Nitric Oxide Production by High Voltage Electrical Discharges For Medical Uses: A Review

Plasma Chem Plasma Process (2016) 36:737–766
DOI 10.1007/s11090-016-9698-1
REVIEW ARTICLE
Nitric Oxide Production by High Voltage Electrical

Discharges for Medical Uses: A Review
Muhammad Arif Malik1
Received: 12 January 2016 / Accepted: 19 February 2016 / Published online: 2 March 2016
Ó Springer Science+Business Media New York 2016
Abstract Nitric oxide (NO) is a vasodilator and antihypertensive agent as well as a

universal anti-microbial factor killing bacteria, fungi and parasites without killing human
cells provided that an appropriate dose level and treatment time are applied. Exogenous
NO is often employed in inhalation therapies for treating pulmonary hypertension in
children and adults. NO generation from air in high voltage electrical discharges is being
developed for medical uses because it is technologically simple, economical and portable.
The related literature is reviewed here. The plasma can be a thermal plasma, where the
temperature is of the order of 10,000 K, or it can be a non-thermal plasma, where the
electron temperature is very high but the average gas temperature can vary over a wide
range from close to room temperature to thousands of degrees above room temperature.
The plasma temperature has significant effects on the chemical composition of the treated
gas. These effects are explained based on the chemical reaction mechanism. Further, NO
generated by electrical discharges is usually contaminated with nitrogen dioxide and
sometimes with ozone and particulate matter. The techniques that have been successfully
hybridized with the electrical discharge devices or that can potentially be hybridized for
the purification of NO are also reviewed. Recent successful testing of electrical discharge-
based NO generators for inhalation therapy on animal models in the US and routine use of
them in Russia and east Europe for wound decontamination and fast heeling suggests that
the technique has a great potential for applications in future.
Keywords Nitric oxide Thermal plasma Nonthermal plasma High voltage electrical
discharge Pulmonary hypertension Inhalation therapy Wound decontamination
Wound healing Plasma medicine
& Muhammad Arif Malik

marifmalik@gmail.com; mmalik@odu.edu
1
Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way,
Suite 300, Norfolk, VA 23508, USA
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738 Plasma Chem Plasma Process (2016) 36:737–766
Introduction
Nitric oxide, having the molecular formula NO, is sometimes also called nitrogen
monoxide. It was called ‘‘nitrous air’’ at the time of its discovery [1]. It is one of nitrogen
oxides that include nitrous oxide (N2O), nitric oxide (NO), dinitrogen dioxide (N2O2),
dinitrogen trioxide (N2O3), nitrogen dioxide (NO2), dinitrogen tetraoxide (N2O4) and
dinitrogen pentaoxide (N2O5). There are several other oxides of nitrogen as well, including
anions like nitrite (NO2-), nitrate (NO3-), peroxonitrite (ONO2-) and cations like
nitrosonium (NO?) and nitronium (NO2?). Among these, nitric oxide is important in
various ways: (1) as an intermediate in the synthesis of nitric acid, fertilizers, explosives,
etc. [2], (2) as an air pollutant responsible for acid rain, photochemical smog and ozone
production in the lower atmosphere, ‘‘troposphere’’, and ozone depletion in the upper
atmosphere, ‘‘stratosphere’’ [3], and iii) as an important biochemical [4, 5].
Nitric oxide was synthesized by the Birkeland–Eyde process based on the following
endothermic reaction taking place in electric arc discharges [6, 7].
N2 þ O2 ! 2NO ð1Þ
Later, the commercial NO production by Birkeland–Eyde process was replaced with the
Ostwald process which is oxidation of ammonia at *850 °C with platinum as catalyst [8]:
4NH3 þ 5O2 ! 4NO þ 6H2 O ð2Þ
Nitric oxide produced by the above process is used mainly in the production of nitric
acid [9]. This conversion happening in atmosphere is a cause of acid rain.
Nitric oxide as a biochemical helps maintain blood pressure by dilating blood vessels and it
also serves as a universal anti-microbial factor killing bacteria, fungi and parasites without
killing human cells [10–12] provided that an appropriate dose level and treatment time are
applied [13]. Nitric oxide-inhalation therapy is being used for the treatment of pulmonary
hypertension and acute respiratory failure [14–16]. Use of inhaled NO for the treatment of
hypoxic respiratory failure and persistent pulmonary hypertension in term and near-term
infants has been approved by US FDA [12, 16, 17]. It is also used to treat acute pulmonary
hypertension in adults [18] and children [17] and in several other medical applications [11, 16,
19] including the prevention of brain injury after cardiac arrest [20, 21], in cardiac surgery
[22] and as a universal antimicrobial agent for reducing bacterial load and faster healing of
chronic wounds [11, 13, 23, 24]. Plasma produced nitric oxide is also being developed for
agricultural uses, such as enhancing seed germination and plant yield [25].
Biological and chemical methods of nitric oxide production for medical uses have been
reviewed in literature [10, 12]. A conclusion from one of the reviews is [10]: ‘‘To date, the
only consistent delivery of gNO is through direct application of gNO from a tank delivered
via tube and topical applicator. Unfortunately, this renders patients non-ambulatory and
bears significant cost.’’ Another review also highlights the cost of inhaled nitric oxide
treatment [12]: ‘‘This approval delivery modality for NO is expensive. The cost of the NO
is *$6/l, bringing the cost of treating a newborn with this gas to almost $12,000, with a
minimum charge of $3000 to open the tank of gas for any application.’’ A simple, eco-
nomical and portable nitric oxide production device for medical uses can be built based on
high voltage electrical discharges in atmospheric pressure air. Research and developments
in the last few decades show that the electrical discharge reactor can deliver NO of
suitable concentration for the medical therapies on demand with a warm-up time in sec-
onds [26, 27]. Feasibility of nitric oxide produced by electrical discharges has already been
123
Plasma Chem Plasma Process (2016) 36:737–766 739
demonstrated for inhalation therapies using a lamb model [27]. A review of literature on
one of the plasma based NO generating device called ‘‘Plason’’ has been published [11].
Here a review of literature on all the NO generators based on electrical discharges is
presented. It will be helpful for researchers in the area of plasma science, specifically the
beginners who would like to step in this important area of applied research. Further, it will
be useful for the medical science community engaged in the NO therapies for the purpose
of gaining necessary background knowledge of the technique.
The review is divided into several sections and subsections for the following reasons. The
second section following this introduction briefly describes mechanism of arc or spark for-
mation and chemical reaction mechanism for NO generation from air. The plasma formed in
electrical discharges is a partially ionized gas. The plasma is classified as a thermal or non-
thermal plasma, depending on the temperature of the free electrons (Te) and the bulk of
neutral particles, i.e., gas temperature (Tg). In a thermal plasma, the temperature of free
electrons, the ions and the bulk of neutral particles are in thermal equilibrium. The plasma
temperature is usually high—on the order of 10,000 K. In a non-thermal plasma, the electron
temperature is high but the bulk of the neutral particles have significantly lower temperature,
i.e., Te Tg. The chemical composition of the air treated with the electrical discharges
changes with the shift from thermal to non-thermal plasma. Further, the average gas tem-
perature varies over a wide range in non-thermal plasmas, from about 10,000 K to close to
room temperature. The change in plasma temperature significantly affects NO generation and
the chemical composition of by-products in the treated gas. These effects will be discussed
with the help of practical examples from the literature reviewed.
The third section is devoted to arc or spark discharges because they appear to be the
most developed among electrical discharge based NO generators. Microwave discharge-
based NO generators will be discussed in the fourth section. The fifth section discusses all
other electrical discharges employed for NO generation and the sixth section compares the
characteristics of the plasma based NO generators.
A portion of the nitric oxide converts to nitrogen dioxide upon coming into contact with
atmospheric oxygen by the following reaction.
2NO þ O2 ! 2NO2 ð3Þ
The rate equation for reaction 3 is: d[NO2]/dt = 2 k[NO]2[O2], where k is a rate
constant equal to *7.3 9 103 (mol/L)-2 s-1 [*1.45 9 10-11 ppm-2 s-1, if concentra-
tions are expressed in parts per million (ppm)] [28]. This conversion happens irrespective
of whether the nitric oxide is coming from electrical discharge-based devices or from any
other source. Further, the plasma-treated gas may be contaminated by metal nanoparticles
originating from the etching of electrodes. Sometimes ozone may also be found in the gas
treated by electrical discharges, especially in the cases of non-thermal plasmas. The
contaminants, i.e., nitrogen dioxide, ozone and particulate matter, have to be removed,
especially when the nitric oxide is going to be used for inhalation therapy. Purification of
nitric oxide is discussed in the seventh section. Conclusions are presented at the end.
Mechanism of Arc Formation and Nitric Oxide Generation from Air
Mechanism of Arc Formation
The high voltage electrical discharges are usually produced by applying an electric
potential difference across two electrodes with the gap between the electrodes filled with
123
gas. The gas can be air, other mixtures of oxygen and nitrogen, or an inert carrier gas like
helium or argon with a mixture of oxygen and nitrogen added in it, etc. It can be at reduced
pressure, atmospheric pressure or above atmospheric pressure. Nitric oxide production
using atmospheric pressure air as a working gas is the main focus of this review because of
the easy availability of air and the technological simplicity associated with atmospheric
pressure conditions.
The mechanism of electrical discharge development has been described in literature
[29–32]. Here a brief summary is presented. Air always has some ions in it due to natural
radioactivity or cosmic rays. The ions start drifting under the influence of strong electric
fields in the discharge gap. Due to less weight, free electrons accelerate much faster
compared to bulky ions under the influence of electric fields. The electrons ultimately face
collisions with ambient gas molecules causing excitation, dissociation, electron attach-
ment, or ionization of the target molecule. Ionization produces more free electrons which
repeat the process resulting in an electron avalanche. The electrons drift towards the anode
through the partially ionized gas channel (plasma) while cations accumulate at the end of
the partially ionized gas channel. The plasma channel in this specific case is called a
‘‘streamer’’ which usually has a fraction of a millimeter diameter comprising a quasi-
neutral column and a positively charged head [29, 32]. The electric field is enhanced at the
positively charged head of the streamer that initiates more electron avalanches in front of
the streamer. The electrons from the avalanches drift towards the anode and neutralize the
previous positive streamer head and leave a new accumulation of positive charge in front.
In this way the streamer propagates in the inter-electrode gap as illustrated in Fig. 1.
A streamer discharge is a relatively resistive and low current discharge. However, when
the streamer bridges the gap between the electrodes, another ionization wave develops
propagating backward, i.e., from cathode to anode that intensifies the plasma channel
making it a conductive and high current arc discharge [30, 31, 33]. The high current and,
Fig. 1 Cathode-directed
streamer with secondary
avalanches moving towards the
positive head of the streamer and
wavy arrows are photons that
generate secondary electrons for
the avalanches
123
consequently, the frequent collisions raise the temperature at the core of the arc to on the
order of 10,000 K. An arc discharge is a thermal plasma where the temperature of all the
particles, i.e., free electrons, heavier ions, and neutrals, approaches thermal equilibrium.
Light emission from de-excitation of the excited states make the arc appear bright, as
shown in Fig. 2.
Chemical Reaction Mechanism for NO Generation in Arc Discharge
The chemical reaction mechanism for NO formation in electrical discharges involves

