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Zhuang, et al.
A

B

Figure 2. Schematic illustration of using spheroids as building blocks in 3D bioprinting for healthy/disease tissue construction. (A) Overview
of spheroid formation techniques. (B) 3D Printing and its adaptions in assisting spheroid assembly.

3.2. Agitation-based methods monitored. The combined stirrer’s mechanical stress
coupled with the fluid’s shear stress generated from the
Agitation-based methods promote spheroid formation high stirring rate may cause cell damage and reduce the
by maintaining cells in suspension using specialized spheroid formation, whereas a low stirring rate may not
equipment, such as spinner flasks, roller bottles, gyratory be able to prevent cell sedimentation.
shakers, or a NASA bioreactors through continuous
stirring by an impeller(s) or magnetic stirrer(s) [41,56-59] . 3.3. LOT
This approach enables mass production of spheroids Different from agitation-based technique (subjecting cells
with long-term culture, while also allows tracking of to high shear stress), LOT is a static technique that suspends
these spheroids during constant culture (Figure 2A-b). In cell culture on non-adhesive surfaces, prevents cell-to-
particular, using a bioreactor facilitates the control over substrate adhesion, and promotes cell-to-cell interaction,
pH, oxygenation and nutrient concentration . However, advantageously with low shear stress (Figure 2A-c).
[60]
these spheroids are generated in a single compartment, Typically, this non-adhesive surface is achieved by pre-
resulting in poor control over size and uniformity. The coating with biocompatible materials such as agarose [61-63]
stirring rate and the culture time need to be constantly and poly-2-hydroxyethyl methacrylate (polyHEMA) [64-66]

International Journal of Bioprinting (2021)–Volume 7, Issue 4 5