See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/261566836

One-stop microfiber spinning and fabrication of a fibrous cell-encapsulated

scaffold on a single microfluidic platform

Article  in  Biofabrication · April 2014

DOI: 10.1088/1758-5082/6/2/024108

CITATIONS READS

21 155

6 authors, including:

Doyeun Park Cho Hay Mun

Korea University Korea University
11 PUBLICATIONS   121 CITATIONS    25 PUBLICATIONS   193 CITATIONS   

SEE PROFILE SEE PROFILE

Jongil Ju Sang-Hoon Lee

ABM (Advanced Bio Micro) Scientific Co. & Dankook University Korea University
27 PUBLICATIONS   558 CITATIONS    713 PUBLICATIONS   11,332 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Three-Dimensional Electrospun Poly(Lactide-Co-ɛ-Caprolactone) for Small-Diameter Vascular Grafts View project

Hollow Alginate Microfibers View project

All content following this page was uploaded by Doyeun Park on 19 May 2017.

The user has requested enhancement of the downloaded file.

Home Search Collections Journals About Contact us My IOPscience

One-stop microfiber spinning and fabrication of a fibrous cell-encapsulated scaffold on a

single microfluidic platform

This content has been downloaded from IOPscience. Please scroll down to see the full text.

2014 Biofabrication 6 024108

(http://iopscience.iop.org/1758-5090/6/2/024108)

View the table of contents for this issue, or go to the journal homepage for more

Download details:

IP Address: 163.152.242.241
This content was downloaded on 11/04/2014 at 10:52

Please note that terms and conditions apply.

 Biofabrication
Biofabrication 6 (2014) 024108 (7pp) doi:10.1088/1758-5082/6/2/024108

One-stop microfiber spinning and

fabrication of a fibrous cell-encapsulated
scaffold on a single microfluidic platform
D Y Park 1,3 , C H Mun 1,3 , E Kang 1 , D Y No 1 , J Ju 1 and S H Lee 1,2,4
1
Department of Biomedical Engineering, College of Health Science, Korea University, Seoul 136-703,
Korea
2
KU-KIST Graduate School of Converging of Sciences & Technologies, Korea University,
Seoul 136-713, Korea
E-mail: dbiomed@korea.ac.kr

Received 28 May 2013, revised 16 October 2013

Accepted for publication 31 October 2013
Published 10 April 2014

Abstract
This paper provides a method for microscale fiber spinning and the in situ construction of a 3D
fibrous scaffold on a single microfluidic platform. This platform was also used to fabricate a
variety of fibrous scaffolds with diverse compositions without the use of complicated devices.
We explored the potential utility of the fibrous scaffolds for tissue engineering applications by
constructing a fibrous scaffold encapsulating primary hepatocytes. The cells in scaffold were
cultured over seven days and maintained higher viability comparing with 3D alginate
non-fibrous block. The main advantage of this platform is that the fibrous structure used to
form a scaffold can be generated without damaging the mechanically weak alginate fibers or
encapsulated cells because all procedures are performed in a single platform without the
intervention of the operator. In addition, the proposed fibrous scaffold permitted high diffusion
capability of molecules, which enabled better viability of encapsulated cells than non-fibrous
scaffold even in massive cell culture.

Keywords: microfluidic, 3D alginate fibrous scaffold, cell-laden fibers, porosity

S Online supplementary data available from stacks.iop.org/BF/6/024108/mmedia

(Some figures may appear in colour only in the online journal)

1. Introduction bio-degradable with an appropriate degradation time, and

In the human body, the extracellular matrix (ECM) plays a key
role in positioning cells for tissue regeneration, temporarily
substituting tissue functions, guiding tissue ingrowth and
maintaining the overall tissue functions [1]. Scaffolds used
for tissue engineering should resemble the structural and
chemical properties of the target tissue’s ECM as closely as
possible, and should include high porosity for nutrient/waste
flow and tissue ingrowth, appropriate structural geometries
and pore dimensions. In addition, the scaffolds should be
3 These authors contributed equally to this study.
4 Author to whom any correspondence should be addressed.
they should maintain their mechanical integrity over a pre-
determined timeframe [2–7]. To date, numerous studies have
attempted to produce scaffolds that satisfy these requirements
by employing methods that involve particulate leaching
[8, 9], gas foaming [10], micro- and nano-fiber networking
[11, 12], solution casting [13], microstereolithography
[14], rapid prototyping [15–17] and combinations of these
techniques. Among these methods, fiber-based scaffold
fabrication has attracted much attention due to its advantages
in the context of guided cell growth, cell networking and for
the ability to control the porosity. Recent progress in electro-
spinning technologies has led to the development of nanofibers
with a diversity of shapes and sizes. These nanofibers have

