This paper presents the applicability of a microtechnologically fabricated microbubble column as a screening tool for submerged aerobic cultivation. Bubbles in the range of a few hundred micrometers in diameter were generated at the bottom of an upright-positioned microdevice. The rising bubbles induced the circulation of the liquid and thus enhanced mixing by reducing the diffusion distances and preventing cells from sedimentation. Two differently sized nozzles (21 × 40 µm(2) and 53 × 40 µm(2) in cross-section) were tested. The gas flow rates were adjustable, and the resulting bubble sizes and gas holdups were investigated by image analysis. The microdevice features sensor elements for the real-time online monitoring of optical density and dissolved oxygen. The active aeration of the microdevice allowed for a flexible oxygen supply with mass transfer rates of up to 0.14 s(-1). Slightly higher oxygen mass transfer rates and a better degassing were found for the microbubble column equipped with the smaller nozzle. To validate the applicability of the microbubble column for aerobic submerged cultivation processes, batch cultivations of the model organism Saccharomyces cerevisiae were performed, and the specific growth rate, oxygen uptake rate, and yield coefficient were investigated.
Intact SLN were not incorporated into the cells, i.e., C-6 was passively redistributed from SLN to lipophilic cellular compartments. C-6 was enriched up to a given limit in HCE-T cells within 5 min of contact with the dispersions both under static and under flow conditions. The C-6 delivery rate from liposomes was superior to that from SLN whereby the suspension exhibited the lowest rate. C-6 release rates were comparable for static and flow conditions. Alternate flushing with formulations and buffer revealed that cells accumulated C-6. The results suggest that combining microfluidics with live cell imaging provides a valuable option for in vitro studies of ocular drug delivery.
This paper presents a vertically positioned microfluidic system made of poly(dimethylsiloxane) (PDMS) and glass, which can be applied as a microbubble column (μBC) for biotechnological screening in suspension. In this μBC, microbubbles are produced in a cultivation chamber through an integrated nozzle structure. Thus, homogeneous suspension of biomass is achieved in the cultivation chamber without requiring additional mixing elements. Moreover, blockage due to produced carbon dioxide by the microorganisms-a problem predominant in common, horizontally positioned microbioreactors (MBRs)-is avoided, as the gas bubbles are released by buoyancy at the upper part of the microsystem. The patterned PDMS layer is based on an optimized two-lithographic process. Since the naturally hydrophobic PDMS causes problems for the sufficient production of microbubbles, a method based on polyelectrolyte multilayers is applied in order to allow continuous hydrophilization of the already bonded PDMS-glass-system. The μBC comprises various microelements, including stabilization of temperature, control of continuous bubble formation, and two optical configurations for measurement of optical density with two different sensitivities. In addition, the simple and robust application and handling of the μBC is achieved via a custom-made modular plug-in adapter. To validate the scalability from laboratory scale to microscale, and thus to demonstrate the successful application of the μBC as a screening instrument, a batch cultivation of Saccharomyces cerevisiae is performed in the μBC and compared to shake flask cultivation. Monitoring of the biomass growth in the μBC with the integrated online analytics resulted in a specific growth rate of 0.32 h(-1), which is almost identical to the one achieved in the shake flask cultivation (0.31 h(-1)). Therefore, the validity of the μBC as an alternative screening tool compared to other conventional laboratory scale systems in bioprocess development is proven. In addition, vertically positioned microbioreactors show high potential in comparison to conventional screening tools, since they allow for high density of integrated online analytics and therefore minimize time and cost for screening and guarantee improved control and analysis of cultivation parameters.
Im letzten Jahrzehnt hat die Mikrobioreaktor (MBR)‐Technologie rasche Fortschritte in der biotechnologischen Prozessentwicklung und der Untersuchung biologischer Systeme von der industriellen Biotechnologie bis hin zur Pharmabioverfahrenstechnik erzielt. Zahlreiche MBR‐Systeme werden in der Literatur vorgestellt, die als automatisierte, parallele Bioreaktoren für den Laboreinsatz entwickelt wurden, um einen sinnvollen Scale‐up/‐down konventioneller biotechnologischer Pilotanwendungen und industrieller Prozesse zu ermöglichen. Die MBR‐Technologie bietet die Möglichkeit, die Kultivierung mit einer hohen Datendichte von Prozessvariablen in‐situ durchzuführen und quantitative Daten aus dem Mikro‐Volumen in Echtzeit zu erhalten. Der Beitrag gibt einen Überblick von mikrotechnisch hergestellten MBR, über ihre Gestaltung, Vorteile bei biotechnologischen Applikationen sowie Grenzen und zukünftige potentielle Herausforderungen.
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