Journal of Biomaterials and Nanobiotechnology, 2011, 2, 477-484
doi:10.4236/jbnb.2011.225058 Published Online December 2011 (http://www.scirp.org/journal/jbnb)
477
Controlling Drug Release from Titania Nanotube
Arrays Using Polymer Nanocarriers and
Biopolymer Coating
Moom Sinn Aw, Karan Gulati, Dusan Losic*
Ian Wark Research Institute, The University of South Australia, Adelaide, Australia.
Received September 9th, 2011; revised October 14th, 2011; accepted November 10th, 2011.
ABSTRACT
Titania nanotube arrays (TNT) prepared by self-ordering electrochemical anodization have attracted considerable at-
tention for the development of new devices for local drug delivery applications. Two approaches to extend drug re-
lease of water insoluble drugs by integrating TNTs with polymeric micelles and biopolymer coatings are presented in
this work. The proposed strategies emphasized on remarkable properties of these materials and their unique combina-
tion to design local drug delivery system with advanced performance. The first concept integrates TNTs with drug
loaded polymeric micelles (Pluronic F127) as drug nanocarrier, until the second concept includes polymer coating of
drug loaded TNT with biodegradable polymer (chitosan). The water insoluble, anti-inflammatory drug, indomethacin
was used as a model drug. Both approaches showed a significant improvement of the drug release cha racteristics, with
reduced burst release (from 77% to 39%) and extended overall release from 9 days to more than 28 days. These results
suggest the capability o f TNT based systems to be applied for local drug delivery d eliver over an extended period with
predictable kinetics that is particularly important for bone implant therapies.
Keywords: Drug Delivery, Titania Nanotubes, Polymeric Micelles, Pluronic F127, Chitosan, Indomethacin
1. Introduction
To overcome limitations of the systemic therapy and
conventional drug delivery systems such as limited drug
solubility which leads to poor biodistribution, poor
targeting and efficacy, uncontrolled pharmacokinetics,
and serious side effects in non-target tissues, local drug
delivery using implantable systems has become accept-
able as an attractive solution to address these challenges
[1,2]. The majority of drugs like antibiotics, anti-cancer
and anti-inflammatory drugs are insoluble in water or be-
come unstable during their transport to the targeted sites,
hence they require special delivery systems [3,4]. Porous
materials have been demonstrated as excellent candidates
for the design of therapeutic implants, not only because
porous structures support tissue integration, but also be-
cause pores act as remarkable reservoirs for slow drug
elution over extended time periods [5]. Advances in
nanoscience and nanotechnology have led to the devel-
opment of several new nanoporous materials for local
drug delivery administrations. Among them, vertically
aligned titania nanotube (TNT) arrays on Ti surfaces
prepared by self-ordering electrochemical anodization
has been recognized as one of the most promising solu-
tions for the development of advanced implantable and
local drug delivery systems [6,7].
TNTs have excellent biocompatibility, thermal and
chemical stability, controllable dimensions, tunable sur-
face chemistry and high surface-to-volume ratio due to
their long and well aligned hollow nanotube structures.
These advantages render favourable for bone cell growth,
cell differentiation, and apatite-forming abilities, which
make TNTs ideal platforms for bone drug delivery ap-
plications [8-10]. The application of TNT films for im-
plantable medical devices such as orthopaedic implants,
vascular stents, immunoisolation capsules, dental im-
plants, for the prevention of bacterial adhesion, and
growth support for bone and stem cells has been recently
reported [11-15]. For drug delivery applications of TNTs,
it is important to achieve controlled and sustained release
pattern with uniform drug elution over time. Controlling
the pore diameters and lengths of TNTs by anodization
process is used as a simple method to control drug re-

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating 478
lease characteristics, but this method has considerable
limitation for applications where sustained drug release is
required [16]. In our previous studies, we showed that the
surface modification of pore structures via plasma poly-
merisation that allows control over pore diameter, has the
potential to significantly improve drug delivery perfor-
mance of porous and nanotubular materials [17-20].
Even, progress is encouraging; the development of new
strategies able to provide sustained and controllable drug
release is still required. The integration of TNTs with
nanocarriers and biodegradable polymers currently used
for designing of nanoparticle drug delivery systems,
seems to be a promising approach to advance delivery
and biocompatibility properties of this material.
