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Selective Treatment of Pancreatic Cancer Cells by Plasma-Activated Saline Solutions

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  • National Innovation Center for Advanced Medical Devices

Abstract and Figures

Atmospheric discharge between a metal pin cathode and saline solution anode with different air gap lengths was considered for investigating plasma selforganization patterns (SOPs) at the liquid anode surface. We report the effect of plasma-activated saline solutions on human pancreas adenocarcinoma cancer cells line (BxPC-3) and human pancreatic duct epithelial normal cells line (H6c7). The presence of reactive oxygen species (ROS) and reactive nitrogen species (RNS) resulted in the anti-cancer properties of plasma-activated saline solution.
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116 IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES, VOL. 2, NO. 2, MARCH 2018
Selective Treatment of Pancreatic Cancer Cells
by Plasma-Activated Saline Solutions
Zhitong Chen , Li Lin, Eda Gjika, Xiaoqian Cheng, Jerome Canady, and Michael Keidar
Abstract—Atmospheric discharge between a metal pin cathode
and saline solution (SS) anode with different air gap lengths
was considered for investigating plasma self-organization patterns
at the liquid anode surface. We report the effect of plasma-
activated SSs on human pancreas adenocarcinoma cancer cells
line (BxPC-3) and human pancreatic duct epithelial normal cells
line (H6c7). The presence of reactive oxygen species and reactive
nitrogen species resulted in the anti-cancer properties of plasma-
activated SS.
Index Terms—Cancer therapy, cold atmospheric
plasma (CAP), saline solution (SS), self-organization
pattern (SOP).
I. INTRODUCTION
SELF-ORGANIZATION is generally referred to as a pro-
cess of spontaneous transition from a homogeneous
stable state to a regular pattern in a spatially extended
system [1], [2]. Self-organization is a complex and fascinating
phenomena commonly observed in both natural and techno-
logical contexts within diverse varieties of physics, chem-
istry, and biology [3], [4]. Different types of self-organization
phenomena have been reported in a wide range of plas-
mas, such as dielectric barrier discharge [5], high frequency
discharge [6], gas flow stabilized discharge [7], [8], resis-
tively stabilized discharge [9], and discharge with liquid
electrodes [10]–[12]. The self-organization phenomena associ-
ated with the formation of electrode patterns are significantly
different from these discharges, which typically occur in
the anode or cathode layer [13], [14]. Self-organization pat-
terns (SOPs) of plasma include square-textures, square-lattices,
square/hexagonal superlattices, hollow-hexagonal, multiarmed
spirals, rotating-wheels patterns, etc. [15], [16]. The for-
mation of these patterns depends on various parameters,
such as driving current, electrolyte conductivity, gap length,
Manuscript received August 6, 2017; revised September 2, 2017; accepted
September 28, 2017. Date of publication October 12, 2017; date of cur-
rent version March 1, 2018. This work was supported in part by the U.S.
Patent Innovations Inc. (Plasma Medicine Initiative), and in part by the
National Science Foundation under Grant 465061. (Corresponding authors:
Zhitong Chen; Michael Keidar.)
Z. Chen, L. Lin, E. Gjika, and M. Keidar are with the Department
of Mechanical and Aerospace Engineering, George Washington
University, Washington, DC 20052 USA (e-mail: zhitongchen@gwu.edu;
keidar@gwu.edu).
X. Cheng and J. Canady are with the Research Institute for Advanced
Biological and Technological Sciences, U.S. Medical innovation LLC,
Takoma Park, MD 20912 USA.
Color versions of one or more of the figures in this paper are available
online at http://ieeexplore.ieee.org.
Digital Object Identifier 10.1109/TRPMS.2017.2761192
gas species, and so on [17]–[19]. Recently, plasma dis-
charges with the liquid electrode have been studied refer-
ring to applications ranging from water decontamination
and activation [20], [21], to nanoparticle and materials
synthesis [22], [23], and medicine [24]. Therefore, self-
organization in plasma interacting with surfaces is interesting
not only from a fundamental point of view as intrinsic and fas-
cinating characteristics of nature, but also from practical stand-
point in current and emerging technological applications [25].
Plasma interacting with the liquid generates reactive oxy-
gen species (ROS) and reactive nitrogen species (RNS) that
act as key intermediate for cancer therapy [26], [27]. In this
paper, we created plasma with different SOPs to activate saline
solution (SS) and investigated the anti-tumor effects of the
plasma-activated SS on human pancreatic normal and can-
cer cells. We have recorded different self-organized patterns
formed at the liquid surface. The spectra of plasma with SOPs
were characterized by UV–visible–NIR optical emission spec-
troscopy. The concentration of hydrogen peroxide (H2O2) and
nitrite (NO
2) was measured by using a Fluorimetric Hydrogen
Peroxide Assay Kit, and the Griess reagent system, respec-
tively. The cell viability of H6c7 and BxPC-3 was measured
via Cell Counting KIT 8 assay. Typically, SS is used to treat
dehydration by injection into a vein, and it is also used to dilute
medications to be given by injection. Based on our results, one
can suggest that SOP plasma-activated SS has potential to be
utilized as an oral medicine or drug which can be injected into
tumors.
