DEVICE FOR WOUND CARE

Abstract

The present invention relates to electro-therapy of wounds. Specifically, a device for applying electro-therapy to a wound is provided. The device of the invention is useful for treating any kind of wound, and is especially useful for facilitating the healing of chronic wounds.

Claims

1. A device for applying electro-therapy to a wound of a mammal, comprising at least two stimuli electrodes, at least two sense electrodes, the stimuli electrodes and the sense electrodes being configured to be electrically in contact with skin surrounding a wound, a control module, a voltage measurement circuit, the voltage measurement circuit being in connection with the sense electrodes and being configured to communicate with the control module, and a controlled voltage source being in connection with the stimuli electrodes and being configured to communicate with the control module; wherein the control module is configured to perform a frequency sweep via the at least two sense electrodes at a calibration voltage delivered by the controlled voltage source, receive one or more measured voltage drops from the voltage measurement circuit, the voltage drop(s) being measured with the sense electrodes; and adjust the voltage outputted from the controlled voltage source, based on the measured voltage drop(s).

2. The device according to claim 1, wherein the device further comprises a current measurement circuit, the current measurement circuit being in connection with the stimuli electrodes and being configured to communicate with the control module, and wherein the control module is further configured to receive one or more measured current levels from the current measurement circuit; and adjust the voltage outputted from the controlled voltage source, based on the measured voltage drop(s) and the measured current level(s).

3. The device according to claim 2, wherein the control module is further configured to calculate an impedance from one or more measured voltage drop(s) and one or more measured current level(s) and adjust the voltage output of the controlled voltage source to a level at which the voltage drop measured between the sense electrodes is in the range of 0. 05V to 1V per numerical Ohm of the calculated impedance.

4. The device according to claim 1, wherein the controlled voltage source is configured to output DC pulses having a frequency in the range of 50 to 500 kHz.

5. The device according to claim 1, wherein the voltage outputted from the controlled voltage source has a duty cycle in the range of 1-50%.

6. The device according to claim 1, wherein the device further comprises two supporting structures, wherein at least one of the stimuli electrodes and at least one of the sense electrodes are attached to each supporting structure.

7. The device according to claim 1, wherein on each supporting structure at least one of the stimuli electrodes has at least one sense electrode located within 5 to 50 mm of it.

8. The device according to claim 1, wherein at least one of the electrodes and/or, when present, at least one of the supporting structures may be one or more of cuttable by a sharp tool, foldable by hand, or tearable by hand.

9. The device according to claim 1, wherein the control module is further configured to adjust the voltage outputted from the controlled voltage source based on at least one further condition being a pre-defined distance.

10. The device according to claim 9, wherein the control module is further configured to regulate the voltage outputted from the controlled voltage source to a level at which the measured voltage drop is in the range of 30-350 mV per mm of pre-defined distance.

11. The device according to claim 1, wherein the average current outputted from the controlled voltage source is limited to the range of 1 to 10 mA.

12. The device according to claim 1, wherein the control module is further configured to increase the voltage outputted from the controlled voltage source from a first level to a second level.

13. The device according to claim 12, wherein the control module is further configured to increase the voltage outputted from the controlled voltage source gradually and/or stepwise from a first level to a second level.

14. The device according to claim 2, wherein the control module is further configured to wirelessly communicate to an external unit one or more measured voltage drop values and one or more of the measured current levels, and/or one or more impedance values calculated from one or more measured voltage drop values and one or more of the measured current levels.

15. The device according to claim 14, wherein the control module is further configured to receive instructions from the external unit via wireless communication, wherein the instructions regulate the voltage output and/or the current output of the device.

16. The device according to claim 1, wherein the control module is further configured to: receive an input regarding a size of the wound adjust the voltage outputted from the controlled voltage source, based on the size of the wound.

17. The device according to claim 16, wherein the control module is further configured to regulate the voltage outputted from the controlled voltage source to a level at which the measured voltage drop is in the range of 30-350 mV per mm.

18. The device according to claim 1, wherein the at least two sense electrodes and/or the at least two stimuli electrodes comprises a plurality of markers with a known dimension.

19. The device according to claim 1, wherein the control module is further configured to: apply the voltage outputted from the controlled voltage source in a first plurality of treatment cycles, wherein each treatment cycle comprises a treatment time period wherein the control module is configured to apply the voltage outputted from the controlled voltage source to the wound, and a down time period wherein the control module is configured to stop the voltage outputted from the controlled voltage source.

