Treatment instruction |  Active components |  Effect  |   Study situation  |   Side effects  |  Reimbursement

Treatment with the CPTpatch

For treatment, a CPTpatch must be applied to the wound area and using a CPTcube. Application of the wound dressing is simple and safe (Figure 1).

Treatment starts automatically after pressing the start/stop button on the CPTcube. After the treatment period of 2 minutes, which is defined internally by the device, has elapsed, the CPTcube automatically goes into standby mode. However, the treatment can be stopped at any time by pressing the Start/Stop button on the CPTcube. This interrupts the voltage supply to the CPTpatch and the CPTcube immediately goes into standby mode.

The treatment can be repeated as often as necessary until the desired therapeutic success has been achieved. However, it should be noted that there should be at least 24 hours between each plasma treatment. The treatment can and should be used adjuvantly to other forms of therapy or recommendations of the corresponding guidelines at the discretion of the treating physician. Following plasma treatment, the wound can be covered with commercially available wound dressings.

The active components explained.

Active components (excerpt from position paper on risk potential and application perspectives of cold atmospheric pressure plasma in medicine, NZPM)

According to current international research, the main active components of cold atmospheric pressure plasma are reactive nitrogen and oxygen species (RNS, ROS), UV radiation and electric fields.

Reactive nitrogen and oxygen species (RNS, ROS) are formed locally and for a short time by coupling electrical energy into gases that are not biologically active per se (argon, helium, nitrogen, oxygen, air as well as mixtures thereof) and subsequent interacting with adjacent media (atmospheric air, liquids, surfaces). In principle, the same reactive species are sometimes produced in the human body as part of normal metabolism and in some cases have important functions in controlling and mediating physiological and pathological processes. Briefly elevated doses of these RNS and ROS can be effectively detoxified by endogenous systems.

UV radiation is used medically in phototherapy and photochemotherapy, among other applications. In this context, as well as from the point of view of general personal and occupational safety, also outside the medical environment, limit values have been established for UV exposure, which are significantly lower in cold atmospheric pressure plasma devices.

Two important findings of basic plasma medical research in recent years are:

1. biological plasma effects on cells and in tissues are mediated by changes in the fluid cell environment.

2. oxidizing species, so-called reactive oxygen and nitrogen species (ROS, RNS), put into the liquid or formed in the liquid play a dominant role in biological effects induced by plasma action.

The same reactive species (ROS, RNS) are also produced in the human body as part of normal metabolism and in some cases have important functions in controlling and mediating physiological and pathological processes. The most important ROS and RNS are hydroxyl radical (OH-), hydrogen peroxide (H2O2), superoxide or hyperoxide (O2–), nitric oxide (NO-), nitrogen dioxide (NO2-) and peroxy nitrite (ONOO-). They play an important role in wound healing processes, for example. This finding provides an essential scientific basis for the concept of plasma-assisted wound healing, in which, in addition to the well-known antibacterial/disinfectant plasma effect, stimulation of tissue regeneration is also to be achieved by plasma action. One mechanism of plasma action is thus based on the support of endogenous functions which – for example in the case of non-healing chronic wounds – cannot be sufficiently effective due to disease-related disorders. Furthermore, it is known that a certain basic concentration of RNS and ROS is always present in human cells. Due to the physiological occurrence of these species, short-term elevated concentrations can be effectively detoxified by endogenous systems [16-24]. Using transcriptome analyses of in vitro plasma-treated human cells, it has been shown that genes associated with the cellular stress response are increasingly upregulated and antioxidant active enzymes are produced as a result of plasma treatment [25]. Since plasma treatments are localized and time-limited, under normal conditions, the risk of side effects associated with entry of these ROS and RNS into tissues is expected to be exceptionally low.


3. Ultraviolet Radiation (UV radiation).

UV-B radiation in particular is used in dermatology as part of phototherapy. According to the recommendations of the German Dermatological Society (DDG) on phototherapy and photochemotherapy, initial doses between 20 and 60 mJ/cm2 are recommended for broad-spectrum UV- B application (280-320 nm), depending on the skin type, and doses between 200 and 600 mJ/cm2 are recommended for narrow-spectrum UV-B treatment (311 nm) [30].

