Experimental Evaluation of a Cell Module for Hybrid Liver Support

Jc, Gerlach; Botsch, M; Kardassis, Dimitrios; Lemmens, P.; Schön, Michael P.; Janke, Jürgen; Puhl, Gero; Unger, Juliane K.; M, Kraemer; Busse, Benedikt; Böhmer, Clarisse J M; Belal, R; Ingenlath, M; Kosan, Murat; Kosan, B; Sültmann, J; Patzold, A; Tietze, Stefan; Rossaint, Rolf; Müller, Christiane; Mönch, E; Sauer, Igor M.; Neuhaus, P.

doi:10.1177/039139880102401105

Cited by 34 publications

(17 citation statements)

References 23 publications

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“…Four discrete capillary membrane systems are woven to create a three-dimensional framework for decentralized cell perfusion with low metabolite gradients and decentralized oxygenation and CO 2 removal [141][142][143][144]. Such systems have primarily been characterized and proposed as a liver-support device [145][146][147][148][149][150]. Recent studies have also shown the suitability of the system as a tool to measure drug metabolism and enzyme induction in long term cultures of primary hepatocytes [140,151].…”

Section: Multicompartment Bioreactor Culturesmentioning

confidence: 99%

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

Sivaraman

Leach

Townsend

et al. 2005

CDM

285

230

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In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when maintained under standard in vitro cell culture conditions. Many modifications to conventional culture methods have been developed to foster retention of hepatocyte function. Still, not all of the important functions -- especially the biotransformation functions of the liver -- can as yet be replicated at desired levels, prompting continued development of new culture systems. In the first part of this article, we review primary hepatocyte in vitro systems used in metabolism and enzyme induction studies. We then describe a scalable microreactor system that fosters development of 3D-perfused micro-tissue units and show that primary rat cells cultured in this system are substantially closer to native liver compared to cells cultured by other in vitro methods, as assessed by a broad spectrum of gene expression, protein expression and biochemical activity metrics. These results provide a foundation for extension of this culture model to other applications in drug discovery -- as a model to study drug-drug interactions, as a model for the assessment of acute and chronic liver toxicity arising from exposure to drugs or environmental agents; and as a disease model for the study of viral hepatitis infection and cancer metastasis.

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Section: Multicompartment Bioreactor Culturesmentioning

confidence: 99%

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

Sivaraman

Leach

Townsend

et al. 2005

CDM

285

230

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“…Adequate oxygen supply inside BAL devices is crucial for maintenance of sufficient and stable liver-specific functions. Therefore, several BAL devices have been equipped with incorporated membrane or capillary oxygenators (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Oxygen Availability Improves Liver‐specific Functions of the AMC Bioartificial Liver

Poyck¹,

Mareels²,

Hoekstra³

et al. 2007

Artificial Organs

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Long-term culturing of primary porcine hepatocytes (PPH) inside the Academic Medical Center (AMC)-bioartificial liver is characterized by increased anaerobic glycolysis. Recommendations to increase oxygen availability were proposed in a previous numerical study and were experimentally evaluated in this study. Original bioreactors as well as new configuration bioreactors with 2.2-fold thinner nonwoven matrix and 2-fold more capillaries were loaded with PPHs and oxygenated with different gas oxygen pressures resulting in medium pO(2) (pO(2-med)) of either 135-150 mm Hg or 235-250 mm Hg. After 6 days culturing, new configuration bioreactors with pO(2-med )of 250 mm Hg showed significantly reduced anaerobic glycolysis, 60% higher liver-specific functions, and increased transcript levels of five liver-specific genes compared to the standard bioreactor cultures. Changed bioreactor configuration and increasing pO(2-med) contributed equally to these improvements. Histological examination demonstrated small differences in cell organization. In conclusion, higher metabolic stability and liver-specific functionality was achieved by enhanced oxygen availability based on a prior modeling concept.

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“…8 We addressed technical issues by developing a hollow fiber-based four-compartment bioreactor technology, enabling decentralized oxygenation with low solute gradients and high-performance mass exchange. 9 Many cell types have been investigated to address the cell source issue. 10 Despite limited availability, primary human liver cells, isolated from explanted donor organs discarded from transplantation programs, would be a good cell source for addressing human liver metabolism.…”

mentioning

confidence: 99%

Mouse Fetal Liver Cells in Artificial Capillary Beds in Three-Dimensional Four-Compartment Bioreactors

Monga¹,

Hout²,

Baun³

et al. 2005

The American Journal of Pathology

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Bioreactors containing porcine or adult human hepatocytes have been used to sustain acute liver failure patients until liver transplantation. However, prolonged function of adult hepatocytes has not been achieved due to compromised proliferation and viability of adult cells in vitro. We investigated the use of fetal hepatocytes as an alternative cell source in bioreactors. Mouse fetal liver cells from gestational day 17 possessed intermediate differentiation and function based on their molecular profile. When cultured in a three-dimensional four-compartment hollow fiber-based bioreactor for 3 to 5 weeks these cells formed neo-tissues that were characterized comprehensively. Albumin liberation, testosterone metabolism, and P450 induction were demonstrated. Histology showed predominant ribbon-like three-dimensional structures composed of hepatocytes between hollow fibers. High positivity for proliferating cell nuclear antigen and Ki-67 and low positivity for terminal dUTP nick-end labeling indicated robust cell proliferation and survival. Most cells within these ribbon arrangements were albumin-positive. In addition, cells in peripheral zones were simultaneously positive for ␣-fetoprotein, cytokeratin-19, and c-kit, indicating their progenitor phenotype. Mesenchymal components including endothelial, stellate, and smooth muscle cells were also observed. Thus, fetal liver cells can survive, proliferate, differentiate, and function in a three-dimensional perfusion culture system while maintaining a progenitor pool, reflecting an important advance in hepatic tissue engineering.

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Experimental Evaluation of a Cell Module for Hybrid Liver Support

Cited by 34 publications

References 23 publications

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

Enhanced Oxygen Availability Improves Liver‐specific Functions of the AMC Bioartificial Liver

Mouse Fetal Liver Cells in Artificial Capillary Beds in Three-Dimensional Four-Compartment Bioreactors

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