Patent Description:
Diabetes is considered to be the most critical global noncontaqious disease. There are several scientific opinions relating to this disease. While there is no doubt that it is a metabolic disorder characterized by hyperglycemia, on the other hand the onset of diabetes is accompanied by other factors, such as obesity and cardiovascular disorders. In any case, this disease provides a significant socio-economic burden since it is a chronic disease, which must be kept under control for the entire life of patients and affects millions of people around the world.

If diagnosed late, due to a delay in the actions to control the glycemic level compared to the time of the onset of the disease, this provides effects that deeply compromise the functionality of the patients' feet and leqs, causing severe neuropathic pain, circulation problems and the formation of chronic ulcers in these areas of the body. The progression of all these factors can also lead to the amputation of part of the leq/foot.

Diabetic ulcers are characterized by a chronic inflammatory environment and an altered or interrupted skin regeneration mechanism. These unresolved wounds are a gateway for pathogenic microorganisms due to the lack of skin tissue. Furthermore, wound exudate is a perfect medium for bacterial proliferation and as a result, the difficult management of the infection makes the treatment of diabetic ulcers a major concern.

The condition of persistent hyperglycemia, typical of diabetes, deeply affects the lower limbs causing circulation problems, poor blood circulation, peripheral neuropathic pain, and loss of skin sensitivity, leading to tissue death (maceration, gangrene).

Pharmacological treatments are known to the state of the art, which include wound dressings, which are designed to control and support the healing of ulcers locally. The dressings are made in the form of films, fibrous mats, sponges and hydrogels for the in situ administration of antibiotics, antioxidant and anti-inflammatory molecules and growth factors. The modern biomaterials used in these dressing devices try, at the same time, to counteract the invasion and proliferation of microorganisms, eliminate free radicals present in the exudate, rebalance the persistent inflammatory condition and promote the proliferation of skin cells in order to achieve proper wound repair.

However, the low scalability, high production cost, local side effects and bacterial resistance still deeply limit the introduction of these technologies. Furthermore, the dressings are not designed to deal with neuropathic pain and the circulation problem related to diabetic ulcers, completely limiting their use to a local application, and making the results, in terms of healing effectiveness, relatively limited also in relation to the therapy duration. The therapeutic process that makes use of this kind of dressings requires interventions by healthcare personnel who, in addition to performing the replacement of the device, also control the evolution of the pathological condition and/or direct interventions on the ulcer itself, such as for instance cleaning, extemporaneous application of further drugs and other actions. However, this requires a constant and cyclical intervention of the healthcare personnel which is not limited to a mere control activity, so that the treatment costs become relatively high.

In the state of the art, biomedical devices for therapeutic applications by electrical stimulation are also known.

<CIT> discloses an electrical stimulation apparatus with pulse generators and electrodes on flexible supports for independent channel treatment, featuring control units and interfaces, adaptable for drug administration.

<CIT> discloses a method for treating dermatological conditions using neuromodulatory agents, including pharmacological and electrical stimuli, targeting conditions like psoriasis and ulcers with potential implantable devices.

In general, these are devices that provide for the emission through the skin, by means of electrodes applied to the skin itself, of electrical impulses configured according to particular sequences and according to particular parameters such as signal power, voltage, current intensity, frequencies and waveforms. They are therefore non-invasive therapeutic biomedical devices that show efficacy in the treatment of neuropathic pain, in the improvement of circulatory flow and in the treatment of vascular disorders related to diabetes as well as in the treatment of skin lesions such as ulcers related to diabetes.

Furthermore, current electrostimulation techniques used in the treatment of diabetic ulcers require a relatively long treatment time, which causes patient discomfort and increases treatment costs.

Particularly, electrostimulation devices operating according to FREMS technology have proved effective both in the treatment of neuropathic pain and in increasing blood flow in the anatomical areas where they are applied. Studies and experiments related to this technology show an ability to increase the release of growth factors such as vascular endothelial growth factor (VEGF), valid for the treatment of diabetic ulcer.

Frequency and amplitude modulated neuronal electrical stimulation or FREMS ~ (Frequency Rhythmic Electric Modulation is described in documents <CIT>), <CIT>, <CIT> and <CIT> (incorporated herein by reference) and is characterized by the use of transcutaneous electrical currents, produced by sequential electrical impulses with variable frequency and duration. The frequency can vary from <NUM> to <NUM>, the duration of the stimulus is between <NUM> and <NUM> and the voltage, constantly maintained above the perceptual threshold, is comprised between <NUM> and <NUM> V (preferably <NUM> V).