II. EXPERIMENTAL SECTION
A. Discharge Setup
Fig. 1shows a schematic representation of the SOP dis-
charge setup capable of producing well-defined self-organized
patterns at the surface of the liquid/plasma interface. Anode
(thin copper plate, thickness d=0.2 mm, diameter
Ø=22 mm) was placed at the bottom of a glass-made
well. The tungsten cathode of Ø =2 mm was then installed
above the SS surface. A ballast resistor (90 k) was connected
between the cathode and the direct current power supply unit
(Power Design, Model 1570 A, 1–3012 V, 40 mA). Voltage
was applied between the cathode and the liquid-immersed
anode, and a small (2–10 mm) gap between the cathode and
liquid surface accommodated a plasma formation. SS was
treated by discharge with distance of 2, 4, 6, 8, and 10 mm
air gap length to obtain plasma solutions for treating cancer
cells. 6 ml volume of SS was treated with the plasma.
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CHEN et al.: SELECTIVE TREATMENT OF PANCREATIC CANCER CELLS BY PLASMA-ACTIVATED SS 117
Fig. 1. Schematic representation of the SOP plasma discharge setup. Different
air gap distance between the cathode and surface of liquid accommodated
plasma. (dis the distance of air gap).
B. Cell Cultures
The human pancreas adenocarcinoma cancer cell line
(BxPC-3) was acquired from American Type Culture
Collection (ATCC). Cell lines were cultured in RPMI-
1640 medium (ATCC 30-2001) supplemented with 10%
(v/v) fetal bovine serum (Atlantic Biologicals) and 1% (v/v)
penicillin and streptomycin (Life Technologies). The human
pancreatic duct epithelial normal cell line (H6c7, Kerafast)
was cultured in Keratinocyte SFM (KSFM, Gibco) sup-
plemented with prequalified human recombinant epidermal
growth factor 1-53 (EGF 1-53, Gibco), bovine pituitary extract
(BPE, Gibco), and 1% (v/v) penicillin and streptomycin
(Life Technologies). Cultures were maintained at 37 Cin
a humidified incubator containing 5% (v/v) CO2.
C. Evaluation of Hydrogen Peroxide (H2O2) Concentration
Fluorimetric Hydrogen Peroxide Assay Kit (Sigma-Aldrich)
was used for measuring the amount of H2O2in SS. A detailed
protocol can be found on the Sigma-Aldrich website. Briefly,
we added 50 μl of standard curves samples, controls, and
experimental samples (SS treated by SOP plasma with 2, 4, 6,
8, and 10 mm air gap) to the 96-well flat-bottom black plates,
and then added 50 μl of master mix (including red peroxi-
dase substrate stock, 20 units/mL peroxidase stock, and assay
buffer) to each of wells. We incubated the plates for 20 min at
room temperature protected from light on and measured fluo-
rescence by Synergy H1 Hybrid Multimode Microplate Reader
at Ex/Em: 540/590 nm.
D. Evaluation of Nitrite (NO
2) Concentration
Nitrite level was determined by using the Griess Reagent
System, including 50 ml sulfanilamide solution, 50 ml NED
solution, and 1 ml nitrite standard, (Promega Corporation)
according to the instructions provided by the manufacturer.
Briefly, we added 50 μl of standard curves samples, controls,
and experimental samples to the 96-well flat-bottom plates.
Then dispense 50 μl of the sulfanilamide solution to all sam-
ples and incubate 5–10 min at room temperature. Finally,
dispense 50 μl of the NED solution to all wells and incubate at
room temperature 5–10 min. The absorbance was measured at
540 nm by Synergy H1 Hybrid Multimode Microplate Reader.
E. Measurement of Cell Viability
The cells were plated in 96-well flat-bottom microplates at
a density of 3000 cells per well in 70 μL of complete cul-
ture medium. Cells were incubated for 24 h to ensure proper
cell adherence and stability. Confluence of each well was
confirmed to be at 40%. 30 μl of RPMI, SS, and plasma-
activated SSs were added to the corresponding cells. Cells
were further incubated at 37 C for 24 and 48 h. The viability
of the pancreas normal and cancer cells was measured with
Cell Counting Kit 8 assay (Dojindo Molecular Technologies,
MD, USA). The original culture medium was aspirated and
10 μL of CCK 8 reagent was added per well. The plates were
incubated for 3 h at 37 C. The absorbance was measured at
450 nm by Synergy H1 Hybrid Multimode Microplate Reader.
We normalized data according to control group (RPMI for
BxPC-3 and KSFM for H6c7). We calculated the mean and
standard deviation independently.
F. Optical Emission Spectra Measurement
UV–visible–NIR, a range of wavelength 200–850 nm, was
investigated on SOP plasma to detect various RNS and ROS
(nitrogen [N2], nitric oxide [–NO], nitrogen cation [N+],
atomic oxygen [O], and hydroxyl radical [–OH]). The spec-
trometer and the detection probe were purchased from Stellar
Net Inc. The optical probe was placed at a distance of 2 cm
in front of the plasma beam. Integration time of the collecting
data was set to 100 ms.
G. Statistical Analysis
All results were presented as mean ±standard deviation
plotted using origin 8. Student’s t-test was applied to check
the statistical significance (*p<0.05, **p<0.01, ***p<0.001).
III. RESULTS
A. Current–Voltage Characteristics of Discharge
Fig. 2shows the current–voltage characteristics of the dis-
charge with air gap at distance of 2–10 mm. With gap
increasing, the discharge current decreases while discharge
voltage increases. Similar features of the discharge voltage
increasing with air gap length are found in the case of elec-
trolyte anode/cathode discharge [28], [29]. The SOP appears
at the plasma-liquid interface and the discharge is stabilized
when the air gap length is about 6 mm. At 2 mm gap, the
discharge voltage is low while discharge current is high, and
the discharge pattern represents a single filament. As the air
gap length increases from 2 to 4 mm, the anode spot changes
to a double ring-like structure. At air gap length of 8 mm, var-
ious types of SOPs are formed above the liquid media surface
as shown in Fig. 2. When the air gap is within the range of
2–8 mm, the plasma discharge is stable. When the air gap is
118 IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES, VOL. 2, NO. 2, MARCH 2018
Fig. 2. Current–voltage dependence for different air gap lengths with optical
photographs of the self-organized interface patterns.
