1 s2.0 S0370157313001634 Main

Physics Reports 530 (2013) 291–320
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Physics Reports
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Plasmas for medicine

Th. von Woedtke a , S. Reuter a,b , K. Masur a,b , K.-D. Weltmann a,∗
a
INP Greifswald e.V, Felix-Hausdorff Str. 2, 17489 Greifswald, Germany
b
Centre for Innovation Competence Plasmatis, Felix-Hausdorff Str. 2, 17489 Greifswald, Germany
article info abstract

Article history: Plasma medicine is an innovative and emerging field combining plasma physics, life science
Accepted 7 May 2013 and clinical medicine. In a more general perspective, medical application of physical plasma
Available online 18 May 2013 can be subdivided into two principal approaches. (i) ‘‘Indirect’’ use of plasma-based or
editor: R. Redmer
plasma-supplemented techniques to treat surfaces, materials or devices to realize specific
qualities for subsequent special medical applications, and (ii) application of physical
Keywords:
plasma on or in the human (or animal) body to realize therapeutic effects based on direct
Atmospheric pressure plasmas
Plasma medicine
interaction of plasma with living tissue. The field of plasma applications for the treatment
Reactive oxygen species of medical materials or devices is intensively researched and partially well established
Reactive nitrogen species for several years. However, plasma medicine in the sense of its actual definition as a new
field of research focuses on the use of plasma technology in the treatment of living cells,
tissues, and organs. Therefore, the aim of the new research field of plasma medicine is
the exploitation of a much more differentiated interaction of specific plasma components
with specific structural as well as functional elements or functionalities of living cells.
This interaction can possibly lead either to stimulation or inhibition of cellular function
and be finally used for therapeutic purposes. During recent years a broad spectrum of
different plasma sources with various names dedicated for biomedical applications has
been reported. So far, research activities were mainly focused on barrier discharges and
plasma jets working at atmospheric pressure.
Most efforts to realize plasma application directly on or in the human (or animal) body
for medical purposes is concentrated on the broad field of dermatology including wound
healing, but also includes cancer treatment, endoscopy, or dentistry.
Despite the fact that the field of plasma medicine is very young and until now mostly in
an empirical stage of development yet, there are first indicators of its enormous economic
potential. This ambivalent situation fundamentally requires a responsible use of plasma
sources, which are specifically designated for biomedical applications. To enable physicians
as well as life scientists to decide whether a given plasma source is really suitable for
medical applications or biological experiments, a meaningful and mandatory spectrum of
indicators has to be compiled to allow for a basic estimation of the potential of this plasma
source.
© 2013 Elsevier B.V. All rights reserved.
Contents
1. Plasma medicine — a new field of plasma technology in the 21st century......................................................................................... 292
2. Well-known and established plasma applications in the medical field.............................................................................................. 292
3. Scientific basis of modern plasma medicine — gradable, specific and selective plasma effects on living cells................................ 296
4. Atmospheric pressure plasma sources for biomedical applications — special focus on dermatology.............................................. 299
∗ Corresponding author. Tel.: +49 3838554310; fax: +49 3838554301.

E-mail address: Weltmann@inp-greifswald.de (K.-D. Weltmann).
0370-1573/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.physrep.2013.05.005
292 Th. von Woedtke et al. / Physics Reports 530 (2013) 291–320
4.1. Dielectric barrier discharges (DBDs) ......................................................................................................................................... 302