A comparison with solar radiation shows that the UV intensity emitted by the cold atmospheric pressure plasma sources used in clinical trials or approved as medical devices to date is far below that of sunlight [31-33].

For the plasma sources currently certified as medical devices, it has been shown that under the recommended conditions of use (working distance, treatment time), the maximum permissible daily UV dose is significantly undercut [34, 35].


4. Electric Fields

Electric fields can first be divided into direct and alternating fields. In addition, the pulsation of such signals as well as monophasic or biphasic modulation allows for a high parametric diversity. Technical frequencies are in the range of a few Hz up to the GHz range. Devices using only electric fields have been established for many years for application in and on the human body and can induce an electric current flow in biological tissue as a result of the electric fields. Regardless of the device, the use of electrical signals for electrostimulation offers a variety of proven applications in medical care. For example, cell movement of immune cells (macrophages and granulocytes) and migration of skin cells (keratinocytes) and corneal epithelium can be specifically influenced in response to an electric field, proliferation behavior of connective tissue cells (fibroblasts) is stimulated, and for new vessel formation (angiogenesis) and nerve growth, the electric field is also important. Finally, in vivo studies using electric fields have shown an antibacterial effect on both gram-negative and gram-positive bacteria [36-40].

In recent years, research in the field of bioelectricity has demonstrated significant links between endogenous electric fields and the wound healing process [41-43]. A meta-analysis by Gardner et al. was performed using data sets from 15 clinical trials with the aim of quantifying the effect of electrical stimulation (ES) on chronic wound healing. Treatments with ES achieved an average wound reduction of 22.2% per week, compared with only 9.1% in control groups [44]. In the published partial results of Cochrane Review #077, the healing success (wound closure) using electrical stimulation was compared with placebo control. This question was investigated in 13 of the 20 studies. The analysis showed that twice as many (OR=2.12; 95% CI: 1.55 – 2.90) wounds were healed by treatment with electrostimulation (verum) compared to controls [45].

