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High density animal cell culture systems using porous supports Lee, Daniel W.

Abstract

Monolithic porous ceramic and porous polystyrene microcarriers were examined as supports for large scale mammalian cell culture. Vero cells and transformed baby hamster kidney (BHK) cells which produced human transferrin were grown in three different reactor configurations: a fixed bed ceramic perfusion system, an airlift systemwith draft tube made of porous ceramic and a stirred tank configuration which used porous polystyrene microcarriers. The porous matrices provide an increased surface area for cell attachment and growth and protect the entrapped or immobilized cells from shear stress in the bulk fluid. Steady state cell concentrations in all three systems were found to be in excess of 108 cells per mL porous matrix. All three systems intensified the culture process by increased cell mass per unit volume — a minimum five—fold increase in reactor volumetric cell density over simple suspension cultures. The airlift and microcarrier stirred tank system offer the potential to scale—up by increasing reactor volume. The fixed bed ceramic perfusion system can be used as a cell propagator to produce the required inoculum for other large scale bioreactors. Unlike the Opticore of the Opticell systems, the ceramic foam element can be reused. Its multiple interconnected channel structure greatly reduces the possibility of channel blockage due to over—grown cells. The biologically inert porous polystyrene microcarriers tested have distinct advantages, in terms of product purification, over the collagen based porous microcarriers such as Cultispher—G and Informatrix microcarriers. Cell attachment rates onto the porous polystyrene microcarriers treated with sulphuric acid were comparable to those of Cytodex-1 and Cultispher—G particles while the cell growth and productivity per unit carrier volume were 20% superior to the two tested commercial microcarriers. The use of airlift eliminates the need for a separate oxygenator or spin filter for gas exchange. The input gas created a differential pressure drop across the porous draft tube and forced the medium to perfuse through the porous draft tube. A simple mathematical model was formulated to describe the hydrodynamic behaviour of the porous draft tube airlift system. The model allows gas holdup, liquid superficial velocity, and liquid perfusion rate through the porous draft tube to be predicted for a given gas input. For the cases examined, the predictions are in satisfactory agreement with the overall trend of experimental measurements.

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