WO2009144615A1

WO2009144615A1 - Moisture control within a multi-electrode patch for monitoring and electrical stimulation of wound healing

Info

Publication number: WO2009144615A1
Application number: PCT/IB2009/052063
Authority: WO
Inventors: Dirk J. Broer; Roel Penterman; Emiel Peeters; Ralph Kurt; David Halter; Murray F. Gillies; Hendrik De Koning
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2008-05-26
Filing date: 2009-05-18
Publication date: 2009-12-03

Abstract

The present invention provides a device for electrical treatment of a skin wound comprising a flexible substrate adapted for attaching to the skin wound and the surrounding skin, a matrix of electrodes, means for determining the presence of the wound and/or its perimeter and/or means for controlling a liquid load between the matrix (1) and the wound, and means for applying a voltage between the wound and the surrounding skin. The present invention further provides a method for electrical treatment of a skin wound comprising the following steps: placing a matrix of electrodes attached to a flexible substrate on top of the skin wound and the surrounding skin; determining the presence of the wound and/or its perimeter and/or controlling a liquid load between the matrix of electrodes and the wound; and applying a potential differential between particular electrodes, wherein the absorption or release of the liquid load is controlling to maintain optimum moisture content at and/or close to the wound.

Description

Moisture control within a multi-electrode patch for monitoring and electrical stimulation of wound healing

FIELD OF THE INVENTION

The present invention relates to moisture control with a multi-electrode patch for electrical stimulation and monitoring of wound healing and to a method for controlling moisture in the electrical treatment of a skin wound.

BACKGROUND OF THE INVENTION

Electrical stimulation (ES) of wound healing has been suggested as an adjunctive treatment for wound healing for many years. It involves the placement of electrodes in direct contact with, or in close proximity to, a skin wound thereby creating an electrical current or voltage that passes through either the wound or peripheral tissue.

This form of accelerated wound healing has been the subject of many clinical trials over recent years which have culminated in health insurance companies (such as

CIGNA) recognizing it as a genuine treatment and agreeing to compensate incurred treatment costs. The phenomenon of acceleration of electrical wound healing by electrical currents was reported 150 years ago by the German physiologist Emil Du Bois-Reymond.

Josef Penninger of the Austrian Institute of Molecular Biotechnology in Vienna and Min

Zhao of the University of Aberdeen, UK, have demonstrated that natural electric fields and currents in tissue play a vital role in orchestrating the wound-healing process by attracting repair cells to damaged areas. Researchers have also identified the genes that control the process (" 'Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN", Nature, vol 442, p 457, 27 JuI 2006).

While the effects of ES have been known for several decades it is only recently that the mechanism behind the effect is being revealed. This process has been termed electrotaxis and has been observed by several other authors. In particular a publication from

Huttenlocher (NEJM 356(3), 2007) clearly shows the movement of a cell under the influence of an electrical field. The movement is directed towards the cathode. Wound healing is a complex process with several distinguishable stadia (cf: Gurtner et al, Wound repair and regeneration, Nature Insight 453, 314-321 (2008)). In general it can be categorized into the following four healing phase conditions:

1. The necrotic condition refers to the wound healing phase condition where catabolic processes have been resulting in dead tissue.

2. The fibrinous slough or infection condition refers to the circumstance where the wound is in the inflammatory phase, where dead cellular debris fills the base of the wound with an off-white to yellow layer,

3. The granulation condition refers to the healing phase when the wound has reached the proliferative stage of healing and when the wound cavity is slowly filled with the "repair-material" of the body which consists of fϊbro -vascular tissue and is called granulation.

4. The epithelialisation condition describes the wound healing phase wherein the keratinocytes (epidermal cells) are dividing and gradually crossing the wound surface from the margins towards the opposite side. Once the cells make contact with each other the cells stop dividing (contact inhibition).

Normal treatment of wounds is predominantly based on controlling the moisture conditions around the wound. A moist wound environment has been shown to promote re-epithelialisation and healing, as shown by Winter, Formation of the Scab and the Rate of Epithelialisation in the Skin of the Domestic Pig, Nature 193, 293-294 (1962); and Kan et al, The Role of Moisture Balance in Wound Healing, Advances in Skin & Wound Care, 20 (1), 39 (2007). Exposing wounds during healing to air dries the surface of the wound and might impede the healing process. However, the wound environment should also not be too wet as this may cause maceration and may enhance the risk of bacterial infection. Numerous commercial products that support a moist wound healing environment are available. Dressings that maintain a moist wound may be, for instance, based on hydrocolloids that are applied directly over the wound. This dressing is impermeable to oxygen, moisture and bacteria. Alternatively, absorptive dressings can be utilized. They are not pre -moisturized but rather absorb moisture from exudates in the wound to keep a moist environment. Normally, they can absorb up to 20 times their weight and may be especially suited for wounds with large amounts of exudates. Calcium alginate dressings such as

Sorbsan® or Kalostat® are two types of soft, fibrous absorptive dressings that are derived from seaweed. U.S. Patent 6,915,950 discloses methods that record the wound conditions in relation to moisture conditions. In order to avoid infections, a gradual release of disinfectants is sometimes helpful to support wound healing. Suitable disinfectants are saline or silver sulfadiazine (e.g. Silvadene®). In general, administration with systemic antibiotics is not warranted unless the patient is demonstrating signs of a systemic infection. In that case the goal of antibiotic treatment is not wound sterilization, but rather control of bacterial growth. Often ointments containing a number of topical agents including sugar, antacids, vitamins A and D are used. The research supporting the effectiveness of these ointments is not clear and often their function can mainly be ascribed to moisturizing the wound environment. Wound healing is reported further to be promoted by addition of steroids such as estrogens and comparable products such as dehydroepiandrosterone (DHEA). See, e.g., Ashcroft et al, Topical estrogen accelerates cutaneous (skin related) wound healing in aged humans associated with an altered inflammatory response, Am J Pathol. 155 (4), 1137-1146 (1999).

