Modelling Oxygen Transport, Microcarrier Aggregation, and Hydrodynamic Constraints in Stirred Bioreactors for Scalable Developmental Engineering

Developmental engineering (DE) is a bottom-up strategy for generating functional tissues from modular tissues (MTs), offering potential advantages over conventional top-down approaches. However, scalable MT production remains constrained by limited understanding of scaffold aggregation, oxygen transport, and hydrodynamic effects in bioreactors. This study integrates theoretical simulations with empirical correlations to analyze these factors and provide a systematic basis for MT production. Microcarrier aggregates were modelled to evaluate minimum oxygen concentration (Cmin). Results indicate that larger microcarrier diameters (dmc) are associated with increased Cmin due to longer diffusion distances. Aggregate geometry and packing configuration, including hexagonal close packing and the “kissing number,” influenced oxygen distribution and may explain observed Cmin plateaus. Hydrodynamic behaviour was assessed using the Zwietering correlation and Kolmogorov turbulence scaling. Denser microcarrier aggregates required higher minimum stirring speeds (Nmin), while larger dmc increased susceptibility to shear. Increased agitation intensity and more aggressive impeller designs reduced Nmin but were associated with potential cell damages. Higher medium density (e.g., 20% FBS) reduced shear stress and energy dissipation. A unified framework integrating oxygen diffusion, aggregate geometry, microcarrier properties, and hydrodynamics is proposed to estimate oxygen limitation and cell damage, highlighting trade-offs relevant to MT production in DE.