several reactions, some lead to NO formation and others to NO removal [34–39]. A brief
summary based on important reactions is presented here, especially for the case of arc or
spark discharge, for the purpose of explaining NO generation characteristics reviewed
later.
At high temperature, i.e., *1900 K or higher as in the arc or spark plasma zone,
molecular nitrogen (N2) and oxygen (O2) dissociate into atomic species, i.e., N and O.
Then NO is formed by thermal mechanism (Zeldovich mechanism) through reactions such
as the following [40].
N2 þ O ! NO þ N: ð4Þ
N þ O2 ! NO þ O: ð5Þ
If water molecule (H2O) are present in the process gas they dissociate into H and OH
and lead to additional NO, e.g., through the following reaction [41].
N þ OH ! NO þ H: ð6Þ
In addition to the thermal reactions mentioned above, electron-impact initiated reactions
also take place in parallel, such as the following [39].
O2 þ e ! O þ O þ e; ð7Þ
O2 þ e ! O þ O þ e; ð8Þ
N2 þ e ! N2 þ e; ð9Þ
N2 þ O2 ! N2 þ O þ O; ð10Þ
where * represents the excited state. The rates of excitation and dissociation reactions are
dependent on temperature, electron density and electron energy distribution [42, 43]. High
Fig. 2 Rod–rod shape cathode–

anode pair with hemispherical
ends enclosed in an acrylic tube
filled with atmospheric pressure
air and arc discharge in the inter-
electrode gap
123
energy electrons, especially during the streamer phase before the streamer-to-spark tran-
sition, cause ionization of ambient gas molecules producing cations like O2? and N2?. The
electron density is high during the spark phase ([1017 cm-3) but the electron temperature
decreases (*10,000 k) due to a voltage drop during the streamer-to-spark transition.
However, the low energy electron can produce O and N atoms through dissociative
electron–ion recombination reactions, such as the following [31].
Oþ
2 þ e ! O þ O; ð11Þ
Nþ
2 þ e ! N þ N; ð12Þ
The reactive species, i.e., the excited states and the radicals, react with each other forming
new reactive species [44, 45]. For example, nitric oxide is produced mainly through the
following reaction [34, 39, 42, 43, 45, 46].
N2 þ O ! NO þ N; ð13Þ
N þ O2 ! NO þ O; ð14Þ
N2 þ O2 ! 2NO: ð15Þ
A small fraction of NO is also formed by the following reaction of radicals [43].
N þ O ! NO: ð16Þ
Some of the NO is reduced, e.g. through the following reaction (35, 39, 43).
N2 þ NO ! N2 þ N þ O; ð17Þ
N þ NO ! N2 þ O; ð18Þ
O þ NO ! N þ O2 : ð19Þ
Ozone may be formed through reaction such as the following.
O þ O2 þ M ! O3 þ M; ð20Þ
where M is a third collision partner that may be O2, N2, etc. Ozone, being unstable at high
temperature, rapidly decomposes in the case of arc discharge or other thermal plasmas, e.g.
through the following reactions [42].
O3 ! O2 þ O: ð21Þ
O þ O3 ! 2O2 : ð22Þ
Since the rate of ozone formation decreases while the rate of ozone destruction increases
with an increase in temperature [42], ozone is usually not observed in the case of thermal
plasmas like arc discharge.
Some of the NO may be oxidized, e.g., through the following reaction [39, 43].
NO þ O þ M ! NO2 þ M; ð23Þ
But at high temperature conditions this reaction is countered by the following reaction
[35].
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O þ NO2 ! NO þ O2 : ð24Þ
Another reaction that dominated conversion of NO2 back to NO under thermal plasma
conditions is the following [43].
N2 þ NO2 ! NO þ O þ N2 : ð25Þ
The reaction mechanism described above is supported by the fact that NO was a major
product from air treated with an arc discharge while there was no ozone observed and NO2
remained low in the range of 5–20 % of NO [27, 47, 48].
In the case of non-thermal plasmas, e.g., the streamer phase before the streamer-to-spark
transition, ozone is not fully destroyed by thermal effects [31]. In fact low temperature
non-thermal plasmas, such as streamer corona discharge are employed as ozone generators
[49–52]. Therefore, the residual ozone oxidizes NO to NO2, for example, through the
following reaction [37, 53].
O3 þ NO ! NO2 þ O2 ð26Þ
In the presence of a high concentration of ozone, especially in non-thermal plasmas, nearly
all of the NO is oxidized to NO2.
NO2 may be oxidized further, for example through the following reactions.
NO2 þ O3 ! NO3 þ O2 ; ð27Þ
but this reaction is countered by the following reaction [53].
NO3 þ NO2 ! NO þ NO2 þ O2 : ð28Þ
Similarly, NO2 may convert to N2O5:
NO3 þ NO2 ! N2 O5 ; ð29Þ
but N2O5 reverts fast through the following reaction [53].
N2 O5 ! NO3 þ NO2 : ð30Þ
N2O may also be formed under non-thermal plasma conditions, e.g. through the following
reaction [34, 54].
O þ N2 þ M ! N2 O þ M; ð31Þ
N2 þ O2 ! N2 O þ O: ð32Þ
N þ NO2 ! N2 O þ O: ð33Þ
However, these reactions are slow and also the product are oxidized to NO, e.g.,
through the following reaction, implying that N2O remains low compared to NO and
NO2 [54].
N2 O þ O ! 2NO: ð34Þ
The formation and conversion mechanism of nitrogen oxides and ozone, especially in non-
thermal plasmas, is illustrated Fig. 3.
123
Fig. 3 Illustration of the

reaction mechanisms involved in
the formation and removal of
nitrogen oxides and ozone in
non-thermal plasmas
Nitric Oxide Generators Based on Arc Discharges
Nitric Oxide Generators for Inhalation Therapies
NO generation in a device based on pulsed arc discharge in a rod–rod configuration has

