gms | German Medical Science

GMS Hygiene and Infection Control

Deutsche Gesellschaft für Krankenhaushygiene (DGKH)

ISSN 2196-5226

Cold atmospheric plasma in orthopaedic and urologic tumor therapy

Kaltes atmosphärisches Plasma in der orthopädischen und urologischen Tumortherapie

Review Article

  • Denis Gümbel - Department of Trauma, Reconstructive Surgery and Rehabilitation Medicine, University Medicine Greifswald, Germany; Department of Trauma and Orthopaedic Surgery, BG Klinikum Unfallkrankenhaus Berlin gGmbH, Berlin, Germany
  • Georg Daeschlein - Department of Dermatology, University Medicine Greifswald, Germany
  • Axel Ekkernkamp - Department of Trauma, Reconstructive Surgery and Rehabilitation Medicine, University Medicine Greifswald, Germany; Department of Trauma and Orthopaedic Surgery, BG Klinikum Unfallkrankenhaus Berlin gGmbH, Berlin, Germany
  • Axel Kramer - Institute for Hygiene and Environmental Medicine, University Medicine Greifswald, Germany
  • corresponding author Matthias B. Stope - Department of Urology, University Medicine Greifswald, Germany

GMS Hyg Infect Control 2017;12:Doc10

doi: 10.3205/dgkh000295, urn:nbn:de:0183-dgkh0002955

Published: August 8, 2017

© 2017 Gümbel et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at


Cold atmospheric plasma (CAP) is a highly reactive ionized physical state thereby provoking divers biological effects. In medical applications, CAP treatment promotes wound healing, provokes immunostimulation, and is antiseptically active. Moreover, CAP interacts with antiproliferative mechanisms suggesting CAP treatment as a promising anticancer strategy. Here we review the current state of science concerning the so far investigated CAP effects on different cancer entities in orthopaedic and urologic oncology.

Keywords: cold atmospheric plasma, oncology, osteosarcoma, bladder cancer, prostate cancer


Kalte atmosphärische Plasmen (CAP) induzieren auf Grund ihres hoch reaktiven ionisierten Zustands eine Reihe biologischer Wirkungen wie Immunstimulation, Förderung der Wundheilung und Antisepsis. Außerdem werden durch CAP apoptotische Prozesse induziert und Zellregulationen carcinomatös entarteter Zellen mit dem Ergebnis einer antiproliferativen Wirkung beeinflusst, so dass der Einsatz von CAP im Rahmen eines multimodalen Konzepts zur Krebsbehandlung aussichtsreich erscheint. Im vorliegenden Minireview wird der Erkenntnisstand zur Wirkung von CAP auf orthopädische und urologische Krebserkrankungen analysiert.

Schlüsselwörter: kalte atmosphärische Plasmen, Onkologie, Osteosarkom, Blasenkrebs, Prostatakrebs


Physical plasma is defined as a highly reactive ionized physical state containing diverse biologically reactive factors including charged particles, free radicals, excited atoms and molecules, photons, and electromagnetic fields. Advances in physics have enabled the use of pulsed physical atmospheric plasma (cold atmospheric plasma: CAP) for medical purposes, which operate by low pressure and at temperatures between 36°C and 52°C. In the beginning, CAP treatment of biological surfaces, e.g. in skin pathologies and dental diseases, took center stage. Here, primarily CAP-induced anti-microbial and immunostimulating effects have demonstrated beneficial effects for medical applications [1], [2], [3], [4], [5], [6], [7].

In surgery, and particularly in oncological surgery, the preservation of adjacent tissues and the protection of neighboring structures and organs is an important objective. An oncologically required degree of resection, however, is frequently prevented due to neighboring structures, such as blood vessels and nerves. Because of its anti-neoplastic properties [8], [9], [10], [11], [12], [13], [14], [15] as well as its quality to facilitate wound healing [16], [17], CAP application in oncology has increasingly moved into the focus of interest, constituting a novel field in plasma medicine: plasma oncology. Intraoperative CAP treatment of patients undergoing resection may inactivate cancer cells adjacent to critical sites and, moreover, may promote subsequent healing due to CAP’s antimicrobial and immunostimulating efficacy.