Controlling moist conditions is obviously important for wound healing. However, controlling the hydration conditions over a longer period is a problem. This is normally done by regular renewal of the moisturizing ointment. The ointment is filled with particles which are loaded with water, and eventually other additives, which may be released in time. The particles may be embedded in viscous liquids such as peptide mixtures, glycerine, etc. The emission of water from the particles is high at the onset, but decreases in time. Alternatively semi-solids, such as gels, are used to cover the wound. See U.S. Patent 5,905,092 which describes a composition with water loads of more than 60%. Also, here the water content offered to the wound decreases with time and, in order to create acceptable average conditions, is too high at the onset and too low at the end, before renewal of the composition. Another limitation often not addressed is that, under certain conditions, the wound might be exuding moisture by itself, thereby increasing the moisture conditions to an excessive level. Also, over time, as the wound healing process approaches fmalization, the ideal moisture concentration will change, though at the end of the healing process the maintenance of moisture control is less important.

It would therefore be beneficial to have a means, e.g., in the form of a special plaster, gel, ointment or other composition, that allows for controlling the moisture conditions over time by measuring the moisture concentration associated with a wound and subsequently releases or uptakes moisture to maintain optimal moisture levels. In addition, it would be supportive for wound healing if the same means can be used to emit disinfectants/antibiotics or wound-healing promoters, such as steroids. It would be even more supportive for wound healing if the moisture content could be locally regulated, e.g., providing a water load or moisture content at the periphery of the wound that is different from the center of the wound. A proposal was addressed by McCoIl et al, Real-time monitoring of moisture levels in wound dressings in vitro: An experimental study, International Journal of Surgery, 5 (5), 316-322 ( 2007). However, they propose a patient - inconvenient method based on sensors placed at the wound/dressing interface and a fluid injection path to moisturize a foam-type wound coverage.

There are several problems with prior art ES:

In the trials of ES that have so far been carried out one of the main problems is skin irritation and in extreme cases, skin burning. This is caused by too much current being locally drawn by the electrode section situated on top of the wound. If the wound or an adjacent area of skin has a low conductivity then the majority of current passes through this point, causing Joule heating and burning.

In existing devices, there is little lateral movement of cells due to the electrical current. The only movement is upwards from the stratum directly below the wound. There is no monitoring of the wound and the healing process.

It has been shown that some waveforms are more effective for ES than others. These waveforms are limited to variations of the applied current in time. There are no possibilities to create any spatial variations, such as lateral electrical field patterns and currents directed towards the perimeter of the wound. Such waveforms could prove more efficient in accelerating healing.

There is therefore a need for an improved device for electrical stimulation of a skin wound and for an improved method of electrical treatment of skin wounds.

SUMMARY OF THE INVENTION The present invention provides a device for electrical treatment of a skin wound comprising a flexible substrate adapted for attaching to the skin wound and the surrounding skin, a matrix of electrodes, means for determining the presence of the wound and/or its perimeter and/or and means for applying a voltage between the wound and its surrounding. The means for determining the presence of the skin wound may comprise one or more sensors for detecting the real-time state of the skin wound.

A "skin wound" according to the present invention may be any injury, burning or lesion of the skin including irritations and inflammations. In particular, ES is preferably applicable in case of chronic wounds such as stage III or stage IV pressure ulcers, arterial diabetic ulcers and venous static ulcers.

According to a preferred embodiment, the means for applying a voltage is adapted to control the matrix of electrodes in such a way that the electrodes at and/or close to the wound are charged opposite with respect to the electrodes surrounding the wound or its perimeter at a predetermined distance. For example, the electrodes around and on top of the wound may be made negative and other electrodes further away may be made positive, or vice versa. Alternatively a counter electrode may be incorporated in the patch. In one preferred embodiment, the electrodes further away are chosen at a fixed distance from the perimeter of the wound, wherein the number of positive electrodes equals the number of negative electrodes. Naturally, a voltage between the wound and its surrounding may as well be achieved by different means. In general, the electrodes at and/or close to the wound and the electrodes surrounding the wound or its perimeter at a certain distance have to be set on different electric potentials. For instance, the electrodes around and on top of the wound may be grounded and other electrodes further away may be set on a positive potential.

More complex patterns of charge or potential may also be applied. It is, e.g., preferred that the means for applying a voltage is adapted to control the matrix of electrodes in such a way that the electric potential gradually increases or decreases from the electrodes at and/or close to the wound towards the electrodes surrounding the wound or its perimeter at a predetermined distance. This may be achieved by providing several rings of electrodes which are set on different electric potential. In another preferred embodiment, a gradient in voltage from the electrodes in the most outer regions of the matrix towards the electrodes situated near or on top of the wound is applied. Of course, the gradient may alternatively be directed from the center towards the periphery. It is preferred that the device further comprises means for measuring the electric current caused by the applied voltage. Furthermore, the means for applying a voltage is adapted to control the matrix of electrodes in such a way that the measured current does not exceed a predetermined threshold. It is thus prevented that skin under the electrodes is irritated or even burned due to excessively high currents, which can cause Joule heating and consequently burning of skin.

The presence/location of the wound and/or its perimeter may be determined by measuring the impedance between each electrode and its neighboring electrodes. The voltage to be applied between at least some of the electrodes is then determined or calculated by an on-board or external control module in response to the location of the wound and/or its perimeter. Preferably the device is adapted for repeatedly determining the location and/or perimeter of the wound and readjusting the applied voltage pattern in predetermined time intervals. For instance, some wounds tend to heal from the perimeter towards the center. Accordingly, the largest voltage should be applied at the perimeter of such wounds. After some progress in healing the wound may be smaller and its perimeter may have migrated. Thus, the applied voltage pattern has to be re-adjusted in predetermined long-time intervals.

The means for applying a voltage may also be adapted to apply a varying voltage over short time intervals. For example, short DC current pulses may be applied, which travel towards the wound. Alternatively, AC electric fields may be used utilizing the effect of dielectrophoresis to stimulate the movement of cells towards the wound. Preferably, the voltage is between 1 V and 10 V and the frequency between 10 kHz and 100 kHz.

