Journal of Biomaterials and Nanobiotechnology, 2011, 2, 1-7
doi:10.4236 /jbnb.2011.21001 Published Online January 2011 (http://www.SciRP.org/journal/jbnb)
1
Self-Assembly of Colloidosome Shells on
Drug-Containing Hydrogels
Rachel T Rosenberg, Nily Dan
Department of Chemical and Biological Engineering, D r exel U niversity, Philadelphia, Pennsylvania 19104
Received August 30th, 2010; revised September 22nd, 2010; accepted Sept ember 28th, 2010.
ABSTRACT
Colloidosomes are composed of an aqueous or hydrogel corethat is coated by a semi-permeable colloidal shell. The
properties of the shell can be varied to control the rate of release of encapsulated components such as drugs. Specifi-
cally, the pores formed between the colloidal particles suppress transport of large components, while allowing diffusion
of smaller on es. Self-assembly of colloidal particles on hydrogel films is a convenient method forcolloidosome synthesis,
but to d ate little is kno wn rega rding th e effect (if an y) of the encapsulated drug on the shell packing density. In this pa-
per we examined self-assembly of colloidal shells on alginate films containing four model drugs: aspirin, caffeine,
theophylline and theobromine. We find that the packing density in the colloidal shells is low for all drugs, and ranges
between 0.16 and 0.3. There is no clear correlation between drug properties (in particular, water solubility) and the
packing density of the self-assembled colloidal shell.
Keywords: Drug delivery, Diffusion, Colloids, Colloidosomes
1. Introduction
Selective control of drug transport is of interest for
pharmaceutical, cosmetic, and food applications [1-6].
Colloidosomes [7] are aqueous microcapsule volumes
coated by a shell of colloidal particles (see Figure 1)
[7-16]: The packed colloidal particles form a barrier for
transport, whose pore size may be controlled through
choice of the colloidal particle size and the packing den-
sity in the shell [7-16]. As a result, colloidosomes allow
size exclusion, namely, inhibition of transport of com-
ponents whose size is larger than a critical value, while
allowing transport of smaller molecules.
Several methodologies have been developed to form
the colloidal shells of colloidosomes. Typically, they
utilize the tendency of the particles to assemble at the
interface between hydrophilic and hydrophobic fluids
[7,13,14,15]. Although effective, the conditions involved
are often not compatible with those needed for biological
agents. As a result, they cannot be used for drug encap-
sulation.
Kim, et al [11] utilized a different method for colloi-
dosome for mation: The co lloid al particles in t he shell are
driven to self-assemble on the surface of a hydrogel core
by electrostatic interactions. The assembly is conducted
in one step, and under benign environmental condition
(i.e. aqueous solutions- includ ing, potentially, serum, at
room or body temperature).
We recentl y studied t he relea se of model drug s from
hydrogels coated by self-assembled colloidal mono-
layers [17,18]. Quite surprisingly, we found that the
release profiles for each drug were insensitive to the
size of the particles in the shell, for p[articles ranging
from 20nm to 3.3μm [17]. To understand these results,
we adapted a two-film diffusion model[18], where the
hydrogel is taken to be one film, and the shell coating the
second film. The shell is modeled as a composite of an
impenetrable phase (the colloidal particles) and a pe-
netrable one that is s imilar in pr op erties to the aqueo us or
hydrogel core (see Figure 1). The mod el fi nds t hat in th e
case of a loosely packed monolayer such as that of the
self assembled shell, the release profile is indeed inde-
pendent of the colloidal particle size, a function of three
parameters only: the diffusion coefficient of the drug in
the hydrogel core, the dimension (thickness) of the hy-
drogel core, and the packing density of particles in the
shell. Thus, controlling the release rate of a drug from a
colloidosome may be achieved through control of the
shell packing density (since the diffusion coefficient is
set by the hydrogel properties, and core size is t ypically
set by the specific system needs).

Self-Assembly of Colloidosome Shells on Drug-Containing Hydrogels
2
Figure 1. A schematic of the system examined. Left: A hy-
drogel containing a diffusant, or drug, is coated by a
self-assembled colloidal monolayer, formed through ad-
sorption of colloidal particles onto the oppositely charged
hydrogel. Due to the self-assembly process, the shell is
loosely packed, typically w ith a colloi dal volu me fra ction of
order ¼. The coll oidal s hell may be take n to be a co mposite
of an impenetrable phase (the particles) and a penetrable
one (hydrogel or aqueous solution). Right: The two-film
diffusion mod el used t akes t he hydr ogel to be one fi lm, an d
the colloidal shell the other. The drug diffuses through the
hydrogel until reaching the interface with the colloi dal shell.
