Journal of Biomaterials and Nanobiotechnology, 2011, 2, 226-233
doi:10.4236/jbnb.2011.23028 Published Online July 2011 (http://www.SciRP.org/journal/jbnb)
A New Nano-Platform for Drug Release via
Nanotubular Aluminum Oxide
Kunbae Noh1, Karla S. Brammer1, Chulmin Choi1, Seung Hyun Kim2, Christine J. Frandsen1,
Sungho Jin1
1Materials Science & Engineering, University of California, San Diego, USA; 2Bioengineering Department, University of California,
San Diego, USA.
Received April 12th, 2011; revised May 10th 2011; accepted May 25th, 2011.
ABSTRACT
Nanotubular materials have many favorable properties for drug delivery. We present here a pioneering study of con-
trolled release of a model drug, amoxicillin, from the internal nanopore structure of self-ordered, periodically spaced-
apart aluminum oxide with an innovative, nanotubular geometry. This aluminum oxide nanotube geometry has not yet
been revealed for biological applications, thus we have selected this oxide nanotube structure and demonstrated its
ability as a drug carrier. Controlled, sustained release was achieved for over 5 weeks. The release kinetics from the
nanotube layer was thoroughly characterized and it was determined that the amount of drug released was proportional
to the square root of time. This type of controlled release and longevity from the nanotube layer has potential for
therapeutic surface coatings on medical implants. Furthermore, this type of geometry has many features that are ad-
vantageous and biologically relevant for enhancing tissue biointegration.
Keywords: AAO, Nanotube, Antibiotics, Drug Release, Implant Surface
1. Introduction
Recently, anodic aluminum oxide (AAO) has become
one of the most popular self-ordered periodic, porous
templates. In general the highly developed, superior or-
dering of nanopores in AAO templates is obtained by
using a two-step anodization process [1], a rather simple
processing method. The AAO porous structure can be
uniquely altered based on processing parameters and both
porous and tubular shapes can be achieved and tailored
with pore diameters between 5 nm - 10 µm and film
thicknesses (vertical height) reaching over 100 µm [2].
AAO has been of great interest due to its outstanding
material properties, including electrical insulation, opti-
cal transparency and chemical stability, and most re-
cently because of its biologically inert and biologically
compatibility properties [2]. In terms of biological appli-
cations, the characteristic periodic porous films of AAO
has been used for encapsulating enzymes [3], implant
surface coatings on Ti alloys for bone in growth [4-5],
membranes for hemodialysis [6], cardiovascular stent
applications [7,8], biofiltration [9], and drug delivery
[10,11].
Owing to porous AAO’s ability to mimic the dimen-
sions and nanoporous structural components of natural
bone and the prospect of housing genes or drugs for
therapeutic treatments within the pores [11], AAO films
can be seen as promising coatings for medical, particu-
larly orthopedic, implants. Research on biomedical ap-
plications of both porous alumina, and along the same
lines nanotubular titania (TiO2) [12-18], has increased
tremendously in the past few years. It is well known that
titania nanotube surfaces elicit favorable properties for
bone cell growth and mineralization in vitro [16,18], os-
seointegration (bone/implant interface bonding) in vivo
[19], enhance differentiation of mesenchymal stem cells
toward osteogenic maturation [17], as well as elicit long
term drug release [15]. Titania nanotubes have been re-
cently recognized for their impact in the future of
nanomedicine [20].
We focused on hard-anodized AAO which is recently
of great interest because of its advantageous characteris-
tics, i.e. 1) AAO film grows rapidly 1) it is well ordered
and 2) there is a wide range of novel AAO nanostruc-
tures that can be obtained during the hard anodized AAO
region which are yet to be discovered [21-24]. For exam-
ple, Zhao et al. reported a special AAO structure grown

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 227
under constant current anodization, which is represented
by a six-membered ring symmetry around the center
pores with a regular hexagonal pore arrangement.