According to a preferred embodiment, the matrix of electrodes may be coated with a therapeutical agent. The therapeutical agent may comprise one or a combination of the following substances: growth factors, e.g. epidermal growth factors, polymer or lipid micells and/or vesicles suitable for drug delivery, corticosteroid-based drugs, anti-inflammatory proteins. If the electrodes, e.g., are coated with an epidermal growth factor and a gradient in voltage towards the wound is applied, the growth factor is "injected" into the wound. This should promote cell migration and accelerate healing.

Alternatively, the composition of vesicles, in particular of transport vesicles, can be tailored to encase therapeutic agents such as drugs or growth factors while the surface of the vesicle can be tailored to a specific charge. Hence such a "drug delivery" vesicle can be designed such that it responds to the electrical fields in a distinct manner from the natural environment (i.e. say inflammatory inducing cells). This can ensure the movement and localization of only said drug delivery vesicle, whilst leaving the surrounding tissue unperturbed.

Naturally, the type of therapeutical agent being suitable strongly depends on the type of wound. For instance, persisting inflammations (i.e. non-open wounds, with swelling, necrosis and inflammation) are often treated with inflammation suppression drugs. Such drugs act to suppress the localization and/or activation of immuno-cell at the sites of inflammation. Nonetheless, these drugs are not recommended for long term use, due to side effects and cellular adaptations. Much like cells can be stimulated electrically to migrate towards a source, one can also "repel" cells electrically and chemically. As described above, an electrically active patch can be applied over an inflamed area and the electric fields tuned to repulse inflammatory cells. This may provide a superior option to corticosteroid based drug therapies, since the negative effects of long term use would be ablated. In addition, as described above, the electric patch can also be used to create a locally defined gradient of chemo-repellant either via a charged drug, or anti-inflammatory protein, or via a complex drug delivery vehicle. Preferably, the device according to the present invention comprises large area electronics on a polyimide release layer. However, the invention is not limited thereto and any type of flexible substrate suitable to be attached to skin may be used in combination with any matrix of electrodes.

In addition temperature sensors can be integrated into the electrically active patch so that the temperature of the wound can be measured. This is advantageous for detecting the presence of an infection as the skin temperature typically increases from 32°C to 37°C when a wound becomes infected. These sensors can also be formed in an array to allow a temperature map of the wound to be created. Most preferably the electrode geometry and material are chosen so that the electrode pad functions as both a resistive temperature sensor, a means for measuring impedance, and also for applying the voltage or current for healing.

In addition heaters can be integrated into the active patch so that the temperature profile over the wound can be controlled to influence the healing process.

Alternatively the moisture of the wound can also be measured via the electrically active patch and this measurement used to monitor the healing process.

Alternatively the active patch can use high frequency radiation, such as THz radiation, generated locally on the patch to monitor the healing process.

The present invention further provides a method for electrical treatment of a skin wound comprising the following steps: placing a matrix of electrodes attached to a flexible substrate on top of the skin wound; determining the presence of the wound and/or its perimeter; and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance.

Preferably, the electric potential gradually increases or decreases from the electrodes at and/or close to the wound towards the electrodes surrounding the wound or its perimeter at a predetermined distance.

As already outlined with respect to the device, the steps of determining the location and/or perimeter of the wound and applying a potential to the electrodes are preferably repeated in predetermined time intervals in order to adjust the resulting applied voltage/current to the actual status of the wound and its progress in healing. The step of determining the location and/or perimeter of the wound may be performed by measuring the impedance between each electrode of the matrix and its neighboring electrodes. Since wounded skin has a different conductivity compared to healthy skin, the local impedance allows for determining the location of the wound. The inventive method further comprises the step of measuring the current between the electrodes. The potential applied to the electrodes is controlled in such a way that the measured current does not exceed a predetermined threshold in order to avoid irritation or burning of the skin due to excessively high currents.

According to a preferred embodiment, the electric potential applied to the electrodes is varied over time. For instance, an AC field is applied between the electrodes, wherein the voltage of the AC field is between 1 V and 10 V and the frequency is between 10 kHz and 100 kHz.

As outlined above, the matrix of electrodes is preferably coated with a therapeutical agent, which may comprise one or a combination of the following substances: a growth factor, e.g., an epidermal growth factor, polymer or lipid micells and/or vesicles suitable for drug delivery, corticosteroid-based drugs, anti-inflammatory proteins.

The device and method according to the present invention provide several advantages over the prior art. Since the current applied during the therapy or stimulation is measured and controlled, skin irritation or even burning can be avoided. A considerable lateral movement of cells may be achieved due to the applied currents. The wound and its process of healing can be monitored during the therapy or stimulation. Accordingly, at every stage of healing the patch of electrodes may be controlled in response to the actual status of the wound. Due to the matrix technology any type of field or waveform can be applied allowing for an enormous versatility of the inventive device. In accordance with a preferred embodiment of the invention, the device for treatment of a skin wound includes a flexible substrate adapted for attaching to the skin wound and the surrounding skin, a matrix of electrodes, a means for determining the presence of the wound and/or its perimeter and/or means for electrically monitoring the water content and controlling a liquid load between the matrix and the wound, and means for applying a voltage between the wound and the surrounding skin. As mentioned above, the measurement and control of the water content in and around a wound is very important for proper healing of the wound. The matrix of electrodes may include a single electrode, and/or multiple electrodes. The single electrode arrangement presents a simple mechanical arrangement, but may require a more complex electronic driving scheme. The matrix of electrodes may be selected from the group consisting of interdigital electrodes, patterned electrodes and transistor- or diode-driven patterned electrodes.

In another preferred embodiment, the means for controlling a liquid load between the matrix and the wound includes a plurality of load-uptaking material, such as a plurality of miniaturized liquid-containing elements. This may include a hydrogel material which is adapted to absorb a liquid load, and is adapted to release the liquid load in response to an electrical stimulation from the matrix of electrodes.

In another preferred embodiment, the plurality of load-uptaking material is arranged within an ointment. The liquid load may be selected from the group consisting of water, buffer salts, disinfectant, saline, silver sulfadiazine, healing steroids, or combinations thereof. A plurality of different liquid loads may be in the plurality of separate load-uptaking materials. This arrangement provides for each of the different liquid loads to be released selectively, depending on the wound conditions.

