ORIGINAL PAPER
Drying characteristics and evolution of the pore space in alginatescaffold with embedded sub-millimeter voids
Dharmendra Kumar Bal • Subhajit Patra •
Somenath Ganguly
Received: 29 April 2013 / Accepted: 23 September 2013 / Published online: 27 September 2013
� Springer Science+Business Media New York 2013
Abstract Alginate scaffold has potential use in the con-
trolled release of drugs and as a three dimensional structure
for the formation of tissue matrix. This article describes the
changes in the alginate scaffold when the moisture was
removed from the scaffold under vacuum. Here, some
scaffolds have self-aligned gas bubbles with average
diameter of 500 lm, introduced through fluidic arrange-
ment, prior to the crosslinking of the aqueous alginate film.
The crosslinked gel film was dried in a vacuum oven at a
constant temperature. The image of the alginate film prior
to crosslinking was acquired under digital microscope, and
was compared with the images of the dried scaffolds from
the scanning electron microscope. The voids retained their
identity at the time of drying, while the diameter was
reduced to half of the initial value. The thickness of the
scaffold was reduced ten folds. The presence of voids
enhanced the drying rate when the drying was conducted at
higher temperature. The drying primarily occurred in the
falling rate period. The constant rate period was approa-
ched at lower moisture content for thin scaffolds without
voids indicating the presence of surface moisture for sub-
stantial period. This feature was not observed for the
scaffolds with voids. For these scaffolds, the shrinkage was
insignificant except for the initial phase of drying. Based
on this information, the conclusions were drawn on how
the de-saturation of the various parts of the scaffold was
phased.
Keywords Alginate � Gel � Scaffold � Void � Drying
1 Introduction
A porous scaffold that provides a three dimensional support
for the formation of a matrix, and also delivers the bio-
logical agents is a subject of extensive investigation. Use of
natural and synthetic polymers, and hydrogels are known,
where the biocompatibility and the biodegradability are
important requirements. A gel layer has the potential to
hold a significant volume of a biological agent that can
diffuse into the host tissue over a period of time. Also the
gel layer, loaded with a matrix forming cell can act as a
scaffold, over which the tissue regeneration takes place. In
these applications, it is important that a substantial porosity
is induced in the gel layer. Additionally, the porosity has to
be uniformly distributed so that the pore to pore distance
remains uniform. This calls for a highly ordered pore
structure.
Emulsion freeze drying, fiber bonding, solvent casting
or particulate leaching, gas foaming, thermal phase sepa-
ration, electrospinning, and use of supercritical CO2 are
some of the methods to induce the voids in a gel layer [1].
Direct introduction of bubbles using a fluidic arrangement
is an alternative method that allows better control of the
void size and the porosity. Under most circumstances, the
bubbles generated by this method are monodisperse. The
bubbles rapidly self-assemble, and provide an ordered
structure. Also, the gel is not exposed to any chemical or
thermal treatment by this method. The method is inex-
pensive, in comparison with the solid free form fabrication
techniques. Alginate is a naturally occurring polysaccha-
ride, sourced from brown algae that grow in warm areas.
Alginate gel has been extensively characterized for con-
trolled release applications [2–14].
Use of pulled microcapillaries to generate a gel scaffold
of alginate has been reported [15–17]. In a general co-flow
D. K. Bal � S. Patra � S. Ganguly (&)
Department of Chemical Engineering, Indian Institute of
Technology, Kharagpur 721302, India
e-mail: [email protected]
123
J Sol-Gel Sci Technol (2013) 68:254–260
DOI 10.1007/s10971-013-3161-z
arrangement, the pulled capillaries are arranged one inside
the other. The inner gas thread is dragged by the co-flowing
liquid until the gas stream snaps to form a bubble. There
are other variants to this arrangement. In a flow focusing
arrangement, the liquid may be injected in a cross-flow
manner to impart a direct squeeze on the gas flow. The
work that is presented in this article is based on a co-flow
device, where an aqueous solution of sodium alginate with
dissolved pluronic F127 as the surfactant made the liquid
phase. After the formation of alginate scaffold with
embedded voids, the polymer was crosslinked by addition
of CaCl2 solution to form a free-standing porous gel film.