20. The device according to claim 19, wherein the control module is further configured to: apply the voltage outputted from the controlled voltage source to the wound in a first plurality of treatment cycles and subsequently apply the voltage outputted from the controlled voltage source to the wound in a second plurality of treatment cycles, wherein a polarity of the voltage outputted from the controlled voltage source is reversed from the first plurality of treatment cycles to the second plurality of treatment cycles.

21. The device according to claim 19, wherein before each treatment cycle the control module may be further configured to: perform a frequency sweep at a calibration voltage delivered by the controlled voltage source to determine an impedance of the wound, receive one or more measured voltage drops from the voltage measurement circuit, the voltage drop(s) being measured with the sense electrodes; and adjust the voltage outputted from the controlled voltage source, based on the measured voltage drop(s).

22. A method for applying electro-therapy to a wound of a mammal, comprising applying a device of claim 1 to the mammal; performing a frequency sweep via the at least two sense electrodes at a calibration voltage delivered by the controlled voltage source, receiving one or more measured voltage drops from the voltage measurement circuit, the voltage drop(s) being measured with the sense electrodes; and adjusting the voltage outputted from the controlled voltage source, based on the measured voltage drop(s).

Description

BRIEF DESCRIPTION OF THE FIGURES

[0106] In the following, embodiments of the present invention will be described with reference to the enclosed non-binding drawings.

[0107] FIG. 1 shows an embodiment of the device according to the present disclosure, wherein the electrodes of the device are arranged on the skin surrounding a wound;

[0108] FIG. 2 shows an exploded view of a patch comprising the supporting structure and the electrodes according to the present disclosure;

[0109] FIG. 3 shows the patch of FIG. 2 in an assembled condition;

[0110] FIG. 4 shows a planar cross-section of the patch of FIGS. 2 and 3, when applied to skin;

[0111] FIG. 5 shows representative light microscope images of scratch assays in monolayers of HaCaT cells exposed to electrical stimulation over 48 hours;

[0112] FIG. 6 shows representative light microscope images of scratch assays in monolayers of HaCaT cells exposed to electrical stimulation over 48 hours;

[0113] FIG. 7 shows a graph of cell migration ability of HaCaT cells exposed to electrical stimulation over 48 hours.

DETAILED DESCRIPTION OF THE INVENTION

[0114] The present invention will be described below relative to specific embodiments. Those skilled in the art will appreciate that the present invention may be implemented in a number of different applications and embodiments and is not specifically limited in its application to the particular embodiment depicted herein.

[0115] In general, the device of the invention is intended to be portable and fastened to a mammal or patient when in use, such that the mammal or patient may move about while electro-therapy is ongoing. In FIG. 1 is shown an example of how the device of the present disclosure may be installed at the wound site of a patient. A central unit 101 comprising a control module 101a, a voltage measurement circuit 101b, and a current measurement circuit 101c, is arranged close to a wound 107 and is connected via a cable 103 to two stimuli electrodes 104a and 104b and two sense electrodes 105a and 105b. The cable 103 splits into two cables 103a and 103b, each connected to a sense electrode 105a or 105b and a stimuli electrode 104a and 104b and optionally supporting structures 106a and 106b. The central unit 101 may optionally be controlled from at least a button 102 on the central unit 101. The electrode pairs 104a and 105a, and 104b and 105b are each respectively connected to supporting structures 106a and 106b arranged on opposite sides of the wound 107, the sense electrodes 105a and 105b being closest to the wound 107. A sense electrode 105b, a stimuli electrode 104b and a supporting structure 106b forms a patch 100p. In this figure, the supporting structures 106a and 106b are illustrated as being transparent, so as to show the configuration of the electrodes. In operation, electricity is outputted by the central unit 101 and conducted via the cables 103, 103a, and 103b, through the stimuli electrode 104a and 104b, and across the wound 107. The voltage drop across the wound 107 is measured via the sense electrodes 105a and 105b and the central unit 101 by the voltage measurement circuit. The control module 101a may calculate a suitable output voltage based on the measurements of voltage and current. A distance, such as the diameter of the wound, may be entered using the button 102, or by a wireless interface (not shown). The entered value can be used by the central unit 101 to calculate suitable voltage output levels.