Particularly, <CIT> describes a microcirculation activation sequence (ATMC) and a muscle fiber decontracting sequence (DCTR), which are capable of soliciting various functional districts, including striated muscle, smooth muscle and peripheral nervous system. The aforementioned stimulation sequences are based on three fundamental parameters: the duration of the stimulus, the frequency of the stimulus and the time intervals during which different duration/frequency combinations follow one another. The operating general pattern of the stimulation sequences mirrors the digital-to-analogic transduction that occurs in the transmission of a nerve impulse.

Frequency and amplitude modulated neuronal electrical stimulation or FREMS ~ (Frequency Rhythmic Electric Modulation described in the aforementioned <CIT> and in <CIT> (incorporated herein by reference), is characterized by the use of transcutaneous electrical currents, produced by sequential electrical impulses with variable frequency and duration. The frequency can vary from <NUM> to <NUM>, the duration of the stimulus is between <NUM> and <NUM> and the voltage, kept constantly above the perceptual threshold, is between <NUM> and <NUM> V (preferably <NUM> V). By suitably combining the aforementioned variations in frequency and duration, a specific sequence is obtained, called DCTR, having a decontracting effect and including a series of sub-phases, called A, B and C. Frequency and amplitude are constant in sub-phase A, the frequency is constant and the amplitude variable in sub-phase B, the frequency is variable and the amplitude constant in sub-phase C.

Experimental studies have made it possible to evaluate the effects of FREMS and the ability of the latter to evoke composed muscle action potentials (cMAP), obtainable in the proper adductor muscle of the big toe by stimulating the posterior tibial nerve, as well as the variation in amplitude of the reflex H using the latter as a conditioning stimulus. As described in <CIT>, the aforementioned experimental studies have also shown that the greater amplitude of the cMAPs (<NUM> ± <NUM> mV) obtainable is about <NUM> times lower than that of the cMAPs obtained with the known devices delivering TENS currents, i.e. of the order of <NUM> ± <NUM> mV with stimuli having a duration typically included in a range of <NUM>-<NUM>. It has also been observed that the maximum amplitude value of the cMAPs is obtained in the presence of a duration/frequency ratio equal to <NUM> (<NUM>/<NUM>).

A further kind of sequence, called ATCM and suitably designed to obtain a vasoactive effect, has a prevalent action on the motility of the microcirculation, that is, of the smooth sphincters of the arterioles and venules of the subcutaneous tissue. In practice, as described in <CIT>, a system is obtained which produces a sequence of vasodilatations and vasoconstrictions with sequential increases and decreases in the blood flow of the microcirculation surrounding the stimulation zone. These vasodilatations and vasoconstrictions produce a "pump" effect evidently produced by a neuromodulation of the sympathetic autonomic system, which influences the vasoaction precisely through the smooth muscles of the capillaries and arterioles. In this way it can be seen that this subsequence, characterized by alternating variations of the rheobase, therefore produces a vasoactive effect consisting of phases of vasodilatation and sequential vasoconstriction phases. This certainly also produces a draining effect and, above all, an elasticization of the microcirculation and a modulation of the latter around a main bearing event that determines its average variation.

Despite the aforementioned clinical effects, even the biomedical therapeutic devices operating according to the FREMS technology lack some crucial aspects to support the wound healing process. For instance, this system does not have antibacterial and antifungal properties, cannot guarantee any covering action of the wound and the ability to absorb exudate. Furthermore, investigations regarding the anti-inflammatory effects for FREMS technology have not yet been reported. Therefore, both for devices operating according to Frems technology, and for electrostimulation devices operating according to other stimulation technologies or methodologies, as regards the configuration of the pulse sequences transmitted to the anatomical districts, the effectiveness remains limited and not completely decisive for achieving the healing of ulcers, particularly diabetic ulcers and particularly as regards the healing times and the level of healing of the lesions.

An aspect of the present invention is therefore that of producing a kit comprising biomedical device for the treatment of ulcers, particularly for the treatment of diabetic ulcers, which has an improved therapeutic efficacy as regards the times and levels of healing of ulcers and particularly of diabetic ulcers.

