Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies
Accurate prediction of metabolism is a significant outstanding challenge in toxicology. The best predictions are based on experimental data from in vitro systems using primary hepatocytes. The predictivity of the primary hepatocyte-based culture systems, however, is still limited due to well-known p...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-09-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fbioe.2016.00072/full |
| _version_ | 1819070630678495232 |
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| author | Jenny M Pedersen Yoo-Sik Shim Yoo-Sik Shim Yoo-Sik Shim Vaibhav Hans Martin Blake Phillips Jeffrey M. Macdonald Glenn Walker Melvin E. Andersen Melvin E. Andersen Harvey J. Clewell Harvey J. Clewell Miyoung Yoon Miyoung Yoon |
| author_facet | Jenny M Pedersen Yoo-Sik Shim Yoo-Sik Shim Yoo-Sik Shim Vaibhav Hans Martin Blake Phillips Jeffrey M. Macdonald Glenn Walker Melvin E. Andersen Melvin E. Andersen Harvey J. Clewell Harvey J. Clewell Miyoung Yoon Miyoung Yoon |
| author_sort | Jenny M Pedersen |
| collection | DOAJ |
| description | Accurate prediction of metabolism is a significant outstanding challenge in toxicology. The best predictions are based on experimental data from in vitro systems using primary hepatocytes. The predictivity of the primary hepatocyte-based culture systems, however, is still limited due to well-known phenotypic instability and rapid decline of metabolic competence within a few hours. Dynamic flow bioreactors for three-dimensional cell cultures are thought to be better at recapitulating tissue microenvironments and show potential to improve in vivo extrapolations of chemical or drug toxicity based on in vitro test results. These more physiologically relevant culture systems hold potential for extending metabolic competence of primary hepatocyte cultures as well. In this investigation, we used computational fluid dynamics (CFD) to determine the optimal design of a flow-based hepatocyte culture system for evaluating chemical metabolism in vitro. The main design goals were 1) minimization of shear stress experienced by the cells to maximize viability, 2) rapid establishment of a uniform distribution of test compound in the chamber, and 3) delivery of sufficient oxygen to cells to support aerobic respiration. Two commercially available flow devices — RealBio® (RB) and QuasiVivo® (QV) — and a custom developed fluidized bed (FB) bioreactor were simulated, and turbulence, flow characteristics, test compound distribution, oxygen distribution, and cellular oxygen consumption were analyzed. Experimental results from the bioreactors were used to validate the simulation results.Our results indicate that maintaining adequate oxygen supply is the most important factor to the long-term viability of liver bioreactor cultures. Cell density and system flow patterns were the major determinants of local oxygen concentrations. The experimental results closely corresponded to the in silico predictions. Of the three bioreactors examined in this study, we were able to optimize the experimental conditions for long-term hepatocyte cell culture using the QV bioreactor. This system facilitated the use of low system volumes coupled with higher flow rates. This design supports cellular respiration by increasing oxygen concentrations in the vicinity of the cells, and facilitates long-term kinetic studies of low clearance test compounds. These two goals were achieved while simultaneously keeping the shear stress experienced by the cells within acceptable limits. |
| first_indexed | 2024-12-21T17:09:00Z |
| format | Article |
| id | doaj.art-88ed7d6f48f94a27a7855aeae14a7820 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-12-21T17:09:00Z |
| publishDate | 2016-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-88ed7d6f48f94a27a7855aeae14a78202022-12-21T18:56:27ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852016-09-01410.3389/fbioe.2016.00072216454Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism StudiesJenny M Pedersen0Yoo-Sik Shim1Yoo-Sik Shim2Yoo-Sik Shim3Vaibhav Hans4Martin Blake Phillips5Jeffrey M. Macdonald6Glenn Walker7Melvin E. Andersen8Melvin E. Andersen9Harvey J. Clewell10Harvey J. Clewell11Miyoung Yoon12Miyoung Yoon13The Hamner Institutes for Health SciencesThe Hamner Institutes for Health SciencesScitoVation, LLCUniversity of North CarolinaUniversity of North CarolinaScitoVation, LLCUniversity of North CarolinaNorth Carolina State UniversityThe Hamner Institutes for Health SciencesScitoVation, LLCThe Hamner Institutes for Health SciencesScitoVation, LLCThe Hamner Institutes for Health SciencesScitoVation, LLCAccurate prediction of metabolism is a significant outstanding challenge in toxicology. The best predictions are based on experimental data from in vitro systems using primary hepatocytes. The predictivity of the primary hepatocyte-based culture systems, however, is still limited due to well-known phenotypic instability and rapid decline of metabolic competence within a few hours. Dynamic flow bioreactors for three-dimensional cell cultures are thought to be better at recapitulating tissue microenvironments and show potential to improve in vivo extrapolations of chemical or drug toxicity based on in vitro test results. These more physiologically relevant culture systems hold potential for extending metabolic competence of primary hepatocyte cultures as well. In this investigation, we used computational fluid dynamics (CFD) to determine the optimal design of a flow-based hepatocyte culture system for evaluating chemical metabolism in vitro. The main design goals were 1) minimization of shear stress experienced by the cells to maximize viability, 2) rapid establishment of a uniform distribution of test compound in the chamber, and 3) delivery of sufficient oxygen to cells to support aerobic respiration. Two commercially available flow devices — RealBio® (RB) and QuasiVivo® (QV) — and a custom developed fluidized bed (FB) bioreactor were simulated, and turbulence, flow characteristics, test compound distribution, oxygen distribution, and cellular oxygen consumption were analyzed. Experimental results from the bioreactors were used to validate the simulation results.Our results indicate that maintaining adequate oxygen supply is the most important factor to the long-term viability of liver bioreactor cultures. Cell density and system flow patterns were the major determinants of local oxygen concentrations. The experimental results closely corresponded to the in silico predictions. Of the three bioreactors examined in this study, we were able to optimize the experimental conditions for long-term hepatocyte cell culture using the QV bioreactor. This system facilitated the use of low system volumes coupled with higher flow rates. This design supports cellular respiration by increasing oxygen concentrations in the vicinity of the cells, and facilitates long-term kinetic studies of low clearance test compounds. These two goals were achieved while simultaneously keeping the shear stress experienced by the cells within acceptable limits.http://journal.frontiersin.org/Journal/10.3389/fbioe.2016.00072/fullMetabolismcomputational fluid dynamicsHepatocyte cultureFluid dynamic modelingQuasiVivoRealBio |
| spellingShingle | Jenny M Pedersen Yoo-Sik Shim Yoo-Sik Shim Yoo-Sik Shim Vaibhav Hans Martin Blake Phillips Jeffrey M. Macdonald Glenn Walker Melvin E. Andersen Melvin E. Andersen Harvey J. Clewell Harvey J. Clewell Miyoung Yoon Miyoung Yoon Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies Frontiers in Bioengineering and Biotechnology Metabolism computational fluid dynamics Hepatocyte culture Fluid dynamic modeling QuasiVivo RealBio |
| title | Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies |
| title_full | Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies |
| title_fullStr | Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies |
| title_full_unstemmed | Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies |
| title_short | Fluid Dynamic Modeling to Support the Development of Flow-based Hepatocyte Culture Systems for Metabolism Studies |
| title_sort | fluid dynamic modeling to support the development of flow based hepatocyte culture systems for metabolism studies |
| topic | Metabolism computational fluid dynamics Hepatocyte culture Fluid dynamic modeling QuasiVivo RealBio |
| url | http://journal.frontiersin.org/Journal/10.3389/fbioe.2016.00072/full |
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