COMBINATION OF WOUND IRRIGATION SOLUTION AND COLD PLASMA FOR WOUND TREATMENT

Description

[0001] The present invention relates to the combination of wound irrigation solution, cold atmospheric plasma, and an activated charcoal dressing for use in a method of treating wounds. The present disclosure further relates to a method of wound treatment comprising irrigating the wound with a wound irrigation solution and treating the wound with cold atmospheric plasma.

[0002] Many wounds, especially chronic wounds, heal very slowly or not at all. This is often due to severe infections, often caused by bacteria that can no longer be treated with antibiotics due to resistance.

[0003] Large, externally accessible, and often chronic wounds are treated, among other things, with wound irrigation solutions for wound cleansing. This is demonstrated by US2015 / 320604, which discloses the use of a wound irrigation solution for treating wounds, further employing a negative pressure activated carbon dressing. US8267884 also covers a method for wound treatment, which includes rinsing the wound with a wound irrigation solution and treating the wound with cold atmospheric plasma.

[0004] On the one hand, wound irrigation solutions are used to remove tissue remnants, necrosis particles, excess exudate, plaque, dressing residues, cell debris, etc., and biofilms are also eliminated - often in conjunction with antiseptics and surgical debridement.

[0005] Such wound irrigation solutions are usually isotonic (physiological) and can contain various antiseptics, which—depending on the site of application and the cause of infection—include bactericidal, bacteriostatic, fungicidal, fungistatic, and / or virucidal agents. Some wound irrigation solutions also contain reactive oxygens such as singlet oxygen, which may initially be complexed (e.g., sodium hypochlorite) and then released (Kammerlander et al., pro care 08 / 2012, pp. 26-29). However, not all wounds can be healed with wound irrigation solutions; recurrences often occur after treatment.

[0006] The present invention addresses this technical problem as set forth in the present description and defined in the claims. Figure 1A shows the patient described in Example 4 before the wound treatment according to the invention. The patient had an infected driveline. Figure 1Bshows a PET-CT scan of the patient described in Example 4 before the wound treatment according to the invention. The patient had an infected driveline. Figure 1C shows the patient described in Example 4 after 3 weeks of treatment with the wound treatment according to the invention. Figure 2 shows a driveline with activated carbon NPWT dressing: Activated carbon foil (1) was placed in the wound bed, enveloping the driveline and protruding from the wound to cover the surrounding skin area; a grey-black NPWT sponge (2) is inserted over the activated carbon foil. Figure 3 shows the alternation of irrigation and cold plasma (CAP) as well as the sealing of the wound with activated carbon NPWT.

[0007] As was surprisingly discovered within the scope of the present invention, a combination of wound irrigation solution, cold atmospheric plasma (hereinafter also referred to as "cold plasma" or "CAP"), and an activated charcoal dressing is highly suitable for use in wound treatment. As demonstrated, chronic wounds can be largely healed in this way, and the number and intensity of recurrences can be significantly reduced. No undesirable side effects were observed. It was found that treating wounds with wound irrigation solution alone, e.g., ActiMaris ®, did not lead to satisfactory results, whereas the combination of wound irrigation solution, cold plasma, and an activated charcoal dressing led to more than satisfactory, and in this case even surprising, therapeutic successes in wound treatment.

[0008] The present invention therefore relates to the combination of wound irrigation solution, cold atmospheric plasma and an activated carbon dressing in a method for treating wounds, comprising the following steps: (a) Irrigating the wound with a wound irrigation solution, (b) treating the wound with cold atmospheric plasma, and (c) applying a negative pressure activated charcoal dressing to the wound.

[0009] The present invention is more particularly set forth in the appended claims.

[0010] Alternatively, the present disclosure relates to the use of a combination of wound irrigation solution and cold atmospheric plasma for use in the treatment of wounds.