All publications

  1. Sagawa et al., Argon plasma coagulation for successful treatment of early gastric cancer with intramucosal invasion. Gut 52 (2003) 334-339
  2. J. Vargo, Clinical applications of the argon plasma coagulator. Gastrointestinal Endoscopy 59 (2004) 81-88
  3. Raiser, M. Zenker. Argon plasma coagulation for open surgical and endoscopic applications: state of the art. J. Phys. D: Appl. Phys. 39 (2006) 3520-3523
  4. Manner et al., Safety and efficacy of a new high power argon plasma coagulation system (hp-APC) in lesions of the upper gastrointestinal tract. Digestive and Liver Disease 38 (2006) 471-478
  5. Manner et al., Second-generation argon plasma coagulation: Two-center experience with 600 patients. J. Gastroenterol. Hepatol. 23 (2008) 872-878
  6. Zenker, Argon plasma coagulation. GMS Krankenhaushyg. Interdiszip. 3 (2008)Doc15
  7. Keller et al., Electrical and spectroscopic characterization of a surgical argon plasma discharge. J. Phys. D: Appl. Phys. 46 (2013) 025402
  8. Keller, Charakterisierung der Argonplasma-Koagulation (APC) für die thermische Behandlung von biologischem Gewebe in der Endoskopie und der Chirurgie. Dissertation zur Erlangung des Grades eines Doktor-Ingenieurs an der Fakultät für Elektrotechnik und Informationstechnik, Ruhr-Universität Bochum 2012
  9. Ianelli et al., Use of PlasmaJet System in patients undergoing abdominal lipectomy following massive weight loss resulting from bariatric surgery: early experience. Obes. Surg. 16 (2006) 1504-1507
  10. Nezhat et al., Use of neutral argon plasma in the laparoscopic treatment of endometriosis. J. Soc. Laparoendsocop. Surg. 13 (2009) 479-483
  11. K. Madhuri, et al., First clinical experience of argon neutral plasma energy in gynaecological surgery in the UK. Gynaecol. Surg. 7 (2010) 423-425
  12. A. Bogle et al., Evaluation of plasma skin regeneration technology in low-energy full-facial rejuvenation. Arch. Dermatol. 143 (2007) 168-174
  13. Kilmer et al., A pilot study on the use of a plasma skin regeneration device (Portrait PSR3) in full facial rejuvenation procedures. Lasers Med. Sci. 22 (2007) 101-109
  14. D. Holcomb et al., Nitrogen plasma skin regeneration and aesthetic facial surgery. Arch. Facial Plast. Surg. 11 (2009) 184-193
  15. Wade Forster et al., Advances in plasma skin regeneration (Review article). J. Cosmetic Dermatol. 7 (2008) 169-179
  16. Dröge, Free radicals in the physiological control of cell function. Physiol. Rev. 82 (2002) 47-95
  17. C. Fang, Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature Rev. Microbiol. 2 (2004) 820-832
  18. G. Rhee, H2O2, a necessary evil for cell signaling. Science 312 (2006) 1882-1883
  19. O. Lundberg et al., The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nature Rev. Drug Discov. 7 (2008) 156-168
  20. K. Sen and S. Roy, Redox signals in wound healing (invited review). Biochim. Biophys. Acta 1780 (2008) 1348-1361
  21. K. Sen, Wound healing essentials: let there be oxygen (perspective article). Wound Rep. Regen. 17 (2009) 1-18
  22. Leonarduzzi et al., Targeting tissue oxidative damage by means of cell signaling modulators: the antioxidant concept revisited. Pharmacology & Therapeutics 128 (2010) 336-374
  23. B. Graves, The emerging role of reactive oxygen and nitrogen species in redox biology and some implications for plasma applications to medicine and biology (topical review). J. Phys. D: Appl. Phys. 45 (2012) 163001
  24. von Woedtke et al., Plasmas for medicine. Phys. Rep. 530 (2013) 291-320
  25. Schmidt et al. Non-thermal plasma treatment is associated with changes in transcriptome of human epithelial skin cells. Free Radical Res. 47 (2013) 577-592
  26. Kramer, O. Assadian (Eds.), Praxis der Sterilisation, Desinfektion, Antiseptik und Konservierung, Thieme, Stuttgart 2008, S. 719 ff.
  27. Fachverband für Strahlenschutz e.V., Leitfaden „Ultraviolettstrahlung künstlicher Quellen“ (FS-2013-157-AKNIR, Stand 28.3.2013); http://osiris22.pi-consult.de/userdata/l_20/p_105/library/data/fs-05-131-aknir_uv_strahlung.pdf
  28. Richtlinie 2006/25/EG des Europäischen Parlamentes und des Rates vom 5. April 2006 über Mindestvorschriften zum Schutz von Sicherheit und Gesundheit der Arbeitnehmer vor der Gefährdung durch physikalische Einwirkungen (künstliche optische Strahlung); http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:114:0038:0059:de:PDF
  29. ICNIRP Statement. Guidelines on UV radiation exposure limits. Health Physics 87 (2004) 171
  30. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), AWMF-Leitlinienregister Nr. 013/029, Empfehlungen der Deutschen Dermatologischen Gesellschaft (DDG) zur UV-Phototherapie und Photochemotherapie, Stand: 12/2009; http://www.awmf.org/uploads/tx_szleitlinien/013-029.pdf
  31. Lademann et al., Risk assessment of the application of a plasma jet in dermatology. J. Biomed. Opt. 14 (2009) 054025
  32. Heinlin et al., Plasma applications in medicine with a special focus on dermatology. J. Eur. Acad. Venereol. 25 (2011) 1-11
  33. Isbary et al., Successful and safe use of 2 min cold atmospheric argon plasma in chronic wounds: results of a randomized controlled trial Br. J. Dermatol. 167 (2012) 404-410
  34. Rajasekaran et al., Characterization of Dielectric Barrier Discharge (DBD) on Mouse and Histological Evaluation of the Plasma-Treated Tissue. Plasma Process. Polym. 8 (2011) 246-255
  35. Bussiahn et al., Plasmaquellen für biomedizinische Applikationen. Hyg. Med. 38 (2013) 212-216
  36. R. Cho et al., Integrin-Dependent Human Macrophage Migration Induced by Oscillatory Electrical Stimulation Ann. Biomed. Eng. 28 (2000) 234-243