1758-5082/14/024108+07$33.00 1 © 2014 IOP Publishing Ltd Printed in the UK

Biofabrication 6 (2014) 024108
been broadly used as biomimetic scaffolds because they
can provide networked structures similar to collagen [18].
Although nanofiber scaffolds have contributed much to our
understanding of cell–ECM interactions, thereby advancing
tissue engineering applications, nanofiber scaffolds are limited
in their practical utility because they are only fabricated
using two-dimensional platforms. We and other researchers
have developed a new spinning method that overcomes this
limitation by the continuous spinning of microscale fibers
using a microfluidic chip [19–24]. This spinning method is
advantageous in providing spatiotemporal control over the
composite material composition, size and morphology, and
encapsulation of cells; however, the use of these fibers as three-
dimensional (3D) scaffolds requires the development of new
processes and devices. Previous methods used an acryl spool
to wind a microfiber and construct a pseudo 3D structure [25].
Although the winding method is advantageous in assembling
aligned 3D structures, microfiber winding requires skill, is
labor-intensive and is a fragile process requiring much care.
Here, we describe a microfluidic spinning PDMS chip that
is integrated with a 3D fibrous scaffold fabrication chamber
on a single microfluidic platform for the one-stop construction
of a fibrous scaffold. We made a single microfluidic platform
system for fibrous cell-laden scaffolds that can easily control
the shape and volume of cell-laden alginate scaffold and
porosity. Recently, the cell-laden fibrous scaffold has attracted
great attention due to its extensive applications [26]. However,
the handling and shape formation of cell-laden alginate
fiber is challenging due to its mechanical weakness. In
addition, the microfluidic device could reduce the possibility
of contamination, cost and labor. Microfluidic spinning was
accomplished using a cylindrical channel to generate a coaxial
sheath and sample flow [27, 28]. The resulting fibers were
collected in an accumulation chamber fabricated at the outlet
of the spinning channel, and a buffer solution was pumped
into the bottom of the chamber through a filter that separated
the fibers from the solution. The performance of scaffold was
evaluated by measuring the porosity of the scaffolds prepared
under different flow rates. We also fabricated a scaffold using
diverse fibers with different compositions to demonstrate the
capabilities with respect to ECM property modulation.
The functionality of the scaffold was briefly demonstrated
by encapsulating primary hepatocytes from a rat within a
fiber during the spinning process, and the cell viability was
evaluated. The proposed method permitted control over the
dimensions of the scaffold, even when many materials were
used to fabricate the microfibers, suggesting that the method is
promising for future tissue engineering applications requiring
careful control over the dimensions and compositions of the
scaffold.
2. Materials and methods
2.1. Method design, spinning process, and collecting chip
We designed and fabricated a microfluidic chip for the one-
stop construction of a fibrous scaffold. The chip consisted
of three layers: top, middle and bottom layers (figure 1(a)).
2
D Y Park et al
Onto the top and middle layers, cylindrical channel patterns
were engraved to generate a coaxial flow, whereas the bottom
layer included a nylon mesh filter (mesh size 70 μm, BD
Falcon). The filter was integrated into the PDMS chip after
cutting the filter with scissors into square-shaped pieces
about 10 mm wide. A piece of the filter was aligned and
bonded to the accumulating chamber of the middle layer
using a PDMS prepolymer as glue. The scanning electron
microscopy (FE-SEM, JEOL) image in figure 1(a) shows
a magnified view of the filter structure. The microfluidic
chip was constructed by bonding layers via oxygen plasma
treatment (CUTE-MP, FEMTO SCIENCE). Into the inlet of
the sheath and sample channels, the sample fluid (collagen-
alginate solution) and sheath fluid (3% (w/v) calcium chloride,
Sigma) were introduced respectively, and the flow speed of
each fluid was controlled using a syringe pump (KDS-100,
KD Scientific). Collagen-alginate solution was prepared as
previously described [29]. The sheath flow not only prevented
contact between the sample flow and the channel wall, but
also it shaped the focused sample flow and induced gelation of
alginate via Ca2+ ion chelation to form a solid microfiber. The
gelled fibers were extruded from the end of the outlet channel
and collected into the accumulating chamber, and the venting
channel was opened to retrieve the lumped fibers only. The
process is summarized in detail in figure 1(b). To show the
spatial coding of fiber with different materials, Janus fibers
were fabricated by preparing a microfluidic spinning chip
consisting of multiple sample inlets (see figure S1(a), available
at stacks.iop.org/BF/6/024108/mmedia). The simultaneous
introduction of alginate solutions containing different types
of nano particles yielded double- or triple-layer Janus fibers.
In addition, by the integration of multiple spinning channels,
we fabricated the complex fibrous scaffold consisting of fibers
with different compositions as shown in figure S1(b) (available
at stacks.iop.org/BF/6/024108/mmedia).
2.2. Porosity control of the fibrous scaffold
The porosity of a fibrous scaffold can be easily controlled
according to the flow rates of both the sample and sheath fluids.
This relationship was explored by calculating the porosity of
the fibrous scaffold based on the volume percentage of fibers
in the accumulating chamber, and the porosity was determined
as follows:
Qsample × T
Porosity = 1 − ,
t × Achamber
where Qsample is the sample flow rate, T is the fiber spinning
time, t is the scaffold thickness and Achamber is the accumulating
chamber area. The scaffold thickness was measured using a
confocal microscope, and the sample flow rate was set to 3,
5 or 7 μL min−1, and the sheath flow rate was set to 20 or
30 mL h−1. The dependence of the resulting porosity on the
respective flow rates could, therefore, be determined.
2.3. Calculation of the diffusion characteristics through the
fibrous scaffolds
Fibrous scaffolds are broadly useful in tissue engineering
applications; for example, they can be used to encapsulate
Biofabrication 6 (2014) 024108 D Y Park et al