(a) (b)
(c) (d)
(e)
Fig. 3. Optical emission spectrum by the SOP plasma discharge above SS
with different air gap length taken using UV–visible–NIR in the 200–850 nm
wavelength range. (a) 2 mm, (b) 4 mm, (c) 6 mm, (d) 8 mm, and (e) 10 mm.
10 mm, however, the plasma discharge becomes unstable. If
the air gap is larger than 10 mm, the plasma discharge cannot
be sustained anymore.
B. Optical Spectrum of SOP Plasma
We have measured spectra of plasma from the plasma-liquid
interface. Typical optical emission spectra are shown in Fig. 3.
One can see that with air gap length increasing, the emis-
sion intensity decreases. The identification of the emission
bands was performed according to Pearse and Gaydon [30].
(a) (b)
Fig. 4. H2O2and NO
2concentrations in SS treated by plasma with
SOP plasma with different air gap length (each air gap length treated by
SOP plasma for 40 s): (a) H2O2 concentration and (b) NO
2concentration.
Student’s t-test was performed, and the significance compared to the 2 mm
is indicated as *p<0.05, **p<0.01, and ***p<0.001. (n=3).
Small gaps (2 and 4 mm) lead to high intensity of spec-
tra. From 6 to 10 mm, the cathode was far to anode
resulting in intensity decreasing. In the 250–300 nm wave-
length range, weak emission bands (258, 267, and 284) were
detected as NO lines [31]. Species at wavelengths of 337 and
358 nm were defined as N2C3uor NO β3g(denoted
as N2/NO), because both species have possible optical emis-
sion at these wavelengths [30]. The emission bands between
300 and 500 nm have still not been clearly identified in [32].
However, we anticipated that OH was present at 309 nm, the
wavelength of 375 nm could be indicative of N+
2/N2, and
atomic oxygen (O) was denoted at the wavelength of 777 nm.
Atomic oxygen (ground/excited states) was believed to have
a significant effect on cells and therefore a broad biomedical
application [33]. The dominant species of the spectra in this
paper were NO or N2 lines (258, 267, 337, and 357 nm), OH
(309 nm), N+
2(391 nm), and O (777 nm).
C. H2O2and NO
2Concentration
Plasma species penetrate through the plasma-liquid
interface, and can produce chemically reactive species in the
SS. Complex chemistry is associated with plasma produced
species in liquid [34]. These reactions lead to the formation
of short- and long-lived species. H2O2and NO
2are relatively
long-lived species in the plasma-activated SS and will be focus
of this paper. The air gap length dependencies of the H2O2
and NO
2concentrations in the plasma-activated SS with gap
distance as a parameter are shown in Fig. 4. The concentration
of H2O2increases with an up to 4 mm air gap then decreased
up to 8 mm before increasing again at 10 mm as shown in
Fig. 4(a). The concentration of NO
2increases with air gap
from 2 to 8 mm, then decreases at 10 mm.
D. Cell Viability of H6c7 and BxPC-3
To investigate the potential of plasma-activated SS, we
treated BxPC-3 human pancreas cancer cells and H6c7 human
normal cells with them. RPMI, KSFM, and untreated SS were
used as controls. Fig. 5shows the cell viability of BxPC-
3 human pancreas cancer cells and H6c7 human pancreas nor-
mal cells exposed to RPMI/KSFM, SS, and plasma-activated
SSs for 24 h and 48 h. We can see that plasma-activated SSs
CHEN et al.: SELECTIVE TREATMENT OF PANCREATIC CANCER CELLS BY PLASMA-ACTIVATED SS 119
(a) (b)
Fig. 5. Effects of seven media: RPMI/KSFM, SS, and five plasma-activated
media (SS activated by plasma with SOP at 2, 4, 6, 8, and 10 mm distance
for 40 s’ treatment) on viability of the BxPC-3 human pancreas cancer cells
and the H6c7 human pancreas normal cells after (a) 24 h and (b) 48 h incu-
bation, respectively. The percentages of surviving cells for each cell line were
calculated relative to controls (RPMI/KSFM).
have stronger effect on the cancer cells than that on the nor-
mal cells. For BxPC-3 cancer cells, when incubated for 24 h
and 48 h, cell viability decreased first, then increased with
air gap length increasing. The minimum cell viability appears
at 4 mm air gap. For H6c7 normal cells, when incubated for
24 h and 48 h, plasma with SOP at 6 mm air gap has the most
significant effect of plasma-activated SSs.