Strategies to protect sensitive drug molecules in bio-
logical environment and to prevent their precipitation, i.e.
keeping drug molecules solubilised at implant sites
would be beneficial for local implant therapies and nano-
carriers such as polymeric micelles are excellent candi-
dates for molecular solubilisation of hydrophobic drugs
[21,22]. Due to their specific colloidal structure (size
range of 20 - 100 nm) with a lipophilic cargo space for
drugs segregated from the environment by hydrophilic
corona like polyethylene glycol (PEG), polymer micelles
can shield drugs against degradation and solubilise/
molecularly disperse lipophilic drugs in biological envi-
ronment [22].
In this work, we present two approaches to explore
sustained drug release from TNTs using polymer mi-
celles as drug nanocarriers and coating TNT with bio-
compatible polymers. The schematics are presented in
Figure 1. The first strategy (Figure 1(a)) is to encapsu-
late drugs inside polymeric micelles with the aim to
achieve an extended drug release from TNTs for water
insoluble and sensitive drugs. Pluronic F127, a common
triblock polymer, consisting of a central hydrophobic
block of polypropylene glycol (PPO), connected by two
hydrophilic blocks of polyethylene glycol PEO), was
selected for the preparation of polymeric micelles as
nanocarrier, because it is biodegradable, biocompatible,
water soluble and provides enhanced drug/protein stabil-
ity [23]. The release of micelles from TNTs is based on
diffusion process and due to their size (20 nm) and inter-
action with the nanotubes wall surface; their release is
expected to considerably slower than drug molecules.
The second approach to control release kinetics of drugs
from TNTs is to employ the coating of a thin polymer
layer on the top of drug loaded TNTs (Figure 1(b) ). De-
pending on the film thickness, chemical properties and
degradability of this polymer film, a controllable and sus-
tained drug release is proposed to be achievable. In this
work, chitosan, biocompatible and biodegradable poly-
mer, was selected, as it is recognised as an ideal material
for implantable drug delivery systems because of its
proven antibacterial, and osseointegration properties [24].
Chitosan has structural characteristics similar to glycol-
saminoglycans, especially to hyaluronic acid, which is
abundant in the extracellular matrix, with the ability to
attract proteins, promote cell attachment and enhance
implant integration, providing additional and consider-
able advantage to the implant [24,25]. Indomethacin, a
non-steriodal anti-inflammatory drug, was selected for
Figure 1. Schematic diagrams of two approaches used for extended drug release from titania nanotube (TNT) arrays. (a)
Pluronic F127 polymeric micelle as nanocarrier was used for encapsulating the water insoluble drug (indomethacin) and (b)
chitosan polymer layer coated on the top of TNT was used to co ntrol release of drug from nanotubes. PBS = Phosphate bu ff-
red saline. e

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating479
this study as the model of water insoluble drugs [26]. The
drug release characteristics of these two systems are ex-
plored to demonstrate their potential for the development
of TNTs as drug eluting implants with extended drug
release characteristics.
2. Materials and Methods
2.1. Materials
Titanium foil, Ti (99.9% purity), with a thickness of 0.25
mm, was supplied by Alfa Aesar (USA). Ethylene glycol,
ammonium fluoride, chitosan (low molecular weight,
75% - 85% deacetylation), and indomethacin (>99%
TLC), Pluronic® F127 (Bioreagent, average Mw~12,600)
were obtained from Sigma Aldrich Co. (Australia). Dialy-
sis sacks (avg. flat width of 35 mm) were ordered form
the same company. High purity water, ultra-pure Milli-Q
grade (18.2 M·Ω·cm) with a final filtering step through a
0.22 m filter was used. All chemicals were of analytic
reagent grade and used without further purification.