(a)

(b)

Figure 1. Production of the fibrous scaffold. (a) Schematic diagram of the microfluidic chip used to fabricate the fibrous scaffolds (the inset
shows a magnified SEM image of the filter). (b) Detailed schematic diagram showing the fibrous scaffold generation process: (bottom, left)
the spinning duct, (bottom, middle) gelation of the sample fluid in a cylindrical channel and (bottom, right) fibrous scaffold construction in
the accumulating chamber. The scale bar indicates 70 μm in (a).

or to seed cells, to guide cell growth and to deliver embedded
bioactive materials. The transportation of molecules through
the fiber scaffold is important in these applications. Here, we
simulated molecular transport through a single fiber using
the finite element method software (COMSOL). A steady-
state solution to the convection and diffusion modules was
established to investigate the concentration of the sample
molecule at each point in the fiber. Glucose (molecule weight:
180.16 g mol−1) was modeled as the sample molecule in
these calculations because glucose is a typical nutrient and
is generally required by all cell types. The initial glucose
concentration at the boundary was set to 5.56 mol m−3, and
the diffusion coefficient characterizing the transport of glucose
to the alginate domain was set to 6.8 × 10−6 m2 s−1 [30].
Molecular transport was quantified by measuring the glucose
concentration change at the center of the fiber over time.
2.4. Isolation of primary rat hepatocytes
Primary hepatocytes were isolated from 8-week-old male
Sprague-Dawley rats (DBL, Seoul, South Korea), weighing
250–280 g, using a two-step collagenase perfusion procedure,
as previously described [31–33]. Primary hepatocytes were
cultured in the high-glucose Dulbecco’s modified eagle’s
medium (DMEM, GIBCO) supplemented with 20 mM
HEPES, 25 mm NaHCO3, 30 mg L−1 proline, 10% fetal
bovine serum (FBS, GIBCO), 25 U mL−1 penicillin,
25 μg mL−1 streptomycin, 10 μg mL−1 gentamicin,
10 ng mL−1 epidermal growth factor (EGF, GIBCO),
50 ng mL−1 insulin, 10−4 m dexamethasone, 10 mm
nicotinamide, and 100 mm L-ascorbic acid. All procedures
adhered to the guidelines of the IRB of Korea University.

