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Journal ArticleDOI

Killing adherent and nonadherent cancer cells with the plasma pencil

08 Jan 2015-Biointerphases (American Vacuum Society)-Vol. 10, Iss: 2, pp 029401

TL;DR: Results indicate that plasma consistently shows a delayed killing effect that is dose dependent, and there is some evidence that apoptosis is one of the pathways that leads to the death of the cells, indicating that plasma initiates cell signaling pathways.
Abstract: The application of low temperature plasmas in biology and medicine may lead to a paradigm shift in the way various diseases can be treated without serious side effects. Low temperature plasmas generated in gas mixtures that contain oxygen or air produce several chemically reactive species that have important biological implications when they interact with eukaryotic or prokaryotic cells. Here, a review of the effects of low temperature plasma generated by the plasma pencil on different cancerous cells is presented. Results indicate that plasma consistently shows a delayed killing effect that is dose dependent. In addition, there is some evidence that apoptosis is one of the pathways that leads to the death of the cells, indicating that plasma initiates cell signaling pathways.
Topics: Plasma pencil (53%), Cancer cell (51%)

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Old Dominion University
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Killing Adherent and Nonadherent Cancer Cells
with the Plasma Pencil
Mounir Laroussi
Old Dominion University0/%427552(7)(7
Soheila Mohades
Old Dominion University
Nazir Barekzi
Old Dominion University
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Killing adherent and nonadherent cancer cells with the plasma pencil
Mounir Laroussi, Soheila Mohades, and Nazir Barekzi
Citation: Biointerphases 10, 029401 (2015); doi: 10.1116/1.4905666
View online: http://dx.doi.org/10.1116/1.4905666
View Table of Contents: http://scitation.aip.org/content/avs/journal/bip/10/2?ver=pdfcov
Published by the AVS: Science & Technology of Materials, Interfaces, and Processing
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Killing adherent and nonadherent cancer cells with the plasma pencil
Mounir Laroussi,
a)
Soheila Mohades, and Nazir Barekzi
Plasma Engineering & Medicine Institute, Old Dominion University, Norfolk, Virginia 23529
(Received 25 November 2014; accepted 29 December 2014; published 8 January 2015)
The application of low temperature plasmas in biology and medicine may lead to a paradigm
shift in the way various diseases can be treated without serious side effects. Low temperature
plasmas generated in gas mixtures that contain oxygen or air produce several chemically
reactive species that have important biological implications when they interact with eukaryotic
or prokaryotic cells. Here, a review of the effects of low temperature plasma generated by
the plasma pencil on different cancerous cells is presented. Results indicate that plasma
consistently shows a delayed killing effect that is dose dependent. In addition, there is
some evidence that apoptosis is one of the pathways that leads to the death of the cells,
indicating that plasma initia tes cell signaling pathways.
V
C
2015 American Vacuum Society.
[http://dx.doi.org/10.1116/1.4905666]
I. INTRODUCTION
Plasma Medicine is a field of research that deals with
the biomedical applications of low temperature plasmas
(LTPs) and m ost specifically plasmas generated at atmos-
pheric pressure and at biologically tolerable tempera-
tures.
1,2
These types of plasmas can be safely applied to
biological systems (cells, t issues, organs, etc.) without
causing thermal damage. The plasma can be tuned to
achieve various effects ranging from killing pathogens, to
stimulating the proliferation of healthy cells, to destroying
cancer cells.
13
Tuning the plasma t o achieve desired
effects involves judicious sele ction of the operating gas
mixture, the type of waveform of the applied voltage (DC,
pulsed DC, RF, pulsed RF, microwave, etc.), and careful
adjustment of the amount of applied power to influence the
electrons energy distribution function and to control the
fluxes of the reactive species. There is a general agree-
ment, based on overwhelming experimental evidence, that
the plasma-generated reactive oxygen species (ROS) and
reactive nitrogen species (RNS) play significant roles in
most of the observed effects of plasma on biological cells
and biological systems. This comes as no surprise as it is
well known from cell biology investigations that ROS and
RNS are involved in various biochemical events that occur
on the cellular and subcellular levels. Some of these
include lipids peroxidation, DNA damage, and the trigger-
ing of cellular signals.
14
Of all the possible applications of LTP in medical therapy
none is expected to have as much of an important scientific
and societal impact as cancer treatment. Today, the work on
cancer is becoming the most exciting topic in plasma medi-
cine research. Here, first what is known about the mecha-
nisms of action of LTP against cancer cells is briefly
reviewed, then the results of the application of a particular
LTP source termed the “plasma pencil” to kill cancer cells
are presented.
II. MECHANISMS OF ACTION OF LTP AGAINST
CANCER CELLS
In general, LTP is applied to cells that are either sub-
merged in a liquid medium or covered by a thin layer of a
liquid/fluid. Therefore, the reactive species generated by the
plasma in the gaseous state have to go through a gas–liquid
interface and then diffuse into the bulk of the liquid. Since
most plasma-generated reactive species are short-lived
whereas the plasma-induced biological effects on cells have
been observed only a relatively long time later, we hypothe-
size that the short lived species first react with the medium
to create reaction by-products that are long-lived and it is
these species that subsequently interact with the cells. These
longer-lived reaction byproducts would include H
2
O
2
,
NO
2
,NO
3
,RO
2
(organic peroxide), etc. Our work showed
that if a medium is treated by LTP, then cells are seeded into
this plasma activated medium (PAM), the effects on the cells
greatly depends on the “age” of the PAM.
5
By age it is
meant how long a time PAM is stored before applied on the
cells. The older the PAM, the lower the killing effect on
cells. Fresh PAM (not aged/applied right after plasma activa-
tion) has the strongest killing effect. Hence, we concluded
that plasma reaction byproducts in the medium are responsi-
ble for killing the cells, but as their concentrations decrease
with PAM storage/aging time (hours) most cells would be
able to cope and survive. It is important to note that the kill-
ing of cells by PAM occurs in a delayed manner, the same as
for the case when cells are directly exposed to LTP.
Based on experimental evidence, several investigators
reported that cancer cells appear to be more vulnerable
to LTP than their healthy counterparts.
6,7
Keidar and co-
workers reported that LTP causes an increase in the expres-
sion of the oxidative stress reporter cH2A.X (pSer 139) and
a decrease in DNA replication in the S-phase of the cell
cycle.
8
The S-phase is the phase in the cell cycle when DNA
replication occurs. These effects were much less pronounced
in the healthy cells. Since LTP appears to interfere with the
DNA replication phase and since cancer cells multiply more
rapidly than their healthy counterparts, they are much more
a)
Electronic mail: mlarouss@odu.edu
029401-1 Biointerphases 10(2), June 2015 1934-8630/2015/10(2)/029401/7/$30.00
V
C
2015 American Vacuum Society 029401-1

