Effects of Enhanced O<sub>2</sub> Transport on Hepatocytes Packed within a Bioartificial Liver Device

McClelland, Randall; Coger, Robin N.

doi:10.1089/107632704322791899

Cited by 22 publications

(24 citation statements)

References 20 publications

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“…The bioreactor has the additional benefit of employing a cellular space (i.e., its cartridge design) that is unique in that it offers the flexibility to easily support any anchorage-dependant cell type. It can also be modified to incorporate modifications proven to further improve functional output (e.g., O 2 transport enhancements [38][39][40] and micropatterned cocultures 27,28 ). The cartridge design also enables cells of the bioreactor to interact with the circulating medium through both of the membrane surfaces of each individual cartridge.…”

Section: Discussionmentioning

confidence: 99%

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

Niu

Hammond

Coger

2009

Tissue Engineering Part A

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There are a number of applications-ranging from temporary strategies for organ failure to pharmaceutical testing-that rely on effective bioreactor designs. The significance of these devices is that they provide an environment for maintaining cells in a way that allows them to perform key cellular and tissue functions. In the current study, a novel cartridge-based bioreactor was developed and evaluated. Its unique features include its capacity for cell support and the adaptable design of its cellular space. Specifically, it is able to accommodate functional and reasonably sized tissue (>2.0Â10 8 cells), and can be easily modified to support a range of anchorage-dependent cells. To evaluate its efficacy, it was applied to liver support in the current study. This involved evaluating the performance of rat primary hepatocytes within the unique cartridges in culture-sans bioreactor-and after being loaded within the novel bioreactor. Compared to collagen sandwich culture functional controls, hepatocytes within the unique cartridge design demonstrated significantly higher albumin production and urea secretion rates when cultured under dynamic flow conditions-reaching peak values of 170 AE 22 mg=10 6 cells=day and 195 AE 18 mg=10 6 cells=day, respectively. The bioreactor's effectiveness in supporting live and functioning primary hepatocytes is also presented. Cell viability at the end of 15 days of culture in the new bioreactor was 84 AE 18%, suggesting that the new design is effective in maintaining primary hepatocytes for at least 2 weeks in culture. Liver-specific functions of urea secretion, albumin synthesis, and cytochrome P450 activity were also assessed. The results indicate that hepatocytes are able to achieve good functional performance when cultured within the novel bioreactor. This is especially true in the case of cytochrome P450 activity, where by day 15 of culture, hepatocytes within the bioreactor reached values that were 56.6% higher than achieved by the collagen sandwich functional control cultures. The success of the novel cartridge-based bioreactor in supporting hepatocytes with good viability and functional performance suggests that it is an effective design for supporting anchorage-dependent cells.

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Section: Discussionmentioning

confidence: 99%

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

Niu

Hammond

Coger

2009

Tissue Engineering Part A

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“…The techniques success in improving O 2 transport is thought to be closely related to the increased porosity of the enhanced ECM, since confocal microscopy (previously reported in McClelland and Coger, 2004) has revealed the presence of a gap thickness between the surface of each microsphere and the ECM gel that surrounds it. It is believed that the conduits for gaseous (e.g., O 2 ) transport-created by these gap thicknessesyield the improved O 2 transport distances achieved by the technique.…”

Section: Ecm Preparationmentioning

confidence: 99%

Optimizing normoxic conditions in liver devices using enhanced gel matrices

Niu

Clemens

Coger

2007

Biotech & Bioengineering

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For in vitro liver replacement devices, such as packed bed bioreactors, to maintain the essential functions of the liver, they must at least successfully support hepatocytes, the parenchymal cell of the liver. In vivo, the liver is a major consumer of oxygen. Hence it is unsurprising that the limited transport distance of oxygen (O(2)) governs the dimensions of the cellular space of engineered devices. Because cellular space capacity directly affects the device's performance, O(2) transport is a critical issue in the scale up of bioreactor designs. In the current investigation, the microporosity of the extracellular matrix (ECM) has been modified to further improve O(2) transport in packed bed devices beyond that previously reported in the literature. These improvements to the O(2) enhancement technique enabled O(2) transport distances of 481.7 +/- 12.5 microm to be achieved under acellular conditions; and distances of 418.1 +/- 6.0 microm to be attained in the presence of 1 million hepatocytes. Both values are significantly greater than the 170 microm baseline attained when 10(6) hepatocytes are packed within normal non-enhanced ECM gels. The study's results also illustrate that the O(2) enhancement technique has the added benefit of preventing regions of severe hypoxia and hyperoxia from developing within the cellular space. As such, enhanced ECM gels enable packed hepatocytes to maintain better hepatocellular metabolic status than is possible with normal non-enhanced gels.

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“…11 We recently developed a unique method for enhancing O 2 transport through packed-bed extracellular matrix (ECM) systems by utilizing a porous modified structure of collagen type I ECM in a concentric cylinder BAL. 12 In previous studies, [12][13][14] this ''enhanced collagen'' ECM showed superior improvement of hepatocyte viability and functions as compared with ''normal collagen'' ECM. The results also demonstrated that the enhanced collagen ECM enables a cellular space to be employed of larger dimensions than in packed-bed designs containing hepatocytes entrapped within normal collagen.…”

Section: Introductionmentioning

confidence: 87%

Antioxidant Functionality in Hepatocytes Using the Enhanced Collagen Extracellular Matrix Under Different Oxygen Tensions

Lee

Coger²,

Clemens³

2006

Tissue Engineering

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Improvement of O(2) supply in bioartificial liver devices remains a critical issue in maintaining hepatocyte viability and functions. Therefore, the current study investigates whether enhanced oxygen (O(2)) transport through collagen extracellular matrix (ECM) can produce a more stable antioxidant defense in different O(2) tensions during prolonged incubation times. Total glutathione concentration of cultured hepatocytes in enhanced ECM was significantly higher than in normal ECM under the lowest O(2) tension phase (2.60mm of thickness from O(2) source), and was also significantly increased in 0.52 mm transport distance of hypoxia as compared to normoxic conditions. Catalase and glutathione reductase activities for hepatocytes within enhanced ECM were also significantly preserved relative to their values for the normal collagen ECM. Specifically, the enhanced ECM produced higher activities at a further transport distance (1.56 mm) from the O(2) source at the 24 h time-point, and remained higher up to the 96 h incubation time. In contrast, the glutathione peroxidase activities in both collagen ECM systems were similar. Hepatocyte viability in the enhanced ECM system was also consistently greater than that for normal ECM. These results suggest that the O(2) enhanced collagen ECM preserves the antioxidant defense system as compared to normal collagen ECM, ostensibly via increased micropathways for O(2) transport to the hepatocytes.

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Effects of Enhanced O₂ Transport on Hepatocytes Packed within a Bioartificial Liver Device

Cited by 22 publications

References 20 publications

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

Optimizing normoxic conditions in liver devices using enhanced gel matrices

Antioxidant Functionality in Hepatocytes Using the Enhanced Collagen Extracellular Matrix Under Different Oxygen Tensions

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Effects of Enhanced O2 Transport on Hepatocytes Packed within a Bioartificial Liver Device

Cited by 22 publications

References 20 publications

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

The Effectiveness of a Novel Cartridge-Based Bioreactor Design in Supporting Liver Cells

Optimizing normoxic conditions in liver devices using enhanced gel matrices

Antioxidant Functionality in Hepatocytes Using the Enhanced Collagen Extracellular Matrix Under Different Oxygen Tensions

Contact Info

Product

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Effects of Enhanced O₂ Transport on Hepatocytes Packed within a Bioartificial Liver Device