A further aspect relates to the production of a biomedical device for the treatment of ulcers and particularly of diabetic ulcers which in combination with an improved therapeutic efficacy presents a greater convenience of application in situ and/or replacement during the therapeutic process and which is also relatively compact, easy to control and use and relatively inexpensive especially with respect to currently known devices.

Sodium alginate is a natural carbohydrate polymer used in the wound healing process such as known from <NPL>";<NPL>" However, pure alginate has poor mechanical properties, being a relatively rigid material and limiting its potential application to a different part of the body. For this reason, glycerol was introduced as a plasticizer in the sodium-alqinate film, thus obtaining a reduction in Young's modulus and tensile stress at maximum load and an increase in the elongation capacity of the films.

According to one embodiment, the dressing film can be obtained by adding to a solution comprising sodium alginate with a concentration of <NUM> to <NUM>% w/v and PVP-I with a concentration of <NUM> to <NUM>% w/v glycerol at a concentration of <NUM> to <NUM> w/w with respect to the total weight of sodium alginate and PVP-I.

This kind of dressing has the advantage of being naturally resorbed, thus avoiding the need for a detachment from the lesion and therefore the possibility of generating new lesions when replacing the dressing. After absorption, in fact, a new dressing can be easily applied simply by superimposing a new dressing film on the lesion and/or possibly what remains of the previous film.

According to one characteristic, the resorption of the dressing by the skin takes place particularly for a thickness of the aforementioned film less than <NUM>, preferably less than <NUM>, even more preferably from <NUM> to <NUM>.

As will be seen in more detail also from the experimental results, the combination of electrical stimulation according to a FREMS technology with the dressing using a film obtained from a solution of sodium alginate, povidone iodine and glycerol, allows to obtain a therapeutic effect on the treatment of ulcers, particularly of diabetic ulcers which is surprisingly and unexpectedly, considerably more effective, than the single treatments separated from each other or the simple sum of the therapeutic effects of the single actions of electro stimulation and pharmacological treatment.

This unexpected and surprising increase demonstrates a synergistic effect of the action of electrical stimulation and pharmacological action.

As regards the configuration of the biomedical device in the form of self-medication and therefore to be practically usable also directly by the patient, the present invention provides several advantageous embodiments.

These and other characteristics and advantages of the present invention will become clearer from the following description of some embodiments illustrated in the enclosed drawings wherein:.

With reference to the more general embodiment of the present invention, the biomedical device for the treatment of ulcers, particularly diabetic ulcers, comprises a pair of electrodes for the transmission of electrostimulation impulses according to a FREMS technology said electrodes being meant to be applied in diametrically opposite positions with respect to the area presenting the lesion. As shown in <FIG>.

This figure compares the results obtained in the treatment of ulcers caused in diabetic mouse models.

In these experiments, were considered untreated mice, mice treated only with the dressing consisting of a NaAlg/PVP-I film, mice treated only with an electrostimulation according to the FREMS technology and mice treated with a device according to the present invention which provides a pharmacological treatment with a dressing using a NaAlg/PVP-I film and simultaneously with an electrostimulation; the main results of the experiment are reported. As it can be seen, during the monitoring period of <NUM> days, in the untreated mice, called CTRL, the ulcerative lesion did not substantially undergo any healing due to the diabetic condition, showing at the end of the observation period <NUM>% of the area of the wound still not healed. The application of FREMS technology showed a gradual wound healing during the observation period (<NUM> days) and led to a recovery of <NUM>% of the area initially affected by the wound. The FREMS technology was statistically better than the CTRL controls as also shown in the lower graph in <FIG>.

Mice treated with the PVP-I based dressing alone, identified with PVP-I, showed a slight difference in the progression of the wound healing process. In fact, as can be seen in <FIG>, a first major effect of the healing process was observed both with respect to controls and FREMS technology up to the first <NUM> days. After <NUM> days, mice treated with PVP-I based patches showed a residual wound area of <NUM>%, which was statistically better than CTRL.

Finally, mice treated with both wound dressing and FREMS technology showed a surprising synergistic effect of the two therapies. In fact, from the very first days, the condition of the wound was statistically improved both in relation to the CTRL group and in relation to the group treated with electrostimulation only and the group treated with dressing only. It is important to note that after <NUM> days, the improvement in repair of the area affected by the lesion was statistically better than in mice treated with the PVP-I based patch alone. Finally, after <NUM> days, the mice treated with the combination of electro-stimulation according to the FREMS technology and the PVP-I dressing showed a complete recovery of the wounds.