4.2. Atmospheric pressure plasma jets (APP jets) ........................................................................................................................... 304
5. Further medical application fields of atmospheric pressure plasma sources under research ........................................................... 308
6. Conclusions and outlook......................................................................................................................................................................... 312
Acknowledgments .................................................................................................................................................................................. 313
References................................................................................................................................................................................................ 313
1. Plasma medicine — a new field of plasma technology in the 21st century
Physical plasmas are excited ionized gases, which contain different concentrations of low-molecular reactive atoms, ions
and molecules and emit several kinds of electromagnetic radiation including infrared, visible and ultraviolet (UV) light which
are generated by energy supply to a neutral gas. Among the many distinctions between different kinds of plasmas, one is
between thermal and non-thermal plasmas. Within thermal plasmas, the electrons and the ions have the same energy. A
non-thermal plasma gains its reactivity from the high energy electrons, while the ions and neutral species remain cold. This
allows for a strong non-equilibrium chemistry. Thermal plasmas are the most abundant naturally occurring phenomena
e.g. the sun, which are tried to simulate technically for power generation in field of fusion research, non-thermal plasmas
are mostly technical ones whose composition and temperature is adjustable in a wide range by parameters like type of
energy input, input power, type of gas, gas pressure and composition and others. In most cases, cold plasmas for technical
applications are generated by applying an electrical field to a neutral gas or gas mixture, respectively [1,2].
At the end of the 20th century, low-temperature plasmas are established in a wide field of technological applications —
in several cases as enabling technology, which the user of consumer is in most cases not even aware. Most important fields
are low-energy light bulbs, pre-treatment of polymer materials e.g. for painting and bonding, improvement of packaging
materials, several surface finishing technologies, waste and air pollution management, microelectronics, flat panel displays,
and many more (Fig. 1) [3–8].
The search for new and innovative fields of plasma application for the new century resulted in new approaches
solving unmet problems by plasma technology: A survey among 148 German companies realized in 2004 by VDI
Technologiezentrum Düsseldorf, Germany, predicted the field of maximum growth of future plasma applications to be
medical technology, biotechnology and pharmacy, respectively (Fig. 2) [5,9].
Despite a huge progress of medicine and especially medical device technology in the second half of the 20th century,
medicine in the 21st century is facing still considerable and increasing challenges. Constantly growing global population in
general and growing older population in the western world are causing increasing needs in the health care sector worldwide.
Together with increasing public health costs especially in the western world this situation makes it necessary to find
innovative, effective, and less expensive ways for medical therapy.
Plasma medicine is one of the most innovative and emerging field combining plasma physics, life science and clinical
medicine. Even if the use of plasma technology in the medical field is not absolutely new in principle, the young and rapidly
growing research field of plasma medicine represents a new quality of plasma application in medicine.
The aim of this review paper is to give an overview of the state-of-the-art as well as future prospects of medical plasma
application with a special focus on requirements and characteristics concerning plasma sources for this promising, but very
specific field of application.
After a short overview about the history of plasma application for health as well as over more or less established fields of
medical plasma research or present applications (Section 2), and a review of the scientific basis of modern plasma medicine
(Section 3), the main focus of this paper will be set on the design, development, characterization and challenges of application
of plasma sources dedicated for specific therapeutic applications (Sections 4 and 5). Finally, an outlook of future prospects
and requirements (Section 6) will be given.
2. Well-known and established plasma applications in the medical field
Very first applications of plasma for health care date back to the middle of the 19th century, emerging from the popularity
of electrotherapy. Beginning with the use of ozone in the 1850s by Siemens generated by dielectric barrier discharges to clean
biologically contaminated water, followed by carbon arc lamps to treat high blood pressure and electrotherapeutic devices
such as ‘‘violet ray’’ machines first experimental approaches to therapeutic plasma applications have been made — without
describing it as ‘‘Plasma Medicine’’ [10–12].
From a more general perspective, medical application of physical plasma can be subdivided into two principal
approaches:
• ‘‘indirect’’ use of plasma-based or plasma-supplemented techniques to treat surfaces, materials or devices to realize
specific qualities for subsequent special medical applications, and
• application of physical plasma on or within the human (or animal) body to realize therapeutic effects based on direct
interaction of plasma with living tissue.
Th. von Woedtke et al. / Physics Reports 530 (2013) 291–320 293
Fig. 1. Plasma technology — industrial application areas.
Fig. 2. German survey industrial plasma applications.
The field of plasma application for the treatment of medical materials or devices is intensively researched and in some areas
well established for several years or even decades. One important field is the plasma-based modification of material surfaces.
Dependent on several plasma parameters like energy input, pressure, working gas composition, addition of primer
substances, etc., as well as the nature of the substrate, a variety of chemical-reaction based interactions with materials
can be enhanced or even enabled by plasma application. These interactions are etching or ablation, thin dielectric film
deposition, chemical and/or physical surface modification, activation or functionalization (see Fig. 3) are basic processes
which are used not only in several industrial applications but also for processing of surfaces, materials or devices intended
for medical application. At the end of the 1960s, plasma was applied to improve the biocompatibility or biofunctionality of
materials, which are supposed to be in direct contact with biological systems [5]. Medical materials or devices range from
medical implants, catheters, or materials in blood purification systems which are in direct short-term or permanent contact
with living tissue, up to laboratory disposals for cell cultivation, diagnostic tools or scaffolds for tissue engineering which are
used for in vitro handling of cells, blood or other biologic material. Because most of these devices are made from synthetic
polymers, low-temperature plasmas are generally preferable for such treatments. One of the most important advantages
Fig. 3. Basic categories of plasma-chemical interaction with material surfaces.
of plasma processes is the fact that all material modifications are limited to the surfaces whilst the bulk properties of the
material are not influenced.
Up to now, a wide range of plasma-based surface treatment techniques has been developed and a number of which
has been commercialized. These treatment techniques are plasma sputtering and etching, plasma implantation, plasma
deposition, plasma polymerization, plasma spraying, and many more. These processes and techniques can be based both
on low-pressure as well as atmospheric-pressure plasmas. The advantage of homogeneous low-pressure plasmas which are
generated in vacuum chambers is that the conditions of plasma ignition are much better controllable and reproducible
compared to atmospheric pressure conditions. These advantages could compensate at least partially the practical
drawbacks of low-pressure plasma use, above all the need of vacuum equipment and the limitation to batch treatment
processes.
With atmospheric pressure plasmas, a non-thermal treatment of surfaces without the necessity of additional vacuum
equipment can be realized opening up the possibility for better integration of such devices i.e. into continuous production
processes. However, a main disadvantage is resulting from the fact that such plasmas are contracted or filamentary plasmas:
in contrast to the mostly homogeneous low-pressure plasmas, activity of atmospheric-pressure plasmas is strictly localized.
Consequently, any possibility to treat larger surfaces strongly depends on the type of plasma source as well as the treatment
parameters. A strong advantage of the strong localization of atmospheric pressure plasmas is that it is possible to bring the
plasma reactivity specifically and well targeted to the place to be treated. This is advantageous if hard-to-reach regions such
as the interior of catheters, porous surfaces and caverns should be treated [13–16].
Modifications of biomaterial surfaces by plasma treatment range from changes of surface morphology and texture to
special physically and/or chemically designed surface properties. These include increase of surface wettability or specific
functionalization of surfaces to increase and optimize adhesion of living cells on the one side as well as realization of non-
fouling surface conditions to inhibit adhesion of organic matter like proteins, bacteria or cells on the other [17–25].
A further important field of plasma application closely related to plasma treatment of surfaces is the use of plasmas
for sterilization or bio-decontamination of materials or devices for medical purposes. The increasing replacement of glass
and steel in medically used devices by polymeric materials in the middle of the last century resulted in an urgent need
of sterilization procedures which are no longer based on heat treatments. Ionizing radiation and antimicrobially active
gases like ethylene oxide have been approved in the pharmacopoeias and other legal regulations as alternative sterilization
procedures. However, because these methods are not unrestrictedly suitable for every material or devices and require long
degassing procedures, the need for further alternative sterilization processes still exists.
For plasma-surface modifications in medicine, the plasma treated object is an abiotic one, such as a medical implant,
which only after treatment comes into contact with living cells. In plasma sterilization or bio-decontamination a direct
interaction of plasma and living cells, namely microorganisms or other pollutants of biological origin is intended. The first
report on the use of plasma as a sterilizing agent was given in a patent by Menashi in 1968 [26]. Even if Menashi used in its
apparatus a pulsed RF field to create argon plasma at atmospheric pressure, dominating plasma sterilization approaches in
the following years are based on the use of low-pressure plasmas.
In several studies, the high potential of low-pressure plasma to inactivate or remove both microorganisms and viruses
as well as other organic matter as proteins, pyrogens or prions could be demonstrated [27–41].
In the 1990s, a new era in the development of atmospheric pressure plasmas was initiated [13–16]. This opened up the
research field of atmospheric pressure plasma sterilization and bio-decontamination in the middle of the 1990s [42]. To
this day, several groups are working on characterization of antimicrobial effects as well as the optimization of atmospheric
pressure plasma sources for different applications to sterilize and bio-decontaminate medical materials and devices as well
for general applications in the field of hygiene [43–57].
Similar to plasma application for biomaterial treatment, the fact that atmospheric-pressure plasmas are mainly localized
and contracted plasmas yield the possibility to bring the plasma specifically and well-targeted to the point that should be