In a preferred embodiment, a method for electrical treatment of a skin wound comprising the steps of placing a matrix of electrodes attached to a flexible substrate on top of the skin wound and the surrounding skin; determining the presence of the wound and/or its perimeter and/or electrically monitoring the water content and controlling a liquid load between the matrix of electrodes and the wound; and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance. The selective application of electric potential to selected areas on or about the wound promotes faster and more effective healing.

In another preferred embodiment of the method, the steps of determining the presence of the wound and/or its perimeter and/or controlling a liquid load between the matrix of electrodes and the wound; and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance are repeated in predetermined time intervals. The same pattern is not necessarily repeated endlessly, but a pattern of electric potential may be applied repeatedly in response to the condition of the wound and the determination of the water content in or around the wound.

In another preferred embodiment, the step of electrically monitoring the water content between the matrix of electrodes and the wound includes measuring an electrical property between each electrode of the matrix and its neighboring electrodes. The electrical property may be selected from the group consisting of impedance, conductance and capacitance. In another preferred embodiment the steps of controlling a liquid load between the matrix of electrodes and the wound, and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance results in the release of the liquid load from a plurality of load-uptaking materials between the matrix of electrodes and the wound. Different load-uptaking materials may be used, wherein each of the different material requires a distinct electrical signal or condition to release the liquid load contained therein.

With the inventive device and method there are many possibilities for influencing the way a wound heals. In many cases the focus will be purely on accelerating healing of chronic wounds, but there may also be driving schemes which are suitable to reduce or avoid scarring. This could extend the application of the device from the area of chronic wounds to scar avoidance post-surgery, for example in cosmetic surgery.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a flexible array of electrodes in a device for treatment of a skin wound, in accordance with an embodiment of the invention;.

Fig. 2 schematically illustrates an arrangement for operation of electrodes in a device for treatment of a skin wound, in accordance with an embodiment of the invention;

Fig. 3 illustrates an applied voltage gradient directed towards a wound, in accordance with an embodiment of the invention;

Fig. 4 shows a traveling wave driving towards a wound, in accordance with an embodiment of the invention; Fig. 5 shows a low field driving towards a wound, in accordance with an embodiment of the invention;

Fig. 6 illustrates a sectional view of a flexible matrix having an ointment with load-uptaking material applied to a wound, in accordance with an embodiment of the invention; Fig. 7 illustrates a sectional view of a flexible matrix having an ointment with load-uptaking material or a polymer or solid gel with load-uptaking and releasing properties between the electrodes applied to a wound, in accordance with an embodiment of the invention; Fig. 8 illustrates a sectional view of a flexible matrix having an ointment with load-uptaking material applied to a wound, including dedicated interdigitated electrodes for determining local water content of the wound, in accordance with an embodiment of the invention; and Fig. 9 shows a schematic view of a device for measuring conductivity and/or thermal heat capacity for determining water content associated with a wound, in accordance with an embodiment of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS Fig. 1 shows a flexible array 1 of electrodes 2 as now for instance also used in displays. Such flexible arrays, e.g., patch or matrix, 1 can be made from large area electronics technology on a polyimide release layer, which is often referred to as EPLAR. Similar technologies may be applied for the device according to the present invention.

Fig. 2 schematically illustrates how a device according to a preferred embodiment of the present invention is used. A patch or matrix 1 of electrodes is placed on top of the wound 3 (see Fig. 2(a)). The electrodes 2 are then scanned and the impedance between each electrode and its neighbouring electrodes is measured. Since wounded skin will have a different conductivity compared to healthy skin, the presence and location of a wound 3 and therefore its perimeter can be determined. As indicated in Fig. 2(b), the electrodes 2b around and on top of the wound may be charged with an electrical potential, e.g., negatively charged. Other electrodes 2a, further away from the wound, may be made positive, or vice versa. There are several options for this, but the most simple arrangement is to charge the electrodes 2a at a fixed distance from the perimeter of the wound 3 positively and to charge the same number of electrodes negatively as were made positive. The current or voltage waveform is applied for a fixed period of time. The resulting current from the positive electrodes 2a to the negative electrodes 2b is indicated with arrows in Fig. 2(c). The amount of current that can be supplied via each segmented electrode is limited to avoid burning. If too large a current is to be supplied between two electrodes 2a, 2b, then the current is redistributed to neighbouring electrodes. The step of scanning the electrodes is repeated and the size and conductivity of the wound is compared to the previous measurement(s). The current or waveform can then be adjusted accordingly to enhance healing. Alternatively, the monitoring is not done via measuring the drawn current, but by measuring the impedance of the skin under each electrode. This is done at either a pre-determined frequency or by performing a frequency sweep. From the impedance data the state of the wound, e.g., both size and stage of healing, can be extracted and compared to previous measurements.

As an alternative to the embodiment shown in Fig. 2, it may be preferred not to create only one ring of positive electrodes but to create a gradient in voltage from the electrodes 2a in the most outer regions of the patch towards the electrodes 2b situated near or on top of the wound, as illustrated in Fig. 3. For example, several rings 4a to 4f may be set on different potentials with the potential gradually increasing or decreasing from the center of the wound to the periphery of the patch or matrix 1.

As mentioned above, such an array patch 1 allows for the generation of time- variable in-plane electrical fields. This creates many new methods for driving the electrodes which were not possible in the case of mono-electrode patches. For example, it has been shown that applying a short DC current pulse is effective for healing. With such an array patch it is possible to create a pulse on an electrode and to allow this pulse to travel towards the wound. Alternatively it is also possible to apply AC electric fields instead of DC fields. The physical effect of dielectrophoresis could then be used to stimulate the movement of cells towards the wound or to spread the cells to provide an array of nucleation sites from which the wound healing initiates thus controlling, among others, scar formation. The voltage applied is typically a few volts and in the frequency range of 10-100 kHz. For example, a so called travelling wave driving waveform can be seen in Fig. 4 where different phases of sine wave voltage are applied to electrodes which surround the wound. This type of driving is, however, not the most effective if the cells are in a saline environment, as may be the case on a wound. Thus, in the alternative, one may use a low field driving scheme, wherein an area of low electrical field is created and moved in the direction of the wound. This is illustrated schematically in Figs. 5(a) to 5(d).