While nanopore configuration has been studied greatly
for potential biomedical and drug delivery type applica-
tions, the nanotube configuration has a unique feature in
that the 10 - 20 nm spacing between neighboring nano-
tubes allow a continuous supply of body fluids, nutrients
and proteins underneath adhered and growing cells that
could potentially aide in tissue development and biointe-
gration. In contrast, simple nanopored configuration gets
covered with adhered cells thus blocking the supply of
body fluid. This has been described for the case of TiO2
nanotubes with significantly enhanced osteoblast (bone
cell) and bone tissue growth16, and applies to other ad-
hered cells on the nanotubes.
To imitate the TiO2 nanotube geometry, we have mi-
crostructurally altered traditional porous AAO to give
rise to a unique nanotube morphology to determine its
use in biological applications. It is projected that we can
utilize the nanotubes as “nanodepots” for advanced drug
delivery therapeutics. AAO nanotubes are an example of
a multidisciplinary approach for combining nanotech-
nology, biomedical engineering, and controlled drug de-
livery where antibiotics, growth factors, etc. are appro-
priately needed as well as proper biointegration (os-
seointegration for example) is desired [11]. The nanotube
geometry, as compared to the nanopore geometry with
comparable pore diameter, provides ~2X more surface
area, which could be utilized to provide more active spots
and functional conjugation locations for increased ad-
sorption or biomolecules, proteins, enzymes, and drug
molecules.
The use of AAO nanotubes is a new clinical approach
not only for orthopedics, but also for the treatment of
several other drug eluting implants which ideally would
release for longer periods of time, on the order of days,
weeks, even months. The aim of this study is to elucidate
the complex phenomenon of drug release from AAO
nanotube drug carriers. Detailed, characterized release
curves, accumulation plots, and kinetics were revealed
for the antibiotic drug, amoxicillin. This type of geomet-
rical structure of AAO is novel in itself, but also the time
scale of prolonged release of amoxicillin from the AAO
nanostructure is incredibly long, on the order of weeks,
with a possibility of extending the drug release to much
longer periods.
2. Materials and Methods
2.1. Aluminum Pretreatment
0.5 mm thick Al foil purchased from Alfar aesar (99.99%)
was used as a starting material. The Al foil was succes-
sively degreased with isopropyl alcohol and acetone for 5
minutes with ultrasonication followed by a D.I. water
rinse and a nitrogen gas blow. Then, the organic-free Al
foil was slightly etched in 1 M NaOH aqueous solution
to remove any surface contamination before the electro-
polishing process. Conducting Cu tape was used as the
electrode pathway to the Al foil and selected portions of
the Al foil, such as the edges or backsides, were pro-
tected by a lacquer (Miccroshield) in order to make it
resistant to the electrolyte used. A mirror-shiny Al foil
was obtained after electropolishing in a mixed solution of
HClO4 and Ethanol (1:4(v/v)) at 5˚C under 20 V for ten
minutes with a Pt counter electrode. For a control sample,
electropolished Al was used in the experiments. For the
experimental nanotube samples anodization was con-
ducted.
2.2. Anodization
Prior to hard anodization, mild-anodized porous AAO
(~800 nm thick layer) was formed under 25 V in 0.3 M
sulfuric acid and then the electrolyte concentration was
changed from 0.3 M to 0.06 M. Next, anodization volt-
age was increased (at a rate of ~0.5 V/s) from 25 V to
35V in order to inhibit local AAO film thickening due to
localized high current concentration which otherwise
would lead to inhomogeneous oxide film growth or even
dielectric breakdown during hard anodization. Power
supply (Agilent; E3612A) was connected to digital mul-
timeter (Keithley; 2100) to monitor voltage-current evo-
lution during anodization.
2.3. AAO Post-Treatment
After the anodization process, the top side of AAO layer
was attached to Si substrate with adhesive glue for han-
dling purpose. Then, Al substrate was selectively re-
moved with a mixed HCl and CuCl2 solution for ten min-
utes when the reaction ends. Any residual Cu debris ad-
hered to the bottom of the AAO barrier layer was re-
moved by placing in nitric acid for a few seconds and
washed in D.I. water immediately after. The AAO barrier
layer was then removed by 5 wt% phosphoric acid for
ten minutes to two hours depending upon barrier layer
thickness of the as-grown AAO and observed under Scan-
ning Electron Microscope (SEM; Phillips XL30 ESEM).
