The constant supply of high cell numbers generated by defined, robust, and economically viable culture processes is indispensable for the envisioned application of human pluripotent stem cells (hPSCs) and their progenies for drug discovery and regenerative medicine. To achieve required cell numbers and to reduce process-related risks such as cell transformation, relative short batch-like production processes at industry- and clinically-relevant scale(s) must be developed and optimized. Here, we will review recent progress in the large-scale expansion of hPSCs with particular focus on suspension culture, which represents a universal strategy for controlled mass cell production. Another focus of the paper relates to bioreactor-based approaches, including technical aspects of bioreactor technologies and operation modes. Lastly, we will discuss current challenges of hPSC process engineering for enabling the transition from early stage process development to fully optimized hPSC production scale operation, a mandatory step for hPSCs' industrial and clinical translation

Computational fluid dynamics (CFD) models have become very effective tools for predicting the flow field within the carotid bifurcation, and for understanding the relationship between local hemodynamics, and the initiation and progression of vascular wall pathologies. As prescribing proper boundary conditions can affect the solutions of the equations governing blood flow, in this study, we investigated the influence to assumptions regarding the outflow boundary conditions in an image-based CFD model of human carotid bifurcation. Four simulations were conducted with identical geometry, inlet flow rate, and fluid parameters. In the first case, a physiological time-varying flow rate partition at branches along the cardiac cycle was obtained by coupling the 3D model of the carotid bifurcation at outlets with a lumped-parameter model of the downstream vascular network. Results from the coupled model were compared with those obtained by imposing three fixed flow rate divisions (50/50, 60/40, and 70/30) between the two branches of the isolated 3D model of the carotid bifurcation. Three hemodynamic wall parameters were considered as indicators of vascular wall dysfunction. Our findings underscore that the overall effect of the assumptions done in order to simulate blood flow within the carotid bifurcation is mainly in the hot-spot modulation of the hemodynamic descriptors of atherosusceptible areas, rather than in their distribution. In particular, the more physiological, time-varying flow rate division deriving from the coupled simulation has the effect of damping wall shear stress (WSS) oscillations (differences among the coupled and the three fixed flow partition models are up to 37.3% for the oscillating shear index). In conclusion, we recommend to adopt more realistic constraints, for example, by coupling models at different scales, as in this study, when the objective is the outcome prediction of alternate therapeutic interventions for individual patients, or to test hypotheses related to the role of local fluid dynamics and other biomechanical factors in vascular diseases.