22nd International Symposium on Plasma Chemistry
July 5-10, 2015; Antwerp, Belgium
Clinical application of cold atmospheric plasma – state and perspectives
Th. von Woedtke1,2, H.-R. Metelmann2, J. Lademann3, A. Schmidt1, K. Masur1, R. Schönebeck4 and K.-D. Weltmann1
1
Leibniz Institute for Plasma Science and Technology (INP Greifswald), Greifswald, Germany
2
University Medicine Greifswald, Germany
3
Charité - University Medicine Berlin, Germany
4
neoplas tools GmbH Greifswald, Germany
Abstract: Based on strong and sound results from basic research on plasma effects on
living cells and tissue, plasma medicine now is starting its successful way into clinical
practice. Currently, four cold atmospheric plasma (CAP) sources are CE-certified as
medical devices. The main focus of plasma medical application is on wound healing as
well as treatment of infective and inflammatory skin diseases. Furthermore, dentistry and
cancer treatment are new and emerging fields of CAP application. The use of plasmaactivated liquids has the potential to open up further innovative fields of plasma medicine
or plasma pharmacy, respectively.
Keywords: plasma medicine, cold atmospheric plasma, medical application
1. General
For more than 10 years, a new independent field of
medical research called plasma medicine is emerging
worldwide. In its strict sense, plasma medicine means the
direct application of cold atmospheric plasma (CAP) on
or in the human body for therapeutic purposes. After a
first period of primarily descriptive research to
characterize several effects of CAP on microorganisms
and mammalian cells in vitro, research activities in recent
years have been focused more and more on basic research
to understand and explain mechanisms of biological
effects using highly sophisticated cell biological and
molecular biological techniques [1]. With these research
results, a sound and reputable scientific basis of plasma
medicine has been provided which will be further
consolidated. This is a main prerequisite not only for
acceptance of plasma medicine in the medical doctor’s
community but also to get strong criteria to distinguish
scientific plasma medicine from obscure players cropping
up again and again also under the level of plasma
medicine.
2. Basic research on plasma effects on living cells
During recent years basic research in plasma medicine
has made excellent progress. One of the first important
findings was the very effective inactivation of a very
broad spectrum of microorganisms by CAP. This can be
used for bio-decontamination of materials and medical
devices [2, 3], but is also important for plasma medical
applications especially because of the fact that also multiresistant microorganisms are susceptible to CAP
inactivation [4-6].
Using several mammalian cell lines, general cellular
responses emerged:
• With lower treatment intensities, CAP is able to
stimulate proliferation of mammalian cells and
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angiogenesis [7].
• Higher CAP treatment intensities lead to apoptosis of
mammalian cells including tumour cells [8-10].
With regard to get more insight into mechanisms of
biological plasma effects, a huge amount of in vitro
studies using microorganisms and mammalian cells [1]
resulted in two fundamental insights:
• Biological effects of cold atmospheric plasmas are
significantly caused by plasma induced changes of the
liquid environment of cells, and
• these processes are dominated by redox-active reactive
oxygen and nitrogen species (ROS, RNS) generated in
or transferred into liquid phases.
It could be demonstrated in detail that resulting from
CAP treatment the redox balance of cells is influenced
with subsequent consequences for cell metabolism and
viability. By plasma-based delivery of reactive oxygenand nitrogen species, cold plasma stimulates or inhibits
cellular processes and triggers hormesis-like processes in
mammalian cells. Previous data show that both gene and
protein expression is highly affected by non-thermal
plasma, and highlights the pivotal role played by NRF2 in
regulating cellular defenses against oxidative stress.
[11-15].
3. General fields of medical application of cold
atmospheric plasma (CAP)
In spring 2012, a group of German researchers in
clinical plasma medicine made the following statement:
“Due to the status quo in clinical research, plasma
treatments in dermatology as well as plastic and aesthetic
surgery have the best prospect to succeed. The focuses of
therapeutic indications are
• the use of antimicrobial plasma effects
• plasma supported stimulation of tissue regeneration as
well as
1
• inflammation modulating plasma effects.
The following application areas can therefore be
identified:
• the support of the healing process with focus on the
treatment of chronic wounds
• the treatment of infected skin diseases and
• the treatment of dermatitis” [16].
This general estimation is true now as before and was
meanwhile approved by several clinical case reports and
clinical trials [17-19]. Even if these activities are growing
worldwide, most clinical experience with CAP is
concentrated in Germany yet.
4. Ar-plasma jet kinpen MED in dermatology and
surgery
At the present time, four CAP sources are known which
being CE certified as medical devices, three of them are
based on sound and comprehensive scientific studies.