2.2. The Fabrication of Titania Nanotube (TNT)
Arrays on Ti
To prepare a TNT layer on Ti foil (TNT-Ti), two anodi-
zation steps were performed using a specially designed
electrochemical cell and computer controlled power sup-
ply (Agilent), using previously described procedures [19,
27,28]. A specially designed electrode holder permitted
only a circular area of diameter 1 cm of Ti metal available
for anodization. In the first anodization step, a constant
voltage of 100 V was applied for 2 hours in NH4F/ethy-
leneglycol electrolyte (3% water and 0.3% NH4F) at a
room temperature of 20˚C. The resultant TNT layer was
removed (mechanically followed by sonication), leaving
the nanotextured titanium surface for the second anodi-
zation. The second anodization step was performed using
the same conditions (100 V) as the first anodization, with
an anodization time of 1 hour to make about 50 µm thick
TNTs layer on Ti with perfectly ordered nanotube struc-
tures. The voltage/current, voltage-time, and current-time
signals were adjusted and continuously recorded (Lab-
view, National Instruments) during the anodization proc-
ess to assure the reproducibility of the fabrication process.
2.3. Synthesis of Pluronic Micelles and Drug
Encapsulation
Pluronic F127 micelles was synthesised using the direct
dissolution technique as described previously [29]. 15
mg of micelles were dissolved in 5 ml chloroform and
upon solvent evaporation in a rotary vacuum evaporator;
micelles were dispersed in 20 ml of Milli-Q water.
Samples were then dialysed against Milli-Q water for 2
days to produce the micelle suspensions. The drug (indo-
methacin) was dissolved in chloroform prior to drying
and then added to the micelle solution (10 ml of Milli-Q
water containing 50 mg of micelles) under moderate
magnetic stirring. The remaining chlroform is removed
under reduced pressure via osmosis effect using regene-
rated cellulose membrane (Spectrum Labs, Inc.) of 15
mm flat width with 20 cm long tubing. The size of the
micelles (Pluronic and Pluronic-Ind) before and after
loading were determined by laser light scattering using
Zetasizer Nano (Malvern Instruments) from 5 repeated
measurements.
2.4. Loading of Drug and Drug-Loaded Micelles
into Titania Nanotubes
The prepared TNT-Ti substrates (12 mm ×12 mm) were
loaded with drug and drug-loaded micelles via a simp-
lified lyophilisation method. Micelle dispersion (10 μl)
was pipetted onto the substrate surface and gently spread
to ensure an even coverage. The surfaces were then
allowed to dry under vacuum at room temperature for 2 h.
After drying, the loading step was repeated 20 times until
the appropriate amount of micelles was present in the
nanopore array. The top of the substrates on the end was
carefully cleaned to remove adsorbed micelles from the
surface. A solution of indomethacin (1% w/v) was pre-
pared in ethanol and 10 µl of the drug solution was
loaded into the nanotube surface and allowed to dry in air
for 15 - 20 min. After drying, the TNT surface was wiped
with a soft tissue to remove excess drug from the TNT
surface. The sample was placed in a vacuum dessicator
under vacuum for 1 h to remove the solvent and water.
The cycles of loading, drying and wiping were repeated
25 times to load a sufficient amount of indomethacin
drug into the nanotubes.
2.5. Chitosan Coating of Drug Loaded Titania
Nanotubes
Polymer solutions of chitosan (1% (w/v), chitosan +
0.8% (v/v) acetic acid in deionised water) was prepared.
The dip-coating process was performed by dipping the
TNT-Ti implant into the polymer solution, followed by
drying in an oven at 70˚C for 10 min. The number of
dipping can control the thickness of the deposited
polymer and for this study; we did 5 times of dipping to
make a thicker polymer film. The film thickness of the
chitosan coat of prepared samples (Chit-Ind-TNT-Ti)
was measured using an ellipsometer (Si wafer as control
sample) and cross-sectional SEM imaging.
2.6. Drug and Drug-Micelles Loading and
Release Characterization
To determine the amount of loaded and released drug and
drug-micelles in TNT samples, thermogravimetric ana-

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating 480
lysis (TGA) was performed (Hi-Res Modulated TGA
2950) after drug and drug-micelles loading, after poly-
mer coating and at the end of the release experiment. In
order to find the correct range of the drug decomposition,
20 - 25 mg drug (indomethacin) was mounted onto the
platinum pan, then heated up to 800˚C at a scanning rate
of 10˚C/min under a nitrogen gas flow of 50 ml/min.