In the embodiments described above, the migration of cells to the wound has been a purely electrically driven process. It is, however, also possible to envisage a process which is indirectly driven by an electrical field, but is of chemical nature. Cell migration in the body is usually driven chemically and is referred to as chemotaxis. The cells at inflammation sites excrete various proteins which include cellular growth and differentiation factors. Specific cell types, e.g., immune cells, or stem cells, respond to these chemically- excreted signals and migrate towards the source. If a gradient in growth factor could be created towards the wound then this would also promote cell migration. Charged molecules, such as drugs or proteins, can be given to a patient transdermally via a process called iontophoresis. This involves applying an electrical field through the skin and "pulling" the charged drug particles into the patient. This is becoming a popular method for sustained drug delivery. According to a preferred embodiment, the electrodes are coated with a growth factor such as EGF (epidermal growth factor) and a gradient in voltage towards the wound is applied (such as in Fig. 3). This will "inject" the growth factor into the skin with a gradient which is determined by the voltages applied to the segmented electrodes. The growth factor gradient is therefore in the direction of the wound and should therefore promote cell migration and accelerated healing.

In addition there have been a lot of developments recently in the area of drug delivery using polymer and lipid micells and vesicles. The composition of these vesicles can be tailored to encase drugs (or growth factors) while the surface of the vesicle can be tailored to a specific charge. Hence, such a "drug delivery" vesicle can be designed such that the vesicle responds to the electrical fields in a manner distinct from the response of the natural environment, i.e., inflammatory inducing cells. This can ensure the movement and localization of only said drug delivery vehicle, whilst leaving the surrounding tissue unperturbed.

The stimulated migration of cells towards damaged tissue can have great benefits with respect to healing and tissue repair. Likewise, persisting inflammations, i.e., non-open wounds, with swelling, necrosis and inflammation, are often treated with inflammation suppression drugs. Such drugs act to suppress the localization and/or activation of immuno -cells at the sites of inflammation. Nonetheless, these drugs are not recommended for long term use, due to side effects and cellular adaptations. Similar to the manner in which cells can be stimulated electrically to migrate towards a source, one can also "repel" cells electrically and chemically. Similar to the embodiment described above, the electrically active patch or matrix 1 can be applied over an inflamed area and the electric fields tuned to repulse inflammatory cells. This may provide a superior option to corticosteroid-based drug therapies, since the negative effects of long term use would be ablated. In addition, as described above, the electrically active patch 1 can also be used to create a locally defined gradient of chemo-repellant either via a charged drug, or antiinflammatory protein, or via a complex drug delivery vehicle.

In addition, temperature sensors can be integrated into the electrically active patch 1 so that the temperature of the wound 3 can be measured. This is advantageous for detecting the presence of an infection as the skin temperature typically increases from 32°C to 37°C when a wound 3 becomes infected. These sensors can also be formed in an array to allow a temperature map of the wound to be created. Most preferably, the electrode geometry and material are chosen so that the electrode pad functions as both a resistive temperature sensor, a means for measuring impedance, and also for applying the voltage or current for healing.

In addition, heaters can be integrated into the active patch 1 so that the temperature profile over the wound 3 can be controlled to influence the healing process.

In an alternative embodiment, or as a stand-alone solution, the moisture of the wound 3 can also be measured via the electrically active patch 1 and this measurement may be used to monitor and manipulate the healing process.

The maintenance of proper moisture levels in and around the wound as it heals is very important. The moisture, e.g., water, content must be measured, as a first step so that it can be adjusted or controlled. Towards that goal, a device for the treatment of a skin wound 3 includes a flexible substrate 1 adapted for attaching to the skin wound 3 and the surrounding skin, a matrix 1 of electrodes 2, means for determining the presence of the wound 3 and/or its perimeter and/or means for electrically monitoring the water content and controlling a liquid load between the matrix 1 and the wound 3, and means for applying a voltage between the wound 3 and the surrounding skin. As mentioned above, the measurement and control of the water content in and around a wound is very important for proper healing of the wound. The matrix 1 of electrodes 2 may include a single electrode, and/or multiple electrodes. The single electrode arrangement presents a simple mechanical arrangement, but may require a more complex electronic driving scheme.

The device electronically monitors the water concentration in and around the wound 3 and electrically stimulates the release or absorption of water, disinfectants and/or treatment drugs in a measure -response-feed-back cycle. The electrode array is a single- electrode or multiple-electrode arrangement which may consist of interdigital electrodes, patterned electrodes, transistor or diode driven patterned electrodes. Interdigital electrodes are electrodes of different types or arrangements which are woven or arranged very closely together so as to be effectively inseparable and to provide the possibility for a number of different types of simultaneous measurements and the application of different electrical potentials simultaneously, or nearly so, in a single matrix 1 array. Preferably, interdigitated electrodes or electrode arrays are used in one embodiment. The electrode array 1 functions to provide local detection and quantification of water in and around the wound 3. The electrode array 1 also functions to release water or other substances, e.g., a liquid load, from miniaturized water containers accommodated in an ointment between the electrode array 1 and the wound 3.

In another preferred embodiment, the means for controlling a liquid load between the matrix 1 and the wound includes a plurality of load-uptaking material, such as a plurality of miniaturized liquid-containing elements. This may include a hydrogel material which is adapted to absorb a liquid load, and is adapted to release the liquid load in response to an electrical stimulation from the matrix 1 of electrodes 2. A plurality of load-uptaking material is meant to include a number of identical or dissimilar discrete load-uptaking elements within an ointment, or a generally solid gel or polymer, which may be homogeneous in composition, having load-uptaking and releasing properties and generally corresponding to the number of identical or dissimilar discrete load-uptaking elements. In another preferred embodiment, the plurality of load-uptaking material is arranged within an ointment. The liquid load may be selected from the group consisting of water, buffer salts, disinfectant, saline, silver sulfadiazine, healing steroids, or combinations thereof. A plurality of different liquid loads may be in the plurality of separate load-uptaking materials. This arrangement provides for each of the different liquid loads to be released selectively, depending on the wound conditions.