According to these data, both NaAlg/PVP-I and FREMS alone were able to accelerate but not complete wound healing, while the combination of NaAlg/PVP-I and FREMS technology was able to heal the induced wound in <NUM> days, suggesting a positive synergistic effect of the two technologies.

In carrying out the experiment, the dressing film was prepared according to the following example:
A solution of Sodium Alginate was prepared at a concentration of <NUM>% w/v, PVP-I (povidone iodine) at a concentration of <NUM>% w/v in a final volume of <NUM> and glycerol at <NUM>% w/w with respect to the total weight of alginate and PVP-I. <NUM> of this solution was placed on a <NUM> x <NUM> glass square. The glass with the solution was spin-coated at <NUM> rpm for <NUM> minutes. The resulting transparent films had an average thickness of <NUM>. After manufacturing, the films were punched into small discs with a diameter of <NUM>.

The combination of film and FREMS technology was evaluated in in vivo diabetic mouse models. The disease was induced by treating the animals with a dose of <NUM>/kg of Streptozotocin for <NUM> consecutive days. After a <NUM>-week period, the blood glucose level of the mice was checked and the mice with blood glucose above <NUM>/dL were considered diabetic. Two experimental cycles were performed. In the first cycle, the speed of wound healing was studied by calculating the wound area at different times. The experiment lasted <NUM> days. In the second cycle, on the other hand, the level of inflammatory mediators was evaluated <NUM> days after the induction of the wound. In both groups, full-thickness excisional wounds were generated to begin the experiments.

In both experiments, immediately after the production of the wound, dressing films were applied to the wounds, said films being made according to the example described above. The next day, FREMS therapy began, and the mice were subjected to electrostimulation every day until the end of the experiments.

The electrostimulation program called "Traumatic Ulcers" (described in detail in documents <CIT>, <CIT>, <CIT> and particularly <CIT>) lasting <NUM> minutes. The voltage was reduced considering the small body size of the mice compared to human applications described in the documents listed above. The voltage was then reduced to <NUM> V. The pulse sequences according to FREMS technology were applied by means of two adhesive electrodes directly on the shaved backs of the mice, one of the electrodes was positively charged and the other negatively. These electrodes were replaced with new ones each time after use to ensure full contact between the electrodes and the skin of the mice. During the electrostimulation the two electrodes were applied at a distance of <NUM> from the wound and in opposition to each other. Every day the two electrodes were applied in reverse, i.e., their polarity has been inverted.

During the experiments, the patch was applied immediately after the wound was generated. The next day, FREMS treatment began in the aforementioned "Traumatic Ulcers" mode, limiting the voltage to 15V.

Disturbances in blood flow and persistence of inflammatory conditions are the main reasons for unresolved diabetic ulcers. Therefore, the measurement of the level of inflammatory mediators was performed after the application of the two combined technologies.

After <NUM> days of injury induced damage in the in vivo diabetic mouse model, TNF-α levels were higher in the CTRL control group, while the values in the group of mice treated with FREMS electrostimulation alone, or with the PVP-I dressing alone and in the group of mice treated with the combination of FREMS electrostimulation and PVP-I dressing were statistically lower. Furthermore, in the group treated with the PVP-I dressing only and in the group treated with the combination of FREMS electrostimulation and PVP-I dressing according to the present invention, these values were also statistically lower than the values of the group treated only with electrostimulation according to FREMS technology.

Also the levels of IL-<NUM> in the group of mice treated only with electrical stimulation according to FREMS technology, in the group of mice treated with only the PVP-I dressing and in the group of mice treated with the combination of FREMS electrostimulation and PVP-I dressing were statically reduced compared to the CTRL control group. However, in this case, treatment with the combination of FREMS electrostimulation and PVP-I medication produced the lowest levels of IL-<NUM>, being statistically lower even than the values for the group of mice treated with only electrostimulation with FREMS technology and in the group treated with only PVP-I dressing.

A similar trend was also observed for IL-1β values with treatment with the combination of FREMS electrostimulation and PVP-I medication, showing the best results in reducing the level of this inflammatory mediator.

<FIG> show different embodiments of a biomedical device for the treatment of ulcers, particularly diabetic ulcers according to the more general concept described above.