  37. Goldman, S. Pollack, Electric fields and proliferation in a chronic wound model. Bioelectromagnetics 17 (1996) 450-457
  38. Song et al., Nerve regeneration and wound healing are stimulated and directed by an endogenous electrical field in vivo. J. Cell Sci. 117 (2004) 4681-4690
  39. E. Pullar et al., β4 Integrin and Epidermal Growth Factor Coordinately Regulate Electric Field-mediated Directional Migration via Rac1. Mol. Biol. Cell 17 (2006) 4925-4935
  40. Daeschlein et al., Antibacterial activity of positive and negative polarity low-voltage pulsed current (LVPC) on six typical Gram-positive and Gram-negative bacterial pathogens of chronic wounds. Wound Repair Regen. 15 (2007) 399-403
  41. C. Recio et al., High-voltage Electrical Stimulation for the Management of Stage III and IV Pressure Ulcers among Adults with Spinal Cord Injury: Demonstration of its Utility for Recalcitrant Wounds below the Level of Injury, J. Spinal Cord. Med. 35 (2012) 58-63
  42. E. Houghton et al., Electrical Stimulation Therapy increases rate of healing of Pressure Ulcers in Community-Dwelling People with Spinal Cord Injury, Arch. Phys. Med. Rehabil. 91 (2010) 669-678
  43. Adunsky et al. Decubitus Direct Current Treatment of Pressure Ulcers: Results of a Randomized, Double-Blind, Placebo-controlled Study, Arch. Gerontol. Geriatr. 41 (2005) 261-269
  44. E. Gardner et al., Effect of electrical stimulation on chronic wound healing: a meta-analysis. Wound Repair Regen. 7 (1999) 495–503
  45. Koel und F. Oosterveld. Review. Electrotherapy for stimulation of wound healing. EWMA Journal 9 (2009) 57
  46. DIN EN 60601-1. Medizinische elektrische Geräte – Teil 1: Allgemeine Festlegungen für die Sicherheit einschließlich der wesentlichen Leistungsmerkmale. Ausgabedatum 2013-12
  47. ICNIRP Statement. Guidelines for limiting exposure to time-varying electric, magnetic, and electromagnetic fields (up to 300 GHz). Health Physics 97 (2009) 257-258
  48. Isbary et al., Ex vivo human skin experiments for the evaluation of safety of new cold atmospheric plasma devices. Clin. Plasma Med. 1 (2013) 36-44
  49. Kalghatgi et al., Effects of Non-Thermal Plasma on Mammalian Cells. PLoS ONE 6 (2011) e16270
  50. OECD 476/1997: OECD Guidelines for the testing of chemicals. In Vitro Mammalian Cell Gene Mutation Test; http://www.oecd.org/chemicalsafety/risk-assessment/1948426.pdf
  51. Boxhammer et al., Investigation of the mutagenic potential of cold atmospheric plasma at bactericidal dosages. Mutation Res. 753 (2013) 23-28
  52. Arndt et al. Cold Atmospheric Plasma (CAP) Changes Gene Expression of Key Molecules of the Wound Healing Machinery and Improves Wound Healing In Vitro and In Vivo. PloS One 8 (2013) e79325
  53. Isbary et al., A first prospective randomized controlled trial to decrease bacterial load using cold atmospheric argon plasma on chronic wounds in patients. Brit. J. Dermatol. 163 (2010) 78-82
  54. Isbary et al., Cold atmospheric plasma: A successful treatment of lesions in Hailey-Hailey disease. Arch. Dermatol. 147 (2011) 388-390
  55. Isbary et al., Non-thermal plasma—More than five years of clinical experience. Clin. Plasma Med. 1 (2013) 19-13
  56. Isbary et al., Cold atmospheric argon plasma treatment may accelerate wound healing in chronic wounds: results of a retrospective in vivo randomized controlled study. Clin. Plasma Med. 2 (2013) 25-30
  57. Isbary et al., Cold atmospheric plasma for local infection control and subsequent pain reduction in a patient with chronic post-operative ear infection. New Microb. New Inf. 3 (2013) 41-43
  58. Heinlin et al., A randomized two-sided placebo-controlled study on the efficacy and safety of atmospheric non-thermal argon plasma for pruritus. J. Eur. Acad. Dermatol. Venereol. 27 (2013) 324-331
  59. Heinlin et al., Randomized placebo-controlled human pilot study of cold atmospheric argon plasma on skin graft donor sites. Wound Rep. Regen. 21 (2013) 800-807
  60. -R. Metelmann et al., Experimental Recovery of CO2-Laser Skin Lesions by Plasma Stimulation. Am. J. Cosmetic Surg. 29 (2012) 52-56
  61. -R. Metelmann et al., Scar formation of laser skin lesions after cold atmospheric pressure plasma (CAP) treatment: A clinical long term observation Clin. Plasma Med. 1 (2013) 30-35
  62. Emmert et al., Atmospheric pressure plasma in dermatology: Ulcus treatment and much more. Clin. Plasma Med. 1 (2013) 24-29
  63. Tiede et al., Plasma applications: a dermatological view. Contrib. Plasma Phys. 54 (2014) 118-130
  64. Emmert et al., Treatment of Chronic Venous Leg Ulcers with a Hand-Held DBD Plasma Generator. Plasma Medicine (2014) DOI: 10.1615/PlasmaMed.2013005914
  65. Lademann et al., Risk assessment of the application of tissue-tolerable plasma on human skin. Clin. Plasma Med. 1 (2013) 5-10
  66. Kramer et al., Suitability of tissue tolerable plasmas (TTP) for the management of chronic wounds. Clin. Plasma Med. 1 (2013) 11-18
  67. Clinical Plasma Medicine Core Group. Clinical plasma medicine – position and perspectives in2012. Paper of consent, result of the workshop “Clinical Concepts in Plasma Medicine”, Greifswald April 28th, 2012. Plasma Med. 1 (2013) 3-4
  68. von Woedtke et al., Clinical Plasma Medicine: State and perspectives of in vivo application of cold atmospheric plasma. Contrib. Plasma Phys. 54 (2014) 104-117
  69. Schlegel et al., Plasma in cancer treatment. Clin. Plasma Med. Vol. 1 No. 2 (2013) 2-7
  70. Rupf et al. Removing biofilms from microstructured titanium ex vivo: a novel approach using atmospheric plasma technology. PLoS One. 10 (2011) e25893

