Cold Plasma Techniques for Pharmaceutical and Biomedical Engineering

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Cold Plasma Techniques for
Pharmaceutical and Biomedical Engineering
Yasushi Sasai1, Shin-ichi Kondo1,
Yukinori Yamauchi2 and Masayuki Kuzuya2
1Gifu Pharmaceutical University
2Matsuyama University
Japan
1. Introduction
Plasmas can be defined as the state of ionized gas consisting of positively and negatively
charged ions, free electrons and activated neutral species (excited and radical), and are
generally classified into two types, thermal (or equilibrium) plasma and cold (or non-
equilibrium) plasma, based on the difference in characteristics.
The thermal plasma is the state of fully ionized gas characterized by a high gas temperature
and an approximate equality between the gas and electron temperature (Tg ≈ Te) and can be
generated under atmospheric pressure. The energetic of this plasma is very high enough to
break any chemical bond, so that this type of plasma can be excluded from most of organic
chemistry, let alone from the field of pahramceutical science.
In contrast, the cold plasma is most characterized by a low gas temperature and a high
electron temperature (Tg << Te), and easily generated by electric discharges under reduced
pressure. The field of plasma chemistry deals with occurrence of chemical reactions in the
cold plasma including atmosphere pressure glow discharge plasma.
One of the characteristics of surface treatment by cold plasma irradiation is the fact that it is
surface limited (ca. 500-1000 Å) so that only the surface properties can be changed without
affecting the bulk properties.
In recent years, biomedical applications of cold plasma are rapidly growing due to the fact
that the use of cold plasmas is very useful to treat heat-sensitive objects such as polymeric
materials and biological samples. The demonstrations of plasma technology in the
biomedical field have created a new field at the intersection of plasma science and
technology with biology and medicine, called “Plasma Medicine”. (Fridman et al., 2008)
When the cold plasma is irradiated onto polymeric materials, the plasma of inert gas emits
intense UV and/or VUV ray to cause an effective energy transfer to solid surface and gives
rise to a large amount of stable free radicals on the polymer surface. In view of the fact that
surface reactions of plasma treatment are initiated by such plasma-induced radicals, study
of the resulting radicals is of utmost importance for understanding of the nature of plasma
treatment. Thus, we have undertaken plasma-irradiation of a wide variety of polymers,
synthetic and natural, and the surface radicals formed were studied in detail by electron
spin resonance (ESR) coupled with the aid of systematic computer simulations. On the basis

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of the findings from a series of such studies, we were able to open up novel plasma-assisted
application works. (Kuzuya et al., 2001a, 2005, 2009)
This contribution focuses on our plasma techniques for pharmaceutical and biomedical
engineering on the basis of findings from a series of studies on plasma-induced surface
reactions in variety of polymers. For the pharmaceutical engineering field, the controlled
drug release technology by using plasma-induced cross-linking and/or degradation of
polymer was developed for the preparation of rate- and time-controlled drug release tablet.
Furthermore, this technique was used to develop the advanced DDS such as gastric floating
drug delivery system (FDDS) possessing gastric retention capabilities and patient-tailored
DDS for large intestine-specific drug delivery. For the biomedical engineering fields, the
durable surface hydrophilicity and lubricity on hydrophobic biomedical polymers were
fabricated by plasma-assisted immobilization of carboxyl group-containing polymer onto
the surface. The surfaces thus prepared were further used for the covalent immobilization
of biomolecules for developing biomedical devices such as cell culture substrate, biosensing
system and blood-compatible material.
2. Nature of plasma-induced polymer radicals
Plasma induced radicals on polymer surface permit reactions for surface modification in
several different ways such as CASING (cross-linking by activated species of inert gas),
surface graft and/or block copolymerization, and incorporation of functional groups. All
these techniques are referred to as plasma techniques. However, research has essentially
been phenomenological, and detailed studies of such plasma-induced surface radicals of
polymer have not been reported.
Over the years, we have been working on the structural identifications of plasma-induced
surface radicals of various kinds of organic polymers as studied by electron spin resonance
(ESR) spectra coupled with the systematic computer simulations. (Kuzuya et al., 1991a-c,
1992a-c, 1993ab, 1994, 1995, 1996a, 1997a, 1998ab, 1999ab) One of the advantages of plasma
irradiation over other types of radiations for the study of the polymer radicals is that the
radical formation can be achieved with a brief plasma-duration by a simple experimental
apparatus such as those we have devised. The experimental setup for the plasma-irradiation
and ESR spectral measurement is schematically shown in Fig. 1. This method makes it possible
not only to study the polymer radicals without a significant change of polymer morphology
but also to follow readily the ESR kinetics for the radical formation, so that we can carry out
systematic computer simulations with a higher credibility.