The gel film was dried in a vacuum oven at constant
temperature. We anticipate that the voids will act as
additional reservoirs, distributed uniformly over the entire
scaffold. These reservoirs enable additional uptake of
drugs. Also, due to the presence of these voids, the resis-
tance to diffusion decreases. Thus a higher release rate can
be achieved. The uniform distribution of voids provide an
excellent platform for harvesting the matrix forming cells,
and can be useful for tissue regeneration. The size and the
frequency of bubbles, and the number of layers of bubbles
can be tuned, over and above the adjustments in physico-
chemical properties of the gel through changes in compo-
sition for the desired effect.
At the time of drying, the moisture leaves the scaffold
[18, 19], and a dual porosity evolves within the scaffold.
One level of porosity is from the gel matrix, and the other
from the induced voids. The application of vacuum under-
standably allows faster removal of moisture. More impor-
tantly, the vacuum can help in opening the voids, and thus
influences the tortuosity of the pore network. The evolution
of dual porosity under combined actions of moderate heat-
ing and vacuum is critical in the subsequent performance of
the scaffold with regard to uptake and release of biological
agents. As such, the process of moisture removal in a dual-
porosity matrix may have a significantly different mani-
festation, compared to the process in a single porosity
matrix. The differential shrinkage of the void-zone and the
surrounding matrix entails tortuosity that in turn affects the
moisture removal. In this article, the shrinkage and the loss
of moisture are analyzed with time vis-a-vis the images of
the internal structure. A digital microscope was utilized to
acquire images prior to the drying of the film. Also, the SEM
images of the dry scaffold are reported in this article. The
weight and the thickness of the scaffold were monitored to
estimate the changes in the moisture content with time.
2 Experimental methods
4 % sodium alginate (Sigma Aldrich) solution in distilled
water was prepared by using a magnetic stirrer at 350 rpm
for 12 h, and subsequently a mechanical mixer at
3,000 rpm for 3 h. The pH of the solution was found to be
7.55. The viscosity of the alginate solution at 25 �C was
measured using Anton Paar Rheometer with parallel plate
geometry at different shear rates. 4 % pluronic F-127
(Sigma Aldrich) solution in distilled water was used as a
surfactant. The pH of the pluronic solution was found to be
6.58. The solution was stirred for 1 h using a magnetic
stirrer at 350 rpm. The solution was then kept in a refrig-
erator at 4 �C for 24 h to ensure complete dissolution. The
alginate and the pluronic solutions were mixed in even
proportion using a magnetic stirrer at 100 rpm for 10 min.
Surface tension and contact angle of alginate solutions
were measured in a Goniometer (Rantac, Germany). The
surface tension was measured by pendant drop method and
contact angle was measured on a glass slide. The solutions
were prepared at least 1 h prior to the measurements and
sonicated by Ultra-sonicator for 30 min.
In the co-flow device, made of pulled glass capillaries,
the gas was flowed through the inner capillary. The aque-
ous polymeric solution flowed through the outer capillary.
Constant flow rate of aqueous solution was maintained by
displacing the solution from a transfer cylinder with the
paraffin oil from a syringe pump (Harvard Apparatus,
USA). The flow of nitrogen was obtained from a gas cyl-
inder through a mass flow controller (Alicat Scientific,
USA). The gas flow rate was maintained at 1 mL/min,
where as the liquid flow rate was set at 5.0 mL/min.
As the flow of the two phases proceeded through the co-
flow device, thin gas thread from inner capillary broke up
to form bubbles. The liquid with embedded bubbles were
collected in a petridish. The digital images of the bubbles
were acquired using a microscope from Labomed with a
camera, attached to the computer. The images were
acquired under in line illumination, and were processed
further using the Davis software from LaVision. 4 % CaCl2solution was sprinkled on the scaffold to form a gel-
structure within the liquid phase. After 5 days, the gel
structure was dipped in distilled water to remove the excess
CaCl2 solution. Similar scaffold without any induced void
was made in a separate petridish for comparison.
Next, the gel scaffolds were dried in vacuum oven at an
absolute pressure of 60 torr. The temperature was set at
50 ± 2 �C. In one case the temperature was set at 30 �C
for comparison. It took about 100–400 min for the weight
of the scaffold to reach a constant value. For comparison,
similar gel scaffolds were made without any induced voids.
