Model of a Split‐Flow Airlift Bioreactor for Attachment‐Dependent, Baculovirus‐Infected Insect Cells

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Abstract
A mathematical model of a split‐flow airlift bioreactor using attachment‐dependent, baculovirus‐infected insect cells is presented. The model is structured to predict the dynamics of human secreted alkaline phosphatase (seAP) production, nonoccluded virus (NOV) production, infected cell density, uninfected cell density, and lysed cell density for a variety of infection conditions in the reactor. Infected cells are divided into subpopulations on the basis of the time of initial infection and spatial location within the reactor. The infection rate is modeled as first order in virus concentration at low virus concentrations but zero order at high virus concentrations. NOV and seAP production in each subpopulation is assumed to be dependent on the age of the culture and degree of confluency. The subpopulation growth rate is assumed to be dependent on dissolved oxygen concentration and cell density. Extracellular degradation of seAP is included. Model parameters were estimated independently from the literature on Trichoplusia ni BTI‐TN‐5B1‐4 cells infected with recombinant Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) encoding seAP. Model predictions of seAP production are in reasonable agreement with laboratory scale bioreactor data for multiplicity of infection (MOI) values ranging from 1 to 30. The model predicts that bioreactor protein productivity could be increased significantly by operating at an MOI of 10, an initial cell density of 2.5 × 105 cells/cm2, an area ratio of riser to downcomer of 25:75, and an airflow rate of 100 mL/min.

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