been reported [55]. Brass rods having diameters of 12 mm and their ends having a radius of
curvature of 5 mm, placed at a gap of 5 mm were employed. A 20 nF capacitor charged at
25 kV was discharged using a rotary spark gap switch to generate the pulsed arc in the rod-
to-rod electrodes. When O2 in the O2 ? N2 mixture was varied from 6 to 93 %, NO
concentration varied from *20 to *460 ppm at a total gas flow rate of 1.5 liter per minute
(lpm) and pulse repetition rate of 3 Hz. The maximum of *460 ppm NO was observed for
the case of 26 % O2. NO from dry air was *420 ppm, which is close to the maximum. The
NO concentration was found to be linearly dependent on pulse repetition rate. NO was also
varied by varying the flow rate of air in the range of 0.9–4.5 lpm, decreasing with an
increase in the flow rate. NO2 was *20 % of NO. The gas temperature in the arc was
estimated to be *10,000 K [56]. The NO2/NO ratio was found to be dependent on the
capacitance of the pulse forming capacitor decreasing with an increase in the capacitance
up to 20 nF and thereafter remaining almost constant [56]. The plasma temperature
reached greater than 10,000 K immediately after the pulse and then gradually decreased
[57]. Emission from NO-c was observed when the plasma temperature was higher than
9000 K. The temperature decay was slower when the capacitance was higher which cor-
related with more NO forming in the latter case.
The electrode geometry was modified to a rod-plate arrangement where a brass rod
having a 10 mm diameter and hemispherical head was placed at a 5 mm gap from the plate
electrode [48, 57]. The electrodes were connected with a trigger pulse circuit that allowed
the pulse repetition rate to be controlled in the range of 10–220 Hz. The effect of pressure
was also studied. Increasing the pressure to above atmospheric pressure caused an increase
in charging voltage that resulted in an increase in power density and a proportionate
increase in NO and NO2 production [48]. The NO2/NO ratio was almost unaffected by the
change in pressure. Ozone was not detected and brass particles having diameters over
0.3 lm were detected and estimated to be \1.39 lg/L in the treated gas. The brass par-
ticles were emitted due to etching of the electrode by the arc discharges. NO concentration
123
*1000 ppm was achieved from 0.3 liter per min air with a warm-up time of 20–30 s [58].
The device could be switched ON and OFF when required, each time reaching the desired
NO level within 30 s. The system was tested and found to be producing stable levels of NO
for up to 75 h of operation [26]. After that the system could be re-stored by adjusting the
discharge parameters.
NO production in pulsed arc discharges between needle-plate electrodes has also been
reported [47]. Both NO and NO2 concentrations were found to be dependent on the inter-
electrode gap, increasing with an increase in the gap. For example, NO increased from 70
to 160 ppm with an increase in the gap distance from 1 to 3.5 mm, and further increased to
200 ppm when the gap was increased to 7.5 mm. An increase in plasma volume with the
increase in the inter-electrode gap is suggested as the reason for the improvement in the
NO generation efficiency. NO2 concentration was also increased with the increase in the
gap but by a different rate compared to that of NO, such that the NO2/NO ratio decreased
from *0.12 to *0.08 with an increase in the gap from 1 to 3.5 mm and then gradually
increased to *0.09 with a further increase in the gap to 7.5 mm. NO was increased and
NO2 decreased with an increase in the plasma temperature. For example, the plasma
temperature was gradually increased from 9000–10,150–10,550 to 11,300 K by increasing
the current from 600–800–1200 to 1400 A, respectively [59]. It resulted in increase of NO
from 14–40–97 to 105 ppm and a decrease of NO2 from 8–9–4 to 5 ppm, respectively. The
NO2/NO ratio decreased from 0.57–0.23–0.041 to 0.048, respectively, with the increase in
the plasma temperature. The efficiency for NO and NO2 generation was also found
dependent on the flow pattern of air through the discharge chamber, improving with
uniformity of the flow, particularly in the discharge gap zone [60].
Spark discharge is the same as arc discharge except that it is of shorter duration. A
portable NO generator based on spark discharge between rod-plate electrodes having a
2 mm inter-electrode gap has recently been reported [27]. The electrode geometry
resembled that of an automobile spark plug. The power supply was an autotransformer
(ignition coil). The current was limited to 15 A using a current-limiting resistor in series to
the electrodes. The NO2/NO ratio was found dependent on the electrode material in the
following order: tungsten [ carbon [ nickel [ iridium. The ratio decreased from *0.13
for tungsten to *0.05 for iridium. NO was found dependent on oxygen content in the
N2 ? O2 mixture showing maximum for 50 % O2. NO concentration was also dependent
on gas pressure, increasing with an increase in the pressure but the NO2/NO ratio was
almost unaffected by the pressure. A stable level of NO production (*50 ppm with
1–3 ppm NO2) for 10 days from 5 lpm air was demonstrated in this study. The NO
generator was tested on a lamb model with acute pulmonary hypertension. Results show
that breathing the electrically generated NO produced pulmonary vasodilation and reduced
pulmonary arterial pressure and the pulmonary vascular resistance index.
A transient spark discharge formed between point-to-rod electrodes made of a stainless
steel rod of 2 mm diameter has been reported for NO and NO2 generation characteristics
[31]. The anode tip was sharpened while the cathode tip was left blunt. The inter-electrode
gap was varied between 4 and 6 mm. The plasma was formed by a DC-driven self-spark
discharge with current limited by employing a 4.92–9.84 MX series resistor. Increasing the
spark frequency increased both NO and NO2 production but with different rates, such that
NO2 that was a major product at frequency \2 kHz became comparable in concentration
with NO at 2 kHz with concentration *100 ppm from 1.7 lpm air. A further increase in
the spark frequency beyond 2 kHz increased NO significantly while NO2 was increased at
a lower rate. At 750 kHz frequency, NO reached *750 ppm while NO2 increased only to
about 170 ppm. One plausible explanation given for the shift of the selectivity in favor of
123
NO is that the transient spark discharge comprised a streamer phase that was non-thermal
plasma followed by a spark phase that was a thermal plasma phase. Ozone was formed in
the non-thermal plasma that oxidized NO into NO2. With an increase in the spark fre-
quency, the temperature of the streamer phase increased, e.g., from \400 K at 1 kHz to
*600 K at 10 kHz which destroyed ozone resulting in less NO into NO2 conversion.
NO Producing Plasma Jets for Wound Decontamination and Healing
The ions, radicals and excited-state species in the plasma zone can be expelled from the
discharge gap based on the following principles [32, 33, 61, 62]:
(1) Rapid gas expansion and shock waves expel the excited/reactive species,
(2) fast gas flow can sweep the excited/reactive species out of the discharge gap, and
(3) re-distribution of electric fields that causes aerodynamics through ion-movement
and guided ionization waves.
The first two principles apply to thermal plasmas, including arc/spark discharges [33]
while the second and third apply to non-thermal plasmas [31, 61]. The excited state species
in the expelled gas de-excite emitting light (afterglow) as shown in Fig. 4. Recent research
suggests that the reactive oxygen species (ROS) and reactive nitrogen species (RNS),
foremost the nitric oxide radical in the plasma jet, play a central role in anti-microbial and
wound healing therapies [13, 63].
A spark discharge in a pin-to-hole electrode configuration provides an example of a NO
producing plasma jet in which the plasma afterglow is expelled mainly by the action of
rapid gas expansion and shockwaves [33, 64]. In this device a stainless steel needle anode
of 1.5-mm diameter was coaxially fixed in an insulator with gas inlet openings, which was
surrounded by an outer stainless steel cylindrical cathode of 7 mm diameter with an axial
opening of 2 mm diameter for the plasma outlet. The electrode configuration resembled
pin-to-ring electrode geometry illustrated in Fig. 5. The inter-electrode gap was set to
1.6 mm and air was passed though it at 0.5 lpm. The needle electrode was connected with a
0.33 lF capacitor charged to 4–8 kV. The spark discharge of *140 ns duration and
*130 A peak current took place under these conditions. A hot pressurized channel formed
during the discharge phase and started the gas dynamic expansion with shockwaves leading
to the formation of a plasma jet (afterglow) emitting from the outlet nozzle. The average
plasma excitation temperature in the spark was estimated to be 9030 ± 320 K, while the
Fig. 4 Plasma afterglow expelled from an arc discharge formed in a tube of *5 mm outer diameter. The
afterglow is bright in a 2 mm 9 3 mm hemispherical zone at the outlet point but the glow remains visible
while decreasing in intensity as the distance increases to *2 cm from the device outlet (unpublished work
form author’s lab.)
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Fig. 5 Schematics of NO generating plasma jet based on arc discharge between pin-to-ring electrodes
average gas temperature was B50 °C at a distance of C2 mm from the outlet hole. The gas
temperature was reduced to B37 °C at a distance of C6 mm. The average electron density
was calculated to be *7.8 9 1016 cm-3 and total plasma UV irradiation was 140 lW/
cm2. Reactive oxygen species, like H2O2, O2-, singlet oxygen and reactive nitrogen
species, like NO, and ONOO- were delivered to a liquid sample [33] as well as several
millimeters deep into tissues and agarose media [64].
The reactive nitrogen species delivered to water increased the nutrient content for plant
growth [65] while the reactive nitrogen and oxygen species delivered to tissues can be
employed for therapeutic purposes [66]. For example, penetration of NO from the pin-to-
hole spark discharge into gas, phosphate saline buffer and endothelial cell culture was
monitored [66]. NO reached a saturation level of *1980 ppm in 50 s in the gas. In
phosphate buffer saline, NO gradually increased and reached *1600 ppm in 250 s after
250 pulses (@ 1 Hz). In an endothelial cell culture, NO reached *1000 ppm in 250 s after
250 pulses [67]. Hydrogen peroxide reached a concentration of *60 lM in 30 s in the
buffer solution but when UV-irradiation was blocked, it reached a saturation level of
1.5–2 lM in 5–10 s [66]. The treatment was found to be safe without a measureable loss of
viability. The same conclusions regarding toxicity of the plasma treatment were reached in
the cases of an experimental model of ulcerative colitis in mice [68], live pig skin tissue
[69] and porcine aortic endothelial cells [67].
A spark-like discharge having both spark and glow phases was formed in atmospheric
air in an electrode assembly resembling an automobile spark plug [39]. The power supply
was quasi-sinusoidal or pulsed DC. The reactive species emitted by the discharge were
accumulated in a box that was used to study decontamination of E coli. Initial NO was
observed that converted to NO2, N2O4, HNO2 and finally HNO3 over a period of tens of
minutes. After 10 min of the plasma exposure, NO was in the range of 100–300 ppm while
NO2 was the major product in the range of 1000–6000 ppm. A 0.15 deionized sample was
placed in the box and after 5 min its pH decreased from 5 to 1, and nitrate content
increased to [50 lM. A 5 min treatment of an E coli sample placed in the box resulted in
up to a 5 log reduction in aqueous saline solution and about a 4 log reduction from a
stainless steel surface.
A NO generator based on a pin-to-ring electrode arrangement as illustrated in Fig. 5 has
been reported [70]. A tungsten needle electrode having 0.2 mm in diameter was placed in a
ceramic tube having 0.4 mm in inner diameter and a ring-type ground electrode attached
on the tip of the ceramic tube at a gap of 0.5–2.0 mm. An arc discharge was formed
between the electrodes by applying 1–3 kV DC power with air at 0.8 l/min. A plasma jet
exited from the exit hole extending a few centimeters in air. The NO concentration in the
treated gas varied in the range of 10–1150 ppm, increasing with an increase of the inter-
electrode gap, increase in current and decrease in air flow rate. The NO2/NO ratio also
decreased with an increase in inter-electrode gap, increase in current or decrease in air flow
rate. For example, when the inter-electrode gap was gradually increased from 0.5 to 2 mm
maintaining the current at 20 mA, the NO increased from 180 to 560 ppm, while NO2
remained *220 ppm. Similarly, gradually decreasing the air flow rate in the range of
123
Fig. 6 Schematic of a
plasmatron: 1 is cathode, 2 is
anode, 3 is plasma afterglow, 4–7
are positions of arc at successive
times, 8 is swirl gas glow
0.4–1.6 lpm increased NO to the range of 240–1150 ppm while NO2 remained almost
constant at *220 ppm.
In a plasmatron device, the plasma column between cathode and anode glides over the
electrode surface due to swirling of the gas flow as illustrated in Fig. 6. For example, a plasma
column was formed between a rod-shaped cathode placed in a cavity in the anode and shifted
by a vortex of air flowing at a rate of 9.4–71 slm (0.2–1.5 g/s) [71]. The nozzle in the anode
cavity had a 5 mm inner diameter resulting in 8–60 m/s gas velocity. The anode cavity was
modified by introducing a ring-shaped groove that allowed the production of a repeatedly
long plasma column before glow-to-arc transition. The plasma terminates at this point and the
cycle is repeated. This is how a low current (0.05–0.2 A) plasmatron operates for NO pro-
duction from air. With a power of 65–160 W and energy density 78–392 J/L (100–500 J/g),
the NO was 747–3733 ppm (1–5 g/m3) while NO2 was 97–487 ppm (0.2–1 g/m3). In another
similar plasmatron 9.5–23.5 lpm air was treated with DC input power of 200–750 W resulting
in plasma temperature 550–1250 K and NO 8000–15000 ppm [54]. Since the plasma tem-
perature was relatively lower (550–1250 K) NO was mainly produced by electron impact
process. NO2 production was not reported in this study.
NO production by thermal mechanism mainly occurs in the hot plasma zone in the arc
discharge [46]. The NO concentration decreases rapidly with distance from the outlet due to
dilution with ambient air. Some of the NO is oxidized to NO2 by atomic oxygen in the plasma
zone (reaction 23) or simply by reacting with oxygen in air (reaction 3). For example, in a NO
generating plasmatron that is often referred to as a ‘‘Plason’’, NO was *2500 ppm and NO2
was *1000 ppm at 20 mm and decreased to *300 ppm NO and *80 ppm NO2 at distance
of 200 mm [11]. These values agree with 400–500 ppm NO and 70–90 ppm NO2 at a distance
of 170–200 mm in the case of the same device reported earlier [72]. The Plason device is used
in two modes: hot mode and cold mode. Hot mode is used for rapid coagulation and steril-
ization of wound surfaces, destruction and desiccation of dead tissue and pathologic growths,
desiccation of biological tissues, etc. [11]. In cold mode, the gas exiting from the arc discharge
is first passed through a condenser/cooler section and the resulting gas at 18–20 °C is used for
wound sterilization, stimulation of regenerative processes and wound healing [73, 74]. These
medical applications of nitric oxide generated using the Plason device have been reviewed in
[11] and also in some sections of the following reviews [75, 76].
Another way to glide the arc along the electrode is by applying a horn-shaped electrode
geometry as in the case of a gliding arc discharge illustrated in Fig. 7 [77, 78]. The arc
starts at the closest point between the electrodes. A fast gas flow moves the arc, expanding
it along the horn-shaped electrodes until the plasma column cannot sustain itself and
extinguishes. The process is repeated by a new arc starting at the closest point between the
electrodes.
123
Fig. 7 Schematics of a gliding

