Modelling of hollow fiber membrane bioreactor for mammalian cell cultivation using computational hydrodynamics

Menshutina, Natalia; Guseva, E. V.; Safarov, Ruslan R.; Boudrant, Joseph

doi:10.1007/s00449-019-02249-9

Cited by 14 publications

(6 citation statements)

References 29 publications

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“…After successful integration of the vector and clonal selection, cell culture work was migrated to a HFBR for large quantity production of Netrin-1. Main factors that will affect final yields and quality are nutrient availability, oxygenation, and inducer concentrations (Knight 1989 ; Menshutina et al 2020 ). The HFBR effectively mimics in vivo “organ” conditions to maximize protein production.…”

Section: Discussionmentioning

confidence: 99%

“…Here, a hollow fiber bioreactor (HFBR) presented an opportunity to set up a continuous protein production system, with the advantage of harvesting smaller volumes containing higher concentrations of protein. HFBR bring a versatile tool to the research laboratory for continuous production of viruses (Tapia et al 2016) and recombinant proteins alike (Menshutina et al 2020). The HFBR system is a capillary bed unit, designed and developed in the early seventies based on the flow of the mammalian circulatory system (Knazek et al 1972;Knight 1989).…”

Section: Introductionmentioning

confidence: 99%

“…The ECS is the space between parallel fibers where cells can grow adherent to the capillary walls (Watson et al 2016 ) or freely in suspension surrounding the external face wall of each capillary. Nutrients and oxygen continuously move into the ECS while metabolic waste products are constantly removed by the perfusion action of media which is recirculated through the system with a low risk of mechanical damage as would happen with the blades of a normal bioreactor (Menshutina et al 2020 ). These semi-permeable capillary membranes provide a larger surface area for a smaller volume as compared to stationary growth flasks.…”

Section: Introductionmentioning

confidence: 99%

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Homogenous overexpression of the extracellular matrix protein Netrin-1 in a hollow fiber bioreactor

Moya‐Torres

Gupta

Heide

et al. 2021

Appl Microbiol Biotechnol

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The production of recombinant proteins for functional and biophysical studies, especially in the field of structural determination, still represents a challenge as high quality and quantities are needed to adequately perform experiments. This is in part solved by optimizing protein constructs and expression conditions to maximize the yields in regular flask expression systems. Still, work flow and effort can be substantial with no guarantee to obtain improvements. This study presents a combination of workflows that can be used to dramatically increase protein production and improve processing results, specifically for the extracellular matrix protein Netrin-1. This proteoglycan is an axon guidance cue which interacts with various receptors to initiate downstream signaling cascades affecting cell differentiation, proliferation, metabolism, and survival. We were able to produce large glycoprotein quantities in mammalian cells, which were engineered for protein overexpression and secretion into the media using the controlled environment provided by a hollow fiber bioreactor. Close monitoring of the internal bioreactor conditions allowed for stable production over an extended period of time. In addition to this, Netrin-1 concentrations were monitored in expression media through biolayer interferometry which allowed us to increase Netrin-1 media concentrations tenfold over our current flask systems while preserving excellent protein quality and in solution behavior. Our particular combination of genetic engineering, cell culture system, protein purification, and biophysical characterization permitted us to establish an efficient and continuous production of high-quality protein suitable for structural biology studies that can be translated to various biological systems. Key points • Hollow fiber bioreactor produces substantial yields of homogenous Netrin-1 • Biolayer interferometry allows target protein quantitation in expression media • High production yields in the bioreactor do not impair Netrin-1 proteoglycan quality Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Homogenous overexpression of the extracellular matrix protein Netrin-1 in a hollow fiber bioreactor

Moya‐Torres

Gupta

Heide

et al. 2021

Appl Microbiol Biotechnol

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“…Among them, hollow fber membrane contactors (HFMCs) are commonly employed in medical, pharmaceutical, biological, and environmental applications. Extracorporeal membrane oxygenation (e.g., biohybrid oxygenators [6][7][8], extracorporeal CO2 removal (ECCO2R) [9,10], arterio-venous CO 2 removal (AVCO2R) and venovenous CO 2 removal (VVCO2R) devices [11][12][13]), hemodialysis [14,15], tissue culturing [16], membrane bioreactors used for wastewater treatment [17][18][19][20], air purifcation (e.g., fue gas absorbing and CO 2 capturing [21][22][23][24][25][26][27]), and reverse osmosis applied in, e.g., water purifcation [28] and concentration process [29] are various examples where HFMCs are employed as one of their major components. In several applications, such as AVCO2R and VVCO2R, aqueous CO 2 removal is considered the signifcant performance objective of HFMCs [30].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Sweeping Media and Temperature on Aqueous CO2 Removal Using Hollow Fiber Membrane Contactor (HFMC): An Experimental Determination