treated. Particularly for sterilization and bio-decontamination purposes, the contracted atmospheric pressure plasmas are
very useful for well-targeted treatment of products with intricate geometry such as e.g. endoscopes or catheters where the
efficacy of conventional sterilization procedures is limited [58–61].
On the other hand, homogeneous and universal sterilization conditions as with the conventional heat, radiation or gas
based procedures are better to be realized using low-pressure plasma technology than atmospheric pressure plasmas.
Advantage of the latter technology is above all the possibility to be integrated into continuous manufacturing processes,
which have to lead finally to microbiologically safe products. However, this requires a new and modern understanding of
sterilization, which will no longer be guaranteed by a single treatment of a final product, but will rather include the complete
manufacturing process and will be integrated in different process steps during manufacturing. Here, atmospheric pressure
plasma technology could play a key and important role [62,63].
Despite strong efforts in scientific research on plasma sterilization and bio-decontamination as well as ongoing focus
on the huge potential of plasmas for practical application in medical device manufacturing [64], there are really few
commercially available sterilization or decontamination devices based on plasma activity. There are some low-pressure
plasma-assisted devices for several years available on the market, where the action of an antimicrobial active gas, mostly
hydrogen peroxide is combined with a plasma ignition in the sterilizer chamber [27,65]. However, even if its sterilizing
efficiency has been proven repeatedly [65–72], it is well known that the biocidal activity of these systems is mainly based
on the action of the oxidative gas and the plasma phase is mainly for the detoxification of gas residues at the end of the
sterilization cycle [73].
At present, the only commercially available system based on atmospheric pressure plasma technology is the
TipCharger⃝ R
, a device for cleaning contaminated fluid delivery systems like pipettes [74].
Despite the undisputable fact that plasma modification or sterilization of surfaces or materials intended for medical use
are plasma applications in the medical field, the term ‘‘plasma medicine’’ in the sense of its actual definition describes a
new field of research where the use of ‘‘plasma technology in the treatment of living cells, tissues, and organs’’ [75], i.e. its
application directly on or within the human (or animal) body to realize therapeutic effects.
On a closer look, however, such a direct plasma application on or within the human body for medical purposes exists
for a very long time, already. In the middle of the 19th century, electrotherapy was introduced as an innovative therapeutic
concept. In such therapeutically approaches, not only electrical fields as well as voltage or current impulses have been
applied to the human body, but also spark and flash discharges have been used to treat several diseases [76]. At the beginning
of the 20th century, the Austrian inventor Valentin Zeileis created the ‘‘Zeileis method’’, an electro-medical therapy, which
is based on the use of high-frequency ac voltage with the human tissue as part of the electrode configuration, to stimulate
the skin or the complete body to induce its self-healing power. One special kind of this therapy is called ‘‘fulguration’’, a skin
stimulation using long-distance spark discharges, which are created between electrode and human skin. Even if this therapy
in 1933 already was referred as ‘‘quackery’’ [77], it could be considered as an early-stage direct application of physical plasma
on human tissue.
Of course, there are several other kinds of electrotherapy which are undisputed and indispensable part of modern
therapeutic concepts in different fields as neurology or rehabilitation.
Another well-established area of medical application of electrical energy is electrosurgery. In electrosurgery, tissue
heating and resulting desiccation of cells, denaturation of proteins or devitalization of tissue, respectively, is used for
selective coagulation or tissue cutting. One of the most established electrosurgical method is argon plasma coagulation
(APC) using argon discharges at atmospheric pressure for tissue coagulation (Erbe Elektromedizin GmbH Tübigen, Germany;
www.erbe-med.com). APC is a monopolar technique where the tissue to be treated serves as counter electrode. Introduced in
medicine in the 1970s and adapted for endoscopic application in the beginning of the 1990s, APC is one of the most common
endoscopic coagulation techniques mainly used in gastroenterology, general and visceral surgery, urology, gynecology as
well as other fields of clinical medicine [78–84]. Since APC is in use for more than four decades — the cases of APC use in
surgery may indirectly serve as the first long term study with respect to side effects of argon plasma treated tissues within
the human body. Even when the direct treated tissues were desiccated and devitalized, the surrounding cells survived the
plasma treatment but still where contacted by all the active components of the plasma (including ROS and UV). So far, to
our knowledge there are no reports about any side effects of such APC treatments, nor data on increased mutagenic events
following those kinds of surgery.
An electrosurgical technique closely related to APC is called coblation (‘‘cool ablation’’ or ‘‘controlled ablation’’;
ArthroCare Corp., Austin, TX, USA; www.arthrocare.de). Here, a compact bipolar electrode system is immersed in a
conductive medium, usually an electrolyte (saline) solution. Highly localized plasma is created comprising ionized or
reactive atoms or molecules, as well as electromagnetic radiation, which are able to break organic molecules. Applied
onto tissue, a controlled non-heat driven ablation can be realized without tissue necrosis. Similar as APC, coblation
can be integrated in endoscopic as well as minimally invasive operation devices. Up to now, medical applications are
mainly reported from spinal and orthopedic surgery as well as from otorhinolaryngology [85–97]. While the coblation
technique is based on the addition of saline solution into the treatment area – which is obligatory anyway during
most surgical procedures – the plasmacision or plasmaknife technique uses tissue electrolytes instead of externally
fed saline to create a localized plasma for tissue dissection or coagulation [98–100]. Further developments of liquid-
phase discharge plasmas are focused on wound antisepsis as well as electrical thrombectomy to dissolve vascular clots
[101,102].
With the PlasmaJet technique (Plasma Surgical, Inc., Roswell, GA, USA; www.plasmasurgical.com), a bipolar electrode
system with low-flow argon as process gas is used to cut or coagulate tissue in a well-defined and localized manner.
PlasmaJet technique is used to remove unwanted tissue from sensitive fields and can be applied in several fields of
surgery [103–105]. Even if this technique is closely linked to the plasma sources which are intended for therapeutic
applications (Section 4), its activity is mostly based on thermal interaction, thus being similar to APC and as APC and coblation
also based on destructive plasma interaction with living tissue.
Fig. 4. Plasma–tissue interaction: the complex system plasma meets the much more complex biological system cell.
3. Scientific basis of modern plasma medicine — gradable, specific and selective plasma effects on living cells
Despite of more or less exotic plasma applications like the Zeileis method, previous direct plasma applications on living
tissue in electrosurgery are based on very drastic interactions of plasma with cells and tissue leading finally to cellular
destruction and local ‘‘sealing’’ of tissue. Contrary to that, the aim of the new research field of plasma medicine is the
exploitation of mild plasma effects, i.e. much more differentiated interaction of specific plasma components with specific
structural elements as well as functionalities of living cells which can possibly lead either to stimulation or inhibition of
cellular function (Fig. 4; see also reviews [106–108]).
In cold non-thermal atmospheric pressure plasma sources, main reactive components will comprise of reactive neutral
species (reactive oxygen and nitrogen species), UV-radiation, and electric current. In some cases charged species are present
in sufficient amount and electromagnetic fields may play a role.
Reactive oxygen and nitrogen species (RONS): Key component of atmospheric pressure plasmas are reactive oxygen or
nitrogen species. With cold plasmas, at tissue tolerable temperatures, oxygen chemistry will dominate and one major long
living component will be ozone. The US Environmental Protection Agency in 2008 revised the level of the 8 h national
ambient air quality standards to 0.075 parts per million (ppm) [109]. In hotter plasmas, with initial temperatures of higher
than 200 °C, nitrogen species dominate the chemistry. NO radical while having high biological impact is very short living.
NO2 is a long living RONS derived from NO. Its standard level are defined by the US Environmental Protection Agency [110]
to 53 parts per billion (ppb) annual national ambient air quality standard. A recent review by Graves highlights the role of
RONS in redox biology and its implications for plasma applications [111].
UV-radiation is emitted by plasma sources albeit usually in low concentrations. Nevertheless is this radiation one
component that needs to be investigated quantitatively to assess possible harmful effects. The International Commission On
Non-Ionizing Radiation Protection has stated the limits of exposure to be 30 J m2 in the spectral region of 180–400 nm within
an 8 h-period spectrally weighted and 104 J m−2 in the region of 315–400 nm, both limits are spectrally weighted [112]. UV
has therapeutic effects not only by induction of vitamin D production, but is also used for treatment of psoriasis or vitiligo.
Harmful effects arise through interaction with biomolecules, especially with DNA, causing strand breakages and possible
repair defects, which can lead to cancer.
Electric current will be flowing in most plasma sources, most dominantly in direct DBD type discharges, but also in some
types of plasma jets. This current has to be limited to a harmless level. The International Commission On Non-Ionizing
Radiation Protection has determined the touch perception limit of current flowing through the human body to 25 mA at
100 kHz as well as at 1 MHz [113]. However, the use of electricity in medicine has a long history and many therapeutic
effects also in wound healing are reported and applied today.
In the following, a detailed overview of plasma application in medicine is given. An early-stage indicator for the possibility
of selective interaction of plasma with biochemical processes was a report of stimulation of blood coagulation by non-
thermal atmospheric pressure plasma treatment given by a research group at Drexel University, Philadelphia, USA [114].
In contrast to the APC technology, where bleeding is inhibited via a localized thermal ‘‘sealing’’ of tissue (cauterization),
a direct interaction of plasma components with the coagulation cascade, resulting in a direct conversion of fibrinogen
into fibrin fibers, which leads to blood clotting, could be proved experimentally [115]. Here a floating electrode DBD with
kHz excitation was used, which means that direct plasma treatment was performed and all plasma species including
charged species were involved. Similar effects have been demonstrated by other groups in vitro [116,117], but also in
vivo using an animal model [118]. Choi et al. used a microwave discharge, which means that no electric potential was
applied and the charged species density was probably lower that is the case for the floating electrode (FE)-DBD. Kuo
et al. used an RF-plasma torch. At least for the microwave plasma but most probably for all plasma sources used, the
temperature is comparably high so that the chemistry is NO dominated as opposed to ozone specific chemistry. Besides
the use of this method for blood coagulation without strong plasma–tissue interaction, another interesting idea is to use it
for the removal of excess plasma proteins and lipid molecules by a plasma-based blood purification and filtration technique
[119].
To the best of our knowledge, first reports of non-destructive manipulation of mammalian cells by plasma have been
given by Eva Stoffels group from Eindhoven University of Technology, Eindhoven, The Netherlands, who showed that cells
