Multiphase Bioreactor Design

Development of HF reactor with L-phenylalanine amonialyase
for the deamidation of L-phenylalanine and L-tyrosine for the
chemotherapy of cancer

Pedersen et al, 1978a, 1978b

Development of HF reactor with L-arginase for the cleavage of
L-arginine to ornithine and urea

Rossi et al., 1981

Extracorporeal removal of heparin from the blood stream by
immobilised heparinase in hollow fibres

Comfort et al, 1989a, 1989b,

1989c

Hydrolysis of urea by urease immobilised in an anion exchange
membrane

Chen et al., 1994

Extracorporeal removal of low density lipoproteins by
phospholipase A2 immobilised in beads and confinée in hollow
fibres

Shefer et al., 1993, 1995

Extracorporeal removal of low density lipoproteins by
phospholipase A2 in a combined packed bed/hollow fibre reactor

Labeque et al., 1993

Biomedical Applications

The application of immobilised enzymes as therapeutic agents for the treatment of
cardiovascular, oncological, intestinal, viral and hereditary diseases is a promising
technology that has been the subject of extensive laboratory and clinical investigation
(Torchilin, 1987). One of the approaches that has been undertaken to immobilise the
enzymes uses membrane bioreactors with hollow fibres or tubular modules as
extracorporeal systems (Table 6.8). The therapeutic enzyme is usually located in the shell
side of the module, while the blood stream (or other biological fluid) perfuses through the
lumen of the fibres. The plasma is separated through the permeable walls of the fibres
into the shell, leaving the cellular components behind. The separation of the enzyme from
the whole blood not only increases its stability but also contributes to a decrease in
immunological reactions (Pedersen et al., 1978a). Typically, the enzyme possesses a
specific degrading ability towards some diffusive low molecular weight metabolite of the
plasma.
For instance, phospholipase A2 has been used immobilised in beads and confined in
the shell of a hollow fibre module to modify low density lipoproteins (LDL) present in
the blood of hypercholesterolemic rabbits (Labeque et al., 1993; Shefer et al., 1993,
1995). The plasma is separated through the permeable walls of the fibres leaving the
blood cells behind (Figure 6.17). The immobilised enzyme is thus able to convert the
plasma lipoprotein to a form that can be removed from the body at an enhanced rate. The
reactor has two outlets, one carrying red blood cells from the lumen of the fibres and the
other carrying treated plasma from the reactor shell. The treated plasma is then
reconstituted with the blood cells before returning to the animal. The total plasma
cholesterol concentration decreased up to 40% and the results of safety tests indicated
that the treatment is safe. Therefore this technique offers a potential new approach for
lowering serum cholesterol and LDL levels which are usually related with coronary heart
disease (Shefer et al., 1993).

Multiphase bioreactor design 174