3
Biofabrication 6 (2014) 024108
(a)
(c) (d )
Figure 2. Fluorescence images of the fibrous scaffolds. (a) Fluorescence image of an alginate fiber in a spinning duct. (b) Merged confocal
images of the fibrous scaffold. (c)–(e) Confocal images of multi-component fibers prepared with (c) one sample, (d) two samples or (e) three
samples. The scale bars indicate 200 μm in (a), 1 mm in (b), 100 μm in (c)–(e) (upper) and 400 μm in (c)–(e) (lower).
2.5. Fabrication of a fibrous scaffold using
hepatocyte-embedded fibers and viability test
Hepatocytes were encapsulated in the fibers using a
microfluidic chip described previously [34]. We dispersed the
prepared hepatocytes in a 2% (w/v) alginate solution at a
concentration of 5 × 106 cells mL−1. The solution containing
hepatocytes was introduced through the sample channel at
an average flow rate of 90 μL min−1. After channel closure,
we removed the cylindrical spinning channel by cutting with
a scalpel blade, and the accumulating chamber, including
the fibrous scaffold, was transferred to the cell culture dish
containing primary hepatocyte culture medium to maintain the
3D scaffold shape. The cells and scaffold were co-incubated
in an incubator over the next seven days, and the cell viability
was assessed by adding 50 mM Calcein-AM and 25 mg mL−1
ethidium homodimer-1 (EthD-1; Molecular Probes, USA) to
the culture medium and by incubating for 40 min at 37 ◦ C.
3. Results
Figure 2(a) shows the dyed alginate sample flow traveling
through a cylindrical channel in the PDMS, followed by the
focusing of the sample flow by the CaCl2 sheath flow. The
gelled and extruded fibers were collected in the accumulating
chamber over 7–8 min, as shown in figure 2(b) (the buffer
solution was vented). The white dotted circle indicates the
4
D Y Park et al
(b)
(e)
accumulating chamber boundary. The Janus chip was used to
fabricate diverse fibers having spatially different compositions
in large quantities, as shown in the 3D confocal image in
figures 2(c)–(e). The inset of each figure shows a schematic
diagram of the cross-sectional view. The characteristics of the
fibrous scaffold, including the scaffold thickness growth rate
and porosity, were quantitatively measured as a function of the
flow rate.
Figure 3(a) shows a 3D confocal image of the fibrous
scaffold. Z-plane images of the fibrous scaffold were collected
from 0 to 2 mm in steps of 0.1 mm using confocal microscopy,
and a stacked image was reconstructed. The thickness of
the scaffold was assessed from the side view of the image
(figure 3(a), XZ projection). Porosity was calculated using the
equation given above. As shown in figure 3(b), the porosity of
the scaffold could be controlled simply by changing the flow
rate (both the sample and sheath flow rates), yielding porosity
values between 0.23 and 0.52. By connecting the outlets of
three separate spinning channels to a single accumulating
chamber, we produced complex fibrous scaffolds in which
three fibers with different compositions were spatially mixed
(figure 3(c)). Figures 3(d) and (e) show, respectively, 3D and
2D confocal images of the complex fibrous scaffold. We
fabricated cell-laden fibers which were composed with rat
primary islet cells and adipose stem cells (figure S4, available
at stacks.iop.org/BF/6/024108/mmedia).
Biofabrication 6 (2014) 024108
(a) (b)
(c) (d ) (e)
Figure 3. Characteristics of the fibrous scaffold. (a) Confocal
Z-stack images obtained during three-dimensional imaging of the
fibrous scaffold. (b) Porosity of the fibrous scaffold as a function of
the flow rate. (c) Schematic diagram showing the fabrication of a
complex fibrous scaffold. Confocal images of a complex fibrous
scaffold in (d) three dimensions and (e) two dimensions. The scale
bars indicate 400 μm in (a) and 1 mm in (d).
Glucose transport was modeled as described above. The
simulation results shown in figure 4(a) reveal that a fiber with
a diameter of 100 μm rapidly transported nutrients (glucose)
into the inside of the fiber. Exposure of the fiber to glucose
increased the glucose concentration at the center of the fiber
from 0 to 5.409 mol m−3 within 10 s (figure 4(b)). We cultured
rat primary hepatocytes three-dimensionally with two types of
culture methods: three-dimensional culture in alginate block