This was performed to obtain its weight loss peak. It was
followed by drug-, (Ind-TNT-Ti) drug-loaded micelle
(Pluronic-Ind-TNT-Ti) and chitosancoated TNTs. The
thermograms were analyzed using TGA data analyzing
software (Universal Analysis, 2000), to calculate the
loading capacity.
In vitro drug release from all prepared TNT samples
(drug and drug-loaded micelles with and without chi-
tosan coating) was investigated by immersing the sam-
ples in 5 ml phosphate buffer (PBS) at pH = 7.4, where
the amount of released drug was measured via UV-Vis
spectroscopy using Varian UV-Vis spectrophotometer.
Measurements were taken at short intervals (every 5 - 15
min) during the first 6 hours to monitor the initial burst
release, followed by testing every 24 h to observe the
delayed release until the total amount of drug was
released into the surrounding PBS. Absorbance was mea-
sured at 320 nm for drug and at 760 nm for drug-loaded
micelles. The corresponding drug concentration was
calculated based on the calibration curve obtained. The
final release profile of each experimental set was ex-
pressed for burst (first 6 hours) and delayed release (7 -
28 days) in a graph with cumulative release (percentage)
vs. time. The release of drug (indomethacin) from TNT
without micelles and chitosan coating is used as the
control for comparing how release can be extended by
these methods.
2.7. Structural Characterization
Structural characterization of the prepared TNT-Ti sub-
strates before and after drug loading and after polymer
coating and drug release were performed using a field
emission scanning electron microscope (SEM) (Philips
XL 30). The samples were cut into small (approximately
10 × 10 mm) pieces, mounted on a holder with double-
sided conductive tape and coated with a layer of platinum
3-5 nm thick. Images with a range of scan sizes at normal
incidence and at a 30 degree angle were acquired from
the top, the bottom surface and cross-sections.
3. Results and Discussion
3.1. Structure and Morphology of Prepared
Titania Nanotube (TNT) Arrays
The structure and morphology of the prepared TNT-Ti
substrates was characterised by SEM and is summarised
in Figure 2. A typical cross-sectional image of free-
standing TNT structures, after removing them from the
Ti substrate (for imaging purposes) is presented in Fig-
ure 2(a). The thickness of the TNT layer was about 50
µm, which was controlled by selecting the appropriate
voltage (100 V) and anodization time (1 hour). A whole
TNT layer with a diameter of 1 cm, formed on a Ti foil
substrate, is shown in Figure 2(a) (inset). SEM images
of the top nanotube surface (Figure 2(b)) show pores
with diameters of 120 ± 20 nm. A high-resolution image
of the cross-sectional SEM image of the TNT layer
shows a vertically aligned and densely packed array of
nanotubes across the entire structure (Figure 2(c)). The
bottom surface of the TNT nanotube layer, after the de-
tachment from the Ti substrate (Figure 2(d)) shows that
the nanotubes were closed with spherical oxide barrier
layer.
For this study, titania nanotubes with pore diameters
~120 nm and a length of 50 µm were prepared, in order
to maximise their drug loading capacity
3.2. Characterisation of Polymeric Micelles
(Pluronic F127) before and after Drug
Encapsulation
The average size of prepared Pluronic F127 micelles was
determined to be 20.0 ± 0.7 nm using dynamic light
scattering measurements (Figure 3). When drug indome-
thacin was encapsulated inside the micelle (hydrophobic
core), the diameter was only slightly increased to 23.0 ±
1.4 nm (Figure 3), showing a minor difference in size
between the drug-loaded and drug-free micelle (~3 - 5
nm). The micelle size was found to be consistent over a
6-month monitoring period, indicating long term stability
Figure 2. SEM image of titania nanotube arrays prepared
on Ti foil by electrochemical anodization showing, (a) side
view (whole structure is shown in inset); (b) the top surface
with open pores; (c) cross-sectional image showing hollow
nanotube structures, and (d) the bottom surface with closed
pores.