In the field of oncology only little is known about biological CAP effects and possible applications for anticancer therapy. An important advantage is that plasma can act selectively against cancer cells [18]. Also CAP-stimulated solutions and culture medium inactivate cancer cells in vitro with specific vulnerability of pancreatic adenocarcinoma cells and glioblastoma cells [19]. One reason is the higher susceptibility of cancer cells to CAP-induced reactive oxygen and nitrogen species (RONS; especially nitric oxide (NO) and nitrogen dioxide (NO2–) radicals) than normal cells, and consequently, CAP induces apoptotic cell responses primarily in cancer cells [14]. Moreover, CAP enhances cancer cell death in vitro by mitochondria-mediated apoptosis [20]. The CAP-induced apoptosis has been observed together with an accumulation of cells in S phase of the cell cycle, which suggests an arrest of tumor proliferation [21].

Here we review the current state of science concerning the so far investigated CAP effects on different cancer entities in orthopaedic and urologic oncology.


Diagnosis of osteosarcoma is routinely evaluated by histochemistry and is followed by a multimodal treatment including wide surgical resection of tumor tissue and multi-agent chemotherapy [22]. Recent in vitro data demonstrating the anticancer capability of CAP treatment in cell culture approaches might represent a promising option for the intraoperative inactivation of osteosarcoma cells.

Two osteosarcoma cell lines (U2-OS cells, MNNG/HOS cells) reflecting two different molecular subtypes of this malignancy indicated a time-dependent and very similar attenuation of cell growth after CAP treatment. A significant cellular growth reduction of 50% could be achieved with a single CAP treatment of 10 s [23]. Subsequent molecular analysis pointed to a CAP induced activation of apoptotic mechanisms. Both, the induction as well as the phospho-activation of the oncogenic p53 protein were detected, followed by nuclear pyknosis, the apoptosis-specific shrinking, and degradation of the nucleus [23]. In comparison of SaOS-2 osteosarcoma cells and human mesenchymal stem cells, the cancer cells died exclusively by induction of apoptosis while non-malignant mesenchymal cells remain fully viable and unaffected after CAP treatment [24]. Moreover, and due to the composition of CAP containing charged and highly reactive particles, the involvement of the cellular redox machinery has been shown in osteosarcoma cells. CAP’s cellular effects could be neutralized by the supplementation of N-acetylcysteine, which could be metabolized to the cellular antioxidant glutathione [25]. Furthermore, CAP treatment led to an inactivation of peroxiredoxin-1 and peroxiredoxin-2, but not the mitochondria-specific isoform peroxiredoxin-3 [25]. Peroxiredoxines are not only involved in cellular redox signalling, but also in apoptosis regulation [26].

Bladder cancer

There are two studies evaluating CAP effects on the SCaBER bladder cancer cell culture model demonstrating anti-proliferative and pro-apoptotic properties of CAP [27], [28]. By transcriptomic profiling of CAP treated cells applying a genome-wide DNA array, Keidar et al. identified 264 genes whose expression rates were significantly modulated after CAP treatment [28]. The genes encoding proteins were primarily involved in cell adhesion, cell growth, and cell death. A subsequent ingenuity pathway analysis (IPA) enabled the prediction of involved signal transduction cascades. Particularly, signal cascades of cell development, cell death, cell motility, and inflammation were affected. All of these regulatory mechanisms are highly engaged in cancer initiation and progression.

Prostate cancer

Similar results were found with prostate cancer cells, promising successful CAP application in prostate cancer therapy [29]. Already a single CAP treatment of 10 s exhibited antiproliferative effects in prostate cancer cells LNCaP and PC-3 incubated over 120 h [30], which was confirmed with DU-145 prostate cancer cells exposed to CAP [31]. The observed effects were comparable to those in the presence of 10 µM docetaxel, a taxane compound clinically used in advanced prostate cancer therapy. On the level of molecular cell biology several factors have been identified interfering with CAP efficacy. The cell cycle regulator p53 as well as the pro-apoptotic factors BAX and p21 were induced following CAP treatment and, vice versa, the expression of the anti-apoptotic protein survivin was attenuated [30]. Consequently, the induction of apoptotic pathways led to the activation of caspases [32] and subsequent induction of DNA strand breaks [33], [34] and nuclear degradation [34]. Similar to CAP-induced effects in osteosarcoma cells, cell response of CAP-treated prostate cancer cells included the activation of redox signalling cascades [35], [36].