In the following description, a flexible support element means a sheet or a flattened element to which are applied or wherein are incorporated by lamination of two or more layers or by drowning, constructive parts such as electrodes, conductors for the transmission of signals or pockets for drugs or for electronic circuits.

Furthermore, the flexible support elements described are intended to be provided with a continuous layer of adhesive or with zones for removable fixing to the skin of the human body.

<FIG> illustrates the block diagram of an electrostimulation apparatus, which according to the present invention is made in the form of a wearable apparatus.

The apparatus comprises one or more flexible supports indicated with <NUM>, <NUM>, 1r. Each flexible support bears stimulation electrodes <NUM>, <NUM>, r, the variable r being indicative of any natural number, since the individual supports <NUM>, <NUM>, 1r may be provided with an identical or a different number of electrodes. In the embodiment of <FIG>, the support 1r bears an electrode r and is illustrated with broken lines in order to show a possible embodiment which provides for more than two electrodes as provided in the previous experiment and in the preferred embodiment of the present invention.

However, it is possible to optionally provide more than two electrodes, each with its separate flexible element for supporting and adhering to the patient's body in a prefixed area and with a prefixed relative position with respect to the other electrodes.

A generator <NUM>, with an associated power supply <NUM> has an output channel for each electrode <NUM>, <NUM>, r through which a sequence of electrical stimulation pulses is fed to the corresponding electrode. The pulse generator <NUM> operates under the control of a logic control unit <NUM>.

This logic control unit is configured to provide the generators with instructions relating to the pulses to be generated in relation to the configuration parameters of said pulses. These parameters are related to one or more of the following quantities: amplitudes, intensity, power, frequency, duration, polarity, waveform and to generate a combination of a temporal succession of different pulses for one or more of the aforementioned parameters as well as to synchronize among them the pulses of the sequences supplied to the electrodes <NUM>, <NUM>, r for their delivery through the skin to the patient.

In the embodiment of <FIG>, a single logic control unit is provided to control the generator <NUM> in a synchronized way, but as will appear below, in this case it is a possible embodiment, being possible to provide alternative architectures which provide for two or more control units dedicated to a single generator or to subgroups of generators and which operate in a synchronized way with each other, automatically negotiating the control timing sequences of the generators.

The logic control unit <NUM> can be made either in the form of dedicated hardware wherein the logic control of the generators is steadily integrated according to one or more options that are selectable but substantially fixed.

Another embodiment, on the other hand, provides that the logic control unit is constituted by generic hardware comprising a processor and peripherals and that the logic control unit <NUM> executes a control software which is stored in a memory <NUM>. In relation to the specific application of the stimulating apparatus, the memory <NUM> can contain databases of different settings corresponding to different types of treatment, both as regards the anatomical region and as regards the effects to which the treatment is aimed.

According to a non-limiting embodiment, a memory area <NUM> can be provided which is dedicated to anatomical maps of positioning of the electrode(s) and/or of the flexible supports <NUM>, <NUM>, 1r in relation to the different conditions of the lesions to be treated and/or the anatomical areas wherein they are present.

Always according to a further embodiment which can be provided in any combination with one or more of the embodiments and variants previously described, it is possible to provide a communication interface <NUM> which allows the control unit to deliver the command signals to the generator <NUM> and to a setting and configuration unit <NUM> or to a man-machine interface unit which allows to perform manual maintenance, setting and configuration operations as well as to upgrade the program executed by the logic control unit <NUM> and/or the databases of the treatment protocols and/or of the anatomical maps of electrode positioning and possibly also of performing diagnostic activities of the units of the apparatus. The communication can take place both by means of cables and by radio, i.e. wireless.

The choice of the communication mode and protocols among those currently known by the skilled in the art is a pure opportunity choice dictated by the required bandwidth, the required signal power, the energy resources provided by the power supply and depends on the kind of architecture of the apparatus and the kind of treatment to be performed.

The setting and configuration unit <NUM>, or the interfacing unit, can consist of a remote unit, such as a mobile device made available to the user. This can also be a mobile device of the kind currently known wherein is installed an application which when executed configures the mobile device to perform the functions of the interface unit <NUM> of the apparatus.

Particularly advantageous examples of this kind of mobile unit can be devices such as smartphones, phablets, tablets or similar devices.

