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Köpf, et al.
of 3D encapsulated cells needs to be thoroughly assessed prävaskularisiertem Luftröhren-Ersatzgewebe’ published
over time in a follow-up study that would consider an in 2019 at the Faculty of Georesources and Materials
equal concentration of viable HUVEC in all samples Engineering, RWTH Aachen University, Aachen,
at the beginning of the experiment. However, taking Germany[37].
into consideration the important finding that 3D pre-
vascularization can equally be achieved with endothelial Funding
cells that were exposed to low shear stress, the pressure We acknowledge the financial support of Deutsche
range below 0.5 bar should be the area of main interest in Forschungsgemeinschaft DFG, Bonn, Germany (Grants
further studies. FI975/23-1+2, JO 764/4-1+2, and 363055819/GRK
Although bioprinting-associated shear stress can 2415).
substantially diminish the number of viable cells, the
results presented in this study indicate that there exists Conflict of interest
a process window for microvalve-based bioprinting in
which cell viability and function of HUVEC are not The authors declare no competing financial interest.
negatively affected. Due to exposure to the high shear Author contributions
stresses that occur by setting the printing pressure to
3 bar, a significant viability loss immediately after Conceptualization – Marius Köpf and Horst Fischer;
printing as well as reduced capillary-like network Supervision – Horst Fischer and Stefan Jockenhoevel;
formation in long-term 3D culture experiments can be Investigation – Marius Köpf with support of Franziska
observed. Kreimendahl (experimental), Ramin Nasehi (numerical
simulations); Formal analysis – Marius Köpf, Ramin
5. Conclusion Nasehi, Franziska Kreimendahl, Stefan Jockenhoevel,

In this work, we used a FEA-based simulation model to and Horst Fischer; Funding acquisition – Horst Fischer
determine the mechanical conditions imposed on cells and Stefan Jockenhoevel; Writing – original draft: Marius
Köpf with support of Horst Fischer and Ramin Nasehi.
during bioprinting. The simulation model offers for the
first time detailed spatiotemporal information about the References
printing-induced shear stress and hydrostatic pressure
that, together with experimental studies, can be used 1. Malda J, Visser J, Melchels J, et al., 2013, 25 Anniversary
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with different hydrogels. The experimental in vitro Mater, 25:5011–28.
cell culture analysis revealed that the cells maintain http://doi.org/10.1002/adma.201302042
their capacity to proliferate and to assemble into 2D
and 3D multi-cell capillary networks after exposure 2. Wang Z, Kapadia W, Li C, et al., 2021, Tissue-specific
to bioprinting-associated hydrostatic pressure and Engineering: 3D Bioprinting in Regenerative Medicine.
resulting shear stress. However, this is true only if the J Control Release, 329:237–56.
key parameters, such as bioink viscosity and printing http://doi.org/10.1016/j.jconrel.2020.11.044
pressure, are properly balanced. We therefore conclude 3. Jain RK, Au P, Tam J, et al., 2005, Engineering Vascularized
that microvalve-based bioprinting is a suitable technique Tissue. Nat Biotechnol, 23:821–3.
for the manufacture of pre-vascularized constructs when
the printing parameters and thus the shear stress level https://doi.org/10.1038/nbt0705-821.
are thoroughly controlled. 4. Subbiah R, Thrivikraman G, Parthiban SP, et al., 2021,
Prevascularized Hydrogels with Mature Vascular Networks
Acknowledgments Promote the Regeneration of Critical-size Calvarial Bone
This work was supported by the Core Facility Two- Defects In Vivo. J Tissue Eng Regen Med, 15:219–231.
Photon Imaging of the Interdisciplinary Center for https://doi.org/10.1002/term.3166
Clinical Research (IZKF Aachen) within the Faculty of 5. Zimoch J, Zielinska D, Michalak-Micka K, et al., 2021,
Medicine at RWTH Aachen University. We thank Dr. Bio-engineering a Prevascularized Human Tri-layered
Michael Vogt, operation manager of this Core Facility for Skin Substitute Containing a Hypodermis. Acta Biomater,
his support. This publication uses data collected within
the framework of the PhD thesis of the first author Marius 134:215–27.
Köpf entitled ‘Synthese sowie rheologische, mechanische https://doi.org/10.1016/j.actbio.2021.07.033
und zellbiologische Charakterisierung von Agarose- 6. Kreimendahl F, Köpf M, Thiebes AL, et al., 2017,
Kollagen-Hydrogel-Mischungen für den 3D-Druck von Three-dimensional Printing and Angio-genesis: Tailored

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