Page 286 - IJB-10-3

International Journal of Bioprinting Design and optimization of 3DP bioscaffolds

(such as digital light processing [DLP]) has been widely cultivation process or to predict the spatiotemporal
used in tissue engineering due to its advantages of high evolution of the physical fields, enabling analysis of oxygen
precision, rapid printing speed, and biocompatibility, distribution within the scaffold under various physical
and has been upgraded as a specialized “light-cured conditions, prediction of cell growth patterns, guidance
bioprinting technology” for biofabrication. 9-11 Significant for optimizing experimental parameters, and optimization
progress has been made in manufacturing complex of architectural parameters of scaffolds. Allen and Bhatia
25
organ constructs and tissue scaffolds with biomimetic developed a two-dimensional (2D) steady-state model to
functions using light-cured bioprinting technology, such predict oxygen distribution in a biodegradable scaffold
as cardiovascular networks, lung systems, and other organ with mouse liver cells, which was later expanded by Brown
models. 12-15 However, most bioprinted tissue scaffolds et al. for cultivating cardiac tissue scaffolds in vitro
26
and organ models reported to date face several obstacles and validated through hypoxia experiments. Yu et al.
27
(such as poor vascularization) that hinder their progress incorporated fluid dynamics into their oxygen distribution
toward clinical application. The in vitro biocompatibility model, emphasizing the importance of fluid dynamics on
and functions of tissue scaffolds and organ models still do oxygen transport within the scaffold. However, coupling
not meet expected requirements. 16,17 A fundamental issue with a cell growth model was absent, and its impact on cell
is the hypoxia within biofabricated constructs, leading to viability was thus not investigated. Mokhtari-Jafari et al.
28
insufficient cell viability and thus deteriorated biological simplified the fluid dynamics model based on the previous
functions. 18 steady-state model, which was then successfully coupled
Mechanistically, cell growth in scaffolds is a complex with cell growth and oxygen consumption to simulate
multi-physical-biological process involving oxygen bone tissue engineering scaffolds. The 2D modeling has
diffusion and convection, nutrient consumption, and limitations for architecturally complex scaffolds that
cell proliferation; each is influenced by a large number possess strong anisotropy, and 3D modeling is needed for
of parameters. During in vitro cultivation, the effective accurate simulation of cell growth and oxygen transport
29
diffusion length of oxygen in the biocompatible materials in bioreactors. Coletti et al. simplified the spatial
is generally within the range of 100 µm to 200 µm; such a dimensionality by using 2D axisymmetric theory and
short diffusion distance creates significant challenges for integrated processes of oxygen mass transfer, cell growth,
cells encapsulated in scaffolds to survive without adequate and oxygen consumption, attempting to achieve multi-
30
nutrient channels. 19,20 When the cell density of the physics modeling of cell growth in 3D space. Ioana et al.
engineered structure is high, localized hypoxia can occur, focused on the control solver for the cell growth model and
resulting in cellular inactivation and uneven distribution described spatiotemporal evolution of cell density within
that cause the loss of overall activity and functionality of 3D polymer scaffolds in perfusion bioreactors. Most
cells. To enhance the cell activity of scaffolds, perfusion scaffold optimization studies have focused on designing
21
bioreactors are generally employed to facilitate oxygen microchannels or biomimetic vascular networks. 31-34 Fang
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uptake by means of the fluid convection effect. However, et al. optimized the fractal vascular network of a 2D
22
the structural characteristics, material properties, cardiac tissue by coupling the cellular oxygen consumption
and ex vivo cultivation parameters of 3D-printed cell- model with an oxygen distribution model. However, these
laden scaffolds with diverse topological structures can optimization methods were based mainly on manually
significantly impact oxygen mass transfer and subsequently adjusting the number of microchannels or the tiers of
influence cell growth behaviors within the scaffold. 23,24 the vascular network. On the one hand, a comprehensive
Changes in initial cell densities in bioinks may disturb the model able to account for the multi-physical-biological
oxygen distribution within scaffolds, resulting in variations processes of cell growth and the geometric complexity
in final cell count and density. Nevertheless, a purely trial- of the scaffold is needed as bioengineering scaffolds or
and-error approach is considered problematic because models are becoming increasingly sophisticated due to
it is not only time-consuming and expensive but also the emergence of 3D printing. 35-39 On the other hand,
challenging to obtain an optimal design of a scaffold. further research on linking models with actual bioprinting
11
process parameters and establishing optimization criteria
Mathematical modeling can be adopted not only for
investigating underlying oxygen transfer mechanisms is required to guide the structural design and optimization
of bioprinted constructs.
in dynamic cultivation processes but also as an efficient
tool to optimize the design of the scaffolds for achieving In this paper, we propose a 3D multi-physics coupling
optimal cell viability. Many models, 25-30 particularly modeling system based on the Contois cell growth
mechanistically realistic modeling, have been developed equations that incorporate oxygen mass transfer, fluid
to capture the phenomena observed during the dynamic dynamics, and cellular oxygen consumption, in order to

Volume 10 Issue 3 (2024) 278 doi: 10.36922/ijb.1838