arc discharge
NO production was studied in gliding arc discharges formed between two copper
electrodes made of copper tubes, each being 8 mm in diameter and 20 cm long diverging
from each other at an angle of 20° from the closest point of 0.5 mm [79]. The electrodes
were powered with a DC power supply having 5000 V and 2500 X internal resistance. The
gliding arc was operated with an air flow rate of 50 and 133 lpm, the plasma temperature
was estimated to be 5200 and 6200 K and it produced 3000 and 500 ppm NO, respectively.
The NO production calculated based on the temperature of the plasma agreed with the
experimentally measured values.
A gliding arc discharge is a non-thermal plasma in which the plasma temperature can vary
over wide range, depending on power dissipation and gas flow rate. The NO production based
on the plasma temperature (thermal mechanism) decreases as the plasma temperature
decreases or increases from *3000 K [44, 74, 80, 81]. In one of the nitrogen oxide generation
studies using gliding arc discharge, the power density was low and, consequently, the cal-
culated plasma temperature was low (598–731 K) which agreed with the measured tem-
perature (309–333 K) [81]. The predicted values of NO and NO2 were \13 and \0.5 ppm
based on the thermal nitrogen oxides production mechanism which were significantly dif-
ferent from experimental values of 3445–6982 ppm NO2 and no NO was observed in this
study using dry air as working gas. Clearly, thermal mechanism for NO production do not play
a significant role in this case. High energy electron produced in the non-thermal plasma
collide with and excite, dissociate or ionize the ambient gas molecules, which, in turn, drive
the plasma chemical reactions [81, 82]. In another study a mini-scale gliding discharge was
operated with 1 lpm air with AC power having 3–14 kHz frequency and *43 kV peak-to-
peak voltage for NO and NO2 generation [83]. Feed ratio of N2/O2 varied the NO to NO2 ratio
in the products. For example, gradually varying the N2/O2 ratio from 1 to 4 gradually
increased NO from *4000 to *5500 ppm while NO2 was gradually decreased from *3500
to *2700 ppm with energy yield for NO ? NO2 around 70 g/kWh at 43 kV peak-to-peak
voltage and 9 kHz frequency. Water can be sprayed directly into the gliding arc working gas.
Nitric acid is the main product that accumulates in water which is verified by nitrate ion
measurement. For example, 400 ml water was sprayed in 15 min though a gliding arc
operating with *500 W power. Nitrite and nitrate in the treated water were found to be 50
and 444 ppm, respectively, and pH dropped form 5.4 to 2.8 [84]. The energy efficiency for the
reactive species production was improved significantly when AC power was replaced with a
pulsed DC power supply in the gliding arc reactor [85].
Nitric Oxide Generators Based on Microwave Discharge
NO Generation in Thermal and Non-thermal Plasma by Microwave