A.N. Idlibi et al. Destruction of oral biofilms formed in situ on machined titanium (Ti) surfaces by cold atmospheric plasma. Biofouling 29 (2013) 369-79]

Effect

Clinical dermatological studies have shown the following:

  • Inactivation of healing-inhibiting wound germs, including MRSA.
  • No formation of resistance
  • Increase of microcirculation in the tissue
  • Promotion of angiogenesis
  • Stimulation of wound healing – independent of wound architecture
  • Reduction of the pH value in the wound area
  • Prompt onset of action
  • Painless treatment

Studies on cold plasma

An extensive study shows the efficacy of cold plasma (jet plasma/DBD) by inactivating all 105 investigated and partly antibiotic-resistant wound germs (11 different species), which were placed on the intact skin (fingertips) of nine healthy volunteers for testing (32). The antimicrobial efficacy was confirmed by further studies. Thus, chronic wounds of 34 patients were treated with cold plasma or in combination with a wound antiseptic. The combination therapy showed the best efficacy [1].

In a monocentric, randomized, controlled clinical trial, seven patients each with chronic ulcers (at least 12 weeks old) were subjected to plasma treatment or no treatment in addition to normal wound care. The plasma source was a dielectric-disabled discharge powered by air. Wound healing occurred similarly to standard therapy, while wound areas colonized with bacteria decreased by a mean of 88% in wounds treated with Plasma [2].

Sixteen patients included in the study (ten women and six men) with chronic leg ulcers were each treated with cold plasma three times a week over a period of two weeks. In addition to measuring antimicrobial activity, the aim of the study was to investigate the effect on wound healing. The parameters compared were, in addition to the number of bacterial colonies per square centimeter, the size of the wound surface and the change in wound volume. The authors concluded that the immediate antimicrobial effect of the two treatment methods was largely comparable. Plasma therapy was very well tolerated by patients and, according to the authors, is unlikely to cause allergies due to its physical principle of action [4].

