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: snganguly@che.iitkgp.ernet.in

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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