There are several suitable miniaturized water-containing materials, e.g., hydrogel materials, that can be loaded with water by swelling and which may be directed to release their water load by electrically-stimulated de-swelling, e.g., contraction, shrinking. The liquid load may be as simple as water, or it may be water that contains buffer salts to make it more physiologically normalized. However, the liquid load may also contain disinfectants or antibiotics such as saline, silver sulfadiazine or steroids that promote healing, such as estrogens. Combinations of these materials may also be used.

Direct information regarding the water concentration and water distribution over, on or around the surface of the wound 3 may be obtained from high frequency impedance/conductance or capacitive measurements through the electrodes at the various locations of the device-wound interface. This measurement is not trivial given the complex composition of the various components and the presence of ion-rich water-containing materials. Of direct interest is the amount of water concentrated at or near the interface with the wound 3. Some detailed solutions will be provided in the next section. Alternatively, single-electrode methods may be used to make the design of the water-releasing element more simple, but may be more complicated in an electronic sense.

In a preferred embodiment, a method for electrical treatment of a skin wound comprising the steps of placing a matrix 1 of electrodes 2 attached to a flexible substrate on top of the skin wound 3 and the surrounding skin; determining the presence of the wound 3 and/or its perimeter and/or electrically monitoring the water content and controlling a liquid load between the matrix 1 of electrodes 2 and the wound 3; and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance. The selective application of electric potential to selected areas on or about the wound promotes faster and more effective healing.

In another preferred embodiment, the step of electrically monitoring the water content between the matrix of electrodes and the wound includes measuring an electrical property between each electrode of the matrix and its neighboring electrodes. The electrical property may be selected from the group consisting of impedance, conductance and capacitance.

In another preferred embodiment the steps of controlling a liquid load between the matrix of electrodes and the wound, and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance results in the release of the liquid load from a plurality of load-uptaking materials between the matrix of electrodes and the wound. Different load-uptaking materials may be used, wherein each of the different material requires a distinct electrical signal or condition to release the liquid load contained therein. As shown in Fig. 6, in a first preferred embodiment the load-uptaking material

6 is present as particles in an ointment 5. The load-uptaking material 6 may be a swelling polymer made by lithographic means or by replication processes, e.g., as described in [M.H.M. Oudshoorn, R. Penterman, R. Rissmann, J.A. Bouwstra, D.J. Broer, W.E. Hennink, Preparation and Characterization of Structured Hydrogel Microparticles Based on Cross- Linked Hyperbranched Poly 'glycerol, Langmuir 23 (23), 11819-11825 (2007)], although for this specific application other materials of a different chemical nature may be selected. Suitable materials may include copolymers made from acrylamide and acrylic acid crosslinked by small amounts of bisacrylamide. These materials may be made by photopolymerization of the monomer mixtures and loaded with water and other components. Upon the application of an electrical field these copolymers are know to contract (de-swell) at the anode side thus releasing their load, as illustrated in Fig. 6 and in [Tanaka, T., Nishio, L, Sun, S. -T., and Ueno -Nishio, S., Collapse of gels in an electric field, Science 218, 467-469 (1982)]. By reversing the cathode and anode, the opposite part can be contracted to release its liquid load. The loaded particles may be embedded in a viscous base material, e.g., glycerol, polyethylene glycol oligomer, mixture of proteins, etc., to make an ointment as schematically shown in Fig. 6. Preferably, the viscous base material is electrically (ionic) conductive and transparent for water diffusion to some extent. Flaked materials as liquid-loaded materials are of special interest because they simplify the manufacturing of ointments. In another embodiment, different liquid-bearing particles 6 may be filled with different liquid loads or fluids, e.g., first particles 6 loaded with water or physiological salt solution and a second particles 6 loaded with antibiotics/disinfectants. These different liquid- bearing particles 6 may be triggered by different stimuli, e.g., different voltages. This arrangement provides the possibility for different fluids or liquid load to be release at different times, in a controllable manner. One fluid, e.g., water, could be continuously applied, whereas the second fluid, e.g., disinfectant, could be released for a short time every couple of hours to keep the wound sterile.

As mentioned above, the use of flake material for liquid-loading may be desirable because: 1. Ointments may be easily made from such materials, and

2. A blend of different flakes may be used, i.e., with different liquid-loading, e.g., water and water plus drug, or having different electrical or thermal response.

In another preferred embodiment, the ointment 5 containing the loaded hydrogel material 6 is applied as a coating in between electrodes 2 of the electro- stimulating device, as is illustrated in Fig. 7. The hydrogel ointment 5, or a gel or polymer having liquid- uptaking and releasing properties, may be embedded in small notches in the matrix 1 to generate more volume. Before the use of the device, the hydrogel material 6 is loaded with the liquid-loading/healing-promoting ingredients. As explained above, this liquid load can be as simple as water, or it can be water-containing buffer salts to make it more physiologically normal. It may also contain disinfectants such as saline, silver sulfadiazine or healing- promoting steroids, such as estrogens. Combinations of these materials may be used as well. In another preferred embodiment, the device may include a stack of multiple layers which may be applied onto the wound 3. A first layer of the stack, which may be in contact with the wound 3, may comprise a plurality of hydrogel 6 aggregates or hydrogel flakes for triggered release of the substances as described above. A second adjacent layer in contact with the first layer and the electrodes 2, which may also separate the electrodes 2 from each other, may include an anti-adhesive property to prevent the wound tissues from sticking and promote new tissue formation. In this way the electrodes 2/electrode array 1 may be removed easily when healing is complete. The second layer could be a hydrogel ointment 5, 6 layer as well but with additional ingredients, e.g., immobilized antifouling agents. In another preferred embodiment, each of the stored agents/liquid load materials 6 may be released on command, i.e., each different type of load-uptaking material 6 may be release at a different moment in time. Toward this end, different types of hydrogels and load-uptaking materials may be applied, each of which may be separately triggered to start and/or stop release of said agent/load uptaking materials 6.