[0011] In one embodiment relating to the present disclosure, an activated carbon dressing is also used for wound treatment, preferably a negative pressure activated carbon dressing. Examples of suitable activated carbon dressings are known to those skilled in the art and include, among others, Actisorb®, Askina®, Carbosorb, CarboFlex®, Vliwaktiv® AG absorbent compress, and others. A dressing made of activated carbon and negative pressure sponge, known to those skilled in the art, for example, as "advanced Negative Pressure Wound Therapy (aNPWT)" or, in German-speaking countries, also as activated carbon NPWT, can be used as a negative pressure activated carbon dressing. When using such an activated carbon NPWT (aNPWT), intensive wound therapy with shorter change times (every 2-3 days) is possible, since the carbon foil ensures active cleansing. The release of oxygen radicals is expressly desired in this application.

[0012] However, the aNPWT treatment method must be distinguished from the standard NPWT procedure used in the state of the art, e.g., Avance ®< Flex (Mölnlycke ®< ). This involves the use of a green sponge, which allows the detection of blood loss through the discoloration of the sponge. In this procedure from Mölnlycke Health Care, the use of hypochlorite solution and hydrogen peroxide is expressly discouraged due to the release of oxygen radicals. It is simply a modified NPWT procedure (the use of a green sponge), but without the activated charcoal dressing used for wound cleansing as in aNPWT.

[0013] When using an activated carbon NPWT, the activated carbon can also fix residual germs under the negative pressure sponge and thus reduce the recurrence of infection. Thus, according to the invention, the treatment progress can be further supported by the combination of wound irrigation solution and cold atmospheric plasma. Particularly preferred for the application according to the invention is an activated carbon dressing in which the activated carbon-containing part is applied (i.e., placed) directly onto the wound. This allows bacteria to be bound without a barrier. A preferred activated carbon dressing that allows direct application of the activated carbon-containing part of the dressing is Zorflex® Activated Carbon (Chemviron (England)). To date, no company has recommended the use of carbon foil in direct contact with the wound bed.

[0014] The present disclosure further relates to a method for wound treatment, comprising (a) Flushing the wound with a wound solution, and (b) treating the wound with cold atmospheric plasma.

[0015] Preferably, a moist film of the irrigation solution remains in the wound bed before the wound is treated with cold atmospheric plasma.

[0016] In one embodiment of the present disclosure, the method may also include a further step (c) Rinsing the wound again with a wound irrigation solution (preferably with the same wound irrigation solution as in step (a)) and / or (d) applying an activated charcoal dressing to the wound. According to the invention, steps (a), (b) and optionally (c) and / or (d) are preferably carried out in the order (a), (b), (c), (d).

[0017] The disclosed method may further comprise a further step of treating the wound irrigation solution with cold atmospheric plasma, preferably before step (a) and / or before step (c).

[0018] In the context of step (d), the invention also preferably involves a vacuum activated carbon dressing. Examples of suitable (vacuum) activated carbon dressings are known to the person skilled in the art, as already explained above.

[0019] As already stated above, the present invention relates to a combination of wound irrigation solution, cold atmospheric plasma and an activated charcoal dressing for use in a method of treating wounds, comprising: (a) Irrigating the wound with a wound irrigation solution, (b) treating the wound with cold atmospheric plasma, and (c) applying a negative pressure activated charcoal dressing to the wound.

[0020] Preferably, a moist film of the irrigation solution remains in the wound bed before the wound is treated with cold atmospheric plasma.

[0021] In one embodiment of the present invention, the above-described combination of wound irrigation solution, cold atmospheric plasma and an activated charcoal dressing for use in a method of treating wounds may also comprise a further step: (d) Rinsing the wound again with a wound irrigation solution (preferably with the same wound irrigation solution as in step (a)). According to the invention, steps (a), (b), (c), and optionally (d) are preferably carried out in the order (a), (b), (c), (d).

[0022] In one embodiment of the present invention, the above-described combination of wound irrigation solution, cold atmospheric plasma, and an activated charcoal dressing for use in a method of treating wounds may further comprise the further step of treating the wound irrigation solution with cold atmospheric plasma, preferably before step (a) and / or before step (d).

[0023] In the context of step (c), the invention also involves a vacuum activated carbon dressing. Examples of suitable (vacuum) activated carbon dressings are known to the person skilled in the art, as already explained above.

[0024] Preferably, a moist film of the irrigation solution remains in the wound bed before the wound is treated with cold atmospheric plasma.

