Plasma Technology for Health

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Borchardt, Thomas; Ernst, Jennifer; Helmke, Andreas; Tanyeli, Murat; Schilling, Arndt F.; Felmerer, Gunther; Vioel, Wolfgang (2017): Effect of direct cold atmospheric plasma (diCAP) on microcirculation of intact skin in a controlled mechanical environment. In: Microcirculation (New York, N.Y. : 1994) 24 (8). DOI: 10.1111/micc.12399.

"diCAP treatment of intact skin notably enhances microcirculation for a therapeutically relevant period. This effect is specific to the plasma treatment and not an effect of the applied pressure. Prolonged treatment durations lead to more pronounced effects."

Brehmer, Franziska; Haenssle, H. A.; Daeschlein, Georg; Ahmed, R.; Pfeiffer, S.; Görlitz, A. et al. (2015): 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). In: Journal of the European Academy of Dermatology and Venereology : JEADV 29 (1), S. 148–155. DOI: 10.1111/jdv.12490.

"Cold atmospheric plasma displays favourable antibacterial effects. We demonstrated that plasma treatment with the PlasmaDerm® VU-2010 device is safe and effective in patients with chronic venous leg ulcers. Thus, larger controlled trials and the development of devices with larger application surfaces are warranted."

Daeschlein, Georg; Napp, Matthias; Podewils, Sebastian von; Scholz, Sebastian; Arnold, Andreas; Emmert, Steffen et al. (2015): Antimicrobial Efficacy of a Historical High-Frequency Plasma Apparatus in Comparison With 2 Modern, Cold Atmospheric Pressure Plasma Devices. In: Surgical innovation 22 (4), S. 394–400. DOI: 10.1177/1553350615573584.

"DBD with the largest electrode produced the largest IAs. VW showed results similar to 2 different modes of the kINPen 09. IAs of VW were enlargeable by attaching a larger electrode. Against biofilms, VW was less effective than DBD but more effective than ethanol 70% and polyhexanide."

Daeschlein, Georg; Scholz, Sebastian; Ahmed, R.; Woedtke, Thomas von; Haase, H.; Niggemeier, M. et al. (2012): Skin decontamination by low-temperature atmospheric pressure plasma jet and dielectric barrier discharge plasma. In: The Journal of hospital infection 81 (3), S. 177–183. DOI: 10.1016/j.jhin.2012.02.012.

"Both the APPJ and DBD were highly effective in eradicating PF and AF from the fingertips of healthy volunteers. No plasma-resistant isolates were observed. Cold plasma appears to have potential for skin disinfection. For hand hygiene purposes, plasma exposure times would need to be reduced significantly by technical means."

Emmert, Steffen; Brehmer, Franziska; Hänßle, Holger; Helmke, Andreas; Mertens, Nina; Ahmed, Raees et al. (2013): Atmospheric pressure plasma in dermatology: Ulcus treatment and much more. In: Clinical Plasma Medicine 1 (1), S. 24–29. DOI: 10.1016/j.cpme.2012.11.002.

" In plasma treatment antiinflammatory, antipruritic, antimicrobial, tissue stimulation, stimulation of microcirculation, and other therapeutic effects are achieved in a single treatment due to the combined action of ultraviolet radiation, reactive oxygen species (e.g. ozone), reactive nitrogen species, and electric fields. In line with other reports, we have already demonstrated the use of direct plasma treatment in skin disinfection, in atopic eczema (superinfected dermatitis), in modulating the epidermal barrier, as well as in chronic wound treatment. We as well as others did not notice any side effects of plasma treatment so far. In summary, cold atmospheric pressure plasma constitutes a new and innovative treatment option especially for superinfected skin diseases. These promising relatively new clinical applications warrant further carefully conducted translational research to delineate the modes of actions of plasma as well as potential long term side effects. This should lead to norms for the technical devices to allow a standardized treatment of given diseases in the mid-term."

Geimer, Till; Blatner, Carolin; Ruzicka, Thomas, Sattler, Elke (2016): Kaltes Atmosphärenplasma zur Behandlung von Wundheilungsstörungen: Ansprechmuster und Therapieverläufe. Ludwig-Maximillians-Universität München, Klinik und poliklinik für Dermatologie und Allergologie, 2016.

