A model‐driven approach towards rational microbial bioprocess optimization

Due to sustainability concerns, bio‐based production capitalizing on microbes as cell factories is in demand to synthesize valuable products. Nevertheless, the nonhomogenous variations of the extracellular environment in bioprocesses often challenge the biomass growth and the bioproduction yield. To enable a more rational bioprocess optimization, we have established a model‐driven approach that systematically integrates experiments with modeling, executed from flask to bioreactor scale, and using ferulic acid to vanillin bioconversion as a case study. The impacts of mass transfer and aeration on the biomass growth and bioproduction performances were examined using minimal small‐scale experiments. An integrated model coupling the cell factory kinetics with the three‐dimensional computational hydrodynamics of bioreactor was developed to better capture the spatiotemporal distributions of bioproduction. Full‐factorial predictions were then performed to identify the desired operating conditions. A bioconversion yield of 94% was achieved, which is one of the highest for recombinant Escherichia coli using ferulic acid as the precursor. 1. An integrated experimental‐modelling framework coupling cell kinetics of engineered microbes and 3D bioreactor hydrodynamics to show spatiotemporal profiles for bioprocess optimization. 2. Performed minimal experiments to achieve full‐factorial predictions. 3. Assessed impacts of stirring speed and air flow rate on cell growth and production, and found a non‐linear relation between cell growth and productivity of bioproduction.