CFD–DEM characterization of a 250 mL stirred-tank bioreactor for shear-sensitive stem cell microcarrier cultures

Human stem cells hold great potential for creating novel and curative therapies for variousdifferent diseases. Producing clinically relevant number of stem cells requires controllableand scalable systems such as stirred-tank bioreactors. Fortunately, recent advances in 3Dcultivation protocols, such as the use of microcarriers, have enabled the expansion anddifferentiation of stem cells as suspension cultures. To make a stem cell bioreactor processscalable, it is critical to understand how the bioreactor operating conditions influence microcarrier suspension, oxygen transfer rate, and hydrodynamic stresses experienced by thestem cells. Here we present a comprehensive computational fluid dynamics and discreteelement method (CFD-DEM) model of stem cell microcarrier cultures in a 250 mL stirred-tank bioreactor. We validated our model extensively using literature and experimentaldata and showed that our model predicted important engineering parameters, like powerinput, mixing time, free surface kLa, and microcarrier suspension, within 20% accuracyover a wide range of operating conditions. We then investigated the effect of various operating conditions on the suspended fraction of microcarriers and hydrodynamic stressesexperienced by the stem cells on microcarriers. Based on the experimental and numericaldata, the results indicated that down-pumping at 90 rpm was the preferred operationalmode to reach sufficient microcarrier suspension while minimizing hydrodynamic stress.Ultimately, this validated CFD-DEM modeling approach of microcarrier cultures can beused to characterize different bioreactor scales, which will help decrease scale-up risk andaccelerate the time-to-market of novel stem cell-based therapies