Engineering research on the production of useful biologicals by mass culture of animal and plant cells

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1. We could succeed in regulating a dissolved oxygen concentration (DO) of the medium in PID manner by using DO electrode, DO converter, PID controller and mass flow controller, in which the gas flow rate was used as the manipulated variable. By using the DO control system, it was found that there were optimum DO level in cell growth (3.0ppm) and beta-carotene production (0.05ppm) of carrot cells in an air-lift column with draft tube. Highest productivity (0.24mug/10^8cells/day) was obtained in DO-stat (0.15ppm) semi-continuous culture of carrot cells and this value was 7.5 time higher than that in the usual batch culture. We also succeeded in high density culture (1.1X10^8cells/cm^3) of animal cells by regulating a out-put DO level (more than 5.8ppm) of polyurethane foam (PUF) packed-bed culture system.2. The three-dimensional laminar flow of culture medium in an agitated vessel with 2-bladed paddle imoeller was simulated numerically by finite element method. The Carreau model was used as the constitutive equation. We succeeded in obtaining the fields of the velocity and the shear stress under a certain agitation rate (10-60 rpm).3. Adult rat hepatocytes formed spherical multicellular aggregates (spheroids, about 100mum in diameter) when they were cultured in the pores of PUF. Highly differentiated hepatic functions were maintained in the spheroid, These spheroids were partly attached and immobilized in the pores of PUF. We designed a PUF/spheroid packed-bed culture system. Albumin and urea production activities of hepatocyte/spheroid immobilized in the PUF packed-bed were higher than those of usual hepatocyte/monolayer culture in petri dish, and these activities were maintained for 26 days. These results indicated that the PUF/spheroid packed-bed culture system provided a promising prototype of hybrid type artificial liver support system.