Discharge
A simplified schematic of a microwave plasma device is illustrated in Fig. 8. Like arc

discharges, a microwave discharge can form a thermal or non-thermal plasma depending
123
Fig. 8 Schematics of a
microwave plasma device
on the input power and gas flow rate. A thermal plasma having a 5000–5500 K temperature
was generated by absorbing microwaves of frequency 1.25 GHz in air flowing at 53–132
lpm in a quartz discharge tube of 18 mm inner diameter [80]. It produced up to 25000 ppm
NO. In another study, microwave power of 1.3 kW was dissipated in air flowing at the rate
of 150 lpm [86]. The plasma temperature was estimated to be *6000 K and it produced
1248 ppm NO and *120 ppm NO2. It was modified by introducing a water cooling device
attached to the plasma exit to cool the NO-containing gas for medical uses [43, 87]. The
main working gas was nitrogen (10–30 slm) with a small amount of oxygen (0.1–0.5 %)
mixed in and it operated at 400 W. The plasma temperature was 2950 K and NO was
produced up to *1200 ppm, increasing with an increase in oxygen content in the process
gas. The nitric oxide was applied to spores of a fungus N. crassa in water [88]. Nitric
oxide, nitrite and nitrate in water increased and enhancement of the fungal sporulation and
activation of a sporulation-related gene were demonstrated. The nitric oxide produced by
the microwave plasma device [43] was also applied to coriander seeds and improvements
in germination and seedling development were observed [25].
A non-thermal plasma was generated by absorbing microwaves of frequency 2.46 GHz
in 6–10 lpm air dissipating 60–90 W, where the energy density was \0.9 kJ/L [37]. The
product gas contained 32–4300 ppm NO2 while NO was only 180–200 ppm. Increasing
oxygen content in the process gas increased the NO2/NO ratio. A non-thermal microwave
plasma in air at slightly below atmospheric pressure (0.79 atm) was generated by applying
a pulsed microwave to achieve low power (0.2–40 W) [89]. NO2 was about the same or
higher than NO in this case and their concentrations were increased with an increase in the
power following logarithmic curves, irrespective of whether the power was varied by
varying the pulse repetition rate or pulse duration. For example, at *4 W NO was
*900 ppm and NO2 was also *900 ppm but at *30 W NO was 2100 ppm while NO2
was *4500 ppm.
NO Producing Plasma Jets Based on Microwave Discharge
As in the case of the arc discharge, plasma can be expelled from the microwave plasma
device forming a jet of plasma afterglow. It can be used for direct exposure of the target to
the plasma, e.g., wound decontamination and healing. A plasma jet based on a microwave
discharge has been reported as a source of NO for biological uses. A 2.4 GHz microwave
reactor employing a copper resonator of 12 mm length and 8 mm diameter and 0.6 mm
nozzle integrated with a solid state power oscillator was used to form a plasma jet [42].
With 24 V DC, 30–40 W, 0.101 lpm of N2 ? O2 gas mixture, the temperature in the
123
plasma was 1000–1400 K [90]. When the O2 flow was kept at 0.05 lpm and N2 flow was
gradually increased from 0.2 to 0.7 lpm, ozone at 25 mm distance from the outlet nozzle
gradually increased from 25 to 360 ppm while NO gradually decreased from
750–200 ppm. Decreasing the oxygen decreased the NO for the same total flow rate [42].
When air was employed as the working gas, the NO concentration showed a parabolic
curve with respect to the flow rate of air with a maximum of *200 ppm in the range for
0.25–0.30 lpm air while ozone gradually increased from *20 ppm for 0.1 lpm air to
*130 ppm for 1 lpm air [91]. This source was tested for biological effects on human skin
cells. When a curved capillary tube was used to deliver the plasma-produced reactive gases
without UV-irradiation, no sign of apoptosis in primary human keratinocytes was observed
after 15 min of plasma exposure. In human skin endothelial cells however, toxicity was
observed after treatment for more than 10 min. Direct exposure allowed UV-irradiation
along with NO and ozone and resulted in maximal cell death after 10 min in both cell
types. This study proved that NO reached and penetrated into these cells and modulated
proliferation in both cell types.
A microwave plasma jet in which a microwave generator of 2.45 GHz and 18–55 W
power was connected to a pin electrode placed in a tube of 12 mm inner diameter at ground
potential has been studied for special distribution of NO in the plasma jet operating in open
air [92]. The working gas was helium (6 slm) mixed with 0–6 % air. The plasma tem-
perature at the nozzle was *2200 K for 55 W and decreased with a decrease in power,
e.g., to *1600 K for 18 W. The temperature also gradually decreased with an increase in
distance from the nozzle. NO increased with an increase in power, saturating at *30 W at
a value of *1. 9 1021 particles per cubic meter at a distance of 4–10 mm from the nozzle
for the case of 3.2 % air in helium. The NO density was lower close to the nozzle due to
gas expansion by plasma heating. The NO density also decreased with an increase in
distance both in the axial and lateral directions from the maximum NO area due to dilution
with ambient air. The NO concentration gradually increased with an increase in air in the
working gas which was tested up to 6.3 % air.
Nitric Oxide Generators Based on Nonthermal Plasmas
NO generators based on nonthermal plasma versions of arc and microwave discharges have
been described in previous sections. In addition to those, the following NO-generators
based on nonthermal plasmas have been reported [93–96].
NO Generator Based on a High Current Version of Sliding Discharges
A scalable plasma reactor based on a high current version of sliding discharges is being
developed for environmental applications [97–99]. A schematic of the reactor overlaid on a
time-integrated image of the sliding discharge is shown in Fig. 9. Application of pulsed
DC voltage to edge-to-edge electrodes adhered to a dielectric layer forms plasma channels
sliding at a solid–gas interface. Extending one of the electrode to cover the inter-electrode
gap on the opposite side of the dielectric layer significantly increases the electric fields and
the current flow through the plasma for the same applied voltage compared to the simple
sliding discharge [97, 100]. Externally heating the discharge chamber to a few hundred
degrees above room temperature further increased the energy density by more than an
order of magnitude compared to room temperature operation [94]. Heating reduces the gas
123
Fig. 9 Schematics of a sliding discharge reactor overlaid on a time-integrated image of the sliding
discharge
density without affecting pressure or electric fields, which results in an increase in average
energy of free electrons. It led to an increase in ionization, increasing the current flow
through the discharge. Heating not only increased the current flow, it destroyed ozone,
minimized NO2 and resulted in more NO production with a higher energy yield. For
example, 400–4500 ppm ozone and 12–180 ppm NO2 (without any NO) produced at room
temperature changed to 160–1070 ppm NO and 60–250 ppm NO2 without ozone at
420 °C.
Plasma devices based on the high current version of sliding discharge has been used for
bacterial decontamination of surfaces both with and without applied air flow [101, 102].
The reactive species, including neutrals like ozone and NO and ionic species like H3O?,
O2-, OH-, NOx-, etc. could be transported to the target even without the applied gas flow
due to a strong electric wind associated with the sliding discharge [103]. Deposition of the
ionic species on the membrane of the target cells can potentially cause electric fields and
electroporation that can facilitate delivery of molecules to the cells. Delivery of DNA to
cells has been demonstrated using the plasma device that supports the view described
above [104, 105]
NO Generating Plasma Jet Based on Radio-Frequency Discharge
A schematic of a plasma jet based on a radio-frequency discharge is illustrated in Fig. 10.