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating481
Figure 3. The size of polymeric micelle (Pluronic F127) be-
fore and after encapsulation of drug (indomethac in).
under a freeze storage condition of 1˚C. As Pluronic
F127 was prepared in dilute solution above its critical
micelle concentration (CMC) and critical micelle tem-
perature (CMT), it is ensured that no gelation occurred
and that it forms self-assembling, non-aggregating mi-
celles in adequate concentration and proper suspension in
PBS [30]. Its hydrophobic PEO blocks associate to form
the core region, whereas the hydrophilic PPO segments
position between the core and the external aqueous me-
dium, serving as an interface between the bulk PBS and
the hydrophobic domain. The amount of Pluronic F127
loaded in TNT nanotubes was 22.6 ± 1.0 wt% as mea-
sured in TGA. The size measurements after release show
no difference confirming the preservation of micelle
structure after its release from TNTs.
3.3. Characterisation of Chitosan Polymer
Coating on Titania Nanotube Arrays
The deposition of chitosan polymers onto drug-loaded
TNT-Ti by the dip-coating process was evaluated by
SEM characterisation. Typical images of a prepared poly-
mer layer showing thick chitosan layer covering the TNT
surface are presented in Figures 4(a)-(b). SEM image
shows a featureless top surface of TNT confirming that
pores were covered by polymer layer. Corresponding
cross-sectional image (Figure 4(b)) confirms the forma-
tion of thick polymer layer. The thickness of this layer
was estimated to be between 2 - 2.5 µm by SEM and
ellipsometry. It was shown, that by controlling the num-
ber of dip-coating it is possible to control the thickness of
the polymer film (data not shown). Thus, the film thick-
ness can be used as controlling parameter to tune drug
release characteristics of TNTs.
3.4. Thermogravimetric Analysis (TGA) of Drug
and Drug Loaded Micelles
Before release studies were performed, TGA measure-
ments were performed to evaluate the loading (wt%) of
drug and drug-loaded micelles into the TNT substrates.
Figure 5 summarises these TGA graphs, showing their
single stepwise decrease of weight loss and loading
characteristics. The temperature change corresponds to
the decomposition temperature for both polymeric micelle
and drug (indomethacin). It was between 200˚C and
375˚C. But, it remains difficult to detect separate micelle
and drug weight loss due to their close temperature range
for vaporisation, Based on the weight loss, the loading
capacity of TNT-Ti substrates for drug or drug-loaded
micelle was determined to be 16.2 to 24.6 wt%, which is
reasonably high. TGA on two control samples including
chitosan-coated and bare (uncoated) titania nanotubes
without drug/micelle loading confirmed that the weight
of both samples remain constant throughout the heating
and that the weight loss of chitosan is negligible, since
Figure 4. SEM images of chitosan coated nanotube titania
arrays with loaded drug showing (a) the top surface and (b)
cross-sectional view.
Figure 5. TGA graphs showing the amount of weight loss
for drug and drug-micelle samples from bare and coated
titania nanotube (TNT) arrays.

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating 482
lease of drug.
it is an extremely light biopolymer film which comprises
<0.001% of the total sample weight. Results show that cumulative burst release in compa-
rison with the control sample (77%) was significantly
reduced when the drug is loaded in polymeric micelles
(58%) and when drug is loaded in the TNT covered with
chitosan film (39%). Both approaches also showed a
considerably extended overall drug release from 9 days
to 12 and 28 days, confirming their capability to provide
extended release of poorly water soluble drugs. It was
found that a 44.4% improvement (4 days longer) in re-
lease duration was obtained using micelle as the drug
nanocarrier, compared to drug only loaded in titania.
3.5. Controlling Drug Release from TNTs Using
Drug-Loaded Micelle and Polymer Coating
Comparative drug release profiles of drug (indomethacin)
loaded into TNT with and without micelles and with and
without polymer film (chitosan) coatings are presented in
Figure 6. Release characteristics are listed in Table 1, to
shows release efficiency (% drug release) at various time
intervals (1 h, 6 h, 24 h, 7 days, 14 days, 21 days and 28
days). According to Figure 6, all release curves display a
biphasic behaviour (except for the free drug), showing
initial burst release during the first 6 h with 39% to 77%
of release, followed by a gradual, slow release that lasted
from 10 to 28 days. The burst release can be explained
by the high concentration gradient across the pores, with
the large diameter pores (~120 nm) allowing rapid re-
These results suggest that the release behavior of poly-
mer nanocarriers from the nanotube structures is different
from release of small drug molecules. That is expected
because the release kinetics of micelles is based on diffu-
sion process and is influenced by their considerable lar-
ger size (>20 times than drug molecules) showing slower
Figure 6. Comparative drug release graphs of anti-inflammatory drug (indomethacin) from TNTs using polymer micelles as
drug carrier (Pluronic-Ind) and polymer (c hitosan) c oating showing overall and burst dr ug release.