It cannot penetrate through the particles, and must go
through t he pores i n betw een t he coll oids , so th at the rat e of
release is reduced when compared to the uncoated hydro-
gel.
Fitting our expe rimental re sults to the theoretic al mod-
el [18] yielded that the packing density in the
self-assembled colloidal shells is independent of the col-
loidal particle size. Moreover, it was similar for caffeine
and aspirin, despite the differences in their chemical
struct ure. This observation is so mewhat surprising, since
it has been previously found that the properties of a drug
can significantly affect the properties of the encapsulat-
ing hydrogel, and thus the release profile: For example,
studies of drug release from biodegradable polymeric
films have clearly demonstrated that the drug properties
can significantly affect the degradation rate, and thus
release profile [19,20]. It may be expected that the pres-
ence of a drug in the hydrogel would affect the adsorp-
tion, and thus packing, of the colloidal particles.
To determine whether drug properties affect the pack-
ing density of a colloidal shell, and thus the release pro-
file of the drug, we compared systems containing four
model drugs: caffeine, theophylline, theobromine and
aspirin. The first three are similar in structure, and even
cause similar physiological effects (stimulation of the
central nervous system and gastric acid secretion) [21].
Yet, they differ significantly in their solubility in water.
The solubility of caffeine is 21.7 mg/mL [22], theophyl-
line is 8 mg/mL [22], and theobromine is 0.5 mg/mL [23].
All drugs, including aspirin, have similar MWs (180 for
aspirin, theophylline and theobromine, and 194 for
caffe ine), a ltho ugh asp irin d iffer s fro m the thr ee dr ugs in
its chemical structure. The solubility of aspirin in water
has an intermediate value similar to that of theophylline,
of order 3-10 mg/ml [22].
It is somewhat dif ficult to predict, a-prio ri, what effect
would drug properties have on the self-assembled col-
loidal shell. Self-assembly in these systems is driven by
electrostatic interactions between charged groups on the
hydrogel surface, and oppositely charged ones on the
colloidal particles. It is possible that a hydrophobic drug
(as determined by low solubility in water) may cause the
hydrogel to collapse, thereby reducing the availability of
the hydrogel surface groups to bonding with the colloidal
particles. On the other hand, highly hydrophilic drugs
may interact with the charged surface groups, thereby
reducing particle adsorption. Regardless of the mechan-
ism, it is expected that if the encapsulated drug has an
effect on shell formation (and thus on the rate of drug
release), the packing density of the colloidal particles in
the she ll would scale in so me manner with dr ug solubil i-
ty in aqueous solutions.
We find tha t the two-film model fit the release rate of
all drugs well, for both uncoated and colloidal-shell
coated hydrogels. However, the effect of the encapsu-
lated drugs on the packing density of the shells is found
to be weak: In all systems, the packing density of the
colloids in the shell (namely, the volume fraction of par-
ticles) was calculated to be in a narrow range of 0.16-0.3.
The packing density did not vary systemat ically with the
drug properties, and in particular did correlate with the
drug’s water solubility. Indeed, the packing density for
theobromine, which had the lowest solubility of all the
drugs tested, was the lowest (~0.16). However, the high-
est packing density was found for theophylline (~0.3),
which has intermediate water solubility.
2. Materials and Methods
2.1. Materials
Sodium alginate, calcium chloride, aspirin, caffeine,
theobromine and theophylline were purchased from
Sigma-Aldrich (St. Louis, MO and Milwaukee, WI,
USA). 3.3 µm amidine (C(NH2)=NH+) functionalized
polystyrene particles were purchased from Invitrogen
Molecular Probes. All reagents were used as purchased
with no further purification.
2.2. Synthe sis of Hydrogel Fi lms
To a llow consistent meas urements o f transport thro ugh a
colloidal shell, the system consisted of an alginate hy-
drogel film (rather than spherical drops) impregnated
with a given concentration of the chosen drug. The film
was then coated by a monolayer of colloidal particles,
and transport determined by measurement of the drug
concentration in the medium surrounding the film

Self-Assembly of Colloidosome Shells on Drug-Containing Hydrogels
3
[17,18]. Unlike transport from microgel colloidosomes,
this geometry allows exact control over the system pa-
rameters (e.g. drug content in the hydrogel). The sur-
rounding medium was kept, for all four drugs, at a con-
centration that is well below the relevant solubility limit
even at 100% release.