All samples were cut into identical size pieces (1 × 1 cm2)
and autoclaved before use as drug carriers.
2.4. Porosity and Surface Area Calculation
In order to characterize the AAO nanotube film structure,
a porosity and surface area calculation was carried out. A
theoretical porosity can be computed geometrically based
on structural parameters such as pore size and inter pore
distance assuming ideal hexagonal arrangement. The fo-

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 228
llowing equation, Equation (1), was used to approximate
the porosity, P, of the samples,
2
int
2π
3
r
PD



(1)
where r is the inner pore radius and Dint is the inter pore
distance. The overall surface is assumed to be filled with
Al2O3 except the empty pore space, which is somewhat
complex in the case of a tubular structure. The apparent
porosity can be calculated based on pore area of the unit
cell and divide by unit cell area. To determine the surface
area of the samples with an area of 1 cm2, first the nano-
tube density was established based on SEM images by
counting the number of nanotubes per field for a given
area. The nanotube density, N, was ~2.19 × 1010 (nano-
tubes/cm2). The following equation, Equation (2), was
used to approximate the surface area, SA, of the samples



22
2π2πSARrh RrN (2)
where R is the outer tube radius, r is the inner pore radius,
and h is the height or length of the film. This equation is
based on the surface area of a tube multiplied by the
number of tubes in the sample area. This is a theoretical
estimation. It may be that the voids located around the
center pore are not completely void the length of the tube,
nonetheless SA is dramatically increased based on the
introduction of tubes on the surface.
For a 1 cm2 sample, the porosity and surface area was
calculated to be 25% and 1830 cm2, respectively.
2.5. Antibiotic Loading, Release, and Collection
Insertion of liquid into AAO nanotubes is not always
easy as the surface tension of the liquid has to be over-
come. At room temperature (25˚C), the nanotube samples
were placed in a vacuum (~10–4 torr) for approximately
5 - 10 minutes to rid nanopores of any trapped air. Ap-
proximately 1 ml of 1% amoxicillin (Sigma) in phos-
phate buffered solution (PBS) pH 7.4 (Invitrogen) was
loaded onto each sample placed individually in separate
wells of a 12-well plate (Nunc). To ensure dissolution of
the amoxicillin prior to loading, a few microliters of 1N
HCl was added until the solution became clear. The sam-
ples were incubated overnight to allow sufficient time for
the drug to fully penetrate into the nanotube structure.
The drug-loaded nanotube samples were washed 3X with
ice cold PBS (to restrict diffusion from the reservoir).
Next, the samples were individually placed in new wells
(Nunc, 12-wells) incubated in a humidified 95% air/5%
v/v CO2 incubator at 37˚C in 1ml fresh simulated body
fluid (PBS was used in this study). The solution was col-
lected at hourly time points initially (hours 1 - 6) and
daily time points thereafter (up to day 35 or 5 weeks) and
1ml fresh PBS was added after each collection. Drug
concentration was determined by measuring the absorb-
ance of the fluid using a UV-VIS spectrophotometer at λ
= 230 nm (Biomate_3, Thermo Electron, Madison, WI).
The assay was calibrated by use of PBS blanks and a
standard curve was determined up to 2 mg/ml amoxicil-
lin. Three replicates per experimental sample for each
time point were measured and the average values ± stan-
dard error (SE) was graphed to obtain release profiles,
release rate, accumulation, and release kinetics.