In a more extensive study with 70 patients, a tendency toward improved healing was determined in chronic ulcers treated with cold plasma – compared to untreated wounds [5]. In addition, another randomized-controlled trial with 40 patients showed significantly improved healing after plasma treatment of acute wounds after skin grafts [6]. A summary of the current status of plasma use in animal experiments, in vivo, and clinical studies and case reports is also the subject of a recent review [7].

A risk assessment with reference to plasma species (temperature, UV radiation and free radicals) did not reveal any increased risks for humans [8].

Based on the level of clinical research achieved, plasma applications in dermatology and plastic and aesthetic surgery currently have the highest prospects of success. The use of antimicrobial plasma effects, plasma-assisted stimulation of tissue regeneration, and inflammation-modulating plasma effects are the focus of therapeutic indications.

References
[1] M. Klebes, C. Ulrich, F. Kluschke, A. Patzelt, S. Vandersee, H. Richter, A. Bob, J. Hutten, J.T. Krediet, A. Kramer, Combined antibacterial effects of tissue‐tolerable plasma and a modern conventional liquid antiseptic on chronic wound treatment, Journal of biophotonics, 8 (2015) 382-391.

[2] F. Brehmer, H. Haenssle, G. Daeschlein, R. Ahmed, S. Pfeiffer, A. Görlitz, D. Simon, M. Schön, D. Wandke, S. Emmert, Alleviation of chronic venous leg ulcers with a hand‐held dielectric barrier discharge plasma generator (PlasmaDerm® VU‐2010): results of a monocentric, two‐armed, open, prospective, randomized and controlled trial (NCT01415622), Journal of the European Academy of Dermatology and Venereology, 29 (2015) 148-155.

[3] S. Vandersee, H. Richter, J. Lademann, M. Beyer, A. Kramer, F. Knorr, B. Lange-Asschenfeldt, Laser scanning microscopy as a means to assess the augmentation of tissue repair by exposition of wounds to tissue tolerable plasma, Laser Physics Letters, 11 (2014) 115701.

[4] C. Ulrich, F. Kluschke, A. Patzelt, S. Vandersee, V. Czaika, H. Richter, A. Bob, J. von Hutten, C. Painsi, R. Hügel, Clinical use of cold atmospheric pressure argon plasma in chronic leg ulcers: A pilot study, Journal of wound care, 24 (2015).

[5] G. Isbary, W. Stolz, T. Shimizu, R. Monetti, W. Bunk, H.U. Schmidt, G.E. Morfill, T.G. Klämpfl, B. Steffes, H.M. Thomas, J. Heinlin, S. Karrer, M. Landthaler, J.L. Zimmermann, Cold atmospheric argon plasma treatment may accelerate wound healing in chronic wounds: Results of an open retrospective randomized controlled study in vivo, Clinical Plasma Medicine, 1 (2013) 25-30.

[6] J. Heinlin, J.L. Zimmermann, F. Zeman, W. Bunk, G. Isbary, M. Landthaler, T. Maisch, R. Monetti, G. Morfill, T. Shimizu, J. Steinbauer, W. Stolz, S. Karrer, Randomized placebo-controlled human pilot study of cold atmospheric argon plasma on skin graft donor sites, Wound Repair Regen, 21 (2013) 800-807.

[7] T. Von Woedtke, H.R. Metelmann, K.D. Weltmann, Clinical plasma medicine: state and perspectives of in vivo application of cold atmospheric plasma, Contributions to Plasma Physics, 54 (2014) 104-117.

[8] J. Lademann, H. Richter, A. Alborova, D. Humme, A. Patzelt, A. Kramer, K.-D. Weltmann, B. Hartmann, C. Ottomann, J.W. Fluhr, Risk assessment of the application of a plasma jet in dermatology, Journal of biomedical optics, 14 (2009) 054025-054025-054026.

Side effects/tolerability of cold plasma

At the current state of clinical research, no clinically relevant side effects are known.

Reimbursement

Please contact the responsible staff member. Hier vielleicht der Link zur PZN ind Deutsch und der PPN in Englisch

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