A 2% (weight/volume) sodium alginate in water solu-
tion was shaken and sonicated to remove any excess air.
1 mg of a model molecule was dissolved in 400 µL of the
sodium alginate solution and placed in a 30 mL (25 mm
x 95 mm) glass vial. The vials were placed in a convec-
tion oven at 40ºC overnight to evaporate the excess sol-
vent. 500 µL of a 10% wt. solution of calcium chloride in
water was added to the alginate and allowed to crosslink
for 5 minutes. Excess calcium chloride was removed and
polystyrene particles were added to the hydrogel film and
incubated overnight. The films were subsequently
washed with deionized water.
2.3. Ultraviolet Spectroscopy
Concentrations of molecules released were calculated
using a linear calibration curve. 8 samples were made
with pure water as the lowest concentration. The absorp-
tion spectra showed peaks for the following drugs:
caffeine at 273 nm, aspirin at 275 nm, theophylline at
271 nm and theobromine at 272 nm. All further mea-
surements were taken at respective peak wavelengths.
Concentrations were in the linear regime to minimize
error.
2.4. Diffusion Model
The hydrogel-colloidal shell system is modeled as a
two-fil m syst em [ 18] , wher e t he hydr o gel is o ne film a nd
the colloidal shell t he other (see Figure 1 ). The transport
of drug in such two-film systems is defined by three pa-
rameters: The hydrogel film thickness, a, the diffusion
coefficient of the drug in the hydrogel, D, and a dimen-
sionless parameter L that accounts for the shell permea-
bility: L is infinity when there is no shell (or when the
shell does not offer resistance to transport), and zero
when the shell is completely impenetrable to the drug
[18]. The fraction of drug released at time t is given in
this approach by
() ( )
22
22 222 2
11
1
1
n
D t/a
nn
nn nn
e
f(t) LL LL
β
ββ ββ
−
∞∞
= =
= −+− +−
∑∑
(1)
where βn are the roots of the expression [18]
01cot =−+ L
nn
ββ
(2)
Modeling the colloidal shell as a composite of an im-
penetrable phase (the colloidal particles) and a penetrable
one yielded, in the case of a colloidal monolayer, the
following relationship for L [18]:
( )
( )
21
33
1 216L πϕ ϕπϕ ≈− +
(3)
where φ is the volume fraction of colloids in the shell.
Equation (3) is appropriate only for a loosely packed
colloida l shell (where the p acking de nsity of the pa rticles
in the shell is less than ~0 .5) and whe re t he h ydro gel core
thickness a is much larger than the co lloid al par ticle shell
thickness. The thickness of the monolayer colloidal shell
is equal to the dia meter of the co lloid al pa rticles which i n
this case, is much smaller than the thickness of the hy-
drogel film.
From (1-3) we see that the transport of a drug through
a colloid al shell coating a hydrogel is expe cted to depend
onl y on t he h ydro gel cor e th ic kness a, the dif fusio n co ef-
ficient throug h the hydrogel D, and the c olloidal packing
density (volume fraction) in the shell φ. It should not
vary with the particle diameter, as indeed verified by our
previous experiments [17,18].
3. Results and Discussion
Our earlier work [17,18] suggests that the release profile
of drugs from hydrogels coated by a (loosely packed)
self-assembled colloidal shell depends only on three
parameters: The hydrogel film thickness, the diffusion
coefficient of the drug in the hydrogel, and the packing
density of the particles in the shell. Therefore, to deter-
mine t he di ffusi on co effi cie nt o f the d rug s in our algi nate
gels, we measured the release of the four drugs from un-
coated hydrogels, as shown in F igure 2.
Literature values were published for the diffusion
coefficient of some of the drugs in water [25,26]. How-
ever, those values cannot be directly applied to transport
of these drugs through other media - such as our hydro-
gel. Moreover, altho ugh it might have b een a ssume d that
the relative ratios of the diffusion coefficients would be
independent of the type of media (namely, if diffusion
coefficient of one drug in water is higher than that of a
second one, the same could be said of their rates in other
aque ous-based media), studies show that this is not the
case: For example, in water, caffeine and theophylline
have similar diffusion coefficients [25,26]. Additionally,
their release rate from alginate gels [24] and through
Buccal tissue [27] has been found to be similar as well.
Yet, in other media- transdermal tissue [27] and pig ear
skin [28]- the transport rate of caffeine was found to be
two orders of magnitude faster than that of theophylline.
Besides the medium, the specific formulation also af-
fects the absolute and relative rates of the transport of
different drugs [27,28].