"Diese drei Verläufe verdeutlichen, dass die Therapie mit CAP - vermutlich aufgrund unterschiedlicher Therapieregime - diverse Effekte auf die Geweberekonstition haben kann. In Zukunft wird durch randomisierte Studien zu klären sein, in wie weit CAP bei Indikationen, in denen eine schnelle Reepithelialisierung gefördert werden soll (z.B. Spalthautentnahmestellen, Z. n. Laser-Resurfacing), bei langsam sekundär heilenden OP-Wunden (z.B. sekundär heilende OP-Wunden bei Acne inversa) und natürlich bei komplexen Wunden, einen Therapievorteil zeigen kann."

Gelker, Monika; Mrotzek, Julia; Ichter, Astrid; Müller-Goymann, Christel C.; Vioel, Wolfgang (2019): Influence of pulse characteristics and power density on stratum corneum permeabilization by dielectric barrier discharge. In: Biochimica et biophysica acta. General subjects. DOI: 10.1016/j.bbagen.2019.05.014.

"Our results provide mechanistic insight into the potential of an emerging interdisciplinary technology - plasma medicine - as a prospective tool or treatment option. While it might become a safe and pain-free method to enhance skin permeation of drug substances, this is also a mechanism to keep in mind when tailoring plasma sources for other uses."

Gelker, Monika; Müller-Goymann, Christel C.; Vioel, Wolfgang (2018): Permeabilization of human stratum corneum and full-thickness skin samples by a direct dielectric barrier discharge. In: Clinical Plasma Medicine 9, S. 34–40. DOI: 10.1016/j.cpme.2018.02.001.

"A CAP treatment in isolated human SC was shown to dramatically reduce electrical resistance and yield a regular pattern of locally permeabilized regions. These regions were greater in number than the natural number of skin appendages and admitted the passage of small hydrophilic substances with Stokes’ radii up to 1.4 nm through human SC subsequent to 2×90 s CAP treatment. Proof-of-principle experiments with full-thickness skin (FTS) confirm these results."

Gelker, Monika; Müller-Goymann, Christel C.; Viöl, Wolfgang (2020): Plasma Permeabilization of Human Excised Full-Thickness Skin by µs- and ns-pulsed DBD. In: Skin pharmacology and physiology, S. 1–8. DOI: 10.1159/000505195.

"The direct treatment of excised human full-thickness skin with CAP, specifically a DBD, can lead to pore formation and enhances transdermal transport of sodium fluorescein."

Hartwig, Stefan; Doll, Christian; Voss, Jan Oliver; Hertel, Moritz; Preissner, Saskia; Raguse, Jan Dirk (2017a): Treatment of Wound Healing Disorders of Radial Forearm Free Flap Donor Sites Using Cold Atmospheric Plasma: A Proof of Concept. In: Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 75 (2), S. 429–435. DOI: 10.1016/j.joms.2016.08.011.

"Cold atmospheric plasma could offer a reliable conservative treatment option for complicated wound healing disturbances. This was exemplarily shown in the case of radial forearm free flap donor site morbidity with exposed flexor tendons in the present study."

Hartwig, Stefan; Preissner, Saskia; Voss, Jan Oliver; Hertel, Moritz; Doll, Christian; Waluga, Richard; Raguse, Jan Dirk (2017b): The feasibility of cold atmospheric plasma in the treatment of complicated wounds in cranio-maxillo-facial surgery.

In: Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 45 (10), S. 1724–1730. DOI:
10.1016/j.jcms.2017.07.008.

"The use of cold atmospheric plasma might offer a reliable, conservative treatment option in complicated wound healing disturbances in cranio-maxillo-facial surgery."

Helmke, Andreas (2013a): Radiometrische und spektrale Charakterisierung von Plasmaquellen der Fa. CINOGY. Hg. v. HAWK Göttingen. Göttingen, zuletzt geprüft am 27.11.2019.