[0116] FIG. 2 shows an embodiment of the invention, wherein a supporting structure 106 and electrodes 104 and 105 comprise components of a patch 111, wherein the patch 111 is shown in an exploded view. A cable 103 comprises two wires 109a and 109b, that are unshielded. When the patch 111 is assembled, the two wires 109a and 109b are respectively in electrical contact with a stimuli electrode 104 and a sense electrode 105 and are sandwiched between the supporting structure 106 and the electrodes 104 and 105. A conductive gel layer 110 may optionally be located between each respective electrode 104 and 105 and the gel layer 110 may optionally be covered by a removable film 108.

[0117] FIG. 3 shows the patch of FIG. 2 in an assembled form. The removable film 108 optionally has a notch 108a to enable easy removal of the film. This embodiment may optionally be cut, for instance, across the width of the patch, such that the length of the patch is reduced. Ideally, the length of the patch is cut, so that it fits roughly with the dimensions of skin surrounding the wound to be treated.

[0118] FIG. 4 shows a planar cross-section of the patch of FIGS. 2 and 3 in an assembled form, where the removable film 108 has been removed, and the conductive gel layer 110 is contacting the surface of the skin 111 surrounding the wound (not shown).

[0119] FIG. 5 shows representative light microscope images of the scratch assay described in Example 2 in which monolayer HaCaT cells were exposed to electrical stimulation under different conditions over 48 hours. The different conditions tested were A, pulse frequency of 0 kHz, duty cycle of 100% and electric field of 200 mV/mm; B, pulse frequency of 100 kHz, duty cycle of 2% and electric field of 200 mV/mm; C, pulse frequency of 100 kHz, duty cycle of 4% and electric field of 200 mV/mm; and D, pulse frequency of 100 kHz, duty cycle of 10% and electric field of 150 mV/mm. The control ∅ represents untreated, i.e. unstimulated, cells. Each condition was tested in triplicates and the images shown in FIG. 5 represents a representative image of the general cell behaviour observed for each condition. Images were acquired after 0 hours, 12 hours, 24 hours, 36 hours and 48 hours of electrostimulation. For all conditions, the electrical stimulation was orthogonal (top to bottom) to the scratches, the scratches being present in the middle of the image. For the control group ∅, the cell-free area, i.e. the scratch, in the middle of the image has the same size over the entire 48 hours. For conditions C and D, the cellfree area in the middle of the images shows only slight reduction in size, i.e. wound healing under these conditions were slow and less efficient. For condition A, a visible change in the size of the cell-free area was observed over the course of treatment. Cells treated with condition B by far showed the largest reduction in the size of the cell-free area, thus representing the best condition for wound healing. The healing properties of conditions A and B are shown more clearly in FIG. 6.

[0120] FIG. 6 shows representative light microscope images of the scratch assay described in Example 2 with monolayer HaCaT cells exposed to electrical stimulation under stimulated conditions (A and B) and unstimulated condition (∅) over 48 hours. The scratch area or cell-free area represents the wound and is seen in the middle of the image as a darker area. During electrical stimulation, the size of the cell-free area is reduced in the treated cells (A and B), whereas for the unstimulated cells (∅) this area remains unchanged in size. Furthermore, the cells treated under condition B (pulse frequency of 100 kHz, duty cycle of 2% and electric field of 200 mV/mm) display the fastest and most efficient wound healing as shown from the substantial reduction in the cell-free area which is visible already after 24 hours. After 48 hours of treatment under condition B, the cell-free area is almost completely reduced. Condition A displays a slower and less pronounced wound healing.

[0121] FIG. 7 shows a graph of the cell migration ability of HaCaT cells treated with conditions A (solid line with squares) and B (solid line with triangles) and for untreated cells 0 (solid line with circles). The graph depicts the change in cell-free area over time, which is calculated using the Image J software, an open-source image processing program used to assess wound closure by tracing the wound perimeter and calculating percentage closure. The width of the scratches at 0 hours is 100%. As seen in FIG. 7, the change in cell-free area over time, i.e. rate of wound healing, is highest for HaCaT cells treated under condition B, which is evident from the approximately 50% change in cell-free area at 48 hours.

EXAMPLES

[0122] Example 1: Demonstration of low impedance and no pain at high AC frequencies in a simulated wound.