A preferred but non-limiting embodiment provides that the generator <NUM>, and all or at least some of the units described above <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, when present, are integrated in a single control device.

In this case, the control unit that integrates all said units or a part of them can consist of a dedicated hardware that incorporates in the hardware itself all the foreseen functions, or said device consists of a generic processing unit which executes a program wherein the instructions are encoded to make such hardware capable of performing the functions required for the execution of the electrostimulation according to the FREMS protocols envisaged in the present invention.

The generator and particularly the control device wherein said generator can be integrated together with one or more of the other units of <FIG>, can be produced as a wearable device, thanks to a wearable support that can be produced according to different embodiments.

With regard to flexible supports, an embodiment can consist of a support film, for instance of canvas or plastic material, to one of the faces of which a layer of adhesive material is applied. The electrode can consist of a sheet of conductive material cut with a prefixed shape and size and which is applied to the adhesive material. Each pole of each electrode is made from a piece in the form of a sheet of electrically conductive material and a power supply conductor is connected to each pole, for instance in the form of a band of conductive material.

The sheet-shaped pieces of conductive material can be attached to the adhesive layer. The conductors connecting the electrodes to the outputs of the channels of the generator or of the control device can also consist of tracks or bands of a sheet of electrically conductive material. As will be described later.

The electrodes and the conductive tracks or bands are further covered to be electrically insulated towards the outside by a band of plastic material, for instance a double-sided adhesive band, which on one side overlaps the conductors or conductive bands adhering against them and against the adhesive layer of the flexible support, while the other side of the double-sided tape restores the continuity of the adhesive layer in correspondence with the path of the conductors.

Several other construction forms are possible, for instance it is possible to provide that the individual layers are laminated on each other or that the conducting elements are fixed in a plastic matrix by molding. A further embodiment can provide for the production of the poles of the electrodes and/or of the conductive tracks by applying them using electrically conductive liquids which are sprayed to form the poles of the electrodes and/or the conductive tracks of the same.

According to an embodiment illustrated in <FIG>, the flexible support for at least two electrodes provided in the preferred embodiment of the present invention is made in the form of a frame that delimits a central window. The frame can be essentially annular in shape which can have any shape such as circular, elliptical, oval, or even polygonal.

On the annular shape it is possible to distribute one or more electrodes <NUM>, in this case two electrodes in diametrically opposite positions.

The flexible element in the shape of an annular frame can bear the connecting conductors of the same integrated inside it as described above, or in the form of electric cables fixed to the external visible surface of said flexible element at least for part of their length to the corresponding generator channel.

The central window is intended to accommodate the lesion or ulcer to be treated, being in this case the dimensions of the frame and/or its shape made so as to form a window of sufficient size to accommodate the lesion and at the same time to determine a position of each electrode relative to the edges of the lesion corresponding to a prefixed optimal distance.

According to one embodiment, this optimal distance is of the order of magnitude of a few centimeters, preferably at least one centimeter. Furthermore, the conformation of the annular frame and the position of the electrodes thereon is such as to make evident the relative positioning of the two electrodes on diametrically opposite sides with respect to the center of the lesion.

A preferred form which allows easy recognition of the disposition of the electrodes with respect to the lesion is the oblong, particularly elliptical, embodiment shown in the figures, however this embodiment, even if preferred, must not be considered limiting.

As far as the dressing film is concerned, this is made with shape and dimensions substantially corresponding at most to the shape and dimensions of the lesion positioning window delimited by the frame.

The dressing film made according to one or more of the previously described embodiments is provided as a separate element with respect to the flexible element that bears the electrodes and must be applied in a subsequent step to the application of the flexible element that bears the electrodes.

According to a still further advantageous feature, the flexible support can be made as a multilayer as indicated in <FIG>. In this case, a first layer consists of the layer <NUM> in contact with the skin. This layer is made of biocompatible material, such as preferably polyurethane material.

Said material can advantageously be further permeable to gases and is provided with a layer of adhesive on the part intended to come into contact with the skin.

According to an embodiment, the adhesive is of medium grade.

Still according to a further embodiment, said layer is of transparent material and/or of thin thickness and in any case such as to be sufficiently plastic to allow deformation both in application to the skin and in movement.

The annular element <NUM> has special housing areas for adhesion of two electrodes distributed at the two ends of the major axis of the elliptical shape of said ring <NUM>.