forming in vitro a two-dimensional monolayer on the substrate of a cell culture dish could be detached by plasma treatment
with a plasma needle in a reversible manner. The cells were detached both from each other as well as from the substrate
without causing necrotic cell destruction [120–125]. These cell detachment effects, which have been reproduced under
varying conditions and with various plasma sources [126–129] could be attributed to plasma-induced influences on the
expression of cell adhesion molecules (CAMs) responsible for cell–cell and cell–substrate interactions [130,131]. Stoffels
et al., Coulombe et al., and Yonson et al. used a modified version of the plasma needle in helium. Höntsch et al. used an
RF plasma jet in argon (kinpen). Differences are mainly in the gas used, the excitation frequency and the electric field
distribution, because in the plasma needle, the surrounding atmosphere or the treated surface acts as counter electrode
whereas with the plasma jet a circular grounded electrode is set around the jets dielectric tube. The substrate in this
case only acts as a third electrode. The cell detachment effects thus seem to be reproducible for different electric fields,
frequencies and type of working gas. Also influences on cell migration in vitro [132,133] can be attributed to plasma induced
influence on CAM expression. Lee et al. postulated that the degradation of adhesion molecules might be a potential strategy
for melanoma cancer therapy [134]. This indicates the possibility to induce specific plasma effects on sub-cellular level
causing consequences for the cell behavior on cellular level.
In connection with the studies on plasma-induced cell detachment, the possibility to induce apoptosis in mammalian
cells by plasma treatment has been described [123,135].
Unlike necrosis which is a premature cell death caused by traumatic external factors, apoptosis is a form of physiologic
cell death internally initiated by several extracellular (extrinsic) and intracellular (intrinsic) signals. Usually, the normal
way of disposing of cells which are damaged, old or non-functional, occurs via apoptosis, which is known as ‘‘programmed
cell death’’, in order to manage homeostasis and the development of an organisms. Apoptosis is induced in response
to a variety of cellular stress factors including toxins, oxidative stress, or DNA damage. However, should the apoptosis
pathway in cells be inactivated or interrupted, development of cancer is possible. Therefore, evasion of apoptosis is
considered to be one of the fundamental hallmarks of cancer. Consequently, induction of apoptosis is one of the therapeutic
approaches for cancer treatment for which several mechanisms are reported [136–144]. The possibility to inactivate
tumor cells (e.g. melanoma cells, human breast cancer cells, lung carcinoma cells, liver cancer cells) via induction of
apoptosis by atmospheric-pressure plasma treatment in vitro was demonstrated repeatedly [101,145–156]. The initial
hypothesis that plasma-induced apoptosis is triggered by plasma-generated reactive oxygen species (ROS) [123,135] could
be proved by several experimental studies using a variety of plasma sources, namely an AC driven plasma jet in Air and
nitrogen [150], or two types of floating electrode DBD [152,154]. Vandamme et al. used two dosages, one of 10 J/cm2
and one of 20 J/cm2 and found a correlation of dose to ROS generation and apoptosis induction [150,152,157]. Other
authors demonstrated that both non-toxic proliferation modulation effects but also apoptosis induction is correlated with
different doses of reactive nitrogen species (RNS), above all NO generated by atmospheric pressure plasma [158]. Here,
Liebmann et al. used an integrated microwave atmospheric pressure plasma jet, which produced NO in the order of 200
ppm and ozone in the order of 100 ppm. Treatment with and without plasma generated UV-radiation as well as RNS
scavenging was applied which led the authors to attribute the most dominant effect to the NO radical and species derived
from NO.
Other experimental studies give rise to the assumption that at least some types of carcinoma cells are much more
sensitive to plasma-induced inactivation compared to normal cells [151,159,160].
Generally, plasma-based direct inactivation of cancer cells is not always realized by apoptosis, only, but also by necrosis
which is strongly dependent on treatment dose. However, there is predicted significant therapeutic advantage in cancer
treatment to kill cells by apoptosis and avoid necrosis and the associated inflammation. Additionally, the fact has to be
taken into account that in cancer cells the ability to go into apoptosis is blocked, which is one main reason for its resistance
against chemotherapeutic drugs. Therefore, the restoration of apoptotic pathways in cells by plasma treatment cannot only
be a way of direct plasma-based cell killing but also to restore sensitivity of cancer cells to chemotherapy. In this case,
plasma-treatment could serve as support for conventional therapy [152].
Several in vivo investigations in animal models show varying results. Partecke et al. have investigated the effect of a
kinpen on the human pancreatic cancer cell line Colo-357 in an in vivo tumor chorio-allantoic membrane (TUM-CAM)
assay [161]. TUNEL-staining showed plasma-induced apoptosis up to a depth of tissue penetration of 48.8 +/− 12.3 µm. The
bottom cell layers were not affected by plasma treatment [161]. The kinpen is a bullet type argon plasma jet in MHz operating
regime [162]. All plasma components can reach the surface, charged species and electric field will be lower in abundance
than e.g. in a floating electrode DBD, which was used by Vandamme et al., who found that the effect of the plasma treatment
on apoptosis of cancer cells was volumetric: Caspase 3 immunostaining revealed apoptotic effects. Moreover, caspase 3
positive cells were homogeneously distributed in sagittal sections from treated tumors [157]. These findings were received
with the use of a floating electrode DBD, where all plasma components can reach the target.
Another promising technique under research for carcinoma treatment, which is related to plasma treatment, is the
use of pulsed electric fields [163–165]. Possibly, combinations of pulse power and plasma technology could open up new
perspectives not only in cancer treatment but also in other fields of medical therapy.
A recent study using mononuclear cells from rat spleen could demonstrate differing sensitivities of lymphocyte
subpopulations to atmospheric-pressure treatment whereas T-cells react more sensitive than B-cells. It has to be clarified
in future studies whether these changes can be used to generate regulatory T-cells to sensitize immune cells or to modify
homing of lymphocytes [166]. The discharge type used was a surface barrier discharge in air or argon. Here the species
are generated at a distance of several millimeters (between 2 and 5 mm). The dissipated power was 2.4 mJ per plasma-on
cycle at a 0.4/1.2 ms plasma-on/plasma-off time. The setup means that only species diffusing onto the liquid surface will
be involved in the plasma effect, largely excluding electrons or ions.
An important trigger of apoptosis induction is damage of cell structures beyond repair, e.g. DNA fragmentation, cell
membrane damage, or mitochondrial defects [150]. In several reports, plasma based apoptosis induction could be correlated
with influence on DNA integrity [152,153,157,167]. These effects seem to be fairly independent on the type of plasma source
used (FE-DBD, HV-plasma needle, needle type bullet jet), not in quantity, but in qualitative aspects.
Influences on cellular DNA by plasma treatment have been investigated not only in connection with strategies of selective
and targeted inactivation of cells by apoptosis induction in cancer cells or killing of microorganisms, but also as an early
indicator for possible unwanted side effects of medical plasma application.
Plasma-caused effects on DNA could be demonstrated using plasmid DNA [149,168], DNA in bacteriophages [169] but
also in mammalian cells [170,171]. Regardless on different evaluation method as well as different interpretation of the
results, authors of all these papers conclude that DNA inactivation is not mainly caused by thermal effects, UV radiation,
or electrical fields and charged particles, respectively, but by mainly plasma-generated reactive oxygen species. A recent
work of Kalghatgi et al. suggested that DNA damage in mammalian cells is mediated not by ozone but by long living
neutral organic peroxides generated in the liquid cell environment [171,172]. They state: ‘‘There is a direct correlation
between the peroxidation efficiency of 11 different amino acids and the level of DNA damage, providing strong support
for the hypothesis that organic peroxides are produced in the plasma treated medium and are responsible for the observed
effects on DNA’’ [171]. Therefore is seems to be reasonable that the secondary induced long living organic radicals formed by
reactions from plasma based ROS and RNS will lead to the transformation of biologic macromolecules such as amino acids
or lipids. Those widespread macromolecules will likely be affected by inorganic radicals within cells and therefore are able
to accumulate the plasma mediated damages due to the fact that those organic peroxides will additionally alter the redox
balance within the cells unless the cellular antioxidants (like glutathione) will stop those reactions [173].
In connection with these studies concerning apoptosis induction it has to be pointed out that different plasma
treatment doses can result in cell necrosis (higher doses), apoptosis (medium doses) or non-lethal influences on special
cell behavior [152,171,174]. Consequently, these studies gave a further indication for the possibility of differentiated and
well-controlled plasma application, i.e. dose dependent differentiation of either cell destruction (strong plasma action —
plasma inactivation) or catalyzing/increasing of special biochemical processes within the cell (soft plasma action — plasma
stimulation). The term dosage has not been defined throughout the involved research groups. While most groups mostly
refer to the plasma treatment duration as a dose, the energy input into the plasma per electrode area has been put forward
by others (see e.g. [107]).
Plasma based stimulation was demonstrated using endothelial cells. It was shown, that plasma-generated reactive
oxygen species are able to enhance endothelial cell proliferation and to stimulate angiogenesis by a specific induction of
growth factor release in the cells. Again in these studies the dose dependent manner of plasma action was demonstrated
because higher plasma doses and resultingly higher ROS concentrations caused cell death instead of stimulation
[171,175–177]. It was hypothesized that this plasma proliferative effect could be related to sub-lethal cell membrane
damage leading to the observed growth factor release. Reversible cell membrane poration has been hypothesized by Stoffels
et al. already with regard to general apoptosis induction by plasma [122]. However, plasma induced non-lethal but reversible
cell permeabilization was also described by other authors who used this phenomenon for the transfection of DNA into cells
without DNA degradation [178–180].
A further stimulating effect by plasma treatment (RF-bullet jet in argon) could be demonstrated for angiogenesis, the
formation of new blood vessels. Using the well-established hens egg test on the chorioallantoic membrane (HET-CAM),
angiogenesis could be demonstrated in a tissue model [181].
Most of the previous investigations on plasma effects on living cells are rather descriptive and characterize general
influences on cell vitality or cell behavior or investigate special single sub-cellular structures, mainly DNA. Recently, in
order to get a more comprehensive yet detailed insight into the mechanisms of plasma–cell interactions, proteomics are
used, i.e. techniques being able to describe changes of the protein pattern of cells or microorganisms in response to plasma
treatment [182,183]. Using this technique combined with e.g. mass spectrometry, single proteins such as enzymes can
be identified. Furthermore their change as well as their up or downregulation in response to plasma treatment can be
monitored. Even if these techniques require severe methodological effort and are very time-consuming, they will help to
get a much deeper insight into plasma induced modulations of cellular behavior.