pressure gauge
torr
Ar
gas
powder
sample
sealed
to vacuum
Plasma
irradiation
RF generator (13.56MHz)
with matching network
POWER LEVEL
MATCHING
POWER WATTS
D.C.
ESR tube
powder
sample

Fig. 1. Schematic representation for plasma irradiation and ESR spectral measurement

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Figure 2 shows the observed ESR spectra of plasma-induced surface radicals formed on
several selected polymers relevant to the present study, together with the corresponding
simulated spectra shown as dotted lines. Based on the systematic computer simulations, all
the observed spectra in addition to those shown here were deconvoluted and the
component radical structures have been identified.
From a series of this work, we were able to establish the general relationship between the
structure of radicals formed and the polymer structural features. Crosslinkable polymers give
the mid-chain alkyl radical as a major component radical, while degradable polymers give the
end-chain alkyl radical as a major component radical, and if polymers are of branched
structure or contain the aromatic ring, the cross-link reactions occur preferentially on these
moieties. And, one of the common features is that dangling-bond sites (DBS) is more or less
formed in all plasma-irradiated polymers resulted from occurrence of CASING.
All kinds of plasma-irradiated polymers are eventually exposed to air for their practical use, so
the studies of the auto-oxidation process are also important for plasma-irradiated polymer.
Figure 3 shows a reaction scheme for the formation of peroxy radical and its ensuing process
(hydroperoxide, alkoxyl radicals formation) demonstrating how auto-oxidation ends up with
introduction of oxygen-containing functional groups such as hydroxyl groups, carboxyl
groups and so on, and dissipation of the surface radical formed. Therefore, we have studied
the nature of peroxy radical formation as an initial process of auto-oxidation.

PMMAPMAAPHEMA
2mT2mT 2mT
PMAAm
2mT
PAAm
2mT
ETFE
2mT
PTFE
2mT
LDPE
2mT
HDPE
2mT
Nylon12
2mT
EVA
2mT
PS
2mT
PET
2mT
PEN
2mT
PC
2mT

Fig. 2. Room temperature ESR spectra of plasma-induced radicals in organic polymers,
together with the simulated spectra shown as dotted lines. Plasma conditions: 40W, Ar 0.5
Torr, 3 min. PMMA: polymethylmethacrylate, PMAA: polymethacrylic acid, PHEMA:
poly-(2-hydroxyethyl) methacrylate, PMAAm: polymethacrylamide, PAAm:
polyacrylamide, HDPE: high density polyethylene, LDPE: low density polyethylene,
PTFE: polytetrafluoroethylene, ETFE: (ethylene-tetrafluoroethylene) copolymer, EVA:
(ethylene-vinylacetate) copolymer, PS: polystyrene, PET: polyethyleneterephtalate, PEN:
polyethylenenaphthalate, PC: polycarbonate

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Figure 4 shows several examples of ESR spectra of peroxy radicals formed immediately after
exposure of the plasma-irradiated polymers to air, which correspond to those shown in the
previous Fig. 2, as well as the simulated spectra as shown in dotted lines. It can be seen that in
some polymers, the spectral pattern remained unchanged with only lowering the intensity,
and in other polymers, the spectra have been completely converted to the one exhibiting a
typical spectral pattern of peroxy radical.
Note that, in most polymers, such an intensity of peroxy radicals usually decreases to less than
30-40% of the original carbon-centered radicals even immediately after exposure to air, except
for polytetrafluoroethylene (PTFE), which can be best discussed on its comparison with that of
high density polyethylene (HDPE) to understand the nature of auto-oxidation in more detail.