A plasma jet of *4 mm length was generated by applying a radio-frequency voltage of
13.56 MHz frequency and 1–10 W power to a tungsten wire of 50 mm length having a
diameter of 1 mm inserted into a quartz tube of a few millimeters in diameter [96]. The
plasma was ignited in a gas mixture comprising 15 % He, 12 % O2 and 73 % N2 at a total
flow rate of 1 lpm through the tube. The plasma temperature at 1.5 mm from the needle
increased from 60 °C for 1 W to 150 °C for 9 W and NO at the same distance was
estimated to gradually increase from 0 to 200,000 ppm (0–20 %) with the same increase in
the power. The device was modified by employing 0.3 mm thick flexible electrode inserted
in a flexible plastic catheter for the purpose of treating biological samples at lower plasma
temperatures. Another similar miniature plasma device based on radio-frequency discharge
in 10 slm argon with 0.25 % air produced 2–8 ppm NO linearly increasing with an increase
in power from 5 to 20 W has been reported [95]. A comparative study for the cases of 5
and 10 slm argon with oxygen varying in the range of 0–10 % showed that NO production
was not much affected by the argon flow rate but showed a parabolic curve with respect to
air content in the gas with maximum NO concentration observed in 0.25 % air.
A radiofrequency plasma jet operated at a frequency of 13.9 MHz (72 ns period),
pulsed at 20 kHz with a 20 % duty cycle and 0.4–7.4 W power has been studied for special
123
Fig. 10 Schematics of a plasma jet based on a radio-frequency discharge (the ground electrode is optional
as the target of the plasma treatment can also act as the ground)
distribution of NO in the plasma jet [106]. The source was a glass tube of 1.5 mm inner
diameter with a needle electrode inside and either a grounded ring on the outside or a
grounded plate with a 5 mm hole in the middle at 3 mm above the tube. The working gas
was 1 slm argon with 0–4 % air. NO was optimum for 2 % air and decreased with either an
increase or decrease of air content from the 2 % value. NO was also dependent on power,
increasing with an increase in power. The plasma temperature was *470 K at the nozzle
and decreased to *350 K at 10 mm distance with an NO particle density of *1 9 1020
m-3 at the nozzle which decreased to *4 9 1020 m-3 (*19 ppm) at 10 mm from the
nozzle for the conditions of 3.5 W, 1 slm argon with 2 % air in the ring electrode. The
results were similar for the case of the plate electrode except that the NO was maximum at
*5 mm from the edge of the tube. These NO measurements were done using a laser-
induced fluorescence (LIF) technique and they agree with the results from both numerical
modeling and measurements using a molecular beam mass-spectrometer [107, 108].
NO Generating DC Plasma Jets
Reducing critical dimensions of the discharge gap to an order of 1 mm allows a stable glow
discharge-type plasma generation at atmospheric pressure in gases including air [109–111]. It
is called a microhollow cathode discharge. When the hole in the cathode is extended to cross
through the anode, the afterglow can be expelled from the discharge gap into open air by gas
flow extending few centimeters in length, as illustrated in Fig. 11 [93, 112]. For example, a
copper tube of 0.8 mm inner diameter and 1.5 mm outer diameter was enclosed in an alumina
tube having 1.5 mm inner diameter which was, in turn, enclosed in a tubular cap-shaped
cathode made of brass having a hole of 0.8 mm diameter at the axis and separated from the
anode by a gap of about 0.4 mm. High voltage of 2 kV was applied to the anode with current
limited to about 30 mA by using a 51 kX ballast resistor in series with the anode. Gas was
pumped through the hole at a rate of about 8 slm which expelled plasma resulting in an
afterglow extending a few centimeters from the exit into ambient air. The temperature can
reach 2000 K in the discharge cavity, but was reduced to *30 °C at distance of about 5 mm
from the outlet. Yeast or bacteria on surfaces were killed upon exposure to the plasma jet
[112–114]. Ozone was below detection limits and UV-irradiation for the plasma was ruled out
as a major factor responsible for the decontamination [113]. The NO radicals and excited
nitrogen molecules produced from the plasma jet were considered to be the main factor
responsible for blocking activity of fungal spores in vitro and in the skin lesions of guinea pigs
Fig. 11 Schematics of a plasma

jet based on a microhollow
cathode discharge
123
[115]. Varying the power (25–6 W) and the air flow rate (1–8 lpm) varied the nitric oxide
(1000–50 ppm), which is considered a major factor responsible for the bacterial decontam-
ination [93]. Nitrogen dioxide was also observed but only when the flow rate was reduced to
*1 lpm or the applied power was reduced to less than 6 W.
A DC plasma jet based on pin-to-mesh electrodes inside a quartz tube having a 5 mm
inner diameter has been reported for NO generation from air [116]. The pin was a tungsten
cathode having a 2 mm diameter with a sharp tip at a gap of 14 mm from an anode made of
fine-meshed metal. The voltage was applied through a ballast resistor of 880 kX and the
discharge current was varied from 5 to 30 mA. The plasma temperature was *2000 K and
dropped rapidly in the afterglow to about room temperature at 1 cm from the exit nozzle.
NO was *1100 ppm at *5 mm from the nozzle and gradually decreased with distance to
*700 ppm at *40 mm for 25 mA. A decrease in current also decreased the NO.
NO Generators Based on Cold Plasmas with Average Gas Temperature Close

to Room Temperature
All the NO generators based on non-thermal plasmas described in previous sections had
average gas temperature above room temperature by about 100° or more. That is, they are
warm versions of non-thermal plasmas. Cold versions of non-thermal plasmas with gas
temperatures close to room temperature, such as pulsed corona discharges or dielectric barrier
discharges have not been employed as NO generators. The reasons are the following:
(1) energy density and, consequently, throughput per unit volume in the cold plasmas is
usually orders of magnitude lower than in thermal plasmas [117],
(2) ozone is a major by-product that converts almost all NO into NO2 [53], and
(3) Energy yield for nitrogen oxides (NOx, i.e., NO ? NO2) production is about an
order of magnitude lower than in thermal plasmas [117].
For example, *0.4 mJ per pulse in a corona discharge is orders of magnitude lower
compared to 0.5–2.5 J per pulse in a spark discharge and an energy yield of 5.7 9 1014
NO2 molecules/J in corona discharge is more than order of magnitude lower compared to
2.76 9 1016 NO molecules/J (with NO2 less than 10 % of NO) [117].
The cold plasmas can potentially be in direct contact with the target surface. Since NO
is the initial product that later converts into NO2, a plasma very close to or in direct contact
with the target surface may still deliver a sufficient amount of NO for bacterial decon-
tamination or therapeutic effects [13, 32]. A dielectric barrier discharge formed directly on
human skin has been employed to study nitric oxide effects but the measured NO was
0.213 ppm which was about three orders of magnitude lower compared to 115 ppm NO2
[118]. Further, a significant amount of ozone (1020 ppm ozone) and UV (7.27 9 10-3
mW/cm2 UV-A and 1.34 9 10-3 mW/cm2 UV-B) were also observed in the dielectric
barrier discharge. A dielectric barrier discharge based plasma jet was also tested for
osteoprogenitor cells early differentiation [119]. Cell viability was maintained and toxicity
was not observed and an early osteogenic differentiation in the absence of pro-osteogenic
growth factors/proteins was induced by the plasma treatment. Dielectric barrier discharge
treatment of Coriander sativum seeds was tested and the results show improved seed
germination and seedling growth [25]. A hand-held self-pulsed DC discharge device
employing an array of 12 stainless steel needles with the needle tips having a radius of
*50 lm has been reported as producing plasma with the plasma plume temperature of
20–28° C [120]. The current was limited by employing a 50 MX resistor in series in order
to prevent the cold plasma from transitioning to a warm or thermal plasma. The device has
123
Table 1 Nitric oxide generation characteristics of some representative electrical discharge base devices
Discharge Power Air NO (NO2) Energy yield mol/ References
(W) (slm) (ppm) (ppm) J
Pulsed arc 1–10 2 25–540 25–150 *4.4 9 1016 [48]