IV. DISCUSSION
We have previously reported that under certain conditions
cold atmospheric plasma can be directly applied to cancer
cells without influencing healthy tissues [35]–[39]. At the
same time plasma-activated media have been reported to have
a cytotoxic effect in oncology. Unique processes at the self-
organized interfaces could be the key to the production of
novel, highly efficient tumor-inhibiting media. SOP pattern-
ing at the interfaces drastically widens the spectrum of the
involved structural, physical, and chemical processes, and thus
opens new horizons to tackling tumors of various origins and
locations. In this paper, SSs were treated by plasma with vari-
ous SOPs to be applied to human pancreatic cancer and normal
cells. Discharge was formed between pin and liquid electrode
and resulted in SOP formation which depended on discharge
gap as shown in Fig. 2. Transport of ROS/RNS across the
plasma/liquid interface is affected by SOP. As such modifica-
tion of SS by discharge is affected and controlled by SOP at
the plasma-liquid interface. Typical optical emission spectra of
such plasmas at different air gap were shown in Fig. 3indi-
cating that plasma at each air gap length contains ROS and
RNS in the gas phase. ROS and RNS were also formed in
plasma-activated SS. RNS are well known to induce cell death
via DNA double-strand breaks and apoptosis, where ROS are
capable of inducing the apoptosis and necrosis [40], [41]. Our
results in Fig. 4show that the H2O2concentration is highest
at 4 mm air gap distance while NO
2concentration is highest
at 8 mm air gap distance. Possible reactions illustrating the
routes of H2O2and NO
2formation in liquid and plasma have
been reported in our previous articles [34], [42], [43]. From
Fig. 2we can see that plasma average discharge power is
growing with increasing air gap, which results in the tem-
perature of plasma-activated SSs going up (except 10 mm).
Since H2O2is thermodynamically unstable, its rate of decom-
position increases with rising temperature [44]. It should be
pointed out that the plasma discharge becomes unstable at
the air gap length of about 10 mm. The discharge has to be
reignited. As such, the discharge instability at 10 mm gap
might lead to a low concentration of nitrite. Fig 5 shows that
plasma-activated SS affects cancer and normal pancreatic cells
in a selective manner. Gain-of-function mutations in onco-
genes and loss-of-function mutation in tumor suppressor genes
drive malignant transformation, which results in cell deregula-
tion that is frequently associated with enhanced cellular stress
including oxidative, replicative, metabolic, and proteotoxic
stress, and DNA damage [45]. Adaptation to this stress phe-
notype is required for cancer cells to survive. Consequently,
cancer cells may become dependent upon nononcogenes that
do not ordinarily perform such a vital function in normal cells.
Thus, SOP plasma-activated SSs might affect these nononco-
gene dependencies in the context of a transformed genotype
and might result in a synthetic lethal interaction and the selec-
tive death of BxPC-3 cancer cell compared to H6c7 normal
cell. Plasma with SOP activating SSs have more effect on
cancer cells. The trend of pancreatic normal and cancer cells
can be attributed to the trend of ROS and RNS concentra-
tion with different air gap distances. On the other hand, H2O2
reacts with NO
2to form peroxynitrite OONOand H2O[46].
ONOOis a powerful oxidant and nitrating agent that is
known to be more damaging to cancer cells [47]. Therefore,
a synergistic effect of ROS and RNS is suspected to play a key
role in the apoptosis of the plasma solutions. For BxPC-3 can-
cer cells, intracellular ROS-mediated up-regulation of DR5 can
leads to apoptosis (procaspase-8 is a direct downstream tar-
get of DR5) [48]. On the other hand, intracellular generation
of ROS induces increasing protein expression of Bax, dis-
ruption of the mitochondrial membrane potential and release
of cytochrome c and AIF into the cytosol resulting in to the
activation of caspase9/3 cascade [49]. Therefore, plasma with
SOP-induced intracellular generation of ROS induced apop-
tosis in BcPC-3 cancer cells might be orchestrated by the
synergistic effects of both extrinsic and intrinsic pathways.
The results indicate the cytotoxicity of plasma-activated SS
is specific to pancreatic adenocarcinoma cancer cells. The
plasma-activated SS at 4 mm air gap distance had the most sig-
nificant affect in inducing cell death in pancreatic cancer cells.
This is related to certain amounts of ROS and RNS generated
by double ring-like structure plasma with SOPs.
V. CONCLUSION
The presented findings demonstrate that self-organized pat-
tern plasma-activated SSs applied to both cancerous and
normal pancreatic cells exhibit selective manners. The air
gap at a distance between 2 and 10 mm results into vari-
ous shapes of SOP on SS anode. A synergistic effect of RNS
and ROS present in the plasma solution is suspected to play
a key role in the cell death. The SOP plasma-activated SS at
4 and 6 mm air gap distance between the pin electrode and
the solution had the most significant effect in inducing cell
death in both pancreatic cancer and normal cells, respectively.
120 IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES, VOL. 2, NO. 2, MARCH 2018
The SOP plasma-activated SSs have more serious effect on
BxPC-3 human pancreatic adenocarcinoma cancer cells than
H6c7 human pancreatic epithelial normal cells. These results
suggest that it might be possible to use SOP plasma-activated
SSs with anti-tumor effect for clinical applications.
ACKNOWLEDGMENT
The authors would like to thank the cell lines used in this
paper were kindly provided by U.S. Patent Innovations LLC.
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... Selective anti-tumor effect was observed in PAM experiment [215,216,217,218]. ...
... In a real patient, tumors are always surrounded by liquid, such as blood and interstitial fluid. Therefore, both of direct and indirect treatment would produce PAM, and PAM treatment is long-time effect (over 24 hours) even though the plasma source has been removed [216]. The most mechanism of PAM treatment is ROS or RNS inducing cell apoptosis, and ROS provides selective expression [210]. ...
... PAM treatment has been applied on several kinds of cancer trial in vitro, including melanoma, breast cancer, pancreatic cancer [216,228], liver cancer [215], ovarian cancer [217], glioblastoma [218], etc. In vitro treatment, cells were cultured and moved in well with constant number of cells. ...