susceptible to LTP-induced damage. In general, cancer cells
have much higher metabolic rate than healthy cells and
therefore exhibit higher levels of intracellular concentrations
of ROS and RNS. Hence, exposure of cancer cells to LTP
leads to an even higher intracellular oxidative stress, there-
fore causing their death.
Other investigators have reported that cell signaling plays
an important role in the interaction of LTP with cancer cells.
One such signaling pathway is the activation of caspases.
Caspases are proteins that play a crucial role in apoptosis or
programmed cell death. The lack of initiation of apoptosis
leads to uncontrolled cell multiplication and tumor
development.
Laroussi and co-workers studied caspase-3 activation in
the case of squamous cell carcinoma and found higher level
of caspase-3 activation in cells treated by LTP than in con-
trol samples (untreated cells), indicating that LTP induces
apoptosis in these cells.
9
Ishaq et al. suggested that because
tumor cells are defective in several regulatory signaling
pathways they exhibit metabolic imbalance, which leads to a
lack of cell growth regulation.
10
According to these authors,
LTP-generated ROS affect the metabolism of the cancer
cells by impairing redox balance, which leads to slowing
down or arresting the proliferation of the cells. These inves-
tigators also reported that LTP up-regulates intracellular
ROS levels and induce apoptosis in melanoma.
11
They iden-
tified that LTP exposure causes a differential expression of
tumor necrosis factor (TNF) family members in the cancer-
ous cells but not in the normal cells. They found that apopto-
sis in the cancer cells was induced by apoptosis signal kinase
1 (ASK1), which is activated by TNF signaling.
III. PLASMA PENCIL
The application of LTP in biology and medicine relies on
the availability of various sources that can produce plasmas
with gas temperatures less than about 40
C, and at atmos-
pheric pressure (760 Torr). This is crucial since if LTP is
to be used as a basis for a medical therapy it has to be gener-
ated at surrounding room conditions such as in a hospital or
clinic setting. Among the various LTP sources, low tempera-
ture, atmospheric pressure plasma jets are most practical for
biomedical applications because they readily provide plas-
mas to a target at room conditions.
1214
These jets can be
powered by sources covering a wide frequency spectrum
that ranges from DC to microwaves. Various types of plasma
jets have therefore been developed with designs tailored for
specific needs. One such device, the plasma pencil, a hand-
held plasma jet generator developed in our laboratory, is pre-
sented here in some detail.
The electrodes of the plasma pencil are disk-shaped and
spaced by a gap that can be varied from 0.5 to1 cm (see Fig.
1).
15
Each of the two electrodes is made of a thin copper ring
attached to the surface of a centrally perforated dielectric
disk. To ignite the plasma, high voltage (few kV) pulses at
repetition rates in the 1–10 kHz range are applied between
the two electrodes and a gas mixture (such as helium and ox-
ygen) is flown through the holes of the electrodes (flow rates
in the 1–10 l/min range). Plasma plumes reaching lengths up
to 5 cm can be launched through the hole of the outer elec-
trode and in the surrounding room air.
15
The length of the
plume depends on the gas flow rate, the magnitude of the
applied voltage pulses, their widths, and the frequency. The
plasma plume exhibits low temperature and can be touched
by bare hands without causing any harm. A photograph of
the plume emitted by the plasma pencil and touching the
author’s hand is shown in Fig. 2. Since the plasma plume
does not cause thermal damage even to delicate tissue, it can
be applied to disinfect skin wounds resulting from cuts or
burns and to destroy cancer cells without damaging healthy
cells.
Using a combination of diagnostics involving intensified
charge coupled device imaging, optical emission spectros-
copy, and electrical probes it was discovered that the plasma
plume is in fact not a continuous volume of plasma, as they
appear to the naked eye, but discrete small volumes of
plasma referred to as “plasma bullets,” which travel at very
high velocities.
16,17
Unlike regular plasma streamers, which
appear at random times and spaces, these plasma bullets ex-
hibit behavior that is highly repeatable and predictable. Lu
FIG. 1. Schematic of the plasma pencil.
029401-2 Laroussi, Mohades, and Barekzi: Killing adherent and nonadherent cancer cells 029401-2
Biointerphases, Vol. 10, No. 2, June 2015