Pulsed arc 0.76–2.7 0.3 200–1060 – 3.4–4.9 9 1016 [26]
Pulsed arc – 1–6 370–90 30–6 – [47]
Pulsed spark – 5 0–55 0–4 – [27]
DC spark – 0.5 0–2000 – – [66]
DC arca – – 2500–300 1000–80 – [11]
DC spark – 0.4–0.6 240–1150 *220 – [70]
DC arc 65–160 9.4–71 747–3733 97–487 12–18 9 1016 [71]
b
AC/pulsed spark – – *100 *500 1.5 9 1016 [39]
Transient spark *6 1.3–2.6 *450 *170 7 9 1016 [31]
DC gliding arc – 50–133 3000–500 – – [79]
AC gliding arc 122–180 20 0 3445–6982 23–32 9 1016 [81]
Microwave 600–8000 35–132 25000 – 11 9 1016 [80]
Microwave 60–90 6–10 180–200 3200–4300 13–15 9 1016 [37]
Pulsed microwavec 0.2–40 0.25 50–2100 20–4500 2.3–5.5 9 1016 [89]
Microwave 1300 150 1248 120 *6.5 9 1016 [86]
Microwaved 400 10–30 0–1150 – 1.2–1.5 9 1016 [43]
Microwavee 30–40 0.2–0.8 2750–100 – –
[42, 90]
Sliding discharge 2–50 1 150–1070 60–250 0.9–2.5 9 1016 [94]
Radiofrequencyf 1–10 1 0–200000 – – [96]
Radiofrequencyg 5–20 10 2–8 – 175–200 9 1016 [95]
Microhollow 0.6–26 0.5–8 1000–100 0–25 2.2–7.0 9 1016 [93]
cathode
a
The concentration gradually decreases over the distance from 20 to 200 mm
b
Working gas was static air in a 1 L box and the NO and NO2 concentrations were from the data of initial
2 min operation
c
Slightly below atmospheric pressure (800 bar)
d
Working gas was N2 with 0.0–2.4 % O2
e
Byproduct ozone was 25–360 ppm
f
Measured at a point 1.5 mm from the needle electrode and working gas was 15 % He, 12 % O2 and 73 %
N2
g
Working gas was Ar 10 slm mixed with 0.25 % air
been tested successfully on an Enterococcus faecalis biofilm. Although the authors argued
the decontamination was primarily due to excited nitrogen and reactive oxygen species, the
nitric oxide most likely also plays a role.
Comparison of Nitric Oxide Generation Characteristics
Nonthermal plasmas operating at or close to room temperature are not a good source of NO
because they produce a lot of ozone that converts all of the NO into NO2 through reac-
tion 26. Therefore, cold plasma sources are not suitable as NO sources for inhalation
therapies. However, they still have a potential use in bacterial load reduction from surfaces
123
and wounds [13, 63, 121]. The wound decontamination application using the cold plasma
apparently relies on the fact that NO is the initial product that converts into NO2 over time.
If the plasma source is close to or in contact with the target the NO can be utilized before it
is converted into NO2. Role of nitrogen oxides in bacterial decontamination is argued by
several researchers [11, 122–124]. Deposition of ionic species, particularly if the target in a
close range to the plasma source can have synergistic effect with the neutral species on the
bacterial decontamination [125–128].
External heating to a few hundred degrees above room temperature can eliminate ozone
and produce NO at a faster rate [94]. Warm plasma, like gliding arc discharge also does the
same that is no ozone and more NO with less NO2. Thermal plasmas are the most energy
efficient for NO production with low NO2 by-product. The energy cost for nitrogen oxides
synthesis varies over a wide range of 0.01 9 1016–200 9 1016 molecule/J in different
plasmas [94]. It varies in the range of 1 9 1016–200 9 1016 molecule/J in the case of
warm versions of nonthermal plasma and thermal plasmas as shown in Table 1 with some
representative examples of NO generators. Purification of byproducts is another important
aspect of the technology that is discussed in the following section.
Purification of Nitric Oxide Produced by Employing High Voltage

Electrical Discharges
With the economics, technological simplicity and durability already in favor the electrical
discharge based NO generators [129], there is a need to address removal of byproducts in
order to deliver pure NO, particularly for inhalation therapies. Nitric oxide is usually
contaminated with NO2. Ozone, charged particles like H3O?, O2-, NOx-, and particulate
matter may also be present in the case of NO produced by electrical discharges. Due to
health hazards associated with the reagents, EPA has set a limit of 0.07 ppm for ozone
[130] and 0.1 ppm for 1 h along with 0.053 ppm annual for NO2 [131].
Research is needed to minimize the contaminants at the source. For example, NO2 that
was about 20 % of NO in the case of arc discharge in a rod-to-rod electrode geometry [55]
was reduced in proportion to NO by increasing the plasma temperature by an increase in
the capacitance of the pulse forming capacitor [56]. NO2 was reduced to about 10 % of NO
by modifying the electrode geometry form rod-to-rod to needle-to-rod and increasing the
discharge gap [47] and to about 5 % by increasing the plasma temperature [59]. Similarly,
a significantly decrease in NO2/NO ratio, i.e., from 4 to 0.4 by increasing the frequency of
a transient spark discharge from *1 to *7.5 kHz has been reported [31]. It has been
recently reduced to less than 5 % by replacing the electrode material to a more suit-
able iridium [27].
It should be mentioned here that some NO2 is usually present along with NO, irre-
spective of whether the source is the electrical discharge or a pressurized gas cylinder of
purified NO balance nitrogen. This is because when NO comes in contact with air, NO
reacts with oxygen through reaction 3. In order to minimize this effect, the initial NO
concentration should be kept as low as needed and be delivered to the patient as quick as
possible after its purification. This is because NO to NO2 conversion occurs faster from
higher initial NO concentration. For example, 50 % of NO will convert to NO2 in 0.35 min
from 10,000 ppm initial NO while the same percentage conversion will take 350 min from
10 ppm initial NO [132]. The NO2 can be removed at the point of delivery as described in
the following.
123
Catalytic Conversion of NO2 into NO
Molybdenum wire [47, 48, 56] or a molybdenum powder filter [133] when heated to
*870 K convert NO2 into NO through the following reaction.
3NO2 þ Mo ! 3NO þ MoO3 ð35Þ
However, reaction 35 does not usually achieve complete removal of NO2. For example, a
decrease of NO2 from 138 to 48 ppm was accompanied by an increase in NO from 455 to
540 ppm [48].
Ascorbic acid loaded on silica gel pellets, barium oxide (BaO) loaded on gamma-
alumina and activated carbon cartridge can potentially be coupled with electrical discharge
base NO generators for selective conversion of NO2 into NO. According to authors
knowledge, these catalysts have not yet been tested on electrical discharge based NO
generators, but they have been tested positive for the conversion as described in the
following.
Ascorbic acid loaded on silica gel has been employed to convert NO2 into NO through
reaction shown in Fig. 12, for the purpose of producing ultra-pure NO for inhalation
therapies [134, 135]. Similarly, BaO loaded on gama-alumina has been tested for absorbing
NO2 followed by conversion of one third of it into NO through the following reaction
[136].
3NO2 þ BaO ! BaðNO3 Þ2 þNO ð36Þ
Carbon particles like carbon suet can also potentially convert NO2 into NO through the
following reactions at [523 K [137].
C þ NO2 ! CO þ NO; ð37Þ
C þ 2NO2 ! CO2 þ 2NO ð38Þ
Selective Adsorption of NO2
Charcoal [133] and calcium hydroxide (Ca(OH)2) [27] have been successfully tested for
selective removal of NO2 from the product gases from electrical discharge base NO
generators. For example, a calcium hydroxide filter brought NO2 from 3 to 4 ppm to below
1 ppm level at room temperature from 5 lpm gas exiting a pulsed spark discharge device
through the following reaction.
CaðOHÞ2 þ NO2 þ NO ! CaðNO2 Þ2 þH2 O ð39Þ
Fig. 12 Illustration of NO2 conversion into NO by reaction with ascorbic acid
123
Besides charcoal and calcium hydroxide, there are several adsorbents known that selec-
tively adsorb NO2 from NOx [138]. These adsorbents are being developed for NOx
remediation of flue gases. They usually have two components: an oxidation catalyst, such
as platinum or palladium that converts NO into NO2 and a storage/adsorbent component,
such as barium or strontium-containing material that adsorbs and retains NOx, preferen-
tially NO2 from the NOx. For the purpose of purification of NO, the oxidation component
is not needed while the storage component can potentially be coupled with electrical
discharge base NO generators for the purpose of selective removal of NO2 in the treated
gas.
Destruction of Ozone
Ozone is usually destroyed by thermal effects in the cases of arc discharge or other thermal
plasma based NO generators. However, low concentrations of ozone may still be found in
the product gases. For example, ozone was observed in the treated gas at a level of
*10 ppm [31, 56] and *0.018 ppm in another [27]. It needs reduced to less than
0.07 ppm limit imposed by EPA. It was successfully removed by bubbling the gas through
water [56] or by using a calcium hydroxide filter [27]. It should be mentioned that ozone
destruction catalysts are commercially available from several sources in pellet as well as in
foam shapes that can destroy ozone at room temperature.
Removal of Particulate Matter
Particulate matter, particularly metal nanoparticles resulting from the etching of electrode
material in the case of arc discharges, may be present in the treated gas. For example,
presence of brass particles [48], copper [56], iron [66], and tungsten [70] in the gas treated
by arc discharge has been indicated. HEPA filters, which are commonly available, have
successfully removed the particulates from the NO generated by electrical discharges [27,
48].
Removal of Charged Particles
Charged particles like H3O?, O2-, OH-, NOx- are usually present along with radical and
neutral reactive species [139]. Both ionic species like O2-, OH-, NOx-, and neutral
species like ozone and NO are known to decontaminate bacteria separately [139] as well as
have synergistic effect along with the neutral reactive species on the bacterial decon-
tamination [125–128]. Hypothesis is that the charged particle deposit on the surface
causing its electroporation that allows delivery of the molecules to the cells [140]. This
effect can be so strong that it has been argued to cause the membrane rupture in some cases
[125]. This hypothesis is the basis of gene delivery to cells facilitated by the plasma
treatment [104, 105, 140]. These synergistic effects of the charged particles apply to the
wound healing and the gene delivery application of the plasmas.
The role of charged particles has not yet been explored for inhalation therapies using
NO. Significant amount of the charged particles may be present in the exhaust stream of
NO generators based on electrical discharges. For example, positive ions were found to be
about 9 9 106 ions/cm3 and anions were about 1.5 9 106 ions/cm3 at a distance of about
15 cm from the plasma source [113]. No study is known to the author in which charged
particle removal from the electrical discharge based NO generator was described. How-
ever, if needed the charged particles are easier to remove because they can be collected and
123
conducted away on an electrical conductor at ground potential. For example, metal mesh at
ground potential has been used to successfully filter out charged particles from plasma
treated gases [126, 127, 139].
Cost Estimate of the Purification and Production of Nitric Oxide by Electrical

