Experiments have shown that secondary fluid hows within the extra-capillary space (ECS) of hollow fiber bioreactors (HFBRs) can lead to the downstream polarization of cells and growth factors and subsequent reductions in reactor productivity. Recent model studies and experimental investigations of this system have demonstrated further that the polarization of ECS solutes can be reduced through increased loading of bovine serum albumin within the ECS, which leads to a concomitant reduction in solute convection via osmotic pressure effects. The following study extends previous models of HFBR hydrodynamics to include the effect of multiple solute species on the transient distribution of ECS solutes. The model is then used to study the relative effectiveness of dextran 500, dextran 70, hydroxyethylstarch 120, and bovine serum albumin, as well as periodic switching of the fiber lumen flow direction, in eliminating solute polarization. The high molecular weight additives are found to be more effective than flow switching in reducing polarization, particularly when the membranes display permeabilities characteristic of some polysulfone fibers (i.e. 6 x 10(-13) m).