Thesis
The objective of this work was to study the interaction between non-thermal plasmas at atmospheric pressure and biological media in perspective of the application of this type of technology to the biomedical sector.In a first step, plasma sources were designed, realized, and characterized. These reactors implement dielectric barrier discharges in various gases in flow (synthetic air, argon, with or without water vapor admixture). The use of argon allowed the selection of conditions in which the plasma remained confined in the inter-electrode zone (relative humidity higher than 95% at room temperature) or on the contrary propagated either in free atmosphere or guided in an insulating tube in which the gas was flowing (dry argon). In the latter case, the propagation phenomenon was examined by time-resolved electrical measurements and the results were discussed with the help of previous works available in the literature. The choice of air as reactor feed-gas was also considered because of the application constraints that do not systematically allow the use of another gas.Two specific studies were conducted, one likely to find applications in the field of "plasma medicine", the other in the field of control of viral epidemics.In the latter case, the work focused on the inactivation of bacterial viruses, bacteriophages, infecting Escherichia coli. These were phage T4, a double-stranded DNA phage, and phage MS2, a single-stranded RNA phage. The phage suspensions were diluted in different buffer solutions and deposited on a water-soluble paper substrate to be exposed to different non-thermal plasma treatments. The original use of this substrate solved the difficult problem of phage particle recovery after treatment. This substrate also corresponds to an unfavorable application situation for this type of treatment (complex surface with volume diffusion of the suspension, as opposed to a smooth non-adsorbent surface such as a glass slide), leading to more realistic results that can be transposed to a real application. Phage inactivation was quantified by counting lysis plaques on E. coli culture. Thus, inactivation rates ranging from 0.66 log/min to 2 log/min were measured depending on the type of phage, the nature of the buffer solution and the type of treatment. The influence of the temperature imposed on the substrate was also examined.For the plasma medicine application, human adenocarcinoma cells (lung cancer) from five patients were treated in-vitro using the dielectric barrier reactor under two operating conditions determined by the composition of the feed-gas: plasma jet with dry argon and reactive oxidizing species (ROS) source with argon saturated with water vapor at room temperature. After a 5-minute exposure to the humid argon discharge treatment, 65% of the cells were in an apoptotic/necrotic state. For the dry argon plasma treatment, the overall proliferation and apoptosis assays did not show much efficacy. However, the dry argon plasma jet exhibited a rapid and localized effect on the cancer cells, inducing inhibition of the cells' ability to proliferate and migrate. These two operating conditions are of interest for clinical application, allowing to have a single plasma device able to deliver a very localized treatment of cells (plasma jet) or to transfer ROS on a larger surface leading to apoptosis mechanisms (humid argon discharge).
... 29 CAP tends to inhibit the growth of cancer cells rather than homologous normal cells in dozens of cell lines. 30,31 CAP treatment can be directly applied to the tumor/tissues/cells. For example, Li et al employed the surface dielectric barrier discharge (S-DBD) to treat the human hepatocellular carcinoma cells. ...
Preprint
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Plasma activated medium, containing reactive oxygen species (ROS) and reactive nitrogen species (RNS), has been used for cancer treatment as an indirect treatment method. Here we report cold atmospheric plasma (CAP) activated deionized (DI) water using helium (He), argon (Ar), and nitrogen (N2) as feeding gas for the cancer therapy. Basic characteristics of CAP activated DI water with different feeding gases were diagnosed and the effects of three solutions on the breast cancer cells and gastric cancer cells were also recorded. Our findings show that DI water treated by CAP with He feeding gas has a much stronger effect on apoptosis in precultured breast cancer cells and gastric cancer cells. These results are attributed to the higher concentration of ROS generated in CAP-activated DI water using He as feeding gas.
... Plasma activation of biocompatible liquids was studied previously so as to quantify the chemical transformations [35,39], the bacterial inactivation [40], and the anti-cancer capacity [31,36,[41][42][43][44][45]. To the best of our knowledge, its injection on a rat skin flap has never been reported in previous studies. ...
Article
Full-text available
The evolution of reconstructive methods for defects of the human body cannot yet replace the use of flap surgery. Research is still preoccupied with the ideal techniques for offering the best chances of survival of the flaps. In our study, we investigated the effects of cold atmospheric plasma (CAP), N-nitro-L-arginine methyl ester (L-NAME), and platelet-rich plasma (PRP) injectable solutions on flap survival using an in vivo model. Twenty-four Wistar rats (four groups) had the McFarlane flap raised and CAP, L-NAME, and PRP substances tested through a single dose subcutaneous injection. The control group had only a saline solution injected. To the best of our knowledge, this is the first study that evaluated a CAP activated solution through injection on flaps. The flap survival rate was determined by clinical examination (photography documented), hematology, thermography, and anatomopathological tests. The image digital analysis performed on the flaps showed that the necrosis area (control—49.64%) was significantly lower for the groups with the three investigated solutions: CAP (14.47%), L-NAME (18.2%), and PRP (23.85%). Thermography exploration revealed less ischemia than the control group on the CAP, L-NAME, and PRP groups as well. Anatomopathological data noted the best degree of angiogenesis on the CAP group, with similar findings on the L-NAME and PRP treated flaps. The blood work did not indicate infection or a strong inflammatory process in any of the subjects. Overall, the study shows that the CAP activated solution has a similar (better) impact on the necrosis rate (compared with other solutions with known effects) when injected on the modified dorsal rat skin flap, and on top of that it can be obtained fast, in unlimited quantities, non-invasively, and through a standardized process.