Up to now, we state in general that atmospheric pressure plasma is able to interact with cells in a dose dependent manner
– where a reliable measure for the plasma dose still remains to be one of the open questions – leading to cell inactivation
by apoptosis or necrosis on the one side or non-lethal manipulation of special aspects of cell behavior as proliferation or
membrane integrity on the other.
A truly new aspect of medical plasma application should be mentioned at this point. To get a deeper insight into
plasma–cell and plasma–tissue interactions and its potential for medical applications, a great number of in vitro studies have
been provided during the last years as it was reviewed in Section 3. One of the key findings is that several biological effects are
not result of a direct plasma–cell or plasma–tissue interaction but are mediated by liquids. It was demonstrated that simple
liquids like water or physiological saline, after treatment by atmospheric pressure plasma are antimicrobial active and that
these effects are attributable to the generation of different low-molecular reactive species [184–188]. Plasma treatment of
more complex liquids like cell culture media result in changes of organic components which could induce various effects on
living cells and their components [129,157,171,175,189].
These results can also form a measure for a comparison of plasma sources. E.g. the ROS-production within liquids can be
taken as means to compare for example different dielectric barrier discharges in their H2 O2 or nitrate/nitrate production in
standard liquids.
Summarizing the available data from literature as discussed in Section 3, the following plasma-induced effects on
mammalian cells or biochemical pathways have been found in vitro already.
Plasma influences
• specific detachment of cells from matrices as well as from cell clusters
• cell migration
• cell proliferation and angiogenesis
• expression of cell surface proteins/cell adhesion molecules (integrins, cadherins,)
• DNA integrity
• apoptosis induction, inactivation of cancer cells
• reversible cell membrane permeabilization (‘‘plasma poration’’)
• blood coagulation by direct influence on the coagulation cascade.
However, an exact definition of what the ‘‘plasma dose’’ exactly is, which plasma-generated compound or compound
mixture is mainly or exclusively responsible for which special biological effect has not been defined yet. Even if there are first
efforts to systematize mechanisms of plasma–cell interactions which are based mainly on indirect evidence and analogies,
respectively [45,107,190], details of plasma–cell interaction are elusive now as before.
One reason among several others for this situation is the fact that, despite plasma medical research is only a few years
old, published results have been achieved using a broad spectrum of different atmospheric pressure plasma sources with
a very limited comparability. Only a systematic comparison of the different plasma sources with their respective reactive
component composition will allow to separate plasma induced biological effects.
4. Atmospheric pressure plasma sources for biomedical applications — special focus on dermatology
The initial intention to use atmospheric-pressure plasmas for medical purposes was first of all based on its use
for microorganism inactivation. Because it was well known that atmospheric-pressure plasma is effective to inactivate
microorganisms on e.g. heat-sensitive surfaces without irritating the surface properties itself, the idea arose to try to
use this technique also on sensitive living surfaces like human skin or wounds for antisepsis, i.e. for local treatment to
inactivate above all infectious microorganisms causing skin diseases or constrict wound healing. Therefore, the first and, up
to now, main focus of plasma medical applications is in the field of dermatology, especially for skin disinfection/antisepsis,
treatment of infectious skin diseases and wound healing [108,191–194]. Several cold atmospheric pressure plasma sources
are designed as well as tested with regard to this field of application.
Besides the fundamental fact that for such applications plasma sources have to be used which work at atmospheric-
pressure conditions or pressures close to it, the following additional requirements have to be taken into consideration:
• In contrast to bacteria inactivation on medical devices or products, i.e., inactivation mostly in a dry condition as well as
in a hostile environment, infectious microorganisms on skin or wounds are in a wet and nutrient-rich environment and,
consequently, have to be inactivated under conditions, which are optimal for growth and infection progression.
• The plasma activity has to be more or less selective leading to microorganism inactivation on the one side without
harming effects onto the surrounding tissue on the other.
Inactivation of vegetative bacteria and fungi under in vivo-like conditions was demonstrated repeatedly using several in
vitro-models mainly based on half-rigid nutrient media (agar) plates or biofilm preparations which are useful to simulate
nutrient-rich as well as wet and thus optimal living conditions for bacteria [145,195–207]. These investigations have been
performed in most cases merely to demonstrate basic performance characteristics of plasma sources which are intended
for biomedical applications. However, at the same time also some understanding of molecular as well as biochemical
mechanisms of microorganism inactivation by atmospheric pressure plasma had been gained.
The second source of actual growing plasma medical research was closely connected with the requirement of selective
antiseptic plasma efficacy without harming surrounding tissue. Such selective effects are very hard to demonstrate in simple
Fig. 5. Atmospheric pressure plasmas — ‘‘tool box’’ [208].
experimental approaches because a simultaneous treatment of bacteria and mammalian cells has to be realized including a
differentiated evaluation of the results.
Most atmospheric pressure plasmas that are intended for biomedical applications are generated by applying electrical
energy to a gas resulting in reorganization of the electronic structure of the gas components and in production of excited
species and ions. In non-thermal atmospheric pressure plasmas, the main part of the applied energy goes into the production
of energetic (‘‘hot’’) electrons whereas the majority of gas atoms, ions and molecules remain in a low-energetic state resulting
in a low plasma temperature [2,16,209]. The composition and temperature of non-thermal plasmas are adjustable in a wide
range resulting in a broad spectrum of different plasma sources (see Fig. 5) which opens up different possibilities to classify
plasma sources for biomedical application.
Fridman et al. have suggested a classification related to the quality of contact of the plasma with the target structure to
be treated. Plasma sources for direct or indirect plasma treatment were distinguished, respectively:
• Direct plasma treatment means that biological samples or living tissue serve as one of the electrodes necessary for plasma
ignition.
• In indirect plasma treatment, the electrodes are part of the plasma-generating device, only. Thus, there is primarily no
electrical contact to the targeted structures [164].
A strict separation between both principles is not always possible. However, plasma generated species potentially eligible
for biological effects can be estimated in general based on this classification. Even if, with direct plasma treatment not in
all cases a direct voltage connection to biological samples or living tissue is necessary, a current flow through the target
structure has to be taken into consideration. This current flux has to be limited in order to avoid detrimental effects. A
great difference between direct and indirect plasma treatment is that in direct plasma treatment besides a flux of reactive
uncharged species, which will take place in indirect plasma treatment, too, a significant flux of charged species (electrons,
ions) will reach the surface to be treated. The amount of UV and other electromagnetic radiation reaching the target sample
or surface depend at least partially upon whether direct or indirect plasma treatment is realized [164].
One of the earliest approaches of indirect plasma application for medical therapy is the so-called plasma dynamic therapy
of wounds with nitric oxide by a plasma generator called Plazon⃝ R
. With this device, a hot DC arc plasma generates a gas
flow with a defined content of nitric oxide which is supplied to the biological tissue to be treated. Unfortunately, very
limited information about this technique and its application is available in the literature. Proof of therapeutic effectivity
is based on summarizing data as well as repeatedly presented case reports [164,210]. However, meanwhile the device
has got a CE certification as medical device class IIb and is commercially available (Onkocet, Ltd., Pezinok, Slovakia;
http://www.onkocet.eu).
During recent years a broad spectrum of different plasma sources with various names dedicated for biomedical
applications has been reported [211], for example plasma needle [212], atmospheric pressure plasma plume [213],
atmospheric pressure plasma jet [214,215], plasma brush [216], floating-electrode dielectric barrier discharge (FE-
DBD) [114], atmospheric pressure glow discharge torch (APGD-t) [126], microhollow cathode discharge air plasma
Fig. 6. Plasma sources suitable for therapeutic applications [221].
jet [200], microwave plasma torch [217], plasma jets and microplasma jets [101,132,134,148,218–221], dielectric barrier
discharges [153,221,222], and nanosecond plasma gun [223]. However, this list is far from being comprehensive. Moreover,
not all plasma sources that are declared to be useful for biomedical applications have been comprehensively biologically
characterized to prove this potential.
Trying a technical classification, generally three types of plasma sources are applicable for biomedical applications,
namely, barrier discharges, plasma jets, and corona discharges [11,214,209,224,225]. So far, research activities were mainly
focused on the dielectric barrier discharges and plasma jets, which are schematically shown in Fig. 6.
Barrier discharges (BDs) are characterized by the presence of at least one isolating layer in the discharge gap [11,224]. The
classical configuration is the so-called volume barrier discharge, where two electrodes with at least one insulating layer form
the discharge gap. In the case that the object to be treated forms one of the electrodes, the volume barrier discharge enables
direct treatment of the object. Since the local current is controlled by the capacity of the discharge configuration, a more
or less ‘‘creeping’’ current flow through the target structure is possible. By limitation of this current a painless treatment of
living tissue is possible. Special configurations of the barrier discharge are the so-called surface discharge and the coplanar
discharge. In a surface barrier discharge (SBD), both electrodes are in direct contact with the isolator. In this geometry, the
plasma is formed around the electrodes on the isolator surface. In the case of the coplanar discharge, both electrodes are
embedded in the dielectric and the plasma is generated at the isolator surface, too. With surface barrier discharges, indirect
treatment of samples can be realized because the target to be treated is not part of the discharge configuration [221]. Surface
barrier discharges can be miniaturized and formed to arrays, in order to build up microplasma arrays [15,226,227].
Atmospheric pressure plasma jets (APP jets) consist of a gas nozzle equipped with one or two electrodes. The plasma is
ignited inside the nozzle and transported to the outside as well as to the object to be treated by a gas flow. Different plasma
jets described in the literature differ in electrode configuration, type of gas, and applied electrical parameters. Plasma jets
can be distinguished between remote plasmas, where the plasma is potential free and consists of relaxing and recombining
active species from inside the nozzle (see e.g. [214,215]), and active plasma jets where the expanding plasma contains free
and high energetic electrons. In the latter case, the targeted substrate forms a second or third electrode, i.e. the plasma is
not potential free [49,221,225].
Due to their respective physical and geometrical differences, each type of plasma source varies in their respective reactive
component composition. Reactive components include radicals, ions and electrons, photons (from sometimes UV to IR