The weight of the scaffold was monitored with time. The
measurements were taken at every 15 min. The thickness
of the scaffold at four pre-identified locations was moni-
tored with time. Once the weight of the scaffold reached a
constant value, a part of the scaffold was further processed
for imaging under scanning electron microscope. The
J Sol-Gel Sci Technol (2013) 68:254–260 255
123
images were taken within the void, as well as in the matrix
part of the scaffold using JSM 5800 from JEOL Limited,
Japan. In addition, several analyses were performed on the
dry scaffolds as follows. The BET analysis of the scaffolds
with and without voids respectively was done using
Autosorb 1 from Quantachrome Instruments, USA. The
X-ray diffraction analysis was performed on the scaffolds
with and without voids respectively using X’Pert PRO
model of PANalytical B.V., The Netherlands. Fe filtered
Co K-alpha 0.178901 nm radiation at 30 mA and 40 kV
were used with minimum step size of 2h as 0.001, and time
per step as 19.685 s. The mechanical strength of the dry gel
samples with and without voids respectively was measured
using a Hounsfield Universal Testing Machine, UK.
Finally, the fully dried scaffold was dipped in the aqueous
solution of Vitamin B-12 (200 ppm) to observe the
absorption capability of the scaffold.
3 Results and discussions
Aqueous solution of alginate was found to be shear thin-
ning from viscometric studies. The viscosity of 2 % algi-
nate solution decreased from 10 Pa-s at a shear rate of
0.0005 s-1 to 0.2 Pa-s at a shear rate 100 s-1. The power
law constants K and n were found to be 0.17 Pa and 0.96
respectively. Increase in concentration of alginate resulted
in increase of viscosity. The surface tension and contact
angle were found to be 33 mN/m, 14� in presence of plu-
ronic, and 60 mN/m and 32� in absence of pluronic,
respectively. The presence of pluronic in the liquid phase
reduced both the surface tension and the contact angle. The
presence of polymer increased the viscosity of the liquid
phase.
The bubbles were generated through coflow of aqueous
solution of alginate and the nitrogen gas. The average
diameter of the bubble was found to be 500 lm. Figure 1
presents the image of the film under the digital microscope.
The film was made to gel by sprinkling an aqueous solution
of 4 % CaCl2 on the petridish. Divalent Ca2? ions partic-
ipate in the inter-chain ionic binding that results in a three
dimensional network of the ionotrophic calcium alginate
gel. The polymer chains entrap a large volume of water.
The gelation process leads to the reorganization of the
network, and expulsion of some water. The exchange of
Ca2? ion with Na? ion in alginate proceeds faster that the
molecular diffusion of CaCl2 in the gel layer. Upon addi-
tion of CaCl2 solution, the aqueous solution immediately
transforms to a milky white structure. The gel film did not
stick to the glass, and developed a robust free-resting film
with the embedded voids within minutes.
The SEM image of the free-resting gel film at the end of
drying under vacuum is presented in Fig. 2. The voids
formed by the bubbles retained its identity and shape after
drying. In comparison with Fig. 1, a moderate shrinkage in
the void dimension was observed. The average diameter of
the bubble in the aqueous film was 500 lm. This size was
reduced to around 200 lm after drying. This is consistent
with the reduction in the surface area of the scaffold.
According to the geometric measurements, the initial sur-
face area of 20 cm2 was nearly halved after drying. The
wrinkles appeared on the scaffold after drying that made
the measurement of area little uncertain. On the other hand,
there were significant reductions in the weight and the
thickness of the scaffold. After drying, the weight of the
scaffold was typically reduced from 4 to 0.15 g, and the
average thickness of the scaffold was reduced from 1.00 to
0.15 mm. A spatial variation of ±0.02 mm in thickness of
the dried scaffold was observed.
Figure 3 shows the SEM image of the void with the
adjoining matrix. Prior to the crosslinking of the scaffold,
the bubbles were floating over a thin aqueous film. After
drying, this film appeared smoother, compared to the other
portions of the gel matrix. This is evident from the SEM
image, taken at higher magnification. The other portions of
Fig. 1 Image of the alginate film in aqueous state
Fig. 2 SEM image of alginate scaffold after drying
256 J Sol-Gel Sci Technol (2013) 68:254–260
123
the gel matrix seem to have surface irregularities, arising
from uneven contact with the crosslinker and possibly due
to some local warping at the time of moisture removal.
