Biomedical Engineering Reference
In-Depth Information
bifurcating network of leaf venation (
Wu et al
.,
2010
). In this approach, a CAD image of leaf vena-
tion was obtained and then a modified direct-write assembly process utilizing fugitive organic ink
was used to create biomimetic microvascular networks of varying design. The authors explored the
effects of network design on fluid transport efficiency and found that fluid transport efficiency is
maximized when the network architecture obeys Murray's law, which relates the radii of branching
vasculature to volumetric flow and velocity profiles showing maximal efficiency of mass transport
(
Murray, 1926; Sherman, 1981
)
.
8.1.3
APPROACHES TO FABRICATE ENDOTHELIALIZED AND CELL-LADEN TISSUE
CONSTRUCTS
Initial efforts to incorporate cells into constructs that resemble vasculature involved seeding of endo-
thelial cells (ECs) inside channels after fabrication of 3D constructs. Lining channels with endothelial
cells is critical for control of vascular functions such as barrier function, blood vessel formation, coagu-
lation, and inflammatory response. To this end, Golden et al. have fabricated perfusable microfluidic
extracellular matrix (ECM) hydrogels by using molded gelatin as a sacrificial element for the transport
of materials in a tissue analogue (
Golden and Tien, 2007
). By encapsulating micromolded meshes of
gelatin inside a gel followed by removal of gelatin by heating and flushing, interconnected channels
as narrow as 6
m
m were obtained. These gels were then seeded with microvascular endothelial cells
(MECs) to demonstrate attachment, spreading, and proliferation of cells on the lumen of the channels,
indicating normal function of seeded cells, which could later be perfused. To produce a multiplanar
network that can be used to transport and exchange materials in a 3D manner, the authors coencapsu-
lated and melted multiple gelatin meshes. Although soft lithography and photolithography techniques
have been extensively used to create 3D microfluidic networks, one limitation of these techniques is
that the fabricated channels contain a rectangular cross-section and sharp transitions between channels,
which do not mimic physiological properties. Furthermore, the presence of rectangular walls and cor-
ners, in addition to nonphysiological blood flow conditions, results in asymmetric shear stress around
the vessel perimeter, limiting the ability to form confluent endothelial cell layers. To this end, Boren-
stein et al. used an electroplating process to obtain sheets with semicircular cross-sections and smooth
transitions at bifurcations and changes in diameter (
Borenstein et al., 2010
). To obtain closed circular
microchannel networks, the sheets were aligned and bonded by applying an adhesive to the outer edges
of the sheets. Cell viability and spreading of human umbilical vein endothelial cells (HUVECs) cul-
tured within the circular channel networks was confirmed after 24 h of culture in channels containing
multiple bifurcations of various diameters.
Although the techniques just discussed have been successful in incorporating ECs inside channel
lumens, to mimic the more complex architecture of vasculature, various methods have been utilized
to fabricate perfusable, cell-laden 3D constructs. One such method, developed by Cuchiara et al
.
, in-
volved a simple and robust multilayer replica molding technique in which PDMS and PEGDA are
serially replica molded to develop microfluidic hydrogel networks embedded within independently
fabricated PDMS (
Cuchiara et al., 2010
). Taking rational network design into account, the authors
sought to determine the optimal microfluidic vessel spacing to maintain cell viability and maximize
construct metabolic density of encapsulated cells to overcome diffusional limitations of nutrients and
waste. Indeed, the viability of 3T3 fibroblasts was shown to depend on culture time, distance from per-
fused channel, and culture conditions. In constructs containing a perfused channel, necrotic cores were
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