ORGAN PRINTING - 3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine - page 330

static in vitro models as promising hepatocyte culture testbeds toward preclinical phase testing of drug
development ( Chang et al., 2008b ; Chang et al., 2010 ).
The authors have implemented a layer-by-layer microextrusion-based printing technique for the
creation of cell-encapsulated alginate-based liver micro-organs, which are then integrated onto a micro-
fluidic chamber fabricated using soft lithographic techniques ( Chang et al., 2008b ; Chang et al., 2010 ).
The system has shown enhanced functionality of HepG2 liver cells within the 3D micro-organ com-
pared to traditional monolayer culture models in terms of cell viability and urea synthesis. Further-
more, the authors have also implemented the microextrusion-based printing in order to construct a
cell-encapsulated multilayered tissue construct in a sinusoidal pattern to mimic the in vivo liver micro-
architecture. The vascularized nature of the liver microenvironment was closely recapitulated by the
application of continuous shear-mediated drug perfusion flow through the printed liver micro-organ
after its integration within the microfabricated chamber. Drug metabolism studies showed that the system
could serve as a reliable 3D in vitro pharmacokinetic platform for drug screening and toxicity studies.
15.1.3.2 Computational Model Setup for Perfused Printed Liver Micro-organ
Intuitively, one can surmise that perfused bioreactors with high cell density, cell encapsulation com-
bined with parallel patterned geometry of biomimetic liver tissue constructs that have been used as
microscale drug screening platforms, appear to be a rational approach for drug screening and tox-
icity studies. However, iterative process design requires advanced computational models that can
capture the transport phenomena not only on the macroscale micro-organ level ( Tan et al., 2013 ; Hsu
et al., 2014 ; Hutmacher and Singh, 2008 ; Truscello et al., 2011 ) but also on the single cellular scale.
Processing parameters such as flow rate, cell density, and shear stresses on the cell surface need to
be correlated with concentration drug profiles and culture time for specific printed liver microarchi-
tectures through appropriate metrics in order to set the design standards that can both predict and
promote in vivo behavior of encapsulated hepatocytes in dynamic printed micro-organ devices under
constant perfusion. The authors have therefore developed a computational modeling strategy for such
in vitro models using a cell kinetics convection-diffusion problem, where the drug media is convected
by the perfusion flow rate from the inlet port of the microscale device, diffused through the hydrogel
channel walls due to its inherent porous material nature, and metabolized within the encapsulated
hepatocytes.
The steady state results obtained from the simulations done for the free and porous flow regime are
presented hereafter. The results obtained by the authors from the transient studies are presented and
systematically analyzed elsewhere ( Tourlomousis and Chang, November 2014 ). Using the velocity and the
shear stress field computed in steady state, the drug transport and metabolism process is coupled by
solving the mass transport equations for the flow and cell domains in time.
15.1.3.3 Steady State Simulations
In the first stage of modeling, the Stokes and Brinkman Equations are solved for an inlet volumetric
flow rate of Q in = 0.25 m l/h to ensure a laminar velocity profile across the microfluidic channel as
shown in Figure 15.1 . The aforementioned value of the inlet volumetric flow rate is prescribed as a
starting point for the present study based on the author's experimental drug flow study protocol ( Chang
et al., 2010 ). Moreover, the order of magnitude is consistent with values found in previous dynamic
bioreactor studies and thus serves as a reasonable starting point. The cells are initially modeled as voids
in the computational domain, experience no-slip boundary condition along the walls and thereafter