[0025] Furthermore, in one embodiment, the present invention alternatively also relates to a combination of wound irrigation solution, cold atmospheric plasma and an activated carbon dressing for use in the treatment of wounds, wherein the wound irrigation solution is prepared for irrigating wounds and the cold atmospheric plasma injection is prepared for treating wounds and an activated carbon dressing is prepared for application to the wound.

[0026] Wound irrigation solutions in the context of the present invention particularly include solutions suitable for wound cleansing and can be adapted to the wound to be rinsed or cleaned, as known to those skilled in the art. In one embodiment, these are wound irrigation solutions that are sterile, pain-free or pain-free, physiological, non-irritating or caustic, and / or heatable to at least 28°C. Wound irrigation solutions in connection with the present invention can include salts (e.g. NaCl, sea salt) and / or electrolytes (e.g. sodium, potassium, calcium), alcohols (e.g. ethanol, isopropanol, phenoxyethanol), quaternary ammonium compounds (e.g. benzalkonium, cetylpyridinium, octenidine, polyhexanide), iodine-containing compounds (e.g. povidone-iodine / PVP-iodine), chlorine-containing compounds (e.g. chlorhexidine), hexetidine, bibrocathol, taurolidine, enzymes (e.g.Varidase, Fibrolan), and / or (other) bactericidal, bacteriostatic, fungicidal, fungistatic, and / or virucidal ingredients (antiseptics). Such bactericidal, bacteriostatic, fungicidal, fungistatic, and / or virucidal ingredients can, for example, include: antibiotics, reactive compounds such as ROS (Reactive Oxygen Species) and / or RNS (Reactive Nitrogen Species). Examples of ROS in this context include singlet oxygen ( 1< O 2 ), oxygen radicals, hydrogen peroxide (H 2 O 2 ), ozone (O 3 ) and others. Examples of RNS include NO and NO 2 . ROS as a potential component of wound irrigation solutions can also be complexed in other compounds according to the invention, e.g. singlet oxygen in the form of sodium hypochlorite (NaOCl). In the case of complexed singlet oxygen such as NaOCl, the singlet oxygen is usually released upon wound contact, as is known to those skilled in the art.In one embodiment of the present invention, the wound irrigation solution contains about 0.01-0.1 wt% NaOCl, preferably about 0.01-0.08, about 0.02-0.08, about 0.02-0.07, about 0.02-0.06 or about 0.02-0.05 or 0.03-0.05 wt% NaOCl.

[0027] In one embodiment of the present invention, the wound irrigation solution contains singlet oxygen (1<O2), which, as already explained, also includes complexed singlet oxygen (1<O2), such as sodium hypochlorite (NaOCl). With complexed singlet oxygen such as NaOCl, the singlet oxygen is generally released upon contact with the wound. In a particular embodiment, the wound irrigation solution also contains salt, e.g. NaCl, and / or sea salt. In a particular embodiment, the salt content (e.g. NaCl content) is below 5, preferably 4 or 3% by weight of the wound irrigation solution. In a further embodiment of the present invention, the wound irrigation solution contains polyhexanide and / or octenidine, preferably polyhexanide. Suitable wound irrigation solutions are known to the person skilled in the art and can be tailored to the wound to be treated. In the context of the present invention, the wound irrigation solution can, for example,ActiMaris ®< , Lavanox ®< , Kerrasol ®< , BIOsept ®< wound irrigation solution, or Microdacyn60 ®< Wound Care, preferably ActiMaris ®< , Lavanox ®< or Kerrasol ®< , and particularly preferably Lavanox ®< or Kerrasol ®< .

[0028] The wounds to be treated according to the invention can, in principle, be any type of wound that is amenable to a wound irrigation solution and treatment with cold plasma. These are preferably wounds on the skin or mucous membrane, which are preferably accessible without surgical intervention (superficial wounds). In one embodiment of the present invention, the wound to be treated is infected or inflamed with one or more bacteria and / or viruses, preferably with bacteria. Typical bacterial infections and inflammations can be caused by, for example, Enterobacter sp. (e.g. E. cloacae ) , Pseudomonas sp. (e.g. P. aeroginosa ) , Staphylococcus sp. (e.g. S. aureus ) , Klebsiellasp. (e.g. K. pneumonia ) , E. coli, Streptococcus sp., and / or Proteus sp. In one embodiment, the wound to be treated according to the invention is acutely or chronically infected or inflamed, preferably chronic (chronic wound). "Chronic" in this context can mean that the wound has not healed within at least 4, 6, or 8 weeks after wound formation, preferably after at least 4 weeks.

