An operating signal generator is used to provide an electrical signal for application to the subject via at least one electrode in contact with the subject's skin, wherein the electrical signal comprises a plurality of series of pulses; and The energy value of each pulse and at least one of the following signal parameters are changed continuously, randomly, and independently: (i) the duration of each of the pulses, and (ii) The time interval between each pair of pulses, The plurality of pulses in a series include: At least one first series of pulses, comprising at least 250 positive pulses and at least 250 negative pulses per second, the pulses having (i) an energy level of 0.5-13 microjoules, (ii) a pulse duration between 0.25 ms and 0.5 ms and (iii) an average energy of 1-4 microjoules; and At least one second series of pulses, comprising at least 100 positive pulses and at least 100 negative pulses per second, the pulses having (i) an energy level of 0.005-7 microjoules, (ii) a pulse duration between 0.05 ms and 0.25 ms and (iii) an average energy of 0.02-1 microjoules.

21. The computer program product of claim 20, wherein the electrical signal comprises an equal number of positive and negative pulses.

22. The computer program product according to any one of claims 20-21, wherein the total charge delivered to the subject by the electrical signal is equal to zero.

23. The computer program product of claim 20, wherein the program instructions are executable to continuously and randomly change all of the signal parameters.

24. The computer program product of claim 20, wherein the series of pulses comprises discrete pulses.

25. The computer program product of claim 20, wherein the signal has a waveform selected from the group consisting of sine waves, square waves, and triangular waves.

26. The computer program product of claim 20, wherein the program instructions are executable to repeat the pattern of the signal parameters no more than once over a predetermined duration.

27. The computer program product of claim 26, wherein the predetermined duration is 0.2 seconds.

28. The computer program product of claim 20, wherein the electrical signal is a random AC signal.

29. The computer program product of claim 20, wherein the at least one electrode comprises at least two electrodes.

30. The computer program product of claim 20, wherein the at least one electrode is positioned to contact the subject's full skin.

31. The computer program product of claim 20, wherein the at least one electrode is positioned near a wound in the skin in contact with the skin of the subject.

32. The computer program product of claim 20, wherein the at least one electrode comprises at least two electrodes, and wherein the at least two electrodes are configured to be placed on two opposite sides of a wound in the skin.

33. The computer program product of claim 20, wherein the at least one electrode is positioned to contact the skin of the subject at a location suffering from oxygenation impairment.

34. The computer program product of claim 20, wherein the at least one electrode is placed upstream of an afferent axon leading to the spinal cord.

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