"Für den Betrieb der 10mm-Al2O3-Elektrode wurde nach einer spektralen Gewichtung der Strahlung entsprechend der physiologischen Wirksamkeit festgestellt, dass eine tägliche Behandlung unter Verwendung des gleichen Parametersatzes von 22 Stunden unbedenklich erscheint. Da sich in der spektralen Verteilung der beiden Experimente keine wesentlichen Unterschiede zeigten und die Intensitäten beim Betrieb mit der flexiblen Spritzguss-Elektrode um ein Vielfaches niedriger liegen, kann davon ausgegangen werden, dass sich keine Reglementierung der täglichen Behandlungsdauer aufgrund der Plasma-UV-Emission während der Behandlung ergibt."

Helmke, Andreas; Franck, Michael; Wandke, Dirk; Vioel, Wolfgang (2014): Tempo-spatially Resolved Ozone Characteristics During Single-electrode Dielectric Barrier Discharge (SE-DBD) Operation against Metal and Porcine Skin Surfaces. In: Plasma Med 4 (1-4), S. 67–77. DOI: 10.1615/PlasmaMed.2014011946.

"Ozone is a major component produced by low-temperature plasmas operating in oxygen-containing gas mixtures. For correlation with biological or clinical results of plasma medical therapies as well as for evaluation of application security, tempo-spatially resolved ozone concentrations need to be considered. When operating a single-electrode dielectric barrier discharge (SE-DBD), the electric field characteristics are dependent on the geometrical setup as well as the electrical properties of the counter electrode. Thus, the counter electrode also affects the plasma input power and hence the total production of chemical species. Therefore, we studied the power input and the tempo-spatial characteristics of ozone concentrations during operation of a SE-DBD operated at voltage pulses in the us regime against a clean metal electrode and a metal electrode covered with porcine skin samples. At energy densities of up to 1.85 J/cm2, the ozone concentrations in the plasma volume amount to as much as 293 ppm whereas at a distance of 5 and 20 cm, respectively, from the discharge, concentrations have decreased beneath recommended safety limits of 0.1 ppm. Furthermore, significantly lower ozone concentrations could be observed when skin samples were used as part of the counter electrode"

Helmke, Andreas; Grunig, Petra; Fritz, Ulrich-Markus; Wandke, Dirk; Emmert, Steffen; Petersen, Karin; Vioel, Wolfgang (2012): Low-temperature plasma–a prospective microbicidal tool. In: Recent patents on anti-infective drug discovery 7 (3), S. 223–230.

"The effects of low-temperature plasma treatment on microorganisms typically related to skin diseases are studied qualitatively by the inhibition of growth and viability assays to evaluate the potential for classifying as a prospective antiseptic agent. A variety of microorganisms enveloping gram- negative and gram-positive bacteria as well as one genus of yeast and fungus each were exposed to plasma in vitro. In a comparative approach, two power supplies, both of which produce high voltage pulses yet at different temporal characteristics, are applied for the growth study. While operation with both devices led to growth inhibition of all microbes, the results indicate a superior antimicrobial efficacy for high voltage pulse lengths in the nanosecond scale. Fluorescence assays reveal the efficacy of nanosecond-pulse driven plasma in reducing germ viability. Furthermore, the technical background for patents related to low-temperature plasma technology in the field of plasma medicine is discussed."

Helmke, Andreas; Wandke, Dirk; Mahmoodzada, M.; Weltmann, Klaus Dieter; Vioel, Wolfgang (2013b): Impact of Electrode Design, Supply Voltage and Interelectrode Distance on Safety Aspects and Characteristics of a Medical DBD Plasma Source. In: Contrib. Plasma Phys. 53 (9), S. 623–638. DOI: 10.1002/ctpp.201200133.

"In the frame of plasma source development for dermatological applications in the field of plasma medicine, operational safety of the devices is of superior priority. For sources based on the concept of dielectric barrier discharges (DBD), electric potentials with amplitudes in the range of some kV are arranged in close proximity to the skin of patients, wherein dielectric strength of the electrodes and leakage currents are crucial for electrical applicability. In this work, ceramic electrodes of 10 mm in diameter and varying ceramic thickness are operated at input powers up to 300 mW against nonbiological counter electrodes. In a combined experimental and numerical approach, electric fields inside the ceramic are determined, whereas values are well below the dielectric strength of the material. The spectrally weighted plasma emission is within limit values of exposure to human skin as long as daily treatment does not exceeded 7 h. Neutral gas temperatures of up to 310 K are determined which underline the minor thermal impact of the plasma exposure. In contrast, values for reduced electric fields are of the order of some hundred Townsend and thus the electrons can initiate various secondary effects such as chemical reaction chains. Consequently, ozone concentrations in the discharges are quantified between 230 ppm and 1140 ppm in close proximity to the actual discharge volume and the results are discussed in the frame of risk assessment for therapeutic applications in dermatology." 