These housing areas consist of Ag-Cl gel and generate contact between the electrode carried by the ring <NUM> and the patient's skin.

The second layer <NUM> of the flexible support is shown in <FIG>. The second layer has an annular shape essentially congruent to that of the first layer <NUM> and adheres to said first layer by chemical and physical adhesion. The second layer constitutes a non-disposable system of more rigid material, preferably of biocompatible polyurethane.

According to a preferred embodiment, the second layer is also of gas permeable material and includes the circuit part indicated with <NUM>, <NUM>.

Preferably said circuit part is made as a flat cable or in the form of electrically conductive tracks as described above.

The ring <NUM> of the second layer bears in a position coinciding with the areas <NUM> of the first layer a corresponding electrode <NUM> which adheres in contact with the gel of said areas <NUM>.

A control device <NUM> connects to the conductors <NUM>, <NUM> and drives the electrodes. The control device <NUM> can be made according to one or more of the embodiments described with reference to <FIG> and can be mounted steadily or in a removable way, for instance in an openable and closable pocket of an adhesive flexible element which has a contact surface with the skin. This flexible support element of the control device <NUM> is also made of biocompatible material, preferably of biocompatible polyurethane.

According to a preferred embodiment, said material is also adhesive on the surface in contact with the skin.

In combination with the adhesive layer, it is possible to provide a mechanical fixing by tightening thanks to an elastic band, not adhesive such as a band provided with a velcro closure, snap buttons or the like. This band indicated with <NUM> in <FIG> has the function of safety fixing of the control unit <NUM>.

In the embodiment wherein the connection between the electrodes and the corresponding output of the control device is of the conductive band or track kind steadily integrated in the flexible element, the control device <NUM> is steadily fixed to an extension <NUM> of the frame <NUM> as shown in <FIG>. In this case, in the "not in use" condition, said extension <NUM> can be foldable against the frame element <NUM> and can be turned outwards in the condition of application at the moment of use.

The control device indicated with <NUM> is inserted in a housing pocket <NUM>.

Inside the elliptical element <NUM>, the dressing film applied above the lesion is placed in the window which is centered with respect to said frame element <NUM> and also provided inside the window.

In a possible embodiment the control device is steadily housed in position between two layers <NUM> and <NUM>. The conductors <NUM>, <NUM> are steadily connected to the electrodes <NUM> and to the corresponding outputs of the control device <NUM>.

In another embodiment, the extension <NUM> of the flexible element forms an openable pocket so that the control device <NUM> is removable. In this case, the two conductors <NUM>, <NUM> can end in a contact base which cooperates with a coupling terminal provided on the control device <NUM>, in such a way that by inserting the same in the pocket, the connection with the control device is automatically generated and extracting the control device from the pocket said contact base is separated from the coupling terminal, interrupting the contact with the electrodes and releasing the control device itself relating to its extraction from the pocket.

<FIG> shows a further embodiment wherein the control device does not integrate all the units referred to in the previous description according to the embodiment of <FIG>, but these are divided into three separate units, each supported together on a flexible element that can be separated from the flexible element supporting the electrodes or connected to the latter as in the example of <FIG>.

In this embodiment is provided a communication unit in transmission and reception <NUM> and a power supply battery <NUM> which are separated from the control device <NUM> which integrates all the other units such as the generator, the control unit, the memories referred to in Example of <FIG>. The control device <NUM>, the communication unit <NUM>, the battery <NUM> are housed in a corresponding pocket <NUM>, <NUM> and <NUM> respectively.

As illustrated, at least the pocket <NUM> of the supply battery <NUM> can be opened to allow it to be replaced with a charged battery.

Alternatively, one or more of the additional pockets can be opened or the battery pocket cannot be opened, but the battery is of the rechargeable kind and has an externally accessible connection socket with a recharging power supply or recharging can be performed using wireless chargers.

In one embodiment, this battery socket can be accessed through a window (not shown) in the wall of pocket <NUM> which can be openable and closable or always open.

The pockets <NUM>, <NUM> and <NUM> are provided for instance on a flexible support element <NUM>, for instance of the adhesive kind such as those carrying the electrodes.

<FIG> illustrates a variant wherein the connection of the control device <NUM> with the electrodes is made by means of independent electrical conductors for each electrode and which are indicated with <NUM>.

Said conductors extend up to the connection connectors of the generators present on each support element for the electrodes and bear corresponding connection pins.