and Laroussi first proposed photoionization as a necessary
mechanism to explain the propagation of the plasma bul-
lets;
17
however, today there is consensus that plasma bullets
are “guided” ionization waves where the electric field at the
head of the plasma bullet plays an important role in its prop-
agation characte ristics.
14
Because plasma bullets are launched in air, they produce
very interesting reactive chemistry that can be exploited in
biological and medical applications. Reactive oxygen spe-
cies, such as O, OH, O
2
, an d reac tive nitrogen species,
such as NO, NO
2
, which are known to have biological
implications, are abundantly generated by the plasma
bullets.
IV. EFFECTS OF THE PLASMA PENCIL ON
CANCER CELLS
To investigate the efficacy of the plasma pencil against
cancer both adherent and nonadherent cancerous cells
were tested. As a representative of nonadherent cell lines
leukemia cells were selected. As a dherent cells, squamous
cell carcinoma and prostate cancer cells were used. The
following is a review of the results obtained. The experi-
mental setup used in these studies is shown in Fig. 3.The
reader is hereby notified that the following is not a
review of the field but rather a review of our own results.
These results were originally published elsewhere, in var-
ious scientific journals. References to the original papers
are provided, where more details of the experiments can
be found. The remainder of this paper mainly summarizes
our work of the last few years on cancer application
using our low temperature plasma generator, the plasma
pencil.
A. Case of nonadherent cells
In this study, T-cell line (ATCC No. CCL-119; aka
CCRF-CEM) originally isolated from the blood of a patient
with acute lymphoblastic leukemia was used. The CCRF-
CEM cells are nonadherent leukemia cancer cells, obtained
from the American Type Culture Collection. They were
grown in complete growth media in 75 cm
2
vented sterile
polystyrene tissue culture flasks at 37
C in a humidified
atmosphere containing 5% CO
2
. The growth media consisted
of buffered RPMI-1640 media supplemented with 10% fetal
bovine serum, 1% antibiotics (penicillin/streptomycin), and
1% glutamine.
Initial experiments revealed that plasma kills the leu-
kemia cells and that the effects of a single dose of
plasma continue for up to few days. Figures 4(a) and
4(b) illustrate results using CCRF-CEM leukemia cells,
in vitro, treated at various doses and evaluated at 12
and 36 h post-treatment, respectively.
18
Figure 5 shows
images that illustrate t he difference in color between
cells that took up the trypan blue dye (dead) and those
that did not (live).
The results revealed that the cell viability did not differ
dramatically at time 0 h postplasma treatment even at the
highest dose of treatment which was a plasma exposure of
10 min. However, when post-treatment analysis of cell via-
bility was determined at 12, 36, or 60 h, statistically signifi-
cant killing was observed even at the lower plasma doses.
Cell survivability data analyzed at 12, 36, or 60 h postplasma
treatment revealed that there was a threshold treatment time
of 3 min beyond which a highly statistically significant
increase in leukemia cell death was obtained.
18
The results
from this study indicate that there is a dose dependent
response in the induction of cell death of leukemia cells and
single doses of plasma treatment continue killing cells up to
2.5 days post treatment. The delayed response of cell death
may be attributed to cell signaling cas cades that may result
in apoptosis. However, for higher doses, such as for 10 min
exposure, necrotic cells were observed immediately after
plasma exposure.
FIG. 3. Experimental setup for the exposure of samples to the plasma pencil.
FIG. 2. Cold plasma plume touching the author’s hand.
029401-3 Laroussi, Mohades, and Barekzi: Killing adherent and nonadherent cancer cells 029401-3
Biointerphases, Vol. 10, No. 2, June 2015