3. Results and Discussion
The vertically aligned, periodic AAO nanotube structure
used as a drug carrier is illustrated in the scanning elec-
tron microscopy (SEM) images in Figure 1 (top row). In
contrast to conventional AAO nanopore structures, AAO
nanotube unit cells are separated from each other while
being loosely connected to each other, which is an inter-
esting feature. In our nanotube samples, the nanotube
center pore size (~20 nm) is practically the same as the
size of the voids (spacing between adjacent nanotubes)
surrounding the center pore. This makes our AAO nano-
tube structure favorable due to larger surface area in
terms of loading drugs or catalyst chemicals into the
AAO nanotubes. The equal size of the center pore and
voids was achieved by the relatively low anodizing volt-
age (35 V) which ensures both relatively small center
pore size and interpore distance compared to the higher
voltage evolution under the constant current anodization
technique conducted by Zhao et al. [24]. The anodic cur-
rent evolution during our nanotube fabrication is given in
Figure 2.
To our knowledge, this is the first study to utilize the
AAO nanotube structure for applications in drug elution.
The nanotube film shows a highly ordered and uniform
nanotube morphology and long-range order with nano-
tube height reaching ~38 µm, which is the tallest used
thus far in nanopore/nanotube ceramic alumina and tita-
nia drug elution studies. Physical details of the AAO
nanotubes are portrayed in the chart shown in Figure 1
(bottom row). One of the advantages of our nanotube
structure is the increased porosity (~25%) and the high
surface-to-volume ratio. Here we show the surface area is
increased by three orders of a magnitude by introducing
the nanostructures on the surface, where a 1 × 1 cm2
sample has perceivably 1830 cm2 of surface area. The
interstitial space between the tube walls and the inner
pore walls aid in this calculation and is an advantage over
a traditional pore structure. Another benefit to our AAO
drug release system is that we can design the nanotubes
to match a desired pore size (20 - 100 nm), structural
shape (pores vs. tubes), available porosity, and surface
area which can help tailor, for instance by chemical

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 229
100 nm500 nm
150 nm
Nanotube
Height (μm) Pore Size (nm)
Wall
Thickness
(nm)
Nanotube
Center-to-Center
Distance (nm)
Porosity (%) Surface Area
(cm2)
38 20 15 73 25 1830
Figure 1. Upper left: Top-view SEM image of vertically aligned periodic AAO nanotubes. Upper right: Oblique view (inset =
higher magnification image). The table describes the physical dimensions of the nanotubes.
Figure 2. Representative anodic current evolution for AAO
nanotube fabrication. Applied voltage was slowly increased
from 25 V to 35 V and remained at 35 V. Anodization was
conducted for 30 minutes overall.
wet etching or pore widening techniques to specific im-
plant needs and controlled release.
Factors such as adsorption properties (interactions be-
tween drug and matrix), pore size, pore connectivity, and
pore geometry are just a few of the aspects to take into
account when designing a controlled drug delivery sys-
tem. It has been suggested that during AAO fabrication,
stress cracking and other residual defects due to the oxi-
dation volume expansion (Al becoming Al2O3) may be
present and these imperfections can leave charges on the
surface, such as Al3+ and O2– [25]. For the purposes of
drug loading, this may aid in electrostatic adsorption of
the drug molecules and help concentrate the drug within
the nanotube “depots” so to speak.
For this study, amoxicillin (AMX), a common phar-
maceutical antibiotic, is used as a model drug in the fol-
lowing AAO drug elution studies. The size of the AMX
molecule is ~0.8 nm [26], a reasonable size to enter and
fill the 20 nm diameter pores and interstitial spaces in
between the nanotubes. Preoperative oral administration
of AMX has been proven to reduce the risk of implant
failure [27,28], and local delivery of AMX during ortho-
pedic surgery reduced the infections associated with open
fractures [29], compound limb fractures [30], and with
osteoinductive and osteoconductive bone-graft substi-
tutes [29]. As well, local delivery of antibiotics was ef-
fective in reducing vascular infections from staphylo-
coccal strains [31]. It can therefore be hypothesized that
localized AMX elution from both orthopedic and vascu-
lar implants would be highly advantageous. With the
more advanced drug delivery, controlled release system
such as AAO nanotubes on implants, would help make
improvements in delivery efficiency and localization
which may also provide a solution for reducing dosages
and help minimize toxic side effects and drug waste. The
nanotube shape also has its advantages over a porous
structure because it provides an optimal surface shape to
allow for cellular adhesion sites for better cell attachment
and proliferation [32], aiding in surface integration and
cellular locking [33].