[0123] Two electrodes were arranged on dry skin on a person's arm, the distance between the electrodes being 50 mm. The electrodes were connected in series to a signal generator with a 50 ohm output impedance. A 100 ohms resistor was inserted in series into the circuit as a measurement resistor for current measurements. A simulated wound was made on the arm by applying a thick layer of Cefar Electrogel to the skin between the electrodes. The Cefar Electrogel was applied on the skin to form a roughly circular gel layer, the gel layer being about 5 mm from each of the electrode's edges. Electrical measurements were made by connecting an oscillometer in series, the first and the second lead of the oscillometer being respectively connected right before and after the 100 ohms resistor. Briefly, the measurements showed that the AC resistance of the simulated wound is strongly frequency dependent and ranges from about 20 kOhm at 1 Hz to <150 Ohm in the range 100 kHz to 1 MHz, and that it has a DC resistance which is voltage dependent and is in the range of 40 kOhm (at 20V) to 263 kOhm (at 1V). After several hours of AC measurements, there is no irritation to the skin, while the DC (non-pulsed) measurements, which took only 10 minutes, and which measured currents below 0.5 mA, nevertheless resulted in red and irritated skin under the positive electrode, as well as some discomfort in the skin already at DC voltage/currents above 15V/150 μA. At AC frequencies of 0.8 to 3 kHz, direct sensation of pain could be felt. Below in table 1 are given impedance values of the simulated wound at different AC frequencies. The table also shows the AC frequencies at which a direct sense of pain is felt.

TABLE-US-00001 TABLE 1 Impedance in AC Frequency model wound [kHz] (ohms) Pain 0.001 19850 NO 0.01 16517 NO 0.02 15235 NO 0.03 12350 NO 0.04 9850 NO 0.05 8941 NO 0.06 8183 NO 0.07 7850 NO 0.08 7257 NO 0.09 6517 NO 0.1 6302 NO 0.2 3696 NO 0.3 2667 NO 0.4 1978 NO 0.5 1719 NO 0.6 1463 NO 0.7 1201 NO 0.8 1116 YES 0.9 1013 YES 1 986 YES 2 554 YES 3 425 YES 4 360 NO 5 326 NO 6 300 NO 7 281 NO 8 263 NO 9 260 NO 10 247 NO 20 205 NO 30 192 NO 40 181 NO 50 173 NO 60 166 NO 70 163 NO 80 163 NO 90 159 NO 100 155 NO 200 148 NO 300 148 NO 400 144 NO 500 144 NO 600 144 NO 700 144 NO 800 144 NO 900 144 NO 1000 144 NO 2000 153 NO 3000 190 NO 4000 263 NO 5000 192 NO 6000 218 NO 7000 250 NO 8000 200 NO 9000 188 NO 10000 188 NO

[0124] Conclusion: levels of current and voltage suitable for electrotherapy may be provided painlessly to a simulated wound through the skin using an AC signal having a frequency of at least 10 kHz. Pulsed DC signals similar to the

[0125] AC signals are expected to generally behave in similar way and may therefore also be used in electrotherapy.

[0126] Example 2: In vitro studies on HaCaT cells stimulated electrically versus control

[0127] The Electrical Stimulation System Setup

[0128] For the basic principle of the electrical stimulation system, the protocol published by Song et al. in 2007 (doi:10.1038/nprot.2007.205) was used as a starting point. The key parts of the stimulation system included cell culture dishes with special structures, including cell culture chambers, salt bridges to transport the electrons, electrical stimulation devices to generate the electrical current, and scaffolding to hold everything in place. The purpose of this setup was to generate the target electric field in the cell culture environment. The protocol of Song et al. 2007 was adapted to accommodate the special requirements of the study, which included long duration of electrical stimulation, microscopic examination, etc.

[0129] Cell Culturing and Method of Scratch Assay

[0130] The HaCaT cells were cultivated in monolayers in thin chambers to avoid cell damage caused by excessive heating of the medium by the electric field. The cells were seeded in the middle of the custom-made petri dishes. Normally, the culture concentration of HaCaT cells is 1×10.sup.4/cm.sup.2. To make the cells confluent as quickly as possible in a limited space, the concentration of the cell suspension used for seeding was 95×10.sup.4/cm.sup.2. Viability of the cells under the provided experimental conditions were confirmed by trypan blue staining to be greater than 95%.