Table 1. Drug release characteristics of drug (indomethacin) and drug loaded micelles (Pluronic-indomethacin) from un-
coated and polymer (chitosan) coated titania nanotubes (TNT). (Mean ± SD, n = 3).
Drug release efficiency (%)
Sample
1 h 6 h 24 h 7 days 14 days 21 days 28 days
Ind (free) 45 ± 1 99 ± 1 100 ± 0 100 ± 0 100 ± 0 100 ± 0 100 ± 0
Ind-TNT 40 ± 1 77 ± 2 88 ± 1 97 ± 2 100 ± 0 100 ± 0 100 ± 0
Pluronic-Ind-TNT 19 ± 2 58 ± 2 68 ± 3 90 ± 3 100 ± 0 100 ± 0 100 ± 0
Chit-Ind-TNT 17 ± 2 39 ± 1 66 ± 2 88 ± 3 90 ± 2 96 ± 3 98 ± 1

Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating483
diffusion from long nanotube structures.
By increasing the size of polymeric micelles, decreas-
ing the diameters of nanotubes or changing the surface
chemistry of TNTs to increase interaction with the mi-
celles it is possible to further extend drug release, show-
ing the flexibility of this approach to control drug deliv-
ery characteristics of TNTs platform.
Figure 6 and Table 1 show that the drug release pro-
files from chitosan coated TNT-Ti have significant changes
with considerably extended drug release (28 days) as a
result of polymer coating. The release kinetics of this sys-
tem is different in comparison with drug loaded micelles
as drug release is mainly controlled by the transport of
drug molecules through the polymer matrix and by the
rate of degradation of the polymer film [31,32]. When
thinner chitosan film was applied (one dip coating) drug
release was significantly reduced to 9 days which con-
firms that the drug release characteristics of polymer
modified TNT-Ti can be tuned by controlling the polymer
film thickness. This is particularly important in the case of
specific applications, to ensure optimal therapeutic dosage
of drug for the required time. Therefore, this approach has
the flexibility to be applied to Ti implants for different
purposes, from short drug release scenarios, for example
to suppress inflammation, moderate term (1 - 2 weeks), to
prevent bacterial infection, or long-term (>30 days) drug
release for other therapies, including improving osseoin-
tegration process, fracture repair or treatment of bone
cancer. Additional advantages of this method are that
chitosan coated TNT-Ti substrates could provide a
greater cell attachment based on positively-charged chi-
tosan chains, with a high density of amino groups which
could attract proteins and promote cell adhesion and pro-
vide superior biocomatability of these structures [33].
4. Conclusions
In summary, we report the preparation of titania nano-
tube (TNT) arrays prepared by self-ordering electro-
chemical anodization, with aim to explore new strategies
to improve their drug release characteristics. Two con-
cepts for controlling and extending drug release of poorly
soluble drugs are demonstrated: the first which integrates
TNTs with drug loaded polymeric micelles as drug na-
nocarrier and the second, which includes the coating of
drug loaded TNTs with biodegradable polymer (chito-
san). The preparation involves simple and inexpensive
processes, including electrochemical generation of TNT
arrays on Ti surface, preparation of polymeric micelles,
drug loading and dip-coating deposition of biodegradable
polymers. Both approaches showed a significant impro-
vement the drug release characteristics of TNTs, with
reduced burst release (from 77% to >39%) and extended
overall release from 7 days to more than 28 days. This
release pattern is especially useful in bone implant thera-
pies that require a large initial dose followed by a pro-
longed maintenance dose over a few weeks. The use of
biodegradable and antibacterial polymer such as chitosan
provides favourable cell adhesion properties and addi-
tional an advantage to enhance integration of implantable
drug delivery device.
5. Acknowledgements
The authors gratefully acknowledge the financial support
and funding from the Australian Research Council
(DP0770930 and LP 0989229) and the University of
South Australia.
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