and in fibrous scaffolds.
The cell densities in the alginate blocks and the
fibrous scaffolds were identical, 5 × 106 cells mL−1,
and the volume of alginate blocks and whole fibrous
scaffolds is almost identical too. Figure S3 (available
(a)
(c)
Figure 4. Glucose diffusion simulation results in the alginate fibrous scaffold and alginate bulk scaffold. (a) Changes in the glucose
concentration across the single alginate fiber, (b) plot of the concentration at the center of the single alginate fiber as a function of time, (c)
changes of glucose concentration in 3D alginate bulk scaffold. Glucose concentration at boundary was set to 5.56 mol m−3. (d) Plot of
concentration at different points (A), (B) and (C) versus time.
5
D Y Park et al
at stacks.iop.org/BF/6/024108/mmedia) shows the resulting
image of Live/Dead assay performed on cells encapsulated
in the fibrous scaffold on day 7 after the cell seeding,
respectively. The green and red colors represent live and
dead cells, respectively. The cell viability on the fibrous
scaffold was compared with the values on the three-
dimensional culture in alginate blocks with the same volume.
Cells encapsulated in the fibrous scaffold survived more
than cells cultured in 3D alginate block (figure S3 and
S4, available at stacks.iop.org/BF/6/024108/mmedia), as
expected. Cells in the fibrous scaffolds showed a much
higher viability during whole culture day than 3D alginate
bulk scaffold culture conditions (figure S5, available at
stacks.iop.org/BF/6/024108/mmedia).
4. Discussion
A one-stop microfiber spinning and fabrication device for
producing fibrous scaffolds was successfully constructed.
The fiber accumulating chamber, outfitted with a 70 μm
mashed filter that vented the buffer solution away from
the fiber, collected the fibrous scaffold structure without
the need for additional processes or devices. All processes
were performed on a single microfluidic platform without
the intervention of the operator. The mechanical strength of
alginate microfibers is weak, which complicates fiber handling
during the construction of 3D structures; however, as the
proposed platform enabled all fabrication processes to be
performed on a single platform, the mechanical weakness of
the fiber was not problematic at all. The accumulated fiber was
distributed uniformly in the chamber, and it aggregates to form
a lump like a skein upon drying. The growth rate of the scaffold
thickness was not affected by the flow rate. The porosity of
the scaffold, on the other hand, could be regulated by varying
the flow rate. By decreasing the sample flow rate, the fiber
diameter could be reduced and the porosity of the fibrous
scaffold could be decreased. A scaffold consisting of a dense
fibrous structure formed by small-diameter fibers was thereby
(b)
(d )
Biofabrication 6 (2014) 024108
formed. An increase in the number of spinning channels
and the introduction of different materials into each channel
permitted the construction of complex scaffolds composed
of diverse materials. Each different fiber was distributed
uniformly throughout the scaffold. Scaffolds generally require
materials that promote cell interactions, adhesion, proliferation
and migration. The bioactivity of our fibrous scaffold may
be controlled by incorporating growth factors, enzymatic
recognition sites and adhesion factors into each fiber. The
fiber itself may be spatiotemporally coded along the fiber axis
by introducing different sample compositions over time, as
reported previously [20]. Modifications to the scaffold on
the microscale or in bulk can, therefore, be achieved. As
shown in this study, cells may be immobilized within the
fibers, and the proposed technology could potentially support
tissue engineering applications that involve diverse cells. The
cell-based study definitively demonstrates the advantages of
the proposed fibrous scaffold. According to figure S3 and
figure S4 (available at stacks.iop.org/BF/6/024108/mmedia),
hepatocytes in the alginate block showed lower viability
than in the fibrous scaffold at the seventh day, possibly
due to the poor diffusion of nutrients, oxygen and wastes.
This result could be explained by figure 4, the 3D fibrous
scaffold had good diffusion properties and could improve