radiation), excited species like metastables and electromagnetic fields. In plasma sources where the treated surface (e.g. the
skin) acts as electrode, ions and electrons will play a key role. These are e.g. the plasma needle (depending on the treatment
condition), the FE-DBD, and some types of volume dielectric barrier discharges. In remote plasma sources, where the active
agents are blown to the treated area, mostly reactive oxygen or nitrogen species will be the acting agents. Most of the
plasma jets and microwave plasma sources can be thus categorized. Here one can also distinguish between cold plasma
sources (close to room temperature), which are mainly producing ROS, especially atomic oxygen or ozone [215], plasma
sources and cold plasma sources (T > 140 °C), which generate NOX -species.
In bullet type plasma jets, the electromagnetic field component is non negligible, since it is known to generate a secondary
plasma within a remote noble gas filled alumina tube. The plasma gun and the plasma plume, but also the kinpen are plasma
sources emitting plasma ‘‘bullets’’.
Fig. 7. Left: schematic of the cylindrical round floating electrode dielectric barrier discharge (FE-DBD). Right: FE-DBD in action (Drexel University,
Philadelphia, USA; by courtesy of Greg Fridman) [114,228].
Finally, plasma sources in which no direct line of sight to the plasma zone exists, are free from photons. These are some
type of plasma jets and remote DBDs.
In the following, a selected spectrum of representative and well-investigated plasma sources which are useful for
biomedical research as well as clinical applications with special focus on dermatology will be presented.
4.1. Dielectric barrier discharges (DBDs)
A prominent and well published DBD-based plasma source forming one of the starting points of modern plasma
medicine is the floating-electrode dielectric barrier discharge (FE-DBD) from Drexel University, Philadelphia, USA. Electrode
configuration can be realized in various shapes whereas the round version has been mostly used for biomedical research
(Fig. 7) [114,164,228].
With this device, the plasma is generated between a quartz-insulated high-voltage electrode and the sample which is not
grounded and remains at a floating potential. Applying a high-voltage (10–40 kV), the discharge ignites when the distance
between the powered electrode and the sample is less than 3 mm. The working gas is ambient air. Typical values of input
power are around 3–5 W resulting in a surface power density of 0.5–1.0 W/cm2 . The operation of FE-DBD can be realized
both in continuous or pulsed mode [107,114,228].
Several biomedical studies have been realized in vitro using this DBD setup. As reported already, one of the first
demonstrations of selective non-thermal interaction of atmospheric-pressure plasma with biochemical processes, namely
blood-coagulation cascade, was demonstrated using this plasma source [114,115]. Several other in vitro studies using
different cell types have been done to gain more insight into mechanisms of plasma–cell interaction [107,145,152,171,172,
175,177,229].
Moreover, investigations using cadaver tissue as well as first animal trials in vivo have been realized to demonstrate the
possibility of non-damaging and non-toxic treatment of living tissue and to define threshold conditions for skin and wound
treatment [114,145,164,230–232]. Based on these investigations, this plasma source is estimated to have a great potential
for medical applications especially in the field of skin and wound antiseptics (see reviews [164,210]).
The FE-DBD from Drexel University works on the same basic principle like a DBD plasma device from University
of Applied Sciences and Arts Göttingen, Germany, originally developed for treatment of materials like wood [233,234].
Additionally, a pre-treatment of human ‘‘material surfaces’’ like finger nails prior to varnishing has been realized using
this DBD plasma [235].
In this device, the high-voltage electrode is covered by ceramic as a dielectric. Human body or another object to be treated,
which has to have a sufficient high electric capacitance or has to be grounded, respectively, serves as counter electrode
(Fig. 8). High voltage pulses (around 13 kV, 100 kHz) are used to ignite the plasma. Additionally, the frequency of these trigger
pulses can be modified in the range of 200–300 Hz. The plasma is ignited in ambient air and no additional gas flow is needed.
The gas temperature of the discharge is around 33 °C. UV emission spectra show emission mainly in the UV-B (280–320)
and the UV-A (320–400 nm) range originating from excited N2 molecules, furthermore, UV-C emission (180–280 nm) can
be measured, indicating the presence of excited NO molecules [222,236–238]. The presence of UV-A to -C radiation shows
the necessity to investigate plasma medical plasma sources with regard to their UV-dosage, which is not covered by the
CE-certificate.
Using this DBD-based plasma source which is the first one that could also be used as a battery powered hand-held
device [235], a consequent and extensive characterization of plasma characteristics, biological effects on microorganisms,
mammalian cells and tissue samples in vitro and ex vivo, respectively, up to animal trails in vivo as well as first case reports
with healthy volunteers has been successfully performed to prepare the application of the DBD device in dermatology [205,
206,222,236–243]. Additional to the fact that the DBD device actually has fulfilled all technical preconditions to get a CE
certification as medical device (CINOGY GmbH Duderstadt, Germany), with these in vitro and in vivo performance tests the
Fig. 8. PlasmaDerm⃝ R
: DBD plasma ignited between a dielectric-covered high-voltage electrode and skin surface (CINOGY GmbH Duderstadt, Germany;
by courtesy of Dirk Wandke).
Fig. 9. Schematic drawing of the surface DBD arrangement for biological sample treatment in atmospheric air in a petri dish arrangement (INP Greifswald,
Germany) [247].
conditions had been met to get permission for a clinical trial according to the actual tightened up German governmental
rules [244]. A clinical trial to use this plasma device to treat ulcerated legs and lower leg sores has been performed
(2011/2012).
A dielectric barrier discharge arrangement specifically designed for systematic biomedical experiments in vitro is the
surface-DBD of the INP Greifswald, Germany.
The discharge arrangement schematically shown in Fig. 9 is based on a setup initially developed for plasma-based thin-
film deposition of silicon oxide layers on particle surfaces as well as for decontamination or sterilization purposes under
atmospheric-pressure conditions [245,246].
The electrode array consists of 1.5 mm-thick epoxy-glass fiber bulk material for circuit boards (50 mm diameter) with a
breakthrough voltage of 40 kV cm−1 . The 35 m-thick copper electrodes were structured by etching. On the one side of the
dielectric, the high-voltage part of the DBD array had a line-like structure consisting of four concentric 0.75 mm-wide ring-
shaped electrodes. The diameter of the outer ring is 35 mm; distances between the ring-shaped electrodes are 3 mm each.
On the other side of the dielectric, a 35 mm-diameter round non-structured flat copper surface serves as counter electrode
at ground potential.
For biomedical experiments, the surface-DBD arrangement was adapted to petri dishes [247], one of the most used
devices for microorganism as well as cell cultivation. The electrode array was mounted by a special construction into the
upper shell of a petri dish (60 mm diameter) in that way that the distance between the high-voltage electrode surface and
the sample in the lower shell of the petri dish can be adjusted variable between 2 and 5 mm to investigate the influence of
the gas phase above the liquid in addition.
With this experimental setup, ambient air can be used as working gas for plasma generation. As a power source, a
commercial Fourier synthesis pulse generator was used with a pulsed sinusoidal voltage of 10 kVpeak (20 kHz) and a
0.4/1.2 s plasma-on/plasma-off time. With this setup, an energy of 2.4 mJ is dissipated into the plasma in each cycle of
high voltage. The power is 0.25 W cm−2 . Optical emission spectroscopy (OES) of the surface-DBD plasma in ambient air
showed emissions in the UV-A and UV-B range between 270 and 470 nm, only, with nitrogen related bands between 297
and 430 nm (second positive and first negative system of N2 ) but neither NOγ bands in the UV-C range (200–280 nm) nor
emission of hydroxyl radicals (HO• ) at 309 nm, mainly because of the low energy input. Using Fourier transformed infrared
spectroscopy (FT-IR), reactive species like nitrous oxide (N2 O), ozone (O3 ), carbon dioxide (CO2 ) as well as the isomerates
nitric acid (HNO3 ) and peroxynitrous acid (ONOOH) have been found in the gas phase around the surface plasma [184].
Fig. 10. Schematic drawing of the surface DBD arrangement for biological sample treatment in a reaction chamber for application of different working
gases at atmospheric pressure conditions (INP Greifswald, Germany) [185].
Fig. 11. Flexible surface-DBD arrangements applicable for treatment of curved surfaces (INP Greifswald, Germany).
To get more flexibility in working gas selection, a special housing has been constructed in such a way that it can be
mounted on the lower shell of a 55 mm petri dish forming a reaction chamber sealing off the outside (Fig. 10). By a special
gas supply channel, this chamber can be flooded with different working gases (gas flow 0.5 slm). Up to now, in most cases
argon gas has been used with this experimental setup. For experiments in argon atmosphere, a pulsed sinusoidal voltage
of 3 kVpeak (40 kHz) with a 0.4/1.2 s plasma-on/plasma-off time is used, because, according to the Paschen curves lower
ignition voltage is needed to generate plasma in argon compared to air.
In contrast to the surface-DBD plasma in ambient air, OES emissions in the visible to infrared range between 700 and
950 nm caused by excited argon atoms have been measured in argon and also a distinct emission of HO• at 309 nm. A
determination of CO2 abundance with Fourier transformed infrared absorption spectroscopy revealed the presence of CO2
in the gas phase around the plasma.
These variable surface-DBD setups have been used for systematic biomedical experiments using biological samples
like cell or microorganism cultures as well as liquids containing cells or microorganisms [166,184,185,189,247,248]. It has
been used specifically for several investigations on plasma–liquid interactions to characterize the potential of atmospheric
pressure plasma to modify liquid composition and, subsequently, to transfer biological plasma effects indirectly via changes
of the liquid environment of cells and microorganisms [184,185,248]. Even if this special surface-DBD arrangement was
used primarily for biomedical experiments, it is possible to create several practically applicable plasma sources based on
corresponding surface-DBD arrangements. For example, in Fig. 11 flexible flat DBD electrodes are demonstrated which can
be used potentially to treat curved surfaces, e.g. in the form of a ‘‘plasma cuff’’ [12].
In another device named ConPlas (‘‘contact plasma’’), a surface-DBD based on isolated wires is integrated in a handpiece
which is constructed in such way that a flooding of different working gases around the electrode arrangement is possible to
allow several variations of the composition and characteristics of the ignited plasma (Fig. 12) [221].
An arrangement of dielectric pin type barrier discharges allows the treatment of larger surfaces with strongly non even
surface topology (see Fig. 13).
4.2. Atmospheric pressure plasma jets (APP jets)
As outlined before, pioneering work on plasma-based influences on mammalian cells has been done by Eva Stoffels
group from Eindhoven University of Technology using the so-called plasma needle. The device consists of a stainless steel
wire serving as the powered electrode placed coaxially in a casing which is supplied with a gas, mainly helium (other gases
are possible), at variable flow rates of a few hundreds of milliliter per min. RF plasma at 13.56 MHz and 200 V is generated
at the tip of the metal pin (Fig. 14 (left)). The typical size of the plasma glow was 2 mm in diameter. However, the plasma
needle can be used in two operation modes representing indirect and direct plasma treatment, respectively. In the unipolar
mode the needle is separated by several millimeters from the (grounded) target to be treated. In the bipolar mode, the
a c
Fig. 12. Functional principle of the plasma source ConPlas⃝ R