For alginate gel film without bubbles, the BET surface
area was found to be 0.56 m2/gm. The average pore
diameter and the pore volume were found to be 0.124 lm,
and 1.802 9 10-2 cc/gm respectively. The data applies to
pores smaller than 3.19 lm. For alginate gel film with
voids, the corresponding figures are 0.79 m2/gm,
0.092 lm, and 1.830 9 10-2 cc/gm respectively. The data
refers to pores smaller than 0.6 lm, and thus does not
include the induced voids. The introduction of voids
increased the BET surface area without changing the pore
structure at submicron level.
Figure 4 presents the X-ray diffraction profiles for the
scaffolds with and without voids respectively. The broad
diffraction peak suggests low crystallinity, or defective
crystals. The peak at the 2h value of 15.1� corresponds to
d-spacing of 0.6805 nm. No shift in the peak was observed
due to the presence of voids. Table 1 describes the
mechanical strength of the scaffold. The maximum tensile
strength was found to be 12.03 MPa for the scaffold
without voids. A four-fold reduction in strength was
observed due to the presence of voids. Figure 5 presents
the force data as function of elongation for the scaffold
with voids. The features of this plot are very similar to the
profiles for scaffolds without voids. The scaffolds with
voids retained its integrity after re-swelling and exposure to
impact loads such as in a vortex shaker for extended per-
iod. A swelled scaffold of diameter 10 cm, and thickness
0.2 cm could be handled like a rubber disc, without any
special precaution.
The experiments were conducted in three sets of scaf-
folds. Each set comprises of two scaffolds, one with voids,
and the other without voids. Each set of scaffolds was dried
together in the vacuum oven under similar condition.
Figures 6, 7 and 8 describe the change in weight and
thickness of the scaffold as the drying proceeds on the pair
of films. The scaffolds in Fig. 5 were thinner, compared to
other scaffolds. Figure 8 describes the changes in the
scaffolds while drying at a reduced temperature. The
conditions, under which each set of scaffolds were dried
are specified in the figure captions. The presence of voids
resulted in faster drop in the weight and the thickness, and
thus enhanced the removal of moisture when the drying
was conducted at higher temperature. No such enhance-
ment was observed when the drying was conducted at
30 �C over a longer period of time. With the similar initial
weight of the scaffold, the final weight after drying was
always less when the voids were present.
Figures 9, 10, and 11 describe the rate of drying curve
for the three sets of scaffolds. The initial moisture content
per gram of bone dry scaffold was almost doubled when
the voids were present. We anticipate that this volume will
induce extra porosity to the scaffold, as intended. When the
voids were present, and the drying was conducted at higher
temperature, the rate of drying was found significantly
higher. That is, the higher temperature resulted in faster
vaporization of water from the void space. A comparison of
Figs. 9 and 10 indicates that for the thinner scaffold
without void, a constant drying rate could be established at
moderately low moisture content. This was not possible in
thicker scaffold or in scaffolds with voids with same level
of moisture content. This indicates that the surface mois-
ture continued to be present in the thin scaffold without
voids for a significant part of the drying period. On the
other hand, in presence of voids the falling rate period
persisting at higher moisture content indicates de-satura-
tion of a part of the scaffold, even when the moisture is
present inside.
Figures 12, 13, and 14 present the reduction in thickness
of the scaffolds as a function of the moisture content. The
moisture content (M) was made dimensionless by dividing
with the initial moisture content of the scaffold (M0). When
the voids were present in the thick scaffold, the shrinkage
Fig. 3 Magnified SEM image of the bubble matrix interface
0
100
200
300
400
500
600
700
10 15 20 25 30
Inte
nsi
ty (
a.u
.)
2 (deg)
Without voids
With voids
Fig. 4 XRD analysis of alginate scaffold
J Sol-Gel Sci Technol (2013) 68:254–260 257
123
was substantial at higher moisture content, and was mod-
erate at comparatively lower moisture content. We
hypothesize that the de-saturation of the voids resulted in
initial shrinkage for the thicker scaffold. This is in line with
the falling rate period of drying, consistently observed for
the scaffolds with voids.