mass transfer through the scaffold [35]. We measured secretion
of albumin at 1st, 3rd, 5th and 7th day to compare function
of hepatocytes in both alginate fibrous scaffold and alginate
block scaffold. An evaluation of albumin secretion in both
groups for seven days showed that a greater amount of albumin
was secreted by alginate fibrous scaffold although hepatocytes
in both scaffolds secreted albumin in figure S5 (available at
stacks.iop.org/BF/6/024108/mmedia). The proposed method
was shown to be suitable for cell encapsulation and scaffold
formation with good diffusion property for exchanging of
nutrients and wastes, and proper 3D culture for maintaining
liver specific functions and phenotype. This approach may
conceivably be extended to the fabrication of massive three-
dimensional cell-based scaffolds in an easy, cost-effective
and non-damageable way [26]. This fibrous scaffold can
encapsulate massive numbers of cells in a fiber, so it can be
used in both massive culture models in vivo transplantational
model with solved diffusion limitation problem of alginate
scaffold in huge mass culture. Also, we can encapsulate various
types of cells together in a fiber through the Janus chip, and we
can study parenchymal–nonparenchymal cell interactions and
make more in vivo mimicking structures through this method.
In this study, we used primary hepatocytes that are quite
sensitive and can easily lose their viability and phenotype.
Although we used difficult cells of in vitro culturing, we
successfully encapsulated them and maintained their high
viability for one week.
5. Conclusion
In this paper, we have described a one-stop method for
fabricating cell-laden microfibers and easy 3D forming of
cell-laden fibrous scaffolds on a single platform without the
intervention of an operator or other complicated devices. The
6
D Y Park et al
porosity of the scaffold could be readily controlled by varying
the fluid flow rates. The porosity of fibrous scaffold was
high compared to the porosity of a bulk hydrogel scaffold,
and these scaffolds are advantageous for easy diffusion of
nutrient, oxygen and other molecules to the encapsulated cells
in fiber. All processes were performed in situ on a single
platform, which avoided damaging the weak cell-laden fibers
and facilitated the easy handling and shape forming of cell-
laden fibers. If prepared using fibers with diverse cells or
materials, the fibrous scaffold may potentially be used to mimic
the partial support or regeneration of an organ or tissue.
Acknowledgments
This work was supported by the National Research Foundation
of Korea (NRF), funded by the Korean Government (MEST)
(no. 201304640). Support was also provided by the Industrial
Core Technology Development Program (no. 10041923),
funded by the Ministry of Knowledge Economy. This work was
also supported by Seoul R&BD program (grant no. SS110011)
References
[1] Dutta R C and Dutta A K 2009 Cell-interactive 3D-scaffold;
advances and applications Biotechnol. Adv. 27 334–9
[2] Peltola S M, Melchels F P W, Grijpma D W and Kellomaki M
2008 A review of rapid prototyping techniques for tissue
engineering purposes Ann. Med. 40 268–80
[3] Billiet T, Vandenhaute M, Schelfhout J, Van Vlierberghe S
and Dubruel P 2012 A review of trends and limitations in
hydrogel-rapid prototyping for tissue engineering
Biomaterials 33 6020–41
[4] Ma P X 2004 Scaffolds for tissue fabrication Mater. Today
7 30–40
[5] Hutmacher D W 2000 Scaffolds in tissue engineering bone
and cartilage Biomaterials 21 2529–43
[6] Griffith L G and Naughton G 2002 Tissue
engineering—current challenges and expanding
opportunities Science 295 1009–14
[7] Freed L E et al 1994 Biodegradable polymer scaffolds for
tissue engineering Biotechnology 12 689–93
[8] Pathi S P, Kowalczewski C, Tadipatri R and Fischbach C 2010
A novel 3D mineralized tumor model to study breast cancer
bone metastasis Plos One 5 e8849
[9] Martin L, Alonso M, Girotti A, Arias F J
and Rodriguez-Cabello J C 2009 Synthesis and
characterization of macroporous thermosensitive hydrogels
from recombinant elastin-like polymers Biomacromolecules
10 3015–22
[10] Salerno A, Netti P A, Di Maio E and Iannace S 2009
Engineering of foamed structures for biomedical
application J. Cell Plast. 45 103–17