[0029] In the context of the present invention, the wound to be treated is treated using a combination of wound irrigation solution as described here and cold (also called "non-thermal") atmospheric plasma (also called "cold plasma"). Cold atmospheric plasma (cold plasma) comprises partially ionized gas (e.g., ambient air, argon, helium mixtures, preferably with a small admixture of oxygen, or nitrogen; preferably argon), which is generated under atmospheric conditions (ambient pressure). The temperature of the plasma preferably does not exceed 50°C, preferably not 40°C. In one embodiment, the cold plasma contains only up to 0.1 to 10 ppb (parts per billion) of ionized particles, e.g., 0.5 to 5 ppb or approximately 1 ppb. In the context of the present invention, cold plasma can generate electrons, ions, radicals, ROS, RNS and / or UV radiation.The generation and application of cold plasma is known to those skilled in the art, such as that offered, for example, by terraplasma medial GmbH (Germany; http: / / terraplasma-medical.com / ). Typical gases for plasma generation according to the invention can include, among others: air, argon, helium mixtures, preferably with a small admixture of oxygen, and / or nitrogen, preferably argon.

[0030] Devices suitable for generating and applying cold plasma according to the invention and for use in medical treatment are known to those skilled in the art and include, for example, PlasmaDerm® (Cinogy), kINPen® (INP Greifswald), Plasma One (plasma Medical Systems GmbH), and SteriPlas® (Adtec Healthcare). The cold plasma can, in principle, be applied in any suitable manner, as known to those skilled in the art and as described, for example, in Eswaramoorthy et al., Biophys (2017), 9: 895-917.

[0031] As already described, in connection with the present invention, the wound is first rinsed with a suitable wound irrigation solution. The exposure time can vary depending on the wound and is typically approximately 5-10 minutes, preferably approximately 7 to 8 minutes. Depending on the accessibility of the wound, the wound irrigation solution can be applied directly or with aids such as soaked compresses. Likewise, within the scope of the present invention, infected areas near the wound that are not themselves part of the wound but could promote reinfection of the wound (e.g., cables, tubes, implants, or other devices) can also be treated with the wound irrigation solution. Thereafter, if necessary, the wound irrigation solution can be largely removed using suitable measures (e.g., compresses). In one embodiment of the present invention, the wound irrigation solution is not completely dried off, so that a residual light remains.According to the invention, it is also possible, in the subsequent step of cold plasma treatment, to treat not only the wound or the areas near the wound but also the remaining wound irrigation solution with cold plasma. Subsequently, according to the invention, the wound and, optionally, any infected areas near the wound are treated with cold, atmospheric plasma. The treatment depends on the specific wound, as will be readily apparent to a person skilled in the art. Relevant parameters include the size and depth of the wound, as well as the degree of infection, if any. A typical treatment time with cold plasma can also be approximately 5-10 minutes, preferably approximately 3-5 minutes; for larger wounds such as sternal wounds, it is generally more like 5-10 minutes. After the plasma treatment, a further wound irrigation step can follow, analogous to the first wound irrigation, whereby the same wound irrigation solution is preferably used in both cases.In one embodiment of the present invention, the plasma treatment is followed by a further rinsing step with a wound irrigation solution, preferably with the same wound irrigation solution as used in the previous rinsing. Afterward, the wound irrigation solution can again be largely removed using suitable measures (e.g., compresses).

[0032] In one embodiment of the present invention, the wound irrigation solution itself can also be treated with cold plasma, for example for approximately 5-10 minutes, or approximately 3-5 minutes. This can be the case in particular if the wound irrigation solution has not been completely dried after wound irrigation, as already described above.