Plasma oncology opens up completely new opportunities for oncological surgery. As an additional option, the intraoperative direct CAP treatment of malignant tissue as well as CAP treatment of wound edges after resection may become a promising option in cancer therapy. Notably, CAP efficacy is not limited to specific antiproliferation, but also to further beneficial effects including microbial decontamination, immunostimulation, and promotion of wound healing and scarring.


Competing interests

The authors declare that they have no competing interests.


Arndt S, Landthaler M, Zimmermann JL, Unger P, Wacker E, Shimizu T, Li YF, Morfill GE, Bosserhoff AK, Karrer S. Effects of cold atmospheric plasma (CAP) on ß-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS ONE. 2015;10(3):e0120041. DOI: 10.1371/journal.pone.0120041 External link
Weiss M, Daeschlein G, Kramer A, Burchardt M, Brucker S, Wallwiener D, Stope MB. Virucide properties of cold atmospheric plasma for future clinical applications. J Med Virol. 2017 Jun;89(6):952-9. DOI: 10.1002/jmv.24701 External link
Matthes R, Assadian O, Kramer A. Repeated applications of cold atmospheric pressure plasma does not induce resistance in Staphylococcus aureus embedded in biofilms. GMS Hyg Infect Control. 2014 Sep 30;9(3):Doc17. DOI: 10.3205/dgkh000237 External link
Matthes R, Koban I, Bender C, Masur K, Kindel E, Weltmann KD, Kocher T, Kramer A, Hübner NO. Antimicrobial efficacy of an atmospheric pressure plasma jet against biofilms of pseudomonas aeruginosa and staphylococcus epidermidis. Plasma Process Polym. 2012;10(2):161-6. DOI: 10.1002/ppap.201100133 External link
Matthes R, Bender C, Schlüter R, Koban I, Bussiahn R, Reuter S, Lademann J, Weltmann KD, Kramer A. Antimicrobial efficacy of two surface barrier discharges with air plasma against in vitro biofilms. PLoS One. 2013 Jul 24;8(7):e70462. DOI: 10.1371/journal.pone.0070462 External link
Matthes R, Lührman A, Holtfreter S, Kolata J, Radke D, Hübner NO, Assadian O, Kramer A. Antibacterial Activity of Cold Atmospheric Pressure Argon Plasma against 78 Genetically Different (mecA, luk-P, agr or Capsular Polysaccharide Type) Staphylococcus aureus Strains. Skin Pharmacol Physiol. 2016;29(2):83-91. DOI: 10.1159/000443210 External link
Hoffmann C, Berganza C, Zhang J. Cold Atmospheric Plasma: methods of production and application in dentistry and oncology. Med Gas Res. 2013 Oct;3(1):21. DOI: 10.1186/2045-9912-3-21 External link
Keidar M, Walk R, Shashurin A, Srinivasan P, Sandler A, Dasgupta S, Ravi R, Guerrero-Preston R, Trink B. Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy. Br J Cancer. 2011 Oct;105(9):1295-301. DOI: 10.1038/bjc.2011.386 External link
Partecke LI, Evert K, Haugk J, Doering F, Normann L, Diedrich S, Weiss FU, Evert M, Huebner NO, Guenther C, Heidecke CD, Kramer A, Bussiahn R, Weltmann KD, Pati O, Bender C, von Bernstorff W. Tissue tolerable plasma (TTP) induces apoptosis in pancreatic cancer cells in vitro and in vivo. BMC Cancer. 2012 Oct;12:473. DOI: 10.1186/1471-2407-12-473 External link
