Tangential flow filtration (TFF) and alternating tangential flow (ATF) filtration technologies using hollow fiber membranes are commonly utilized in perfusion cell culture for the production of monoclonal antibodies; however, product retention remains a known and common problem with these systems. To address this issue, commercially available hollow fibers ranging from several hundred kilo-Daltons (kDa) to 0.65 μm in nominal pore size were tested and were all demonstrated to undergo moderate to severe product retention. Further investigation revealed accumulation of particles in the same size range (approximately 20-200 nm) as the pores. Based on the assumption that these particles contribute to product retention and membrane plugging, a hollow fiber with an unconventionally larger pore size was subsequently identified and demonstrated to drastically reduce product retention with no impact to cell clarification, Furthermore, these hollow fibers demonstrated surprisingly high membrane capacities, making them an attractive solution to the problem of product retention in perfusion reactors.
Alternating tangential flow (ATF) filtration has been successfully adopted as a low shear cell separation device in many perfusion‐based processes. The reverse flow per cycle is used to minimize fouling compared with tangential flow filtration. Currently, modeling of the ATF system is based on empirically derived formulas, leading to oversimplification of model parameters. In this study, an experimentally validated porous computational fluid dynamic (CFD) model was used to predict localized fluid behavior and pressure profiles in the ATF membrane for both water and supernatant solutions. The results provided numerical evidence of Starling flow phenomena that has been theorized but not previously proven for the current operating parameters. Additionally, feed cross flow velocity was shown to significantly impact the localized flux distribution; higher feed cross flow rates lead to an increased localized permeate flux as well as irreversible and reversible fouling resistance. Further, the small average permeate flux values of 2 L·m−2·h−1 traditionally used in perfusion bioreactor membranes lead to approximately 50% of the membrane length utilized for permeate flow during each pressure and exhaust phase, leading to a full membrane utilization during one ATF cycle. Our preliminary CFD results demonstrate that local flux and resistance distribution further elucidate the dynamics of ATF membrane fouling in a perfusion‐based system.
Organophosphate pesticides are known to inhibit acetylcholine esterase, an enzyme that degrades acetylcholine at the cholinergic synapse. In this study zebrafish were used to understand the impact chlorpyrifos, dichlorvos, and diazanon on vertebrate developmental physiology. Pre‐epiboly zebrafish embryos were exposed pesticides at concentrations ranging from 1μM to 1mM. Survival, spontaneous movements, heart rate, swimming behavior, and physical abnormalities were examined. All three pesticides were found to be toxic to developing zebrafish embryos at concentrations at or above than 100 μM. However, disruption of physiological processes controlled by the cholinergic neurons was only seen in embryos exposed to chlorpyrifos and dichlorvos. Chlorpyrifos and dichlorvos exposed embryos exhibited increased spontaneous movements, decreased embryonic heart rate, and a transient decrease in larval swimming ability. Although diazanon was the most toxic, it had no effect on these physiological systems. The effects of organophosphate pesticide exposure on vertebrate development are diverse and may be mediated through pathways other than the inhibition of acetylcholine esterase.
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