To demonstrate the enhancement of uptake by the
scaffold due to the presence of voids, the fully dried
scaffold was dipped into aqueous solution of Vitamin B-12
(200 ppm). The volume of displaced solution provided an
estimate of the dry volume, whereas the volume of the
remaining solution after removal of the swelled scaffold
Table 1 Results from tensile strength analysis
Scaffold
tag
Thickness
(mm)
Length
(mm)
Width
(mm)
Yield stress
(MPa)
Max. stress
(MPa)
Tensile modulus
(MPa)
Elongation at break
(%)
Without void 0.1 31 13 12.03 12.03 923 1.939
With voids 0.1 31 13 2.391 2.892 269.3 3.129
0
0.5
1
1.5
2
2.5
3
3.5
4
0 0.2 0.4 0.6 0.8 1 1.2
Fo
rce
(N)
Extension (mm)
Fig. 5 Force-deformation plot for alginate scaffold with voids
0.1
1
0.1
1
10
0 50 100 150 200 250
Th
ickn
ess(
mm
)
Time (min)
Without bubble weight With bubble weight
Without bubble thickness With bubble thickness
Wei
gh
t o
f sc
affo
ld(g
m)
Fig. 6 Weight and thickness of thin scaffold for drying at 50 �C
0.1
1
10
0.1
1
10
0 50 100 150 200 250 300
Thic
knes
s(m
m)
Time (mm)
Without bubble weight With bubble weight
Without bubble thickness With bubble thickness
Wei
gh
t o
f sc
affo
ld(g
m)
Fig. 7 Weight and thickness of thick scaffold for drying at 50 �C
0.1
1
10
0.1
1
10
0 100 200 300 400 500
Thic
knes
s(m
m)
Time (min)
Without bubble weight With bubble weight
Without bubble thickness With bubble thickness
Wei
gh
t o
f sc
affo
ld(g
m)
Fig. 8 Weight and thickness of scaffold for drying at 30 �C
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 10 20 30 40
Moisture content (weight of moisture/weight of dry scaffold)
Without bubble
With bubble
Fig. 9 Rate of drying for thick scaffold dried at 50 �C
258 J Sol-Gel Sci Technol (2013) 68:254–260
123
provided the estimate of the hydrated volume of the scaf-
fold. For the scaffolds without voids, an absorption
amounting to 600 % of its dry volume was observed. The
level of absorption was enhanced to 1,000 % when the
voids were present.
4 Conclusions
The article presents the changes in the alginate scaffold
with induced voids, as the scaffold undergoes vacuum
drying. By the use of a fluidic arrangement, the voids were
introduced in the form of mono-dispersed and self-assem-
bled bubbles prior to the gelation of alginate. The image of
the film at this stage, acquired under digital microscope
was compared with the SEM image of the dried scaffold.
The voids retained their identity at the time of drying,
while the diameter was reduced to half of the initial value.
The thickness of the scaffold was reduced ten folds. The
presence of voids enhanced the drying rate when the drying
was conducted at higher temperature. The drying primarily
occurred in the falling rate period. The constant rate period
was approached at lower moisture content for thin scaf-
folds without voids indicating the presence of surface
moisture in these scaffolds for a substantial period. This
feature was not observed for the scaffold with voids. Also,
the shrinkage of a thick scaffold occurred primarily at the
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 10 20 30 40
Moisture content (weight of moisture/weight of dry scaffold)
without bubble
With bubble
Fig. 10 Rate of drying for thin scaffold dried at 50 �C
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0 5 10 15 20 25
Moisture content (weight of moisture/weight of dry scaffold)
Without bubble
With bubble
Fig. 11 Rate of drying for scaffold dried at 30 �C
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1
Sh
rin
kag
e(L
/L0)
Moisture ratio (M/M0)
Without bubble
With bubble
Fig. 12 Shrinkage in thick scaffold for drying at 50 �C
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1
Sh
rin
kag
e(L
/L0)
Moisture ratio (M/M0)
Without bubble
With bubble
Fig. 13 Shrinkage in thin scaffold for drying at 50 �C
0
0.2
0.4
0.6
0.8
1
1.2
0 0.2 0.4 0.6 0.8 1 1.2
Sh
rin
kag
e (L
/L0)
Moisture ratio (M/M0)
Without bubble
With bubble
Fig. 14 Shrinkage in scaffold for drying at 30 �C
J Sol-Gel Sci Technol (2013) 68:254–260 259
123
initial phase of drying, when the voids were present. We
hypothesize that for these scaffolds the de-saturation of the
void part started before the moisture was removed sub-
stantially from the scaffolds.
Acknowledgments Department of Science & Technology, Gov-
ernment of India for financial support.
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