In terms of controlled release, it was found that the
AAO nanotubes were cable of carrying cargo molecules
(AMX, a small drug molecule) and releasing them in a
physiological environment of the simulated body fluid,

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 230
phosphate buffered solution (PBS). There are several
types of controlled release devices and the AAO nano-
tube system presented here can be considered a drug dif-
fusion-controlled release, where the entrapped drug dif-
fuses out of a matrix at a defined rate [34]. An antibiotic
release profile from the AAO nanostructures filled with
AMX was obtained for over 5 weeks (35 days), illus-
trated in Figure 3. For a control experiment, electro-
polished aluminum, without a nanostructured surface,
showed almost zero antibiotic release as expected (data
not shown). This indicated that it was the nanotube de-
sign on the surface which created a reservoir for the
AMX that was responsible for the drug release. Figure 3
shows the total amount of amoxicillin released as a func-
tion of time. A near steady release profile is achieved
after the first week of release (after Day 7). The ideal
release profile for most drugs would follow this type of a
steady release rate so that the drug levels in the body
remain constant while the drug is being administered
[35]. The drug elution from the AAO nanotubes accom-
plishes the primary objective of a controlled release de-
vice which is to provide a sustained release for long pe-
riods of time on the order of days, weeks, even months.
In the inset graph of Figure 3, which shows the initial
release of drug from the nanotubes in the first 6 hours of
release, the highest “burst effect” is in the first hour with
~13 µg of drug release. The “burst effect” is often seen
as controversy as to whether this is due to near-surface
entrapped drug or surface-absorbed drug [36]. The initial
burst and release of drug from the nanotubes may be re-
lated to several factors including 1) high relative top sur-
face area 2) increased drug diffusivity through tube
walls/channels and 3) high porosity. In addition, the spe-
cifics of the pore dimensions and their uniformity as well
as subtle difference in physical form of the nanotubes
may play a role at release during the initial short term
release (first 7 days) before the steady elution (beyond 7
days in Figure 3). At this stage in release, the drugs are
being released from the top portion of the film where the
so called “matrix surface” becomes a factor. After seven
days, however, it is suggested that the drugs are traveling
from a distance that is farther down in the matrix and less
likely to be affected by the very top surface. We have
also studied drug release from AAO ~20 nm and ~40 nm
pore (not tube) structures with the same film thickness or
height as the nanotubes studied in this report (data not
shown), however it has been suggested that it is the
height of the pore, not the pore size, that changes the
diffusion characteristics [15]. Varying film thickness will
impart some of our future studies, but this report focuses
on the unique geometry and beneficial properties of the
AAO nanotube structure.
To further characterize the AMX release from the
AAO nanotubes, Figures 4 and 5 illustrate the accumu-
lative release (showing daily and weekly accumulation)
and release rate per day over the 5 week elution study,
respectively. A near steady release rate occurred over the
course of the 5 weeks. This type of release would help
maintain a drug level in a therapeutic window, avoiding
the extremes of systematic drug over-dosages or un-
der-dosages, eliminating the risks of adverse effects, drug
waste, or being sub-therapeutic.
Figure 3. Absolute release rates of amoxicillin as a function of sampling time for the AAO nanotube drug carriers. The initial
burst of drug from the surface is shown in the inset. The graphs show the mean ± SE (n = 3).

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 231
Figure 4. Accumulative amoxicillin released as a function of
time. The graph shows mean ± SE (n = 3). The dotted line
reveals the daily accumulation over time and the bars rep-
resent the average accumulation per week.
Figure 5. Daily release rate over time (normalized per weekly
time point). The graph shows the mean ± SE (n = 3).
