Computational fluid dynamics enables predictable scale-up of perfusion bioreactors for microvessel production

Scaling up microvessel culture systems is essential for producing vascularized clinically relevant tissues, yet current platforms offer little guidance on how to preserve flow conditions during scale-up. Here, we present a computational-experimental framework using computational fluid dynamics (CFD) to guide the design and scaling of microvessel bioreactors. Interstitial flow distributions were pre-dicted in two perfusion-based platforms-a permeable insert and a rhomboidal microfluidic chamber-across multiple scaling factors and hydrostatic pressures. CFD identified IF ranges conducive to vascu-logenesis and quantified how geometry and pressure modulate flow uniformity. Scaled-up bioreactors generated microvessel networks with consistent morphology and connectivity over a 30-fold increase in culture volume, confirming that maintaining equivalent IF ensures reproducible outcomes. The permeable insert platform maintained uniform IF across scales, while the rhomboidal chamber produced spatially varying IF resulting in heterogeneous but physiologically relevant networks. These findings establish CFD as a predictive tool for rationally scaling perfusion bioreactors, enabling microvessel production at clinically relevant scales with controllable morphology. Significance StatementScaling up microvessel bioreactors is critical for engineering large pre-vascularized tissues. However, larger scales may disrupt flow conditions that drive vessel formation. This study demonstrates that computational fluid dynamics (CFD) can predict interstitial flow and guide the rational scale-up while preserving the vasculogenic microenvironment. Experiments across 30+-fold size increase confirmed that matching inter-stitial flow results in morphologically identical microvessel networks. By linking simulation-based design with experimental validation, this work establishes CFD as design tool for scalable perfusion bioreactors for production of microvessel networks at clinically relevant scales.