... It was recently outlined that ROS are major biomedical effectors of physical plasma treatment in biology and medicine [2]. capacity of plasma in several cancer types such as the brain [23][24][25], skin [26][27][28][29], breast [30][31][32][33][34], colorectal [35][36][37], lung [38][39][40], cervical [41][42][43], leukemia [44][45][46][47][48], pancreatic [49][50][51][52][53][54], liver [55][56][57], and head and neck [58][59][60]. Because of altered metabolism and mitochondrial dysfunction, cancer cells are often found to produce more intracellular ROS than nonmalignant cells [61][62][63]. ...
Article
Full-text available
Despite recent advances in therapy, cancer still is a devastating and life-threatening disease, motivating novel research lines in oncology. Cold physical plasma, a partially ionized gas, is a new modality in cancer research. Physical plasma produces various physicochemical factors, primarily reactive oxygen and nitrogen species (ROS/RNS), causing cancer cell death when supplied at supraphysiological concentrations. This review outlines the biomedical consequences of plasma treatment in experimental cancer therapy, including cell death modalities. It also summarizes current knowledge on intracellular signaling pathways triggered by plasma treatment to induce cancer cell death. Besides the inactivation of tumor cells, an equally important aspect is the inflammatory context in which cell death occurs to suppress or promote the responses of immune cells. This is mainly governed by the release of damage-associated molecular patterns (DAMPs) to provoke immunogenic cancer cell death (ICD) that, in turn, activates cells of the innate immune system to promote adaptive antitumor immunity. The pivotal role of the immune system in cancer treatment, in general, is highlighted by many clinical trials and success stories on using checkpoint immunotherapy. Hence, the potential of plasma treatment to induce ICD in tumor cells to promote immunity targeting cancer lesions systemically is also discussed.
... Various types of pattern formation phenomena have been reported in a wide range of plasmas, such as dielectric barrier discharges (DBDs), arc discharges, high-pressure-lowcurrent glow discharges, high-pressure-high-current-arc discharge, low-pressure-low-current glow, and low-pressure-high-current vacuum arc discharge [3][4][5][6][7] . The self-organized pattern is also often found in plasmas interacting with liquid surfaces, of relevance in applications ranging from water decontamination and activation, to material synthesis, and medicine [8][9][10][11] . The self-organizational restructuration and patterning at the interfaces drastically widen the spectrum of the involved structural, physical and chemical processes, thus opening new horizons to tackling plasma media for medical applications. ...
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Full-text available
The self-organized pattern (SOP) phenomenon is prevalent in plasma, while knowledge about SOP discharge affecting reactive species generated plasma-activated media (PAM) for cancer therapy is poorly documented. The aim of this study focused on the effect of SOP discharge modes on reactive oxygen and nitrogen species (ROS, RNS) in He SOP plasma-activated media with different conductivity (saline solution and deionized (DI) water), and employed them to breast cancer MDA-MB-231 and pancreatic BxPC-3 cancer cells. Optical emission spectrum and Fluorimetric analysis were used to identify and quantify ROS and RNS generated in He SOP plasma-activated saline solution and DI water. Furthermore, He SOP plasma discharge modes are capable of efficiently controlling the ROS and RNS concentration in the plasma-activated saline solution and DI water, which contribute to the cytotoxic effect. On the other hand, stainless steel and copper were used as a lower electrode to compare their effect on cell viability. Taken together, our findings provide insight into potential mechanisms involved in cell death after treatment with He SOP plasma-activated media.
... From Fig. 5, it can also be noticed that, there is a difference in the peaks observed between 5a (0+ mins of activation) and 5b (6+ min of activation). From Fig. 5, it can be seen that the prominent peaks of second positive system of Nitrogen between 315-400 nm range [34][35][36] were present at both activation times. However, the atomic nitrogen peaks at 744.3 nm and 818.3 nm were only observed at the 6 min activation time, indicating that extended activation leads to formation of atomic nitrogen in the PAW setup. ...
... ROS were suggested as a promising anticancer strategy since, for instance, K-Ras-mutated cancer cells such as PDA already have higher baseline levels of oxidative stress and express elevated levels of aquaporins [29], which supports H 2 O 2 influx [30]. We and others have shown that the application of plasma-treated medium and clinically approved liquids such as saline trigger cell death in murine and pancreatic cancer cells as well [31,32]. For plasmatreated medium and plasma-treated Ringer's lactate, in vivo studies provided evidence of the clinical efficacy of this approach [17,20,33]. ...
Article
Full-text available
Macrophages and immuno-modulation play a dominant role in the pathology of pancreatic cancer. Gas plasma is a technology recently suggested to demonstrate anticancer efficacy. To this end, two murine cell lines were employed to analyze the inflammatory consequences of plasma-treated pancreatic cancer cells (PDA) on macrophages using the kINPen plasma jet. Plasma treatment decreased the metabolic activity, viability, and migratory activity in an ROS- and treatment time-dependent manner in PDA cells in vitro. These results were confirmed in pancreatic tumors grown on chicken embryos in the TUM-CAM model (in ovo). PDA cells promote tumor-supporting M2 macrophage polarization and cluster formation. Plasma treatment of PDA cells abrogated this cluster formation with a mixed M1/M2 phenotype observed in such co-cultured macrophages. Multiplex chemokine and cytokine quantification showed a marked decrease of the neutrophil chemoattractant CXCL1, IL6, and the tumor growth supporting TGFβ and VEGF in plasma-treated compared to untreated co-culture settings. At the same time, macrophage-attractant CCL4 and MCP1 release were profoundly enhanced. These cellular and secretome data suggest that the plasma-inactivated PDA6606 cells modulate the inflammatory profile of murine RAW 264.7 macrophages favorably, which may support plasma cancer therapy.