[0033] After treating the wound with cold plasma or after subsequent repeated rinsing with the wound irrigation solution as described in the present invention, the wound is further treated with a negative pressure activated carbon dressing (advanced Negative Pressure Wound Therapy (aNPWT)). Examples of suitable activated carbon dressings are known to those skilled in the art and include Actisorb®, Askina® Carbosorb, CarboFlex®, Vliwaktiv® AG absorbent compress, and others. A dressing made of activated carbon and a negative pressure sponge, known to those skilled in the art as "advanced Negative Pressure Wound Therapy (aNPWT), for example, can be used as a negative pressure activated carbon dressing. The activated carbon under the negative pressure sponge can fix residual germs and thus reduce renewed progression of the infection. Thus, according to the invention, the treatment progress can be further supported by the combination of wound irrigation solution and cold atmospheric plasma.Particularly preferred for the application according to the invention is an activated charcoal dressing in which the activated charcoal-containing portion is applied (i.e., placed) directly onto the wound. This allows bacteria to be bound without a barrier. A preferred activated charcoal dressing that allows direct application of the activated charcoal-containing portion of the dressing is Zorflex® Activated Charcoal (Chemviron (England)).

[0034] In the context of the present invention, the singular forms of the articles der / die / das or ein / eine always also include the corresponding plural forms, unless explicitly stated otherwise.

[0035] Furthermore, the term "and / or" includes both the respective terms "and" and "or", as well as all or any possible combination of the respective elements connected by "and / or".

[0036] The term "about," "approximately," or "approximately" preferably means within 20%, 10%, 5%, or 2% of the respective value or range. Furthermore, the exact values or ranges following the term "about" or "approximately" are also expressly included.

[0037] The term "comprehensive" as used herein means the inclusion of the respective features, concepts, or values, but not the exclusion of any features, concepts, or values not listed. One embodiment of the term "comprehensive" may also be the exclusive term "consisting of," unless explicitly stated otherwise.

[0038] It should be understood that this invention is not limited to the specific methods, protocols, materials, reagents, and substances, etc., described herein and, as such, may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0039] The following examples serve merely to illustrate the present invention and do not limit the scope of the invention in any way. The scope of the present invention is defined by the claims. EXAMPLES Example 1 General treatment regimen

[0040] Before starting treatment, surgical treatment of a wound may be necessary. The wound area is opened as completely as possible. General surgical debridement is performed. Dead tissue and bone fragments are removed if necessary. This serves to initially reduce the bacterial load and prepare the wound bed. Once sufficient hemostasis has been achieved, an initial dressing (activated charcoal NPWT) can be applied.

[0041] The combination therapy according to the invention is usually performed in an outpatient setting. Due to the minimal pain involved, the administration of analgesics or even anesthesia standby is generally unnecessary. Dressing changes are performed under sterile conditions (sterile gloves, work surfaces, and face masks). Therefore, two people are ideally required to perform this therapy safely and quickly. Example 2 Irrigation and cold plasma treatment of wounds Wound irrigation to release singlet oxygen into the wound

[0042] After removing the surgical dressing (photo documentation, swab collection), the wound area is rinsed with a wound irrigation solution containing activated oxygen (e.g., ActiMaris, Kerrasol, Lavanox). In cases where there are external access points to the body, such as Driveline, the areas to be treated are wrapped with appropriately soaked compresses. The contact time is on average 5-8 minutes. The excess fluid is then removed with dry compresses, leaving a moist film of the irrigation solution in the wound bed. Cold plasma treatment

[0043] The wound area to be treated is treated with cold plasma (e.g., Steriplas from Adtec). Argon plasma is generated from argon gas in an electric field, which in turn converts atmospheric oxygen into reactive oxygen species (ROS). These, along with a small amount of UV light, form the active components for combating pathogens and stimulating the body's own cells to improve their defense against infections. In addition to the direct plasma effect (high penetration depth due to the atomic structure), the residual irrigating fluid extends the plasma's exposure time. The exposure time of the cold plasma is approximately 5 minutes per treated area (i.e., 8-10 minutes with an open sternum, for example). Example 3 Wound irrigation with activated oxygen, cold plasma treatment and wound sealing with activated carbon NPWT Repeated wound irrigation with release of singlet oxygen