In a first example, corresponding to the embodiment illustrated in Fig. 6, the hydrogel particles 6 were made by copolymerizing a mixture of: 80 wt-% acrylic acid, 16 wt- % sodium vinyl sulfonate; 2 wt-% N ',N '-methylene bisacrylamide; and 2wt-% 2-Hydroxy-2- methyl- 1 -phenyl- 1-propanone Irgacure 754 - from Ciba Specialty Chemicals.

The mixture was applied in a nickel mould that was provided with a release agent. The mould included a number of small containers of approximately 50x50x5 μm and the mixture was cured by UV light. After fully cured, the polymer flakes were released from the mould by moderate bending. The flakes were saturated with an aqueous NaCl solution by immersion for 2 days at 25 ⁰C. Subsequently, a mixture was made of 70 wt-% of the saturated particles with 30 wt-% of mixture containing 3 parts glycerol and 1 part chitosan. The ointment 5 that is formed is applied between the wound 3 and the device containing the multi electrode array 1, as illustrated in Fig. 6. The hydrogel 6 flakes start to release water at a DC voltage of 3 Volts. It is desired to uncouple the electro -stimulated release of water or other ingredients from the electrical field or current that is utilized for electro-stimulated wound healing. The solution is to use an alternating current for the electrical wound healing stimulation and a direct current for water/drugs release from the hydrogel materials 6. Of course, in the absence of a DC field the hydrogel material 6 tends to start uptaking water again. This is a slow and diffusion-controlled process. To prevent the dehydration of the ointment, the DC voltage should be repeated intermittently in coordination with the AC fields used to stimulate wound healing. An appropriate sequence of DC and AC field-addressing is therefore part of the invention. In another example, corresponding to the embodiment illustrated in Fig. 7, a mixture is made containing: 1 gram hyaluronic acid; 5 ml 1 N NaOH solution; and 0.55 ml of 0.8 g/1 ethylene glycol diglycidyl ether in ethanol.

After degassing, the mixture is poured onto an electrode array 1 where the solution fills the gap between the electrodes 2. The mixture is allowed to react at 60 ⁰C where the hyaluronic acid crosslinks. The formed gel is removed from non-reacted components by placing it in an excess of distilled water for 3 days and dried. Then the gel is loaded by a 1 g/1 solution of estrogen in water over 3 days contact. The electrode structure havine the loaded hydrogel between the electrodes 2, as shown in Fig. 7, is manipulated by applying an AC field for electrical stimulation of wound healing and a DC field for drugs and water release in an alternate basis.

With respect to the measurement of water concentrations, special precautions should be taken and particular device designs are required. With respect to the high frequency impedance measurements for the purpose of measuring water content near the matrix 1 /wound 3 interface, the utilization of high frequency impedance measurements should be made so as to exclude water response due to the presence of the responsive hydrogels 6 between the detection electrodes 2. A solution is shown in Fig. 8. This arrangement provides an example of dissimilar interdigitated electrodes incorporated into a single matrix 1. Numerous variations are possible, whereby numerous measurements may be taken to determine various conditions in or around the wound simultaneously, while numerous dissimilar electric potentials may be applied in different areas of the matrix 1, as a result of the measurements. Though this arrangement may include the risk of a delay between the measured water concentration and the actual water concentration, through the miniaturization of the water measurement electrodes 7 the delay time can be reduced. Instead of paired electrode sets 7 for measuring water concentration, an interdigital array of electrodes may also be used. Examples thereof, e.g., for measuring water contents of oil or paper pulps, are given in literature. Cf. Sundara-Rajan et al, IEEE Sensor Journal (2004).

An insulating dielectric 8 may be included between the water measurement electrodes 7. The insulating dielectric 8 may be a polymer that is applied by lithographic means. In one embodiment the top of the water detection electrodes 7, together with the insulating dielectric 8 may be covered with a thin membrane, e.g., SiO₂, in accordance with the principles of fringe field detection [Cf. Mamishev et al, Inter digital sensors and transducers, Proc. IEEE 92, 808 (2004)]. A single electrode capacitance probe is described by Schϋller et al,

Measurement of Water Concentration in Oil/Water Dispersions with a Circular Single- Electrode Capacitance Probe, IEEE Trans. Instr. Meas. 53 (5), 1378 (2004), and is based on the measurement of capacitance by utilizing the effect the dielectric constant has on the frequency of an oscillator 9. At the specific places in the electrode array 1 that direct the hydrogels 6 to release water oscillator electrical circuits 9 may be integrated to provide capacitive water measurement. The oscillator circuit 9 is illustrated in Fig. 9. This oscillator 9 may operate at a frequency of approximately 20 MHz. The wound 3 and fluid that is present in the vicinity of the capacitor plate 10 affects the oscillating frequency of the circuit 9. This change in frequency is related to an equivalent change in the dielectric permittivity of the mixture. If a gas is present adjacent to the capacitor plate 10, no reduction in frequency is observed, while if pure water is present adjacent to the capacitor plate 10, a much larger reduction in frequency is observed.

The operating frequency ω of the oscillator 9 depends on the inductance of the coil of the oscillator circuit L and the capacitance C_m of the medium located near the electrode

[Hz] ω at - (1)

JLC m

The capacitance change of the medium outside the electrode is related to the operating frequency change of the oscillator as follows:

*^c- ^[F] The capacitance is related to the dielectric permittivity as follows:

C.C-4 [F] (3) where Eo is the dielectric permittivity in vacuum, ε is the dielectric permittivity, A is the area of the capacitor, and d is the distance between the capacitor plates. Thus,there is a proportional relation between the capacitance and dielectric permittivity. Only the frequency shift of the oscillator is recorded, not the loss. The C_m in the equation includes all capacitive influence that contributes to the frequency shift (circuit components, media impedance, etc.). A capacitance value that represents the measured media is then calculated. The length of the electrode is very small compared to the wavelength of the oscillator so the electrode impedance is very high and capacitive.

The range of C_m is highly dependent on the size (area) and shape of the electrode and of the shape (thickness) of the ceramic 11. As an alternative to using a ceramic window 11 , a polymer film may be used, the polymer film being more compliant with respect to the shape of the body and the wound 3.