Article
Cold atmospheric plasma (CAP) has been proved a type of novel and effective anticancer method. However, a current problem lies in the complexity of cancer using the CAP treatment because of the different types and developments of cancers, resulting in the necessity of in-depth investigations on underlying mechanisms. This review will introduce a variety of mechanisms behind the CAP cancer treatment, including apoptosis-related signaling pathways, the ROS/RNS-based “bystander effect,” ferroptosis regulation for lipid peroxidation, genetically DNA damage and cell cycle arrest, amino acid structural modification, calreticulin (CRT) exposure and immune cell maturation, and necrosis. Despite the listed diverse mechanisms, drawbacks and future prospects of CAP treatment are discussed for more in-depth thinking. This review will be of great interest for understanding the current state of the art of cancer treatment of plasma.
Chapter
To identify a malignant primary tumor, detection of neoplasm is most regular yet lethal methods are used. Imaging methods authorize the investigators and medical performer to calculate the disturbance yet action in to the human brain before executing invasive surgery. Either gives the locating or identifying brain and pancreatic tumor distribution and categorization development by different stages of DBCWMF algorithm with median filter and histogram equation, precise fuzzy C-segmentation, SIFT removal, and categorization with sparse representation. Those methods give superior potential at clinical applications expressed as speed, accuracy, and innovation. Artificial Neural Network (ANN) classifier is utilized to analyze pancreatic cancer. The conclusion of investigation is calculated by TCIA database and hospital database, in which suggested applications are demonstrated concurrently along data progressions yet incredibly productive to brain and pancreatic tumor at MR images and CT scan images.KeywordsPancreatic tumorFuzzy C-meansCT scanSIFTANN classifierDBCWMF
Article
As the fourth state of matter, plasma’s unique properties and interactions with other states of matter offer many promising opportunities for investigation and discovery. In particular, cold atmospheric plasma (CAP), operating at atmospheric pressure and room temperature, has remarkable potential for biomedical applications through various delivery methods. These biomedical applications include sterilization, wound healing, blood coagulation, oral/dental diseases treatment, cancer therapy, and immunotherapy. Effective delivery of plasma constituents is critical to its efficacy for these applications. Therefore, this review presents the key research activities related to CAP delivery (including direct CAP delivery, delivery of plasma-activated media, biomedical device-assisted plasma delivery, and CAP delivery with other therapeutics) and needs for future research. This review will be of great interest for understanding the current state-of-the-art of biomedical applications of plasma medicine while also giving researchers from a broad range of communities insight into research efforts that would benefit from their contributions. Such communities include biomedicine, physics, biochemistry, material science, nanotechnology, and medical device manufacturing.
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Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (µCAP) was developed and employed to target glioblastoma tumors in the murine brain. Various plasma diagnostic techniques were applied to evaluate the physics of helium µCAP such as electron density, discharge voltage, and optical emission spectroscopy (OES). The direct and indirect effects of µCAP on glioblastoma (U87MG-RedFluc) cancer cells were investigated in vitro. The results indicate that µCAP generates short- and long-lived species and radicals (i.e., hydroxyl radical (OH), hydrogen peroxide (H₂O₂), and nitrite (NO₂(-)), etc.) with increasing tumor cell death in a dose-dependent manner. Translation of these findings to an in vivo setting demonstrates that intracranial µCAP is effective at preventing glioblastoma tumor growth in the mouse brain. The µCAP device can be safely used in mice, resulting in suppression of tumor growth. These initial observations establish the µCAP device as a potentially useful ablative therapy tool in the treatment of glioblastoma.
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Traditional cancer treatments like radiotherapy and chemotherapy have drawbacks and are not selective for killing only cancer cells. Nonthermal atmospheric pressure plasmas with dielectric barrier discharge (DBD) can be applied to living cells and tissues and have emerged as novel tools for localized cancer therapy. The purpose of this study was to investigate the different effects caused by miniature DBD (mDBD) plasma to A549 lung cancer cells. In this study, A549 lung cancer cells cultured in 12 well plates were treated with mDBD plasma for specified treatment times to assess the changes in the size of the area of cell detachment, the viability of attached or detached cells, and cell migration. Furthermore, we investigated an innovative mDBD plasma-based therapy for localized treatment of lung cancer cells through apoptotic induction. Our results indicate that plasma treatment for 120 sec causes apoptotic cell death in 35.8% of cells, while mDBD plasma treatment for 60 sec, 30 sec, or 15 sec causes apoptotic cell death in 20.5%, 14.1%, and 6.3% of the cell population, respectively. Additionally, we observed reduced A549 cell migration in response to mDBD plasma treatment. Thus, mDBD plasma system can be a viable platform for localized lung cancer therapy.