: (a) 3D-CAD model and (b) schematic side view of the plasma handheld unit, (c) plasma unit
of a lab prototype in operation; 1—isolated wires as high voltage electrodes, 2—grounded electrode, 3—plasma, and 4—object to be treated. (INP Greifswald,
Germany).
Fig. 13. Flexible electrode array arrangement (plasma array): (1) pin type single electrode with dielectric, (2) central power connection and (3) surface to
be treated and counter electrode (INP Greifswald, Germany) [249].
Fig. 14. (left) Schematic drawing of the plasma needle (TU Eindhoven, The Netherlands; by courtesy of Eva Stoffels) [250], Plasma needle in unipolar
(middle) and bipolar (right) operation modes (TU Eindhoven, The Netherlands; by courtesy of Eva Stoffels) [122].
plasma is sustained between the needle tip and the grounded object to be treated if the distance is lower than 3 mm (Fig. 14
(right)) [122,212,250]. Gas temperature is not higher than 35 °C, maximum power outflux is, dependent on the needle-to-
probe distance, about 0.15 W/cm2 with an maximal input power of 20 mW [251].
Optical measurements showed emission of UV at wavelengths between 300 and 400 nm. Active oxygen radicals (O•
and OH• ) have been detected in the plasma as well as nitric oxide (NO• ) radicals [122,124,250,252]. Using this plasma
Fig. 15. Right: use of the plasma torch MicroPlaSter in chronic wound treatment, middle: schematic setup of the plasma torch MicroPlaSter (ADTEC
Plasma Technology Co. Ltd., Fukuyama, Japan); right: bottom view of the plasma between electrodes and outer metal cylinder (by courtesy of Julia
Zimmermann) [253].
needle, several biomedical experiments have been realized using microorganisms as well as cell cultures (see Section 3 and
reviews [122,124]).
The microwave plasma torch called MicroPlaSter (ADTEC Plasma Technology Co. Ltd., Fukuyama, Japan) used at Max
Planck Institute for Extraterrestrial Physics, Garching, Germany, consists of six stainless steel electrodes inside a metal
cylinder. Argon, which was flown around the electrodes, is used as working gas. Microwave power at 2.45 GHz and 85
W is applied producing plasma zones between the electrode tips and the inner surface of the metal cylinder forming the
plasma torch which is cooled by an additional air to adjust the plasma temperature not higher than 320 K (Fig. 15) [217].
Optical emission spectroscopy of the plasma torch shows two strong peaks in the UV-B region, but no emission of
UV-C. The integrated UV power density on the target to be treated with the plasma torch is not higher than 80 W/cm2 .
Antimicrobial effectivity could be demonstrated in vitro, which is partly but not exclusively attributed to UV radiation, but
must be caused by additional reactive components of the plasma [217].
A more comprehensive study using different microorganisms mostly clinical isolates, showed different susceptibilities
to plasma treatment, whereas, in general the plasma torch was more effective against Gram-negative than Gram-positive
bacteria. Inactivation of bacteria in biofilms was possible, too, but depended on the thickness of the biofilm. With an animal
wound infection model using rats, it was demonstrated that a single 10 min treatment could reduce wound infection
significantly. A 5-day course with 10 min wound treatment each day resulted in a tendency of improved wound closure
in the plasma treated animal group [207]. Using this plasma torch, worlds first clinical trial to decrease bacterial load on
chronic wounds in patients was realized (Fig. 15 (left)).
The treatment of 36 patients including 38 chronic infected wounds was performed with this device. As summarized by
Isbary et al. out of a total of 291 plasma treatments with an duration of 5 min each a highly significant reduction of the
bacterial load was observed [253]. This reduction was found in all kinds of germs including multiresistant ones and could
also be reproduced with a 2 min-daily treatment regimen [254,255]. In the investigations, no short term harming effects
(such as thermal effects) of the plasma treated skin were detected. However, it has to be stated at this point, that due to the
relatively short period of time since this study was performed no long term effects could be reported so far. In general, a side
effect assessment including evaluation and estimations of long term effects is required. A tendency of faster closure of these
chronic wounds was stated, too [193]. Further applications to treat other dermatological areas of indication e.g. pruritus or
Hailey–Hailey disease have been started [254,256,257].
Different types of atmospheric pressure plasma jets have been developed by INP Greifswald, Germany, for surface
modification as well as antimicrobial treatment of heat sensitive materials and surfaces [258–265]. One variant of
this plasma jet called kinpen was further developed for numerous biomedical investigations and clinical application
(kinpenMED) (Fig. 16) [266].
The device, which the kinpenMED is based on – the kinpen09 – consists of a hand-held unit (Dimensions:
length = 170 mm, diameter = 20 mm, weight = 170 g) for the generation of a plasma jet at atmospheric pressure, a DC
power supply (system power: 8 W at 220 V, 50/60 Hz), and a gas supply unit. The principal scheme of the plasma source is
shown in Fig. 16) (right). In the center of a quartz capillary (inner diameter 1.6 mm) a pin-type electrode (1 mm diameter)
is mounted. In the continuous working mode, a high frequency (HF) voltage (1.1 MHz, 2–6 kVpp ) is coupled to the pin-type
electrode. The plasma is generated from the top of the centered electrode and expands to the surrounding air outside the
Fig. 16. Atmospheric pressure plasma jet kinpenMED for biomedical applications (INP Greifswald;neoplas tools GmbH Greifswald, Germany) [220,266].
nozzle. In the burst working mode, a constant period of HF voltage supply (plasma on) is followed by a break period (plasma
off) which can be altered by variation of the burst-to-burst interval. With this, integral power input and consequently plasma
temperature can be varied. The whole system works with all rare gases with gas flow rates between 3 and 10 standard liters
per minute (slm). Argon is mostly used as process gas, yet small admixtures (up to 2%) of molecular gases to the feed gas
are possible. With these gas flow rates and a maximal input DC power of 3.5 W to the hand-held unit, the ignited plasma
effluent has a visible length of up to 14 mm.
Measuring the axial temperature profile, temperatures between 63 °C and 38 °C can be measured dependent on the
power input as well as the axial distance from the capillary nozzle of the plasma source. In all cases, at the visible tip of the
bright plasma jet, more or less constant temperatures around 48 °C have been measured. This corresponds to measurements
of thermal output of the plasma, which is between 145 and 160 mW at the visible tip of the plasma jet regardless of the input
power. Driven in the burst working mode with alternating plasma-on/plasma-off phases, net energy input and heating of
the plasma can be further reduced resulting in temperatures below 40 °C over the full length of the plasma jet.
Besides emissions between 700 and 1000 nm caused by excited argon atoms, in the UV-A region between 350 and 400
nm lines of nitrogen emission are measured caused by mixing of the feed gas argon with surrounding ambient air. For
the same reason, emission of OH radicals at 309 nm can be found. There is low (within the noise limit of the detection
system) detectable emission in the UV-C range between 200 and 280 nm [220,221]. However, dependent on the feed gas
mixture, emission of VUV radiation lower than 180 nm has to be taken into consideration [261]. Because it is well known
that UV-B radiation has also effects on biological systems and is used for this reason for therapeutic purposes in dermatology,
integrated irradiance in the range between 260 and 360 nm was measured resulting in a maximum value of 5 mW/cm2 [220].
To fulfil requirements for medical applications, the performance characteristics of the kinpenMED differ slightly to the ones
from the above described kinpen09.
In the effluent of the kinpen, nitrogen monoxide is present whose production can be controlled by air admixture to the
argon working gas as well as by gas humidity [267,268].
Using this plasma jet kinpen, a broad spectrum of microbiological, cell-biological as well as biomedical tests has been
realized to characterize its biological performance and to estimate its useability for medical applications [208].
In vitro, the efficacy of the plasma jet kINPen against typical wound pathogens and bacterial biofilms could be proved
just as against clinical fungal strains and skin parasites [181,203,204,206,269]. A further in vitro experiment using a
co-cultivation approach gave evidence that the selective inactivation of microorganisms by atmospheric plasma jet can
support the regeneration of a wounded skin cell culture [270]. To come closer to the in vivo situation and to get more
information regarding to tissue tolerability of atmospheric pressure plasma treatment, some more complex in-vitro models
like bacterially contaminated eyes from slaughtered pigs or the HET-CAM (Hens Egg Test — ChorioAllantoic Membrane) have
been used [271–273]. Several pre-clinical tests have been realized to estimate potential risks of plasma application on skin.
Using porcine skin in vitro, an effective reduction of bacterial load was shown whereas a special potency of the plasma jet
is its ability to reach hair follicles, an important source for re-emergence of bacteria following conventional skin antisepsis.
In vivo confocal microscopy investigations may hint at some minimal plasma-caused tissue damage only in the upper cell
layers of the constantly regenerating stratum corneum, which could not be confirmed by histological investigations of the
same samples [274–276]. However, in this context an enhancement of substance as well as nanoparticle delivery through
the skin was found which opens up new aspects of plasma-supplemented transdermal drug delivery [277,278]. Based on
these comprehensive pre-clinical investigation and characterization of the atmospheric pressure plasma jet kINPen, first
case reports as well as a clinical trial with healthy volunteers demonstrated that the high efficacy of the plasma treatment
in skin disinfection is based on the local production of free radicals. It was demonstrated further that skin physiological
a b
Fig. 17. Shielding gas to control reactive species composition nitrogen emission from ambient nitrogen (left: no shielding (a), and right: oxygen shielding
(b)), flow simulation of jet in petri dish controlling ambient surroundings [280].
parameters like barrier function, hydration of the stratum corneum, skin temperature and antioxidative potential might be
slightly influenced, but to an extent that was far away from skin damage or permanent influence on skin function. These
results led to the conclusion that skin treatment by the plasma jet kinpen is safe in regard to skin physiology under clinical
conditions [243,279].
Moreover, first case reports demonstrated the successful complementary treatment of long-lasting chronic wounds in
dogs, which could not be healed by conventional treatment using wound antiseptics only [181].
These comprehensive pre-clinical and first clinical, in vivo and in vitro characterization of the atmospheric-pressure
plasma jet kinpen lead to the technical optimization of this plasma device to fulfil all technical preconditions for CE
certification as medical device (Fig. 16). Using this device, a first case report with healthy volunteers to demonstrate positive
influence of plasma treatment in healing superficial laser skin lesions has been realized [266]. Moreover, a clinical trial
to treat ulcerated legs has been realized recently (2011/2012) in co-operation with Charitè - University Medicine Berlin,
Germany, whose data evaluation is still under way.
A new development is the use of a shielding gas device for plasma jets (see Fig. 17 (left)). It allows controlling the
atmosphere around the active effluent zone, in order to control the reactive species composition and be independent from
air humidity or the influence of nitrogen or oxygen diffusing into the jet. Fig. 17 (right) shows a simulation of the flow
conditions of the jet flowing into a petri dish. The shielding curtain can be clearly identified [280]. With this setup it was
possible to identify the role of ROS versus RNS in HaCaT skin cell response of vitality to plasma treatment.
Other groups use different variants of atmospheric pressure plasma jets, e.g. based on helium as working gas, for skin
treatment and wound healing, too [281,282].
Finally, with the plasma skin regeneration system Portrait⃝ R
PSR3 a jet-like plasma device for several skin regeneration
purposes in aesthetic facial surgery like facial rejuvenation has been published. In this hand-held device, nitrogen gas is
activated by an ultra-high frequency radio frequency generator. The generated plasma is directed through a quartz nozzle
out of the tip of the hand-piece. Optical emission spectroscopy shows peaks in the visible and near-infrared range. In contrast
to the plasma sources described above, the effect of this system is mainly based on controlled heating of different skin
layers [283–286].
Generally one can distinguish between plasma jets where the electric field is aligned in direction of gas flow and jets
where the field is perpendicular to the flow. If, in the first type of plasma jets, a dielectric is situated between the electrodes,
usually these type of jets exhibit bullet behavior, even with RF-driven jets of 1 MHz operation frequency [162]. Here it can
be concluded that charged species can reach the treated area. Other jets especially RF-driven jets where the electric field is
perpendicular to the gas flux, such as the APPJ, developed by Selwyn and co-workers [219], exhibit negligible amounts of
charged species. A comprehensive study that compares especially this fact has yet to be conducted.
Generally, with plasma jets spot-like plasma contact zones on the targeted surfaces are realizable. Because of a gas-flow
driven expansion of the plasma outside the device (see e.g. Fig. 17), plasma jets are able to penetrate into small structures and
gaps, e.g. hair follicles [49,275]. However, treatment of larger areas can be realized by moving the plasma jet over the surface,
only. This makes it possible to limit the treated region e.g. on skin in a very flexible manner but might be time-consuming.
A possible alternative is the use of two- and three-dimensional plasma-jet arrays [49,221,287,288]. Such arrays can be
arranged in different geometries enabling effective treatment of larger areas (Fig. 18).
5. Further medical application fields of atmospheric pressure plasma sources under research
Even if, up to now, the main field of plasma medicine is dermatology and above all wound healing, several other promising
medical plasma applications are investigated worldwide. As it was reported in Section 3, the inactivation of carcinoma
cells via induction of apoptosis by atmospheric-pressure plasma treatment is one important field of in vitro research on
biomedical plasma effects. On the background of dermatological plasma applications, treatment of skin cancer is an obvious
Fig. 18. Examples of jet-like plasma arrays. [49,221] (INP Greifswald, Germany).
Fig. 19. Left: experimental setup of the DBD reactor; right: Plasma gun—50 cm long, 4 mm in diameter dielectric guide with plasma plume formation
(GREMI, CNRS-PolytechOrlans, France; by courtesy of Eric Robert) [223].
approach. First in vivo animal studies about treatment of experimental skin tumors in mice have been reported yet [151,154,
157,164,289]. It was demonstrated recently that in vivo antitumour action is based on ROS action leading to DNA damage,
cell cycle alteration and apoptosis induction suggesting that the plasma action scheme might be very close to that at the
base of modern cancer treatment strategies [155].
However, to allow plasma treatment not only on outer surfaces of the body but also in body cavities or inside the body,
respectively, different and specially adapted plasma sources are needed. At GREMI, CNRS-Polytech’Orlèans, France, such a
special plasma source called plasma gun has been developed (Fig. 19) [155,223].
It is based on a pulsed DBD reactor connected with a dielectric catheter-like flexible silicon or polyimide tube. Using a
moderate flow of few standard cubic centimeters rare gases (Ne or He) or rare gas based mixtures, the DBD reactor delivers
fast moving (up to 108 cm s−1 ) plasma bullets of nanosecond duration or bullet bursts which propagate through the flexible
capillary over distances of tens of centimeters with no electrical connection to the high voltage DBD. Even if the generation
of plasma bullets is reported by other authors, too [162,225,290,291], the very original aspect of this device is that as result of
this bullet propagation, downstream the up to 50 cm long capillary guide outlet, a long plasma plume expands in ambient air.
This plasma plume generation occurs in a mixture of air constituents with noble gas species. The optical emission spectrum
is dominated by the second positive band system of nitrogen (309–316 nm) [223]. Using capillary guide setups with T-
shaped branches, splitting and mixing of the bullets and symmetric propagation has been demonstrated [223,292]. This
plasma gun can be used not only for the decontamination of small diameter catheters but, because of the outside expanding
plasma plume also in endoscopic devices to bring the plasma in the tumor vicinity also inside the body. First preliminary
endoscopic experiments in mice both for lung and colon targets have been realized encouraging further work to optimize
