  Large-scale manufacturing of induced pluripotent stem cells (iPSCs) is
essential for cell therapies and regenerative medicines. Yet, iPSCs form large
cell aggregates in suspension bioreactors, resulting in insufficient nutrient
supply and extra metabolic waste build-up for the cells located at the core.
Since subtle changes in micro-environment can lead to a heterogeneous cell
population, a novel Biological System-of-Systems (Bio-SoS) framework is
proposed to model cell-to-cell interactions, spatial and metabolic
heterogeneity, and cell response to micro-environmental variation. Building on
stochastic metabolic reaction network, aggregation kinetics, and
reaction-diffusion mechanisms, the Bio-SoS model characterizes causal
interdependencies at individual cell, aggregate, and cell population levels. It
has a modular design that enables data integration and improves predictions for
different monolayer and aggregate culture processes. In addition, a variance
decomposition analysis is derived to quantify the impact of factors (i.e.,
aggregate size) on cell product health and quality heterogeneity.