Discharges
The cost of NO inhalation therapy is high. For example, the average cost of 5 days of
inhaled NO for persistent pulmonary hypertension of the newborn is estimated to be in the
range of $12,000 to $14,000 [12, 27]. Electrical discharge based NO generators are
expected to be a significantly cheaper option and reusable over a long period of time with a
little maintenance. For example the arc discharge shown in Fig. 4 produced more than
200 ppm NO from 1 lpm air at the cost of a few watts of electric power. It was powered
with an economical DC high voltage power supply that can be fabricated with components
costing less than one hundred dollars [129]. This example is perhaps the lowest cost but
other electrical discharge based NO generators are expected to be similarly economical
compared to conventional NO supply systems. The electrical discharge systems have been
tested and found to produce stable levels of NO for up to 75 h of operation and could be
restored by cleaning and adjusting the electrodes for repeated use [26].
Ozone destruction catalysts, adsorbents for NO2, and HEPA filters for particulates are
commonly available. Removal of charged particles required a metal mesh at ground
potential which is also commonly available. The cost of all of these components for the
nitric oxide purification can be expected to be around one hundred dollars. These filtration
and purification units have been demonstrated to remove particulate matter and bring
ozone and NO2 to below EPA recommended limits [27]. Based on this information, one
can expect the cost of a complete system, e.g., by spark discharges, to be in the range of a
few hundred dollars. Being capable of on-demand nitric oxide production at the desired
dose level, it will eliminate the need for the transportation and storage of pressurized nitric
oxide gas bottles and the risk of accidental leakage of NO that may convert to toxic
substances. These advantages, i.e., a cheaper, technologically simpler and robust system
with fewer associated hazards, are the incentives for developing this technology to realize
its practical applications in the future.
Conclusions
Most of the electrical NO generators being developed are based on arc or microwave
discharges, but some others, like sliding discharges, or radio-frequency and microhollow
cathode discharges have also been reported. The concentration of NO can be adjusted by
plasma parameters like applied voltage, pulse repetition rate, inter-electrode gap, gas flow
rate, etc. Stable NO generation for up to 10 days with a warm-up time in seconds has been
demonstrated in the case of arc/spark discharges. The main factor affecting the yield and
purity of NO is the plasma temperature. NO is produced by thermal mechanisms in the
case of thermal plasma and in non-thermal plasma with high average gas temperature on
the order of 1000 K. However, thermal mechanisms do not seem to play any significant
role in the case of low temperature plasmas. High energy electrons drive the plasma
chemical reactions in the non-thermal plasmas.
123
NO produced by an electrical discharge is usually contaminated with NO2. The NO2/

NO ratio can be decreased by increasing the plasma temperature, increasing the capaci-
tance of the pulse forming capacitors that maintain the higher temperature for a longer
duration, increasing the gap length, which increases the plasma volume, and also by
employing suitable electrode material. The NO is sometimes contaminated with ozone and
particulate matter. The NO can be purified by hybridizing selective catalytic converters,
adsorbents and HEPA filters with the electrical discharge reactors. Charged particles are
usually present with NO generated by electrical discharge technique. The charged particles
have synergistic effect in the case of bacterial decontamination and molecule delivery to
the cells. In the case of NO inhalation therapies they are most likely unwanted byproducts
and can be easily removed by a metal mesh filter at ground potential. The NO generated by
electrical discharges has been successfully tested on an animal model for inhalation
therapy [27]. A nitric oxide generator based on the high voltage electrical discharge, named
Plason has been used for wound decontamination/healing and other related medical uses
[11].
Being technologically simple, compact, economical, and proven effective, NO gener-
ators based on electrical discharges have a great potential for applications in hospitals for
inhalation therapies and wound decontamination and fast healing. There is a need for
further studies on the development of the NO generators based on electrical discharges in
order to understand the plasma characteristics, chemical reaction mechanism in the plas-
mas that can help improve the efficiency of NO generation and improve the efficiency of
byproducts that have synergistic effects and minimize the unwanted or toxic byproducts at
the source. Further research is needed on developing NO purification techniques that can
be hybridized with the plasma generators for making the technique safe for medical uses.
Since the biological process responsible for the beneficial effects are complex and not well
understood, there is need for more studies on the effects in order to make the technique
more effective and successful in the practical applications.
Acknowledgments This work is supported by ‘Frank Reidy Fellowship in Environmental Plasma

Research’ and with internal funds of the Frank Reidy Research Center for Bioelectrics. The author is
thankful to Barbara C. Carroll of the Frank Reidy Research Center for Bioelectrics, for corrections and
improving the English of the manuscript.
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Nitric Oxide Production by High Voltage Electrical Discharges For Medical Uses: A Review

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Plasma Chem Plasma Process (2016) 36:737–766

Nitric Oxide Production by High Voltage Electrical

Muhammad Arif Malik1

Abstract Nitric oxide (NO) is a vasodilator and antihypertensive agent as well as a

& Muhammad Arif Malik

Mechanism of Arc Formation and Nitric Oxide Generation from Air

Mechanism of Arc Formation

Chemical Reaction Mechanism for NO Generation in Arc Discharge

The chemical reaction mechanism for NO formation in electrical discharges involves

Fig. 2 Rod–rod shape cathode–

Fig. 3 Illustration of the

Nitric Oxide Generators Based on Arc Discharges

Nitric Oxide Generators for Inhalation Therapies

NO generation in a device based on pulsed arc discharge in a rod–rod configuration has

NO Producing Plasma Jets for Wound Decontamination and Healing

Fig. 7 Schematics of a gliding

Nitric Oxide Generators Based on Microwave Discharge

NO Generation in Thermal and Non-thermal Plasma by Microwave

A simplified schematic of a microwave plasma device is illustrated in Fig. 8. Like arc

NO Producing Plasma Jets Based on Microwave Discharge

Nitric Oxide Generators Based on Nonthermal Plasmas

NO Generator Based on a High Current Version of Sliding Discharges

NO Generating Plasma Jet Based on Radio-Frequency Discharge

A schematic of a plasma jet based on a radio-frequency discharge is illustrated in Fig. 10.

NO Generating DC Plasma Jets

Fig. 11 Schematics of a plasma

NO Generators Based on Cold Plasmas with Average Gas Temperature Close

Pulsed arc 1–10 2 25–540 25–150 *4.4 9 1016 [48]

Comparison of Nitric Oxide Generation Characteristics

Purification of Nitric Oxide Produced by Employing High Voltage

Catalytic Conversion of NO2 into NO

C þ 2NO2 ! CO2 þ 2NO ð38Þ

Selective Adsorption of NO2

Fig. 12 Illustration of NO2 conversion into NO by reaction with ascorbic acid

Removal of Particulate Matter

Removal of Charged Particles

Cost Estimate of the Purification and Production of Nitric Oxide by Electrical

NO produced by an electrical discharge is usually contaminated with NO2. The NO2/

Acknowledgments This work is supported by ‘Frank Reidy Fellowship in Environmental Plasma

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