Nitric Oxide Production by High Voltage Electrical

REVIEW ARTICLE

Nitric Oxide Production by High Voltage ElectricalDischarges for Medical Uses: A Review

Muhammad Arif Malik1

Received: 12 January 2016 / Accepted: 19 February 2016 / Published online: 2 March 2016� 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 [email protected]; [email protected]

1 Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way,Suite 300, Norfolk, VA 23508, USA

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Plasma Chem Plasma Process (2016) 36:737–766DOI 10.1007/s11090-016-9698-1

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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 ! 4NOþ 6H2O 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 helpsmaintain 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 othermedical 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

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

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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 NOgeneration 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.

2NOþ 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

Plasma Chem Plasma Process (2016) 36:737–766 739

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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-directedstreamer with secondaryavalanches moving towards thepositive head of the streamer andwavy arrows are photons thatgenerate secondary electrons forthe avalanches


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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 ! NOþ N: ð4Þ

Nþ O2 ! NOþ 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].

Nþ OH ! NOþ 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 ! Oþ Oþ e; ð7Þ

O2 þ e ! Oþ O � þ e; ð8Þ

N2 þ e ! N2 � þ e; ð9Þ

N2 � þO2 ! N2 þ Oþ 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 hemisphericalends enclosed in an acrylic tubefilled with atmospheric pressureair and arc discharge in the inter-electrode gap


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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].

Oþ2 þ e ! Oþ O�; ð11Þ

Nþ2 þ e ! Nþ 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 � þO ! NOþ N�; ð13Þ

N � þO2 ! NOþ O; ð14Þ

N2 � þO2� ! 2NO: ð15Þ

A small fraction of NO is also formed by the following reaction of radicals [43].

Nþ O ! NO: ð16Þ

Some of the NO is reduced, e.g. through the following reaction (35, 39, 43).

N2 � þNO ! N2 þ Nþ O; ð17Þ

Nþ NO ! N2 þ O; ð18Þ

O � þNO ! Nþ O2: ð19Þ

Ozone may be formed through reaction such as the following.

Oþ O2 þM ! O3 þM; 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

Oþ 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].

NOþ OþM ! NO2 þM; ð23Þ

But at high temperature conditions this reaction is countered by the following reaction

[35].


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Oþ NO2 ! NOþ O2: ð24Þ

Another reaction that dominated conversion of NO2 back to NO under thermal plasma

conditions is the following [43].

N2 � þNO2 ! NOþ Oþ 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 ! NOþ NO2 þ O2: ð28Þ

Similarly, NO2 may convert to N2O5:

NO3 þ NO2 ! N2O5; ð29Þ

but N2O5 reverts fast through the following reaction [53].

N2O5 ! NO3 þ NO2: ð30Þ

N2O may also be formed under non-thermal plasma conditions, e.g. through the following

reaction [34, 54].

Oþ N2 þM ! N2OþM; ð31Þ

N2 � þO2 ! N2Oþ O: ð32Þ

Nþ NO2 ! N2Oþ 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].

N2Oþ O ! 2NO: ð34Þ

The formation and conversion mechanism of nitrogen oxides and ozone, especially in non-

thermal plasmas, is illustrated Fig. 3.


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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

Fig. 3 Illustration of thereaction mechanisms involved inthe formation and removal ofnitrogen oxides and ozone innon-thermal plasmas


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


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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. Theafterglow is bright in a 2 mm 9 3 mm hemispherical zone at the outlet point but the glow remains visiblewhile decreasing in intensity as the distance increases to *2 cm from the device outlet (unpublished workform author’s lab.)


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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

Fig. 5 Schematics of NO generating plasma jet based on arc discharge between pin-to-ring electrodes


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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

columnwas 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),

theNOwas 747–3733 ppm (1–5 g/m3)whileNO2was 97–487 ppm (0.2–1 g/m3). In another

similar plasmatron 9.5–23.5 lpmairwas treatedwithDC input power of 200–750 Wresulting

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 reactingwith oxygen in air (reaction 3). For example, in aNO

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 ppmNO2 at distance

of 200 mm[11]. These values agreewith 400–500 ppmNOand70–90 ppmNO2 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 coldmode, 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.

Fig. 6 Schematic of aplasmatron: 1 is cathode, 2 isanode, 3 is plasma afterglow, 4–7are positions of arc at successivetimes, 8 is swirl gas glow


123

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. TheNOproduction 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 asworking gas. Clearly, thermalmechanism forNOproduction 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 andNO2 generation [83]. Feed ratio of N2/O2 varied theNO toNO2 ratio

in the products. For example, gradually varying the N2/O2 ratio from 1 to 4 gradually

increased NO from*4000 to*5500 ppmwhile NO2was 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 pHdropped form5.4 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 MicrowaveDischarge

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

Fig. 7 Schematics of a glidingarc discharge


123

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

Fig. 8 Schematics of amicrowave plasma device


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

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

Fig. 9 Schematics of a sliding discharge reactor overlaid on a time-integrated image of the slidingdischarge


123

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 mmouter 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].Ozonewas belowdetection limits andUV-irradiation for the plasmawas 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. 10 Schematics of a plasma jet based on a radio-frequency discharge (the ground electrode is optionalas the target of the plasma treatment can also act as the ground)

Fig. 11 Schematics of a plasmajet based on a microhollowcathode 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 Closeto 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

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

Table 1 Nitric oxide generation characteristics of some representative electrical discharge base devices

Discharge Power(W)

Air(slm)

NO(ppm)

(NO2)(ppm)

Energy yield mol/J

References

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]

AC/pulsed spark – –b *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]

Microhollowcathode

0.6–26 0.5–8 1000–100 0–25 2.2–7.0 9 1016 [93]

a The concentration gradually decreases over the distance from 20 to 200 mmb Working gas was static air in a 1 L box and the NO and NO2 concentrations were from the data of initial2 min operationc Slightly below atmospheric pressure (800 bar)d Working gas was N2 with 0.0–2.4 % O2

e Byproduct ozone was 25–360 ppmf 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


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 VoltageElectrical 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 þMo ! 3NOþMoO3 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 ! Ba NO3ð Þ2þNO ð36Þ

Carbon particles like carbon suet can also potentially convert NO2 into NO through the

following reactions at[523 K [137].

Cþ NO2 ! COþ NO; ð37Þ

Cþ 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.

Ca OHð Þ2þNO2 þ NO ! Ca NO2ð Þ2þH2O 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 ElectricalDischarges

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 PlasmaResearch’ and with internal funds of the Frank Reidy Research Center for Bioelectrics. The author isthankful to Barbara C. Carroll of the Frank Reidy Research Center for Bioelectrics, for corrections andimproving the English of the manuscript.

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