Arndt S, Wacker E, Li YF, Shimizu T, Thomas HM, Morfill GE, Karrer S, Zimmermann JL, Bosserhoff AK. Cold atmospheric plasma, a new strategy to induce senescence in melanoma cells. Exp Dermatol. 2013 Apr;22(4):284-9. DOI: 10.1111/exd.12127 External link
Keidar M, Shashurin A, Volotskova O, Stepp MA, Srinivasan P, Sandler A, Trink B. Cold atmospheric plasma in cancer therapy. Phys Plasmas. 2013;20:057101. DOI: 10.1063/1.4801516 External link
Keidar M. Plasma for cancer treatment. Plasma Sourc Sci Technol. 2015;24:033001. DOI: 10.1088/0963-0252/24/3/033001 External link
Xu D, Luo X, Xu Y, Cui Q, Yang Y, Liu D, Chen H, Kong MG. The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma. Biochem Biophys Res Commun. 2016 May;473(4):1125-32. DOI: 10.1016/j.bbrc.2016.04.027 External link
Kim SJ, Chung TH. Cold atmospheric plasma jet-generated RONS and their selective effects on normal and carcinoma cells. Sci Rep. 2016 Feb;6:20332. DOI: 10.1038/srep20332 External link
Ratovitski EA, Cheng X, Yan D, Sherman JH, Canady J, Trink B, Keidar M. Anti-cancer therapies of 21st century: novel approach to treat human cancers using cold atmospheric plasma. Plasma Proc Polym. 2014;11(12):1128-37. DOI: 10.1002/ppap.201400071 External link
Metelmann HR, Vu TT, Do HT, Le TNB, Hoang THA, Phi TTT, Luong TML, Doan VT, Nguyen TTH, Nguyen THM, Nguyen TL, Le DQ, Le TKX, von Woedtke T, Bussiahn R, Weltmann KD, Khalili R, Podmelle F. Scar formation of laser skin lesions after cold atmospheric pressure plasma (CAP) treatment: a clinical long term observation. Clinical Plasma Med. 2013;1:30-5. DOI: 10.1016/j.cpme.2012.12.001 External link
Bender C, Kramer A. Therapy of wound healing disorders in pets with atmospheric pressure plasma. Tierärztl Umschau. 2016;71:262-8.
Kaushik N, Lee SJ, Choi TG, Baik KY, Uhm HS, Kim CH, Kaushik NK, Choi EH. Non-thermal plasma with 2-deoxy-D-glucose synergistically induces cell death by targeting glycolysis in blood cancer cells. Sci Rep. 2015 Mar;5:8726. DOI: 10.1038/srep08726 External link
Yan D, Cui H, Zhu W, Nourmohammadi N, Milberg J, Zhang LG, Sherman JH, Keidar M. The Specific Vulnerabilities of Cancer Cells to the Cold Atmospheric Plasma-Stimulated Solutions. Sci Rep. 2017;7(1):4479. DOI: 10.1038/s41598-017-04770-x External link
Kaushik N, Uddin N, Sim GB, Hong YJ, Baik KY, Kim CH, Lee SJ, Kaushik NK, Choi EH. Responses of solid tumor cells in DMEM to reactive oxygen species generated by non-thermal plasma and chemically induced ROS systems. Sci Rep. 2015 Feb;5:8587. DOI: 10.1038/srep08587 External link
Vandamme M, Robert E, Lerondel S, Sarron V, Ries D, Dozias S, Sobilo J, Gosset D, Kieda C, Legrain B, Pouvesle JM, Pape AL. ROS implication in a new antitumor strategy based on non-thermal plasma. Int J Cancer. 2012 May;130(9):2185-94. DOI: 10.1002/ijc.26252 External link
Gesellschaft für Pädiatrische Onkologie und Hämatologie, editor. S1-Leitlinie "Osteosarkome": AWMF-RegNr: 025/005. 2011 [cited 10 Jul 2017]. Available from: External link
Gümbel D, Gelbrich N, Weiss M, Napp M, Daeschlein G, Sckell A, Ender SA, Kramer A, Burchardt M, Ekkernkamp A, Stope MB. New Treatment Options for Osteosarcoma - Inactivation of Osteosarcoma Cells by Cold Atmospheric Plasma. Anticancer Res. 2016 Nov;36(11):5915-22. DOI: 10.21873/anticanres.11178 External link