[11] D’Amore A, Stella J A, Wagner W R and Sacks M S 2010
Characterization of the complete fiber network topology of
planar fibrous tissues and scaffolds Biomaterials
31 5345–54
[12] Yim E K and Leong K W 2005 Proliferation and
differentiation of human embryonic germ cell derivatives in
bioactive polymeric fibrous scaffold J. Biomater. Sci.
Polym. Ed. 16 1193–217
[13] Sinha A and Guha A 2009 Biomimetic patterning of polymer
hydrogels with hydroxyapatite nanoparticles Mater. Sci.
Eng. C 29 1330–3
[14] Lee S J, Kang H W, Park J K, Rhie J W, Hahn S K
and Cho D W 2008 Application of microstereolithography
Biofabrication 6 (2014) 024108
in the development of three-dimensional cartilage
regeneration scaffolds Biomed. Microdevices 10 233–41
[15] Wang X et al 2006 Generation of three-dimensional
hepatocyte/gelatin structures with rapid prototyping system
Tissue Eng. 12 83–90
[16] Landers R, Hubner U, Schmelzeisen R and Mulhaupt R 2002
Rapid prototyping of scaffolds derived from
thermoreversible hydrogels and tailored for applications in
tissue engineering Biomaterials 23 4437–47
[17] Choi C-H, Hwang S, Jeong J-M, Kang S-M, Kim J
and Lee C-S 2012 Microfluidic synthesis of anisotropic
particles from Janus drop by in situ photopolymerization
Biomed. Eng. Lett. 2 95–9
[18] Yoshimoto H, Shin Y M, Terai H and Vacanti J P 2003 A
biodegradable nanofiber scaffold by electrospinning and its
potential for bone tissue engineering Biomaterials
24 2077–82
[19] Kang E, Choi Y Y, Chae S K, Moon J H, Chang J Y
and Lee S H 2012 Microfluidic spinning of flat alginate
fibers with grooves for cell-aligning scaffolds Adv. Mater.
24 4271–7
[20] Kang E, Jeong G S, Choi Y Y, Lee K H, Khademhosseini A
and Lee S H 2011 Digitally tunable physicochemical
coding of material composition and topography in
continuous microfibres Nat. Mater. 10 877–83
[21] Yamada M et al 2012 Controlled formation of heterotypic
hepatic micro-organoids in anisotropic hydrogel microfibers
for long-term preservation of liver-specific functions
Biomaterials 33 8304–15
[22] Hu M et al 2010 Hydrodynamic spinning of hydrogel fibers
Biomaterials 31 863–9
[23] Chung B G, Lee K H, Khademhosseini A and Lee S H 2012
Microfluidic fabrication of microengineered hydrogels
and their application in tissue engineering Lab Chip
12 45–59
[24] Kim B Y, Hong L Y, Chung Y M, Kim D P and Lee C S 2009
Solvent-resistant PDMS microfluidic devices with hybrid
inorganic/organic polymer coatings Adv. Funct. Mater.
19 3796–803
View publication stats
D Y Park et al
[25] Hwang C M, Khademhosseini A, Park Y, Sun K and Lee S H
2008 Microfluidic chip-based fabrication of PLGA
microfiber scaffolds for tissue engineering Langmuir
24 6845–51
[26] Jun Y et al 2013 3D co-culturing model of primary pancreatic
islets and hepatocytes in hybrid spheroid to overcome
pancreatic cell shortage Biomaterials 34 3784–94
[27] Kang E, Lee D H, Kim C B, Yoo S J and Lee S H 2010 A
hemispherical microfluidic channel for the trapping and
passive dissipation of microbubbles J. Micromech.
Microeng. 20 045009
[28] Kang E, Shin S J, Lee K H and Lee S H 2010 Novel PDMS
cylindrical channels that generate coaxial flow, and
application to fabrication of microfibers and particles
Lab Chip 10 1856–61
[29] Lee B R et al 2012 In situ formation and collagen-alginate
composite encapsulation of pancreatic islet spheroids
Biomaterials 33 837–45
[30] Hannoun B J M and Stephanopoulos G 1986
Diffusion-coefficients of glucose and ethanol in cell-free
and cell-occupied calcium alginate membranes Biotechnol.
Bioeng. 28 829–35
[31] Dunn J C Y, Yarmush M L, Koebe H G and Tompkins R G
1989 Hepatocyte function and extracellular-matrix
geometry—long-term culture in a sandwich configuration
Faseb J. 3 174–7
[32] Wong S F, No D Y, Choi Y Y, Kim D S, Chung B G
and Lee S H 2011 Concave microwell based
size-controllable hepatosphere as a three-dimensional liver
tissue model Biomaterials 32 8087–96
[33] Seglen P O 1976 Preparation of isolated rat liver cells Methods
Cell Biol. 13 29–83
[34] Lee B R, Lee K H, Kang E, Kim D S and Lee S H 2011
Microfluidic wet spinning of chitosan-alginate microfibers
and encapsulation of HepG2 cells in fibers Biomicrofluidics
5 022208
[35] Park J, Kim K B, Lee J, Kim H C and Huh D 2012
Organomimetic microsystems technologies Biomed. Eng.
Lett. 2 88–94