In our case, the formulation of the hydrogel used for

Self-Assembly of Colloidosome Shells on Drug-Containing Hydrogels
4
(a)
(b)
Figure 2: The release profile of the drugs from uncoated
alginate hydrogels. f defines the fraction of the initially en-
capsulated drug, released by time t. (A) The fractional re-
lease of drug as a function of time. The rate of aspirin re-
lease is fast est. Caffei ne a nd theop hyll ine hav e si milar rates ,
and theobromine is much slower;(B) Fi tting the release data
to the diffusion model (Equations 1-2). Time is normalized
by a factor of a2/D, where a is the thickness of the alginate
film and D the diffusion coefficient of the drug. The solid
line describes the model prediction for uncoated films. The
values of the normalization factor used in the fit are listed
in Table 1.
Table 1. Drug and Mod el data.
Drug MW Solubility
(mg/ml) a2/D*
D**
(cm2/s) L** *
φ
#
Aspirin 180 3-10 [22] 12,000 2.5*10-5 3.5 0.2
Caffein e 194 21. 7 [22] 75,000 3.3*10-6 3.5 0.2
Theophyl-
line 180 8 [22] 83,000 3*10-6 2 0.3
Theobro-
mine
180 0.5 [23] 820,000 3*10-7 5.5 0.16
* Based on the fit presented in Figure 2.B to (1-2)
** Usin g an approxim ate value for a of 0.5cm.
*** Based on the fits presented in Figure 4
# Using (3)
the uncoated films and the ones coated by a colloidal
shell is identical, so that comparing the two would allo w
determination of the effect of the colloidal shell on
transport. As shown in Figure 2, the release rate of
theophylline and caffeine from the bare alginate hydrogel
is similar. In contrast, the release of theobromine requires
significantly longer periods, in qualitative agreement
with previous studies of the three drug’s release from
alginate gels [24]. Aspirin has a much faster release rate
than all other drugs, in agreement with our previous ob-
servations [17,18].
To quantify the transport rate of the three diffusants,
the release data were fit to the diffusion model described
by (1-2) [18], as shown in Figure (2.B). Since the gels
are uncoated, the parameter L, which describes the
shell/surface resistance, is equal to infinity for all cases
[18]. To demonstrate the validity of the model, we col-
lapse the data onto one curve using a normalization fac-
tor for the time t that arises from (1-2), namely, a2/D,
where a is the thickness of the alginate film and D the
diffusion coefficient of the drug in the hydrogel core.
The model prediction is plotted as a solid line, and has no
free parameters when plotted in these coordinates.
The fact that all four release profiles can be success-
fully collapsed in this manner onto the model prediction
is a strong indicator for the model validity in the un-
coated gels. The values found by fitting the data are ta-
bulated in Table 1. Unfortunately, we do not have accu-
rate measurements of the film thickness for the gel films
(although, since we use the same volume in the same vial
for all drugs, both in the case of coated and uncoated gels,
it is the same in all experiments) .
Ho wever, esti mati ng a to be 0.5 cm, a value consistent
with our experimental set up, yields the following esti-
mates for the diffusion coefficients of the drugs in our
formulation of alginate: 2.5*10-5 cm2/s for aspirin,
3.3*10-6 cm2/s for caffeine, 3*1 0-6 cm2/s for theophylline,
and 3*10-7 cm2/s for theobromine. The results for caffe-
ine and theophylline are somewhat lower than the values
for the diffusion coefficient of these drugs in water
(6.3*10-6 cm2/s [25] for caffeine and 6.15*10-6 cm2/s [26]
for theophylline), as may be expected since transport
thro ugh the hydro gel s hould b e slo wer t han thr ough pure
water.
In Figure (3.A) we plot the release of the drugs as
measured for alginate hydrogels coated by a
self-assembled colloidal monolayer. As may be expected,
the presence of the colloidal shell reduces the release rate
when compared to the release from uncoated gels. For
example, in the uncoated case both caffeine and theo-
phylline release more that 90% (namely, f >0.9) after
20,000sec, while in the coated case the fraction released
at that time interval is of order 60%.Also as expected, the

Self-Assembly of Colloidosome Shells on Drug-Containing Hydrogels
5
(a)
(b)
Figure 3. The release of caffeine, theophylline and theo-
bromine from alginate hydrogels coated by a monolayer of
3.3mm colloidal particles. f defines the fraction of the in-
itially encapsulated diffusant, released by time t. The sym-
bols are as defi ned in Fig ure 2. (A) The fracti onal rele ase as
a function of time; (B) The fractional release as a function
of the normalized time Dt/a2, where the value of D/a2is as
calculated from the fit to the uncoated hydrogel (Figure
2.B). The solid line describes the model prediction for the
uncoate d gels.
relative rates remain the same as in the uncoated case:
Aspirin is released most rapidly, theophylline and caffe-
ine have similar rates, and theobromine requires the
longest time. However, the raw data cannot distinguish
between the effects of the diffusion coefficient in the
hydrogel, and the potential effect of the self assembled
colloida l mono layer.