Canal C, Fontelo R, Hamouda I, Guillem-Marti J, Cvelbar U, Ginebra MP. Plasma-induced selectivity in bone cancer cells death. Free Radic Biol Med. 2017 Sep;110:72-80. DOI: 10.1016/j.freeradbiomed.2017.05.023 External link
Gümbel D, Gelbrich N, Napp M, Daeschlein G, Kramer A, Sckell A, Burchardt M, Ekkernkamp A, Stope MB. Peroxiredoxin Expression of Human Osteosarcoma Cells Is Influenced by Cold Atmospheric Plasma Treatment. Anticancer Res. 2017 Mar;37(3):1031-8. DOI: 10.21873/anticanres.11413 External link
Kim SY, Kim TJ, Lee KY. A novel function of peroxiredoxin 1 (Prx-1) in apoptosis signal-regulating kinase 1 (ASK1)-mediated signaling pathway. FEBS Lett. 2008 Jun;582(13):1913-8. DOI: 10.1016/j.febslet.2008.05.015 External link
Mohades S, Barekzi N, Laroussi M. Efficacy of low temperature plasma against SCaBER cancer cells. Plasma Process Polym. 2014;11:1150-5. DOI: 10.1002/ppap.201400108 External link
Keidar M, Walk R, Shashurin A, Srinivasan P, Sandler A, Dasgupta S, Ravi R, Guerrero-Preston R, Trink B. Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy. Br J Cancer. 2011 Oct;105(9):1295-301. DOI: 10.1038/bjc.2011.386 External link
Hirst AM, Frame FM, Maitland NJ, O'Connell D. Low temperature plasma: a novel focal therapy for localized prostate cancer? Biomed Res Int. 2014;2014:878319. DOI: 10.1155/2014/878319 External link
Weiss M, Gümbel D, Gelbrich N, Brandenburg LO, Mandelkow R, Zimmermann U, Ziegler P, Burchardt M, Stope MB. Inhibition of Cell Growth of the Prostate Cancer Cell Model LNCaP by Cold Atmospheric Plasma. In Vivo. 2015 Sep-Oct;29(5):611-6.
Barekzi N, Laroussi M, Konesky G, Roman S. Effects of low temperature plasma on prostate cancer cells using the Bovie Medical J-Plasma device. Plasma Process Polym. 2016;13:1189-94. DOI: 10.1002/ppap.201600108 External link
Gibson AR, McCarthy HO, Ali AA, O'Connell D, Graham WG. Interactions of a non-thermal atmospheric pressure plasma effluent with PC-3 prostate cancer cells. Plasma Process Polym. 2014;11:1142-9. DOI: 10.1002/ppap.201400111 External link
Hirst AM, Simms MS, Mann VM, Maitland NJ, O'Connell D, Frame FM. Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells. Br J Cancer. 2015 Apr;112(9):1536-45. DOI: 10.1038/bjc.2015.113 External link
Hirst AM, Frame FM, Maitland NJ, O'Connell D. Low Temperature Plasma Causes Double-Strand Break DNA Damage in Primary Epithelial Cells Cultured from a Human Prostate Tumour. IEEE Trans Plasma Sci IEEE Nucl Plasma Sci Soc. 2014 Sep;42(10):2740-1. DOI: 10.1109/TPS.2014.2351453 External link
Weiss M, Gümbel D, Hanschmann EM, Mandelkow R, Gelbrich N, Zimmermann U, Walther R, Ekkernkamp A, Sckell A, Kramer A, Burchardt M, Lillig CH, Stope MB. Cold Atmospheric Plasma Treatment Induces Anti-Proliferative Effects in Prostate Cancer Cells by Redox and Apoptotic Signaling Pathways. PLoS ONE. 2015;10(7):e0130350. DOI: 10.1371/journal.pone.0130350 External link
Zhunussova A, Vitol EA, Polyak B, Tuleukhanov S, Brooks AD, Sensenig R, Friedman G, Orynbayeva Z. Mitochondria-Mediated Anticancer Effects of Non-Thermal Atmospheric Plasma. PLoS ONE. 2016;11(6):e0156818. DOI: 10.1371/journal.pone.0156818 External link