Research to Optimize Large-Scale iPSC Manufacturing
Two papers titled “Stochastic Biological System-of-Systems Modelling for iPSC Culture” and “Metabolic Regulatory Network Kinetic Modeling with Multiple Isotopic Tracers for iPSCs” led by Wei Xie, assistant professor of mechanical and industrial engineering, were published in the journals Communications Biology – Nature and Biotechnology and Bioengineering.
Xie’s research on bioprocess modeling and AI/ML can facilitate large-scale manufacturing of induced pluripotent stem cells (iPSCs), which have the potential to differentiate into any type of cell in the body, providing a valuable resource for regenerative medicines, cell therapies, drug discovery, and tissue engineering. iPSC manufacturing process development and scale-up can be quite challenging due to confounding heterogeneity and complexity of cell responses. Due to strong cell-to-cell interactions, 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 the micro-environment can lead to a heterogeneous cell population, a novel Biological System-of-Systems (Bio-SoS) framework with modular design is proposed to model cell-to-cell interactions, spatial and metabolic heterogeneity, and cell response to micro-environmental variation. This multi-scale bioprocess mechanistic model, characterizing causal interdependencies from molecular to cellular to macro-scope level, offers valuable guidance for optimizing large-scale iPSC manufacturing, enhancing yield, and ensuring consistent cell product quality.
Key research findings include:
- Multi-scale bioprocess mechanistic model facilitates data integration, including heterogeneous data collected from different production processes with different scales, dynamics, and feeding strategies. This can accelerate iPSC manufacturing process development and scale-up without running extensive experiments.
- Unlike CHOs for mAbs manufacturing, iPSCs cultured in aggregates have heterogeneous micro-environmental conditions and functional behaviors. It is challenging in terms of culture process optimization and cell product quality control. This requires us to understand better the underlying mechanisms and inherent uncertainties of the end-to-end culture process to facilitate large-scale manufacturing and real-time release.
- The Bio-SoS model with modular design supports assembling different production processes. In 2D monolayer cultures conducted in the lab, cells attach to the internal surface of the petri dish, which allows us to collect multi-omics and phenotype data and predict single-cell response to environmental changes. The Bio-SoS model used 2D monolayer culture data and provided reliable predictions of 3D aggregate cultures in stirred suspension bioreactors recommended for large-scale manufacturing.
This Bio-SoS modeling philosophy is extendable and applicable to general biological ecosystems, accounting for complex interactions and inherent stochasticity. Xie’s research was also recently highlighted in Genetic Engineering and Biotechnology News in an article titled, “Optimizing iPSC Manufacturing”.