To determine the effect of the colloidal shell, we again
normalize time the value of a2/D as calculated from the
uncoated gels (Figure 3.B). If the effect of the shell is
simil ar fo r a ll d r ugs, t hen t hey sho uld again co ll ap se o nto
the same cur ve, although this one would differ from that
of the uncoated system, as given in (1-3). We see, how-
ever, that the normalized release profiles do not overlap:
Although all are slower than the predicted rate for the
uncoated gels (as depicted by the solid line), caffeine and
theobromine seem to have a faster rate than that of aspi-
rin, while theophylline is clearly slower than all other
drugs.
The two film model suggests that these differences in
the release rates may be due to the packing density of the
colloidal particles in the shell; since the shell is self as-
sembl ed, the densi ty ma y var y bet ween the d iffer ent s ys-
tems. Therefore, we use (1-2) to fit the release p rofiles of
the four drugs to evaluate the value of L, the shell trans-
port retardation parameter, and (3) to correlate this para-
meter to the colloidal packing density. The fits are pre-
sented in Figure 4, a nd the values l iste d in Table 1.
We find that the values of the shell permeability para-
meter L fall, for all drugs, in the range of 2-5, which
translated to a range for the packing volume fraction of
particles in the shell of 0.3-0.16. For both caffeine and
aspirin, the best fit is obtained with a value of L=3.5,
which translates to a colloidal packing density in the
shell using (3 ) of
 ≈0.2. For theophylline, the best fit is
for L=2 , namely,  ≈0.3 , while for theobromine the best
fit is for L=5.5, corresponding to
 ≈0.16 . While there
are clear differences between these values, they are all
within the same range for the packing density. Moreover,
there is no clear tr end li nking the dr ug pro per ties and the
colloidal packing density in the shell: Caffeine and aspi-
rin have similar packing densities, despite the differences
in str uctur e, M W and sol ubili ty. The op hylli ne, which ha s
a similar solubility to that of aspirin- which is interme-
diate between caffeine and theobromine- has the highest
packing density, while theobromine has the lowest.
4. Conclusions
Previous studies have shown that the properties of an
encapsulated drug can significantly affect the properties
of the encapsulating hydrogel. In this paper we investi-
gate the effect of drugs, encapsulated in hydrogel films,
on the self-assembly of a colloidal shell. Fourmodel
drugs are investigated: aspirin, caffeine, theophylline and
theobromine. These drugs are similar in MW, and three
of them (caffeine, theophylline and theobromine) have a
similar structure and even similar physiological effects.
However, they differ significantly in their solubility in
water.
We find that the release profiles in all systems (both
uncoated hydrogels and ones coated by the self assem-
bled colloidal shells) can be fit well with a t wo-film dif-
fusion model [18]. The packing density in the
self-assembled colloidal layers is found to vary, between
the drugs, in the range of 0.16-0.3. The lowest packing

Current Distortion Evaluation in Traction 4Q Constant Switching Frequency Converters
6
Figure 4. Fitting the release rate from coated hydrogel to the two-film model (equations 1-2). The dotted line is for a shell
where L=5, and the dashed line where L=2. a ) Aspirin. The solid line is the model with a value of L=3.5; b) Caffeine. The
solid line is the model with a value of L=3.5; c) Theophylline; d) Theobromine. The so lid line i n the inset is for L=5.5 .
density is found for theobromine, which has the lowest
solub ility i n water . Ho wever, the hig hest pa ckin g densit y
is fou nd for theophylline, which hasanintermediate water
solubility (see Table 1). Caffeine and aspirin have iden-
tical packi ng densities, d espite the fact that t he solubility
of caffeine in water is three times as high as that of aspi-
rin.
We conclude that there is some effect of the drug
properties on the packing density in the self assembled
colloidal shells. However, this effect is weak, and cannot
be directly linked to the drug properties, in particular
solubility in water.
5. Acknowledgements
Thanks to NSF/IDBR award number 0649897 for finan-
cial support. RTR acknowledges the NSF-IGERT
DGE-0654313 fellowship.
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