Methods based on conductivity measurements Determining the water concentration in and around a wound 3 by conductivity measurements between two electrodes requires special measures because the water level in the hydrogel 6 easily dominates and conducts the electric current. The water level of the hydrogel 6 may not be of any relevance to the water conditions near the wound 3. To solve this problem conductive particles are added to a hygroscopic thin additional layer. The layer might be applied as additional thin film on top of the hydrogel shown in Fig. 7. This hygroscopic film does not respond in volume under the electrical field. However, the water content hydrogel 6 or load-uptaking material determines the degree of swelling within the ointment 5, and thus the distance between the conductive particles. As a consequence, the conductivity of the ointment 5 with the hydrogel material 6 will depend on the water concentration within. The conductive particles may be any number of small conductive materials, e.g., silver or gold nanoparticles, iron/ironoxide nanoparticles or carbonanotubes. In a preferred embodiment, the conductive particles are covalently coupled to the hygroscopic polymer matrix.

Instead of covering the whole responsive hydrogel film with a coating, a coating may be applied locally. Hygroscopic polymers may be applied between some of the electrodes 2 to provide a number of sensing compartments next to delivering compartments. Controlling and applying local coatings would allow the device to follow the wound perimeter and control wound healing while the wound is getting smaller. This may lead to better and faster wound healing as well as to decreased scar formation. Methods based on thermal heat capacity.

Alternatively, the electrical release substrate, e.g., liquid- loaded hydrogels, could be provided with a miniature Joule heater, or an array of such heaters, and a resistive wire(s) for determining the actual temperature T. With such a set-up, the skin temperature T could be measured, and a sharp pulse in temperature with respect to skin temperature T may be created by applying current to the heater. By measuring either the rate of temperature rise or the rate of cooling down, the heat capacity, and therefore the volume of the water in the gel, may be closely estimated. It is necessary that the rise in T is rapid to avoid the body mass acting as a thermal sink.

The temperature sensors could also be used for determining if an infection is present. Normal skin temperature is 32°C and this can increase to 37°C upon infection. Provided that no infection is detected then the moisture could be maximised.

The invention is concentrating on accelerated wound healing. However, other applications are envisioned, such as beauty treatments with other stimulating agents and/or fragrances. Also electrical stimulation has been reported to be helpful in accelerating the healing process and nerve regeneration after injury. Electrical currents/charges could change cell membrane permeability, stimulate cell activities such as DNA synthesis and cell proliferation. Local electrical currents may improve arterial blood flow and reduce tissue edema and microvascular permeability. This improvement in circulation may increase tissue oxygenation. Electrical stimulation for clinical use can be delivered via various mechanisms, including direct injection of an electrical charge using metal electrodes in resistive contact with tissues, induction of eddy currents in tissues by rapidly changing magnetic fields applied externally, and creation of electrostatic field in tissues by high- voltage external capacitive plates. Among these approaches, externally applied magnetic field and capacitive plate stimulation normally activate a large area of tissue, while the metal electrodes can precisely target a small area in tissue. These effects as well as electrical-stimulated wound healing and moisture control may be presented in a single device.

While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Claims

CLAIMS:

1. Device for treatment of a skin wound (3) comprising: a flexible substrate adapted for attaching to the skin wound and the surrounding skin; a matrix (1) of electrodes (2); means for determining the presence of the wound (3) and/or its perimeter and/or for electrically monitoring the water content and controlling a liquid load between the matrix (1) and the wound; and means for applying a voltage between the wound and the surrounding skin.

2. Device as claimed in claim 1, wherein the means for determining the presence of the wound (3) comprise one or more sensors for detecting the real-time state of the wound (3).

3. Device according to claim 1 or 2, wherein the means for applying a voltage is adapted to control the matrix (1) of electrodes in such a way that the electrodes (2b) at and/or close to the wound (3) are charged opposite with respect to the electrodes (2a) surrounding the wound (3) or its perimeter at a predetermined distance.

4. Device according to claim 1 or 2, wherein the means for applying a voltage is adapted to control the matrix (1) of electrodes in such a way that the electric potential gradually increases or decreases from the electrodes (2b) at and/or close to the wound (3) towards the electrodes (2a) surrounding the wound or its perimeter at a predetermined distance.

5. Device according to claim 1, wherein the means for controlling a liquid load between the matrix (1) and wound includes a plurality of load-uptaking materials.

6. Device according to claim 5, wherein the plurality of load-uptaking materials includes a plurality of miniaturized liquid-containing elements.

7. Device according to claim 6, wherein the plurality of miniaturized liquid- containing elements includes a hydrogel material.

8. Device according to claim 7, wherein the hydrogel material is adapted to absorb a liquid load.

9. Device according to claim 7, wherein the hydrogel material is adapted to release the liquid load in response to an electrical stimulation from the matrix (1) of electrodes (2).

10. Device according to claim 5, wherein the plurality of load-uptaking materials is arranged within an ointment.

11. Device according to claim 5, wherein a plurality of different liquid loads are in the plurality of separate load-uptaking materials.

12. Method for electrical treatment of a skin wound comprising the following steps: - placing a matrix of electrodes attached to a flexible substrate on top of the skin wound and the surrounding skin; determining the presence of the wound and/or its perimeter and/or electrically monitoring the water content and controlling a liquid load between the matrix of electrodes and the wound; and - applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance.

13. Method according to claim 12, wherein steps of: determining the presence of the wound and/or its perimeter and/or controlling a liquid load between the matrix of electrodes and the wound; and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance are repeated in predetermined time intervals.

14. Method according to claim 12, wherein the step of electrically monitoring the water content between the matrix of electrodes and the wound includes measuring an electrical property between each electrode of the matrix and its neighboring electrodes.

15. Method according to claim 14, wherein the electrical property is selected from the group consisting of impedance, conductance and capacitance.

16. Method according to claim 12, wherein the steps of controlling a liquid load between the matrix of electrodes and the wound, and applying a different potential to the electrodes at and/or close to the wound and to the electrodes surrounding the wound at a distance results in the release of the liquid load from a plurality of load-uptaking materials between the matrix of electrodes and the wound.