[0044] Immediately following the cold plasma treatment, the wound bed is treated again as completely as possible with the irrigating solution (if necessary, moist compresses are used for external access, e.g., Driveline). This is done partly to maximize the available treatment time, but also to protect the wound bed from contamination until the sealing dressing is applied. The contact time, which also lasts approximately 5 minutes, is used to prepare the activated carbon NPWT dressing in the final treatment step. Immediately before applying the activated carbon foil, the fluid is removed again with dry compresses. Applying the activated carbon NPWT dressing (aNPWT)

[0045] The NPWT sponge is cut to size on a sterile surface. The activated carbon foil is placed in the wound bed. It is important that the foil fills the entire wound bed if possible (one or two layers) to ensure the best possible contact with the wound tissue. The carbon foil should protrude from the wound to cover the surrounding skin area by 1 to 2 cm (wound edge protection to prevent microbial migration). The appropriately cut NPWT sponge is then inserted and sealed with a sealing foil. ( Figure 2 ). In the case of deep sternal infections, a double layer of film and sponge can also be applied: first a layer of activated charcoal to protect the heart, then an intersternal sponge, then activated charcoal for the presternal soft tissue, and finally a superficial sponge. Change intervals

[0046] The goal of intensified wound treatment is to shorten the treatment time, which ultimately reduces the risk for the patient (wound complications) and helps to save costs in the long term. For these reasons, it is necessary to shorten the change intervals ( Figure 3 ) To shorten the duration of the procedure. While treatment intervals of 4 to 5 days were normal in the previous standard NPWT treatment, dressing changes with cold plasma application should be performed every 2 to 3 days if possible under this treatment regimen.

[0047] The shortened change intervals prevent pathogen regeneration from being significantly hindered during the NPWT period, especially since fresh active substances (especially singlet oxygen) are applied with each treatment. The activated carbon film in the sealed wound inhibits the migration of pathogens, thus helping to more quickly contain potential residual sources of infection. Diploma

[0048] After consolidation of the wound bed (smear results, inflammatory markers (e.g., CRP progression), macroscopic findings, granulation), surgical wound closure is performed. Optionally, further treatment with irrigating solution and cold plasma can also be performed in the operating room. Example 4

[0049] The patient received an artificial heart (LVAD) in 2013. Since the fall of 2015, he was initially treated as an outpatient due to a driveline infection. The first documented treatment of the driveline was with ActiMaris ®< . Several months later, he was admitted to the hospital for surgical treatment of the infection. The infection was so severe that the patient could already smell before entering the door due to the Pseudomonas infection. The degree of infection is in the Figures 1A and 1BThe surgical revision was performed immediately. After the bleeding tendency subsided, the patient was treated with the combination procedure according to the invention. Within only three weeks, the infection parameters normalized (CRP < 0.5) (see Figure 1C ) and the patient was discharged with the wound to outpatient care at his own request.

[0050] It should be noted that treatment with ActiMaris ® alone for six months was unsuccessful, resulting in a significant progression of the infection with an increase in infection parameters. After three weeks of combination therapy, the improvement shown above with normalization of infection parameters was achieved.

Claims

1. A combination of a wound rinsing solution, a cold atmospheric plasma and an activated carbon dressing for use in a method for the treatment of wounds, comprising the following steps: (a) rinsing the wound with a wound rinsing solution, (b) treating the wound with cold atmospheric plasma, (c) applying a vacuum activated carbon dressing to the wound.

2. The combination for the use according to claim 1, further comprising (d) rinsing the wound again with a wound rinsing solution.

3. The combination for the use according to any one of claims 1 to 2, further comprising treating the wound rinsing solution remaining on the wound with cold atmospheric plasma.

4. The combination for the use according to any one of claims 1 to 3, wherein the wound rinsing solution contains reactive oxygen.

5. The combination for the use according to any one of claims 1 to 4, wherein the wound rinsing solution contains singlet oxygen.

6. The combination for the use according to any one of claims 1 to 5, wherein ambient air or argon is used for plasma generation.

7. The combination for the use according to any one of claims 1 to 6, wherein the salt content of the wound rinsing solution is less than 4% by weight.

8. The combination for the use according to any one of claims 1 to 7, wherein the part of the activated carbon dressing containing activated carbon is applied directly to the wound.