Heuer, Kiara; Hoffmanns, Martin A.; Demir, Erhan; Baldus, Sabrina; Volkmar, Christine M.; Röhle, Mirco et al. (2015): The topical use of non-thermal dielectric barrier discharge (DBD): nitric oxide related effects on human skin. In: Nitric oxide : biology and chemistry 44, S. 52–60. DOI: 10.1016/j.niox.2014.11.015.

" Dielectric barrier discharge (DBD) devices generate air plasma above the skin containing active and reactive species including nitric oxide (NO). Since NO plays an essential role in skin physiology, a topical application of NO by plasma may be useful in the treatment of skin infections, impaired microcirculation and wound healing. Thus, after safety assessments of plasma treatment using human skin specimen and substitutes, NO-penetration through the epidermis, the loading of skin tissue with NO-derivates in vitro and the effects on human skin in vivo were determined. After the plasma treatment (0-60 min) of skin specimen or reconstructed epidermis no damaging effects were found (TUNEL/MTT). By Franz diffusion cell experiments plasma-induced NO penetration through epidermis and dermal enrichment with NO related species (nitrite 6-fold, nitrate 7-fold, nitrosothiols 30-fold) were observed. Furthermore, skin surface was acidified (~pH 2.7) by plasma treatment (90 s). Plasma application on the forearms of volunteers increased microcirculation fourfold in 1-2 mm and twofold in 6-8 mm depth in the treated skin areas. Regarding the NO-loading effects, skin acidification and increase in dermal microcirculation, plasma devices represent promising tools against chronic/infected wounds. However, efficacy of plasma treatment needs to be quantified in further studies and clinical trials."

Kisch, Tobias; Helmke, Andreas; Schleusser, Sophie; Song, Jungin; Liodaki, Eirini; Stang, Felix Hagen et al. (2016a): Improvement of cutaneous microcirculation by cold atmospheric plasma (CAP): Results of a controlled, prospective cohort study. In: Microvascular research 104, S. 55–62. DOI: 10.1016/j.mvr.2015.12.002.

" CAP increases cutaneous tissue oxygen saturation and capillary blood flow at the radial forearm of healthy volunteers. These results support recently published data on wound healing after CAP treatment. However, further studies are needed to determine if this treatment can improve the reduced microcirculation in diabetic foot ulcers. Moreover, repetitive application protocols have to be compared with a single session treatment approach."

Kisch, Tobias; Schleusser, Sophie; Helmke, Andreas; Mauss, Karl Ludwig; Wenzel, Eike Tilman; Hasemann, Benedikt et al. (2016b): The repetitive use of non-thermal dielectric barrier discharge plasma boosts cutaneous microcirculatory effects. In: Microvascular research 106, S. 8–13. DOI: 10.1016/j.mvr.2016.02.008.

"These data indicate that the repetitive use of non-thermal atmospheric plasma boosts and prolongs cutaneous microcirculation and might therefore be a potential tool to promote wound healing."

Kuchenbecker, M.; Bibinov, Nikita; Kaemlimg, A.; Wandke, Dirk; Awakowicz, Peter; Vioel, Wolfgang (2009): Characterization of DBD plasma source for biomedical applications. In: J. Phys. D: Appl. Phys. 42 (4), S. 45212. DOI: 10.1088/0022- 3727/42/4/045212.

" The dielectric barrier discharge (DBD) plasma source for biomedical application is characterized using optical emission spectroscopy, plasma-chemical simulation and voltage–current measurements. This plasma source possesses only one electrode covered by ceramic. Human body or some other object with enough high electric capacitance or connected to ground can serve as the opposite electrode. DBD consists of a number of microdischarge channels distributed in the gas gap between the electrodes and on the surface of the dielectric. To characterize the plasma conditions in the DBD source, an aluminium plate is used as an opposite electrode. Electric parameters, the diameter of microdischarge channel and plasma parameters (electron distribution function and electron density) are determined. The gas temperature is measured in the microdischarge channel and calculated in afterglow phase. The heating of the opposite electrode is studied using probe measurement. The gas and plasma parameters in the microdischarge channel are studied at varied distances between electrodes. According to an energy balance study, the input microdischarge electric energy dissipates mainly in heating of electrodes (about 90%) and partially (about 10%) in the production of chemical active species (atoms and metastable molecules)."