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Abstract: Plasma medicine is an innovative and emerging field combining plasma physics, life science and clinical medicine. In a more general perspective, medical application of physical plasma can be subdivided into two principal approaches. (i) “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 (ii) application of physical plasma on or in the human (or animal) body to realize therapeutic effects based on direct interaction of plasma with living tissue. The field of plasma applications for the treatment of medical materials or devices is intensively researched and partially well established 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.

597 citations


Journal ArticleDOI
Abstract: As low-temperature nonequilibrium plasmas come to play an increasing role in biomedical applications, reliable and user-friendly sources need to be developed. These plasma sources have to meet stringent requirements such as low temperature (at or near room temperature), no risk of arcing, operation at atmospheric pressure, preferably hand-held operation, low concentration of ozone generation, etc. In this letter, we present a device that meets exactly such requirements. This device is capable of generating a cold plasma plume several centimeters in length. It exhibits low power requirements as shown by its current-voltage characteristics. Using helium as a carrier gas, very little ozone is generated and the gas temperature, as measured by emission spectroscopy, remains at room temperature even after hours of operations. The plasma plume can be touched by bare hands and can be directed manually by a user to come in contact with delicate objects and materials including skin and dental gum without causing any heating or painful sensation.

584 citations


Journal ArticleDOI
Xinpei Lu1, Mounir Laroussi2, Vincent Puech3Institutions (3)
Abstract: Atmospheric-pressure non-equilibrium plasma jets (APNP-Js), which generate plasma in open space rather than in a confined discharge gap, have recently been a topic of great interest. In this paper, the development of APNP-Js will be reviewed. Firstly, the APNP-Js are grouped based on the type of gas used to ignite them and their characteristics are discussed in detail. Secondly, one of the most interesting phenomena of APNP-Js, the ?plasma bullet?, is discussed and its behavior described. Thirdly, the very recent developments on the behavior of plasma jets when launched in a controlled environment and pressure are also introduced. This is followed by a discussion on the interaction between plasma jets. Finally, perspectives on APNP-J research are presented.

575 citations


Journal ArticleDOI
Mounir Laroussi1, Tamer Akan1Institutions (1)
Abstract: Non-thermal atmospheric pressure plasma jets/plumes are playing an increasingly important role in various plasma processing applications. This is because of their practical capability to provide plasmas that are not spatially bound or confined by electrodes. This capability is very desirable in many situations such as in biomedical applications. Various types of ‘cold’ plasma jets have, therefore, been developed to better suit specific uses. In this paper a review of the different cold plasma jets developed to date is presented. The jets are classified according to their power sources, which cover a wide frequency spectrum from DC to microwaves. Each jet is characterized by providing its operational parameters such as its electrodes system, plasma temperature, jet/plume geometrical size (length, radius), power consumption, and gas mixtures used. Applications of each jet are also briefly covered.

543 citations


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No. of citations received by the Paper in previous years
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20212
20203
20192
20187
20176
201610