One of them is the kinpen MED (neoplas tools GmbH
Greifswald, Germany). In general, argon plasma jets
from the kinpen series basically developed by INP
Greifswald, Germany (Fig. 1) [20] are counted among the
best investigated and characterized CAP sources for
medical applications worldwide.
in decontamination of microbiologically contaminated
sensitive tissue, e.g., buccal mucosa (Fig. 4).
Fig. 2. Lower leg of a male patient with chronic wound
(peripheral artery disease stage IV) contaminated with
P. aeruginosa, before (left) and after the end (right) of
34 treatments by kinpen MED over 17 weeks.
Fig. 3. Infected wound, intra-individual comparison of
CAP effectivity. Left part: non-treated, right part: 12
circles of CAP treatment (1 min/cm², 3 times in 1 week,
followed by a break of 1 week).
Fig. 1. CE-certified medical device kinpen MED.
Under the mandated application conditions, the
maximum temperature kinpen MED’s the plasma jet
contacting the skin surface is 38 °C. UV irradiance at the
visible tip of the plasma jet 10 mm distant from the nozzle
of the capillary is 10.7 µW/cm2 for UV-A (315-380 nm),
14.9 µW/cm2 for UV-B (280-315 nm), and 3.7 µW/cm2
for UV-C (200-280 nm), respectively. With regular
application this is far below the maximum daily UV dose.
No toxic doses of gases like ozon or NO x are emitted
[21, 22]. One of the main advantages of the kinpen MED
is the possibility of contact-free application at a distance
of about 10 mm between nozzle of the jet and surface to
be treated. The spot-like characteristic of the plasma jet
enables its handling similar to a scalpel. The safety of
kinpen application has been proven by several in vitro as
well as in vivo investigations [23-25]. The high potential
of the Ar-plasma jet for medical applications particularly
in the field of tissue regeneration, wound healing and skin
decontamination has been proved by clinical case reports,
clinical trials and applications in animals [21, 26-28].
The routine application in medical practice in first clinics
as well as doctor’s offices has started. Very promising
results are reported especially in the treatment of longlasting chronic wounds where conventional therapies have
been failed (Fig. 2), of infected wounds (Fig. 3) as well as
2
Fig. 4. Contamination of a buccal mucosa ulceration
(left) and effect of decontamination by 3 circles of CAP
treatment (right).
Another jet-like CAP source with a lot of clinical
application experience is the microwave-driven
Ar-plasma torch MicroPlasSter [29-32]. The third wellinvestigated medical device is the dielectric barrier
discharge CAP source PlasmaDerm working with
atmospheric air for plasma generation [33].
5. Perspectives
Wound healing and treatment of infective skin diseases
are in the focus of medical CAP applications today. The
intended use of the CE certified medical devices is mainly
in this field. Therefore, from the present point of view,
dermatology as well as plastic and aesthetic surgery will
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be the medical fields where plasma medicine is expected
to practically succeed at first [16].
Several attempts were made in the past to improve the
skin permeability by chemical, physical or mechanical
manipulations, thus reducing the barrier function of the
skin.
Recently, an enhanced penetration could be
demonstrated for both topically applied substances and
400 nm sized nanocontainers loaded with a model drug by
the application of CAP [34]. However, the drug is to be
applied prior to the plasma-skin interaction, i.e., as long
as the skin barrier is temporarily disturbed. To prevent
the plasma from reacting chemically with the drug, it has
to be encapsulated within nanocontainers that are resistant
to the effects of the plasma. The results demonstrate that
the penetration of the nanocontainers can be effectively
enhanced if applied in combination with CAP, hence
delivering the model drug unaffected by plasma into
deeper skin layers [35].
Another important field of plasma application with a
high practical potential is dentistry [36, 37]. Besides
wound healing especially disinfection of tooth root canal
as well as treatment of dental implants are promising
fields of application. However, despite of a huge research
effort during the last years, relevant clinical application of
CAP in dentistry is not known up to now.
Furthermore, because recent basic research results
potential CAP application in cancer therapy is getting
growing interest [38-40]. This is based above all on the
fact that CAP is able to induce apoptosis in cancer cells
and that these cells seem to be much more sensitive for
CAP treatment compared to non- malignant cells. This
opens up possibilities of supportive CAP application e.g.
in surgical or radiative cancer eradication (Fig. 5) [41].
Fig. 5. Exophytic cancer of the tongue with central
infected ulceration (left) and partial remission under 3
circles of CAP treatment (right).
Finally, it is key finding from basic research in plasma
medicine that plasma treatment of simple liquids like
water, physiological saline or even complex liquids like
cell culture media may result in the generation of some
kind of “activated liquids” causing biological effects on
microorganisms or mammalian cells, too. This opens up
on the one hand additional fields of application in
medicine where direct plasma application is impossible or
has to be avoided, but also in pharmacy to generate,
stabilize or optimize liquid formulations containing active
ingredients [42].
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