Fig. 3. Peroxy radical formation from carbon-centered radical with molecular oxygen and its
reaction, resulted in introduction of oxygen functional groups on polymer surface

PMMAPMAAPHEMA PMAAｍｍ
PEN
PAAｍｍ
2mT 2mT2mT 2mT 2mT
2mT
EVA
2mT
PS
2mT
PET
2mT
PC
2mT
LDPE
2mT
Nylon12
2mT
HDPE
2mT
PTFE
2mT
ETFE
2mT

Fig. 4. Room temperature ESR spectra of various plasma-irradiated polymers after exposure
to air
C C
O O
ROOROO
R R
RHRH
CO O O O R CO O O O R
CO O RCO O R
CO O HCO O H
2 CO 2 CO
O O2 2
2 CO 2 CO
RR
+
OH OH
CO CO
C C
OHOH
C C
O O
H H
R R O O O O
33 33 kcal / m ol ekcal / m ol e
R ROOO O H H
70 7040 90 40 90kcal / m ol e kcal / m ol e
O O 2 2
C C
+ +
C C
OO
OO

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Cold Plasma Techniques for Pharmaceutical and Biomedical Engineering

105
As shown in Fig. 5, exposure of plasma-irradiated HDPE to air at room temperature did not
give the ESR spectra of peroxy radicals, but the ESR spectra did show only the decrease in
the spectral intensity. On the other hand, the peroxy radicals of PTFE are extremely stable
for a long period of time at room temperature. The spectral intensity, therefore, is nearly the
same as that of the original radicals. The extraordinary instability of HDPE peroxy radical
can be ascribed to the rapid chain termination reaction through the hydroperoxide
consuming several moles of molecular oxygen, due to the presence of abundant hydrogen
atoms bonded to sp3 carbons in HDPE. Because of occurrence of this type of oxygenation
reaction, plasma treatment by inert gas plasmolysis has a tendency to result in the
introduction of surface wettability in many polymers. The exceptional stability of PTFE
peroxy radicals can be attributed to the absence of any abstractable hydrogen in PTFE to
undergo the chain termination reactions.

HDPE
O2
0.5h
1h
5h
12h
PTFE
Spin numbers / cm2
= 7.0 x 1013
× × 10
Spin numbers / cm2
= 7.0 x 1013
× × 1
O2
2mT
2mT

Fig. 5. Difference in free radical reactivity with oxygen between HDPE and PTFE
3. DDS preparation by plasma techniques
A drug delivery system (DDS) is a formulation or device that safely brings a therapeutic
agent to a specific body site at a certain rate to achieve concentration at the site of drug
action. Development of more “patient-friendly“ DDS improves drug efficiency and patient
compliance. A wide variety of approaches of controlled-release DDS have been thus far
investigated for oral application. Oral drug delivery is the most desirable and preferred
method of administrating therapeutic agents for their systematic effects such as convenience
in administration, cost-effective manufacturing, and high patient compliance compared with
several other routes.
As an application of plasma techniques to DDS technologies, the encapsulation of drug
particle by plasma-polymerized thin film was reported. (Susut & Timmons, 2005). In this
case, however, the drug molecule is exposed by plasma to cause the undesirable
degradation of drug molecules. On the other hand, we have developed plasma-assisted
preparation of multi-layered tablets (Fig.6). In this method, plasma is irradiated on the
outermost layer of double-compressed (DC) tablets so that the direct exposure of plasma to