When studying the drug release of molecules that have
a size regime on the same scale as the matrix features,
the basic principle of diffusion as a mixing process with
solutes free to undergo Brownian motion in three dimen-
sions may not necessarily apply, in at least on dimension,
for the AAO nanotubes because the solute movement is
physically constrained by the nanotube walls [37]. The
AAO nanotube geometry may impose a rate limiting
condition due to the length of the nanotube walls, be-
cause the length dictates how far the solute molecules
have to travel to be released from the reservoir. While it
is not possible to draw significant conclusions without
varying the wall height of the AAO nanotubes, this in
part will form some of our future work.
Many studies have observed that the release rate of a
drug dispersed in a solid matrix (with no erosion of the
matrix occurring) is proportional to the square root of
time, as predicted by the Higuchi model [38-40]. It was
determined that this was because the release rate is in-
versely proportional to the distance the drug must travel
within the matrix to the matrix surface, since the diffu-
sion distance increases with time, the release rate
decreases with time [38]. The Higuchi equation follows,
t
Qkt
Q
 (3)
where t
Q
Q

is the cumulative fractional release at time t
and k is the release constant.
To identify the release rate mechanism and model the
drug transport in the AAO nanotube system, the hy-
pothesis was made that the release data obtained could be
fitted using Equation (3) and the results are given in Fig-
ure 6, where the cumulative fractional AMX release,
Equation (3), was plotted versus the square root of time.
A near perfect linear fit was observed, demonstrating that
the drug kinetics approximately follow the square root of
time relationship. The chart in Figure 6 describes the
linear fit. The mechanism of release is most likely attrib-
utable to a novel constrained diffusion mechanism pro-
vided by the AAO nanotube walls.
AAO films are simple to prepare and can be easily
modified and structurally tailored. As well they are re-
sistant to most physiologic and chemical reactions (bio-
inert), mechanically strong, and are considered biocom-
patible in vitro and in vivo. By utilizing AAO nanotubes
as drug carriers, a variety of drugs can be loaded into the
device reservoir in a range of physical states, including
solutions and crystalline or micronized suspensions [37].
This flexibility with respect to encapsulated drugs pro-
vides options to substantially increase the load dose and
duration of therapy, as well as stability of drugs that are
unstable in certain biological fluids or different bio-
chemical/acidic/alkaline environments. AAO films are
Figure 6. To assess the mechanism of drug release, a plot of
fractional release 


t
Q
Q
vs. the square root of time was
completed. A near perfect linear fit was observed and de-
tails are shown in the above table.

A New Nano-Platform for Drug Release via Nanotubular Aluminum Oxide 232
structurally robust and will not swell or change its poros-
ity under different pHs or temperatures [41]. Thus, AAO
nanotube drug carriers can be used to address the prob-
lems associated with conventional drug therapies such as
limited drug solubility, poor biodistribution, lack of se-
lectivity and unfavorable pharmacokinetics [11]. Lastly,
the potential for AAO nanotube arrays on implant sur-
faces will help mimic the complex geometries of natural
tissue and will provide a porous template for the growth
and maintenance of healthy cells and tissue [42], aiding
in implant design as well as local delivery of therapeu-
tics.
4. Conclusions
The controlled release of amoxicillin from anodic alu-
mina oxide (AAO) nanotubes was investigated. The
unique AAO nanotube morphology was fabricated using
a simple two-step anodization process that resulted in
highly uniform, structurally robust nanotubes. This is the
first study utilizing the AAO nanotube geometry as a
drug carrier and the diffusion characteristics including a
drug release profile, drug accumulation plot, and release
rate were acquired. The AAO nanotube carriers demon-
strated controlled, sustained release of common antibiotic,
amoxicillin for approximately 5 weeks. This study illus-
trates the potential advantages of using AAO nanotubes
as a unique alternative in terms of therapeutics concepts
for implant surface coatings.
5. Acknowledgements
This research was supported by Iwama endowed fund at
UC San Diego, UC Discovery Grant No. ele08-128656/
Jin, and National Research Foundation (NRF) grant
through World Class University Program (R33-2008-
000-10025-0).
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