The connection among control device <NUM>, communication unit <NUM> and battery <NUM> can take place through conductive tracks or cables, particularly flat cables, integrated in the flexible element <NUM>.

With reference to <FIG>, here is illustrated a further variant of the embodiment, wherein in addition to the first and second layers of <FIG>, said embodiment has a third layer indicated as <NUM> in <FIG>.

According to an embodiment, this third layer is of disposable material and has the function of covering the second layer shown in <FIG> towards the outside.

According to a further characteristic, the third layer can further cover also the central area of the annular shape of the two underlying layers, extending also along said central part.

Advantageously, the central part is retained by the thickness of the two underlying layers lifted up with respect to the skin and in the part coinciding with the window is free of adhesive so as not to adhere to the part of the lesion or to the dressing film.

According to yet another embodiment, the third layer <NUM> can act as an element for closing and opening said central zone of the annular shape of the underlying layers. Said central window indicated with <NUM> being intended to receive the lesion to be treated and the dressing film.

In an embodiment, on one side of said central zone, the third layer is provided or is shaped in such a way as to form a hinge as indicated schematically by line <NUM>. Said hinge is advantageously elastic and has the function of allowing repeated opening and closing actions, for instance to allow the replacement of the dressing film or the like.

According to a preferred embodiment, the material of the third layer has a greater rigidity than the first layer and is in any case made of biocompatible and/or gas-permeable material.

According to another embodiment, it is possible to provide that inside the window delimited by the frame can be provided a removable layer of biocompatible polyurethane sponge which has a prefixed thickness and has a prefixed capacity to absorb liquids, particularly for the removal of the exudate by periodic replacement.

With reference to another embodiment that can be derived from that according to <FIG>, in place of a frame closed on itself, it is possible to provide a flexible element which is provided with two branches connected to each other and which form a concave area intended to accommodate the wound and the dressing film.

The electrodes are provided at the terminal ends of the two branches which are curved or slanted with respect to each other and have a length such that said ends that bear the electrodes are diametrically opposite with respect to the central bisector axis of the concavity.

With reference to the specific embodiment of <FIG>, it is possible to provide that the flexible element ends at the level of the section line indicated with <NUM>.

<FIG> show two examples of application of the apparatus described in <FIG>.

<NUM> indicates the control unit and <NUM> indicates the fastening by tightening element. <NUM> indicates the flexible support composed of the three layers of the example of <FIG>.

<NUM> indicates the connection conductors of the control unit <NUM> to the electrodes of the flexible support according to <FIG>.

Claim 1:
A biomedical device for the therapeutic treatment of ulcers or lesions, particularly diabetic ulcers, said device consisting of a kit comprising in combination an electro-stimulator device and a dressing comprising a pharmaceutical composition and wherein the electro-stimulating device and the said dressing are applied simultaneously for treating an ulcer and which device comprises:
- at least an electrical pulses generator (<NUM>), said electrical pulses being organized in sequences of electrical pulses having prefixed values of typical parameters, said typical parameters comprising one or more of the following parameters: amplitude, duration, frequency and/or waveform of said pulses and said parameters being configured according to the technology called FREMS acronym for Frequency Rhythmic Electric Modulation;
- said generator (<NUM>) comprising at least two separate stimulation channels, through which said sequences are delivered to body areas of an organism independently for each channel;
- at least two stimulation electrodes (<NUM>, <NUM>, <NUM>, <NUM>), each of which is connected or connectable to a respective stimulation channel and each of which is intended to be removably applied to one of two different prefixed body zones of an organism;
- each electrode (<NUM>, <NUM>, <NUM>, <NUM>) being applied externally to the patient's skin in correspondence with said prefixed area and with a prefixed position relationship with respect to the position of the remaining electrode or electrodes;
- a control unit (<NUM>; <NUM>) of said at least one electric pulse generator (<NUM>) communicating with said electric pulse generator;
- a command and/or data entry interface for setting and/or displaying setting data and/or setting settings of said one or more generator (<NUM>);
- said dressing consisting of a film comprising a solution of povidone iodine (PVP-I) and sodium alginate (NaAlq) and intended to be applied while treating the ulcer;
and wherein
- the at least two electrodes (<NUM>, <NUM>, <NUM>, <NUM>) are intended to be arranged on diametrically opposite sides of the lesion at a prefixed distance therefrom.