Marschewski, Marcel; Hirschberg, Joanna; Omairi, Tarek; Höfft, Oliver; Vioel, Wolfgang; Emmert, Steffen; Maus-Friedrichs, Wolfgang (2012): Electron spectroscopic analysis of the human lipid skin barrier: cold atmospheric plasma-induced changes in lipid composition. In: Experimental dermatology 21 (12), S. 921–925. DOI: 10.1111/exd.12043.

" The lipids of the stratum corneum comprise the most important components of the skin barrier. In patients with ichthyoses or atopic dermatitis, the composition of the skin barrier lipids is disturbed resulting in dry, scaly, itching erythematous skin. Using the latest X-Ray Photoelectron Spectroscopy (XPS) technology, we investigated the physiological skin lipid composition of human skin and the effects of cold atmospheric plasma treatment on the lipid composition. Skin lipids were stripped off forearms of six healthy volunteers using the cyanoacrylate glue technique, plasma treated or not and then subjected to detailed XPS analysis. We found that the human lipid skin barrier consisted of 84.4% carbon (+1.3 SEM%), 10.8% oxygen (+1.0 SEM%) and 4.8% nitrogen (+0.3 SEM%). The composition of physiological skin lipids was not different in males and females. Plasma treatment resulted in significant changes in skin barrier lipid stoichiometry. The total carbon amount was reduced to 76.7%, and the oxygen amount increased to 16.5%. There was also a slight increase in nitrogen to 6.8%. These changes could be attributed to reduced C-C bonds and increased C-O, C=O, C-N and N-C-O bonds. The moderate increase in nitrogen was caused by an increase in C-N and N-C-O bonds. Our results show for the first time that plasma treatment leads to considerable changes in the human skin lipid barrier. Our proof of principle investigations established the technical means to analyse, if plasma-induced skin lipid barrier changes may be beneficial in the treatment of ichthyotic or eczematous skin."

Paulßen von Beck, Felix; Mücke, Thomas (2018): Verbesserung der Wundheilung beim Einheilen von Vollhaut durch PlasmaDerm®? – Eine Pilotstudie. Klinik für Mund-, Kiefer- und Gesichtschirurgie, plastische und ästhetische Operationen, Malteser Krankenhaus St. Josefshospital, Krefeld-Uerdingen. Wundkongress Nürnberg, 2018.
• Aktivierung der Wundheilung
• Erhöhung der Mikrozirkulation
• Optimierung der Sauerstoffsättigung
• antimikrobiell, ohne Resistenzentwicklung
• wirksam gegen multiresistente Keime
• Reduzierung von postoperativen Wundheilungsstörungen beim Einwachsen von Vollhauttransplantaten
Rajasekaran, Priyadarshini; Opländer, Christian; Hoffmeister, Dennis; Bibinov, Nikita; Suschek, Christoph Viktor; Wandke, Dirk; Awakowicz, Peter (2011): Characterization of Dielectric Barrier Discharge (DBD) on Mouse and Histological Evaluation of the Plasma-Treated Tissue. In: Plasma Processes Polym. 8 (3), S. 246–255. DOI: 10.1002/ppap.201000122.

“Atmospheric-pressure dielectric barrier discharge (DBD) in air is investigated for medical applications, especially for skin treatment. When the DBD was tested on mouse skin, a homogeneous discharge accompanied by filamentary microdischarges is observed. For characterization of the homogeneous discharge, averaged plasma parameters (namely electron density and electron velocity distribution function) and gas temperature are determined by optical emission spectroscopy, microphotography and numerical simulation. Chemical kinetics in the active plasma volume and in the afterglow is simulated. Fluxes of biologically useful molecules like nitric oxide (NO) and ozone reaching the treated surface and irradiation by UV photons are determined. Skin biopsy results show that DBD treatment causes no inflammation and no changes in the skin-collagen.”

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