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International Journal of Bioprinting A computational model of cell viability and proliferation of 3D-bioprinted constructs

is the critical substance for cell survival, and it confirms developed, and it was fed with experimental data to compare
the hypothesis that lack of nutrients in large tissues is experimental and computational results. Thus, it constitutes
likely to occur. To study the effect of vascularization on a proof of concept of a digital twin for bioprinting, where the
cell proliferation, internal channels in the largest construct outcome of the bioprinted construct is predicted through
model were introduced. The simulations of bioprinted the implementation of phenomenological models together
constructs forecast a spatial gradient of cell density within with data accounting for the high variability of biological
the construct, and a clear presence of a necrotic core in applications. The preliminary validation of the model
constructs of 4.5 mm diameter. When vascular channels was performed on simple droplet-shaped constructs. The
are introduced, the availability of nutrients is redistributed, model was applied to the study of constructs with different
leading to a more uniform cell density within the construct. sizes and geometries, i.e., with and without channels. More
This clearly highlights the importance of introducing complex configurations of bioprinted constructs, with
vascular networks in bioprinted constructs, especially with larger size and hierarchical vascular networks, are going to
large dimensions and high cell concentration. This is aligned be investigated both experimentally and computationally,
with the literature, where many works have attempted with the aim of fabricating vascularized bioprinted tissues.
creating vascular networks within constructs [35-37] . A lot
of effort is invested in bioprinting toward the fabrication Acknowledgments
of vascularized tissues, with different strategies being None.
investigated. Direct and indirect extrusion bioprinting are
the most common ones. The former consists of the direct Funding
fabrication of tissues composed of different cells, including
vascular ones. The latter consists of printing a sacrificial ink This research was partially funded by the European
to be removed afterward to create the channel. Structural Commission under the “HORIZON-CL4-2021-DIGITAL-
stability and resolution remain as the main limitations EMERGING-01 project BioProS - Biointelligent
of these techniques, which are therefore not suitable for Production Sensor to Measure Viral Activity” (grant
the recapitulation of capillary networks. Light-assisted agreement no. 101070120), 2022-2026.”
bioprinting, in particular digital light processing, can
overcome resolution issues and is used for the fabrication Conflict of interest
of perfusable constructs, but the types of materials that can The authors declare no conflict of interests.
be printed are limited and only one material can be printed
at a time. The computational model presented here would Author contributions
allow the user to design the specific vascular structure that Conceptualization: Ludovico Petraro, Patrizia Gironi, Silvia
is needed to keep the tissue of interest viable, thus helping in Santoni, Luca Dedè, Bianca Maria Colosimo
the selection of the most suitable bioprinting technique . Data curation: Ludovico Petraro, Patrizia Gironi
[38]
Formal analysis: Ludovico Petraro, Patrizia Gironi, Silvia
5. Conclusion Santoni
A PDE-based model was developed and simulated at the Funding acquisition: Bianca Maria Colosimo, Luca Dedé
computer for studying cell proliferation in bioprinted Investigation: Ludovico Petraro, Patrizia Gironi
constructs in terms of oxygen and glucose diffusion and Methodology: Ludovico Petraro, Patrizia Gironi, Silvia
consumption as well as cell growth and death rates. The Santoni
computational model was employed to study oxygen and Project administration: Bianca Maria Colosimo, Luca Dedé,
glucose distribution within bioprinted constructs, and Patrizia Gironi
to analyze the entity of the diffusion and consumption Resources: Bianca Maria Colosimo, Luca Dedé
phenomena and their effect on cell proliferation and Software: Ludovico Petraro, Patrizia Gironi
death. The need of vascularization in areas far from the Supervision: Luca Dedé, Bianca Maria Colosimo
boundaries was confirmed. The model also acts as a tool Visualization: Patrizia Gironi, Silvia Santoni
for designing bioprinted tissues, providing important Writing—original draft: Ludovico Petraro, Patrizia Gironi
information on the most penalized regions of the tissue Writing—review & editing: Patrizia Gironi, Silvia Santoni,
that would need additional care, such as by introducing a Luca Dedé, Bianca Maria Colosimo
vascular network for nutrient supply and waste removal, Ethics approval and consent to participate
according to construct geometry, bioink or extracellular
matrix properties, and cell activity. Besides, a volume- Not applicable. The primary cells (CC-2511) were
averaged, ordinary differential equation-based model was purchased from Lonza, Basel, Switzerland.

Volume 9 Issue 4 (2023) 364 https://doi.org/10.18063/ijb.741