this system for plasma endoscopy to treat lung and colorectal cancers which have rather poor prognosis using conventional
therapies [155].
Another DBD-based setup to generate a plasma discharge inside a long flexible tube is the bifilar helix electrode
configuration as presented in Fig. 20.
The electrode arrangement consists of a double-walled PTFE tube with an inner and an outer tube concentrically aligned
with two equidistant twisted electrodes in between. The distance between the electrodes is in the range of mm. The inner
diameter of the double-walled tube is 2 mm, whereas the complete wall thickness is about 1 mm. To ignite the discharge,
an argon gas flow of 1–2 slm (with possible oxygen and/or nitrogen admixture) is used and an alternating voltage of around
10 kHz with amplitude up to 11 kV is applied. In this way, homogeneous plasma can be ignited inside of several meters
long catheters. This electrode configuration was primarily developed as an alternative construction of biopsy channels
of endoscopes to guarantee a better decontamination and reprocessing. However, because of a jet like plasma expanding
outside the end of the tube (Fig. 20, lower left) its use for endoscopic plasma applications e.g. for cancer treatment is thinkable
(Fig. 20, lower right) [12,53,61].
Fig. 20. Upper left: schematic of the bifilar helix electrode configuration to ignite a DBD inside a double-walled PTFE tube with (1) powered electrode,
(2) grounded electrode, (3) outer tube, (4) inner tube, (5) discharge, (6) power supply, and (7) electrical circuit for measuring the consumed power; upper
right: photograph of the bifilar helix discharge electrode and plasma generation at atmospheric pressure in the same tube. Lower left and right: DBD based
bifilar helix discharge configuration integrated in an endoscope channel (INP Greifswald, Germany) (INP Greifswald, Germany) [12,53,61].
For much better targeting of harder-to-reach regions inside the body such as lungs, pancreas and duodenum, a 15
micrometer sized microplasma jet based on a hollow-core optical fiber has been published. With this device exact plasma
targeting and localization on a single-cellular level might be possible. It could be demonstrated that the generated plasma
jets are sufficient to induce apoptosis but not necrosis in different in vitro cultivated tumor cell types [101,148].
Beyond cancer treatment, endoscopic plasma sources might open further applications in gastroenterology because a
combination of antibacterial effects with healing and anti-inflammatory effects could be useful for several indications. Using
an animal model of ulcerative colitis in mice, the possibility of in vivo treatment of inflammatory bowel disease by cold pin-
to-hole spark discharge plasma has been demonstrated [293].
Another field of intensive research activities is plasma application in dentistry. In 2004, Sladek et al. discussed the
possibility to use the plasma needle (see Section 4.2) to clean and disinfect vulnerable infected tissue in a dental cavity
or in a tooth root canal because of its small size and its ability to inactivate bacteria without high electric voltage, high gas
temperature or production of chemically aggressive species [195]. Later, this was supported by demonstration of effective
inactivation of biofilms of the key cariogenic bacterium Streptococcus mutans by the plasma needle [294].
The effective inactivation of different oral bacteria and above all microbial biofilms on different surfaces including
extracted teeth as well as dental implant materials such as titanium has been proven repeatedly using different atmospheric
pressure plasma sources, in particular plasma jets [218,295–303]. Furthermore, atmospheric pressure plasma is tested
successfully as a useful tool for dentin surface treatment to increase the interfacial bonding strength to improve
composite restoration or to enhance wettability and osteoblast spreading on dentin or bone replacement materials such
as hydroxyapatite or dental implant metals to support periodontal regeneration [304–306]. Finally, atmospheric pressure
plasmas are tested for applicability in tooth whitening or bleaching, partially in combination with hydrogen peroxide
[153,307,308].
Generally, up to now all these investigations on dental plasma applications are based on in vitro experiments using plasma
sources designed for surface treatment. However, some of these plasma sources are large in size and, consequently, might
be difficult to use directly inside the mouth. Moreover, the plasma penetrability as well as delivery of reactive species into
narrow but long gaps as teeth root canals is mostly driven by the working gas flow, only. One possibility to overcome these
problems is the generation of the plasma directly inside the root canal. One possibility to solve this problem is a plasma jet
device based on a hollow medical needle (diameter 0.7 mm) which can be introduced directly into a tooth root canal where
the plasma is ignited [309].
A sophisticated alternative is an intermittent negative DC corona discharge which is denoted as hairline plasma (Fig. 21).
A pointed hollow needle electrode is fed with argon gas at a flow rate of 0.5 standard liters per minute and connected to a
negative high voltage in the range 1–14 kV. Between the cathode and the anode, which will be formed by living tissue under
application conditions, intermittent cold plasma develops. This discharge produces nanosecond-short current pulses with
a repetition frequency of about 1.8 kHz and amplitude of several hundred milliamperes. Because of a radial extension and a
length of the plasma are 30 micrometer and up to 1.5 cm, respectively, it is able to enter perfectly narrow cavities as a tooth
root canal (Fig. 21 (right)) [310].
As it was reviewed up to now, most efforts to realize plasma application directly on or in the human (or animal) body for
medical purposes is concentrated on the fields of dermatology, wound healing, endoscopy and dentistry. However, sporadic
publications about several other interesting fields of possible medical plasma applications can be found.
Fig. 21. Hairline plasma: schematic setup (left) and Hairline plasma application to a prepared root canal of a human tooth. (right) (INP Greifswald,
Germany) [310].
Martines et al. and Brun et al. reported in vitro and ex vivo studies of antimicrobial plasma treatment of ocular cells as
well as human cornea which might be used for treatment of corneal infections and could open ophthalmological plasma
applications [311,312]. It should be mentioned that due to the expected proximity of the plasma to the naked eye, UV-
radiation and its possible side effects have to be ruled out before considering a direct plasma treatment.
Furthermore, tissue removal by atmospheric plasma is reported which is, in contrary to electrosurgery, not based on
thermal effects but on chemically driven processes. This technology could open the way to plasma-assisted tissue-selective
surgical procedures [86,313]. Stoffels et al. published a concept for intravascular application of a gas-permeable membrane-
covered plasma needle e.g. for non-inflammatory treatment of blood vessel walls [128]. Again, there are several aspects
which have to be tested; such as connectivity of the plasma treated vascular walls. Furthermore, also long term effects have
to be taken into consideration — which could be ranging from sclerosis to the formation of malignant cells. To be on the safe
side, long terms studies are needed.
The use of indirect plasma treatment as discussed in Section 3 yields way to a new and innovative field of medical plasma
application where the plasma is not applied directly on living structures but is used to generate, optimize and/or stabilize
products, which contain active agents, above all liquids. In contrast to plasma medicine – the direct use of plasmas on or
within the living organism for therapeutic purposes – this field should be called ‘‘plasma pharmacy’’, as a subdivision of
medical plasma application [314]. Pharmacy is a branch of health sciences dealing with preparation, dispensing, and proper
utilization of drugs whereas drugs in this sense are substance used in the prevention, cure, or alleviation of diseases. Based on
the present state of knowledge, application fields of plasma pharmacy might be: preparation of antimicrobial active liquids
for disinfection and antiseptics [184]; modification of complex liquid components to influence cell and tissue behavior,
e.g. stimulation of cell proliferation [175]; solubilization of poorly soluble or non-soluble substances e.g. by stabilization
of shape and size of micelles formed by tensides [315]. Another conceivable possibility is the activation of drugs before
application.
Another very promising field, which might be considered as potential part of plasma pharmacy is the use of atmospheric
pressure plasmas together with nanoparticles for special therapies. As one example it was shown in in vitro studies
that cancer treatment by antibody-conjugated gold nanoparticles could be significantly stimulated by additional non-
thermal air plasma treatment [153,316,317]. The stimulation of nanoparticle penetration into skin was also demonstrated
in an ex vivo animal tissue model [278]. This could possibly lead to a direct plasma treatment of skin shortly before
the application of ointments to increase the uptake of the containing compounds through the loosened skin cell-to-cell
barrier.
Generally, one of the advantages of plasma pharmacy is that direct contact of plasma with living tissue is avoided
and, consequently, some possible side effects (e.g. caused by UV-radiation) can be excluded. On the other hand, most of
such plasma pharmaceutical products have the character of drugs and have to be licensed according to specific regulatory
requirements [314].
In principle, several synergies between plasma technology and nanotechnology could be imagined ranging from
synthesis, functionalization and processing of nanomaterials and nanoparticles up to plasma-enhanced delivery and
stimulation of therapeutic nanoparticles. A perspective paper about this innovative field of modern medicine has been
published recently [318].
Fig. 22. Scheme of systematic multistep research to estimate reliable and safe therapeutic applications of plasma sources [320].
Finally, it can be said that despite that not all of the planned plasma applications in medicine will be realized in practice,
this review could, however, demonstrate the enormous potential of direct application of atmospheric pressure plasma for
therapeutic purposes.
6. Conclusions and outlook
The introduction of physical plasma into clinical practice is not only a big challenge for interdisciplinary research at the
interface between plasma physics and life sciences, but also an option to develop new therapeutic strategies for several of
todays hard-to treat diseases such as chronic wounds or MRSA. Particularly because of several contributions in public media
worldwide, there are growing expectations especially of patients but also of physicians which are waiting for innovative
tools and techniques to address unmet clinical needs. Despite the field of plasma medicine is very new and mainly in an
experimental stage of development yet, there are first signs of its huge economical potential. Here, the plasma-medical
research community has to take responsibility to answer these legitimate public expectations by responsible and reliable
research but without inspiring the hope of short-term and easy to achieve solutions of all medical problems including
healthcare costs. Since the field of plasma medicine is still very young — the question of long-term studies still remains
to be solved. Until then responsible research and open minds in all directions are requested [319].
To take account of this ambivalent situation, a responsible use of plasma sources which are designated for biomedical
applications is needed. A significant amount of basic research has to be done now and in future to identify potential medical
indications and to estimate the risks of plasma in use (Fig. 22).
To put physicians as well as life scientists in a position to decide if a given plasma source is really useful for medical
applications or biological experiments, a meaningful and mandatory spectrum of indicators has to be compiled to enable a
basic estimation of the potential of a plasma source.
A decisive condition for sustained success of clinical plasma medicine is to have medical plasma sources which:
• operate at atmospheric pressure to make possible treatments of living objects,
• are characterized by good manageability for operation at open atmospheres,
• operate stable with regard to reproducibility and reliability of treatment results,
• are well characterized with regard to plasma parameters and ‘‘macroscopic’’ characteristics to make possible process
control and monitoring,
• are matched precisely to the specific application.
Up to now there are no generally accepted criteria according to which atmospheric-pressure plasma sources can be
assessed as to their suitability for medical applications so far. Consequently, definitions of physical–technical as well as
biological criteria need to be established. As a first step to help to evaluate plasma sources for biomedical applications
according to risk analysis, the minimum set of criteria has to include temperature, UV-radiation, emission of gaseous
products and electromagnetic compatibility in relation to geometry and operative parameters [208].
Characterization of biological plasma effects including specific effects on human cells as well as microorganisms in vitro
has to be set up both in consideration of risk analysis and estimation of potential applications. The minimum set of biologic
criteria should include influence on aqueous media (pH changes, generation of stable chemical species) to characterize its
chemical reactivity, antimicrobial efficacy under in vivo-like conditions (wet or humid environment), influence on viability of
mammalian cells, intracellular occurrence of ROS and influence on intracellular DNA. Other criteria can be added optionally
to characterize special biologic effects related to special applications or risks, respectively [208].
A necessary next step is to make such a set of basic plasma physical as well as biological performance parameters
mandatory and to transfer it into legal rules and standards including a risk analysis considering different field of potential
application.
However, besides all technical as well as physical and biological details and features, decision if an atmospheric pressure
plasma source may be useful for biomedical application should be made using the following 10 questions:
1. Is the clinical efficacy proved?
2. Is the absence of undesirable local or systemic side effects (mutagenic, carcinogenic, toxic effects; pains, scars,
pigmentation disorders) proved?
3. Is the medical effect reliable?
4. Is the medical effect well controllable?
5. Can a quick medical effect be realized?
6. Is it possible to exclude the development of resistances when treating infectious diseases as well as co-treating resident
flora?
7. Is it possible to exclude inhibitory effects on normal microbiological flora?
8. Is it cost-effective?
9. Is it sure that there are no alternative solutions with what it could be done easier?
10. Will the plasma treatment be accepted both by patients and physicians?
Only if the majority of these questions can be affirmed, a further development up to clinical proofs is acceptable. Naturally,
the main precondition to deal with these questions is to define an exact field of intended therapeutic application. The first
two questions are playing a key role because plasma medical research has to guarantee the application of plasma with proved
clinical efficacy but without or at most with minimal side effects whose acceptability has to be decided dependent on the
intended therapeutic use. For this purpose, both a comprehensive and careful physical characterization and optimization
of the plasma sources and a comprehensive characterization of biological effects is indispensable. Plasma medicine is a
new field with enormous opportunities for medicine and significant research potential. It is broad enough to promote co-
operations and is an opportunity both for medical therapy and plasma technology.
Acknowledgments
The authors wish to thank the German Federal Ministry of Education and Research for financial support of the
joint research project ‘‘Campus PlasmaMed’’ (grants nos 13N9779 and 13N11188) as well as the Centre for Innovation
Competence plasmatis (grants nos 03Z2DN11 and 03Z2DN12).
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Physics Reports 530 (2013) 291–320

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Plasmas for medicine

article info abstract

∗ Corresponding author. Tel.: +49 3838554310; fax: +49 3838554301.

4.1. Dielectric barrier discharges (DBDs) ......................................................................................................................................... 302

1. Plasma medicine — a new field of plasma technology in the 21st century

2. Well-known and established plasma applications in the medical field

Fig. 1. Plasma technology — industrial application areas.

Fig. 2. German survey industrial plasma applications.

Fig. 3. Basic categories of plasma-chemical interaction with material surfaces.

Fig. 5. Atmospheric pressure plasmas — ‘‘tool box’’ [208].

Fig. 6. Plasma sources suitable for therapeutic applications [221].

4.1. Dielectric barrier discharges (DBDs)

4.2. Atmospheric pressure plasma jets (APP jets)

Fig. 12. Functional principle of the plasma source ConPlas⃝ R

6. Conclusions and outlook

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