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Experiments have revealed a nontrivial cancer-inhibiting capability of liquid media treated by the plasma jet capable of forming thinly stratified self-organized patterns at a plasma-liquid interface. A pronounced cancer depressing activity towards at least two kinds of human cancer cells, namely breast cancer MDA-MB-231 and human glioblastoma U87 cancer lines, was demonstrated. After a short treatment at the thinly stratified self-organized plasma-liquid interface pattern, the cancer inhibiting media demonstrate well pronounced depression and apoptosis activities towards tumor cells, not achievable without interfacial stratification of plasma jet to thin (of several um) current filaments, which therefore play a pivotal (yet still not completely clear) role in building up the cancer inhibition properties. Moreover, thinly stratified, self-organized interfacial discharge is capable to efficiently control the ROS and RNS concentrations in the cancer-inhibiting media, and in particular, abnormal ROS/RNS ratios not achievable in discharges which do not form stratified thin-filament patterns could be obtained. These results were explained in terms of interaction of thin plasma filaments of the self-organized pattern with gas and liquid, where the unusual interaction conditions (i.e., high surface-to-volume ratios etc.) cause accumulation of ROS, RNS and other species in unusual ratios and concentrations, thus forming potentially efficient anti-cancer cocktail. Our funding could be extremely important for handling the cancer proliferation problem, and hence, it should be brought to light to attract due attention of the researchers and explore the possible potential of this approach in tackling the challenging problem of high cancer-induced mortality and rising morbidity trends.
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Full-text available
Cold atmospheric plasma (CAP) was shown to affect cells not only directly, but also indirectly by means of plasma pre-treated solution. This study investigated a new application of CAP generated in deionized (DI) water for the cancer therapy. In our experiments, the CAP solution was generated in DI water using helium as carrier gas. We report on the effects of this plasma solution in breast (MDA-MD-231) and gastric (NCI-N87) cancer cells. The results revealed that apoptosis efficiency was dependent on the plasma exposure time and on the levels of reactive oxygen and nitrogen species (ROS and RNS). The plasma solution that resulted from 30-min treatment of DI water had the most significant effect in the rate of apoptosis.
Article
Full-text available
Over past decade, cold atmospheric plasma (CAP), a near room temperature ionized gas has shown its promising application in cancer therapy. Two CAP devices, namely dielectric barrier discharge and plasma jet, show significantly anti-cancer capacity over dozens of cancer cell lines in vitro and several subcutaneous xenograft tumors in vivo. In contrast to conventional anti-cancer approaches and drugs, CAP is a selective anti-cancer treatment modality. Thus far establishing the chemical and molecular mechanism of the anti-cancer capacity of CAP is far from complete. In this review, we provide a comprehensive introduction of the basics of CAP, state of the art research in this field, the primary challenges, and future directions to cancer biologists.
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Plasma is an ionized gas that is typically formed under high-temperature laboratory conditions. Recent progress in atmospheric plasmas has led to cold atmospheric plasma (CAP) devices with ion temperatures close to room temperature. The unique chemical and physical properties of CAP have led to its use in various biomedical applications including cancer therapy. CAP exhibits a spontaneous transition from a spatially homogeneous state to a modifiable pattern that is subject to self-organization. In this Opinion article, we discuss some new applications for plasma in cancer therapy based on plasma self-organization, which enables adaptive features in plasma-based therapeutic systems.
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Recent breakthroughs in plasma medicine have identified a potential application for the non-thermal plasma in cancer therapy. Most studies on the effects of non-thermal plasma on cancer cells have used traditional two-dimensional (2D) monolayer cell culture. However, very few studies are conducted employing non-thermal plasma in animal models. Two dimensional models do not fully mimic the three-dimensional (3D) tumor microenvironment and animal models are expensive and time-consuming. Therefore, we used 3D collagen matrices that closely resemble the native geometry of cancer tissues and provide more physiologically relevant results than 2D models, while providing a more cost effective and efficient precursor to animal studies. We previously demonstrated a role for non-thermal plasma application in promoting apoptotic cell death and reducing the viability of A549 lung adenocarcinoma epithelial cells cultured upon 2D matrices. In this study, we wished to determine the efficacy of non-thermal plasma application in driving apoptotic cell death of A549 lung cancer cells encapsulated within a 3D collagen matrix. The percentage of apoptosis increased as treatment time increased and was time dependent. In addition, the anti-viability effect of plasma was demonstrated. Twenty-four hours post-plasma treatment, 38% and 99% of cell death occurred with shortest (15 s) and longest treatment time (120 s) respectively at the plasma-treated region. We found that plasma has a greater effect on the viability of A549 lung cancer cells on the superficial surface of 3D matrices and has diminishing effects as it penetrates the 3D matrix. We also identified the nitrogen and oxygen species generated by plasma and characterized their penetration in vertical and lateral directions within the 3D matrix from the center of the plasma-treated region. Therefore, the utility of non-thermal dielectric barrier discharge plasma in driving apoptosis and reducing the viability of lung cancer cells in 3D collagen matrix indicates a therapeutic potential that warrants further research.
Book
Table of Persistent Band Heads.- Individual Band Systems.- Spectra of Deuterides.- Practical Procedure and Precautions.- On the identification of bands.- Sources.- Collimation.- Comparison spectra.- Measurement.- Spurious bands.- Literature.- Description of Plates.- Author Index.
Article
Cold atmospheric plasma (CAP) jet is currently intensively investigated as a tool for new and potentially transformative cancer treatment modality. However, there are still many unknowns about the jet behavior that requires attention. In this paper, a helium CAP jet is tested in an electrostatic field generated by a copper ring. Using Rayleigh microwave scattering method, some delays of the electron density peaks for different ring potentials are observed. Meanwhile, a similar phenomenon associated with the bullet velocity is found. Chemical species distribution along the jet is analyzed based on the jet optical emission spectra. The spectra indicate that a lower ring potential, i.e., lower DC background electric field, can increase the amount of excited N2, N2 ⁺, He, and O in the region before the ring, but can decrease the amount of excited NO and HO almost along the entire jet. Combining all the results above, we discovered that an extra DC potential mainly affects the temporal plasma jet properties. Also, it is possible to manipulate the chemical compositions of the jet using a ring with certain electric potentials.