[0131] Normally, the cell-free area is generated by using a pipette tip to scratch a wound through the center of the Petri-dish, however, for the present experimental setup the use of tips led to issues with the edges of the scratches being irregular, the cells being easier to lift in layers around the edges and the cells at the edges of the scratches breaking. To circumvent these issues, a self-adhesive silicone tape was used instead of tips. The silicone tape was cut into strips of equal width (0.5-0.7 mm) and adhered to the cell culture area in advance. Once sufficient cell growth and cell adhesion was achieved, the tape was removed and satisfactory cell-free areas were generated.

[0132] The Effect of Electrical Stimulation on Cell Migration

[0133] To explore the effects of different modes of electrical stimulation on HaCaT cell migration, electrical signals with different parameters (Table 2) were applied to the monolayer of HaCaT cell culture. Stimulation (Conditions A, B, C, D) and no stimulation (control group ∅) was applied to a monolayer of HaCaT cell culture using Ag/AgCI electrodes connected via agar salt bridges, to prevent electrode products from entering cultures.

TABLE-US-00002 TABLE 2 Parameters tested on HaCaT cell culture systems Pulse frequency Electric field Condition (kHz) Duty cycle (%) (mV/mm) A 0 100 200 B 100 2 200 C 100 4 200 D 100 10 150

[0134] The scratches or cell-free area in the culture system were photographed at 0, 12, 24, 36 and 48 hours after the start of electrical stimulation. At each time point, three photos of each cell-free area were taken (FIG. 5) and the cell-free area was calculated by Image J software. The original microscope magnification was 40×.

[0135] The following formula was used to calculate the migration rate of each group of cells at different time points to evaluate the migration ability:

[00001]$\mathrm{Migration}\mathrm{Rate}=\frac{\mathrm{Cell}-\mathrm{free}\mathrm{area}\left(0H\right)-\mathrm{Cell}-\mathrm{free}\mathrm{area}\left(\mathrm{nH}\right)}{\mathrm{Cell}-\mathrm{free}\mathrm{area}\left(0H\right)}\times 100,n=12,24,36,48$

[0136] Compared with the control group (∅), the migration rate of the experimental groups (A, B) showed an increasing trend (FIGS. 6 and 7). HaCaT cells cultures exposed to the electrical stimulation generated by

[0137] Condition B (100 kHz, 2% duty cycle, 200 mV/mm) showed the most significant increase in migration ability, i.e. the fastest and most efficient wound healing. As seen from FIG. 6, the wound closed substantially after only 24 hours of electrical stimulation treatment and was almost completely closed by 48 hours of electrical stimulation treatment. As seen from FIG. 7, both conditions B and A markedly enhanced the rate of wound closure as compared to the control (∅). Furthermore, condition B significantly outperformed condition A (normal DC stimulation) in that condition B closed wounds roughly 50% faster (*p<0.05, **p<0.01, ***p<0.001).

[0138] Statistics

[0139] Results are presented as mean±standard error of mean (SEM). Each test conditions were performed three independent times (N=3) measured as triplicate or more (technical replicates, n≥3). Statistical analyses were performed using the GraphPad Prism Software (Version 8.0.2, El Camino Real, USA). Data sets were compared by the Kruskal-Wallis H test. α=0.05 was set as the maximum type I error rate. *<0.05, **<0.01, ***<0.001 were used to classify P values in comparisons with the control group.

[0140] Conclusions

[0141] The cell system described in this example meets the requirements of testing cell migration ability.

[0142] Electrical stimulation provided under conditions A and B showed a trend of improving the cell migration ability, with the changes in condition B, i.e. a pulse frequency of 100 kHz, a duty cycle of 2% and an electric field of 200 mV/mm, being the most significant.

[0143] Based on the in vitro studies presented above, it is evident that the electrical stimulation as provided in accordance with the present inventive concept provides superior wound healing properties. Furthermore, in accordance with the data presented in Example 1, it is believed that the electrical stimulation conditions tested herewith cause minimum adverse effects to the patient during the electrotherapy. Thus, it is believed that an optimum stimulation algorithm consisting of high frequency pulses of at least 50 kHz or 100 kHz with a low duty cycle (<10%), results in the highest possible electrical field (EF) strength across a wound at a minimum battery power consumption and with minimum power dissipation in the skin. This maximizes battery life, establishes the desired EF of 50-200 mV/mm across the wound and fully avoids discomfort, such as itching, skin reactions or muscle activation, associated with DC or lower frequency currents through skin.