Tabesh

Gholami

Marefat

2023

International Journal of Chemical Engineering

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Transport phenomena through hollow fiber membrane contactors (HFMCs) indicate the exchange of a component between the two phases, inside and outside of hollow fibers. In this research, we designed and fabricated lab-made HFMCs to assess the difference between water and air as sweeping media for CO2 exchange. The effects of flow rates and temperature ratios on aqueous CO2 absorption were investigated accordingly. A semiclosed circuit incorporating our fabricated HFMCs was set up to regulate the operating parameters and evaluate the aqueous CO2 concentration using an initiative pH-based method. The results of our experiments remarkably reveal that air tends to remove aqueous CO2 more than water when aqueous CO2 concentration is higher than 3.53 × 10−6 mlCO2/l. However, water would surpass air in lower concentrations. Nevertheless, tripling the flow rate of sweeping media from 500 to 1500 ml/min shifts up this cutoff point 50 times to around 1.66 × 10−4 mlCO2/l. The experiments performed at three different temperature ratios of 22 : 22, 44 : 12, and 22 : 12°C (CO2-rich liquid: sweeping medium) demonstrated that a higher temperature gradient deteriorates the CO2 absorption capacity of sweeping media. Nonetheless, temperature gradient becomes highly effective in aqueous CO2 concentrations lower than 1.57 × 10−6 CO2/l. The results of this research could be applied in performance optimization of aqueous CO2 absorbing HFMCs, even in sophisticated medical procedures such as arterio-venous and veno-venous CO2 removal systems where both water and air could be used as blood’s CO2 sweeping media.

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“…It is used to obtain the detailed hydrodynamic characteristics of bioreactors, and mainly provides a basis for optimizing and scaling up the cultivation process of microorganisms (Cappello et al 2021 ; Haringa et al 2018 ; Xia et al 2008 ). Recently, CFD has also been applied in the characterization, optimization, and scale-up or scale-down of bioreactors for animal cell cultivation (Borys et al 2019 , 2018 ; Li et al 2020 ; Menshutina et al 2020 ; Villiger et al 2018 ). Borys et al ( 2018 ) evaluated seven commonly used scale-up parameters including volume average velocity, volume average shear stress rate, volume average energy dissipation, Reynolds number, impeller tip speed, power input, and maximum shear rate to scale up embryonic stem cell cultivation.…”

Section: Introductionmentioning

confidence: 99%

A novel scale-up strategy for cultivation of BHK-21 cells based on similar hydrodynamic environments in the bioreactors

Teng

2021

Bioresour. Bioprocess.

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The scale-up of animal cell cultivation is important but remains complex and challenging. In the present study, we propose a novel scale-up strategy for baby hamster Syrian kidney-21 (BHK-21) cell cultivation based on similar hydrodynamic environments. The hydrodynamic characteristics of the different scale bioreactors were determined by computational fluid dynamics (CFD) and further correlated with the agitation speed. The optimal hydrodynamic environment for cell cultivation and vaccine production was determined from the cultivation experiments of BHK-21 cells in 5-L laboratory-scale bioreactors equipped with different impellers at various agitation speeds. BHK-21 cell cultivation was scaled up from 5-L to 42-, 350-, and 1000-L bioreactors by adjusting the agitation speed to make the hydrodynamic features similar to those in the 5-L bioreactor, especially for the shear rate in the impeller zone (γimp) and energy dissipation rate in the tank bulk zone (εtan). The maximum cell density and cell aggregation rate in these scaled-up bioreactors were in the range of 4.6 × 106 ~ 4.8 × 106 cells/mL and 16 ~ 20%, which are comparable to or even better than those observed in the 5-L bioreactor (maximum cell density 4.8 × 106 cells/mL, cell aggregation rate 21%). The maximum virus titer of 108.0 LD50/mL achieved in the 1000-L bioreactor was close to 108.3 LD50/mL that obtained in the 5-L bioreactor. Hence, the scale-up strategy proposed in this study is feasible and can efficiently facilitate the scale-up processes of animal cell cultivation.

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Modelling of hollow fiber membrane bioreactor for mammalian cell cultivation using computational hydrodynamics

Cited by 14 publications

References 29 publications

Homogenous overexpression of the extracellular matrix protein Netrin-1 in a hollow fiber bioreactor

Homogenous overexpression of the extracellular matrix protein Netrin-1 in a hollow fiber bioreactor

The Effect of Sweeping Media and Temperature on Aqueous CO2 Removal Using Hollow Fiber Membrane Contactor (HFMC): An Experimental Determination

A novel scale-up strategy for cultivation of BHK-21 cells based on similar hydrodynamic environments in the bioreactors

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