Human stem cells hold great potential for creating curative therapies for various different diseases. Producing clinically relevant number of stem cells requires controllable and scalable systems such as stirred-tank bioreactors. Fortunately, recent advances in 3D cultivation protocols, such as the use of microcarriers, have enabled the expansion and differentiation of stem cells as suspension cultures. To make a stem cell bioreactor process scalable, it is critical to understand how the operating conditions influence bioreactor scale-up parameters, microcarrier suspension, and hydrodynamic stresses experienced by the stem cells. We present a comprehensive computational fluid dynamics and discrete element method (CFD–DEM) model of microcarrier cultures in a 250 mL stirred-tank bioreactor. We validated our model using literature and experimental data and showed that our model predicted important engineering parameters, like power input, mixing time, free surface kLa, and microcarrier just-suspension stirring speed, within 20% accuracy over a wide range of operating conditions. Based on the experimental and numerical data, the results indicated that down-pumping at 90 rpm was the preferred operational mode to reach sufficient microcarrier suspension while minimizing hydrodynamic stress from a microcarrier lifeline perspective. This validated CFD–DEM modeling approach provides a basis for identifying suitable operating conditions across stirred-tank bioreactor scales, thereby supporting the process development and rational scale-up of stem cell-based therapies. ... Read more