Diffusion in tissue cultures on gas-permeable and impermeable supports

Jensen, Mona D.; Wallach, Donald F. Hoelzl; Sherwood, Peter J.

doi:10.1016/s0022-5193(76)80085-9

Cited by 44 publications

(20 citation statements)

References 10 publications

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“…This hypoxia situation leads to an inefficient utilization of glucose since the conversion of glucose to lactate leads to the generation of 2 mol ATP/mol glucose compared to 38 mol ATP/mol glucose during oxidative phosphorylation. 47 Enhanced oxygenation is important for the in vitro liver cellular microenvironment 5 and the BAL model. 48 Around half a century ago, Stevens reported that in vitro liver cells obtain 4% of their oxygen requirement and degenerate rapidly.…”

Section: Long-tern Survivalmentioning

confidence: 99%

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Giri¹,

Braumann²,

Giri³

et al. 2013

IJN

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Much effort has been directed towards the optimization of the capture of in vivo hepatocytes from their microenvironment. Some methods of capture include an ex vivo cellular model in a bioreactor based liver module, a micropatterned module, a microfluidic 3D chip, coated plates, and other innovative approaches for the functional maintenance of primary hepatocytes. However, none of the above methods meet US Food and Drug Administration (FDA) guidelines, which recommend and encourage that the duration of a toxicity assay of a drug should be a minimum of 14 days, to a maximum of 90 days for a general toxicity assay. Existing innovative reports have used undefined extracellular matrices like matrigel, rigid collagen, or serum supplementations, which are often problematic, unacceptable in preclinical and clinical applications, and can even interfere with experimental outcomes. We have overcome these challenges by using integrated nanostructured self-assembling peptides and a special combination of growth factors and cytokines to establish a proof of concept to mimic the in vivo hepatocyte microenvironment pattern in vitro for predicting the in vivo drug hepatotoxicity in a scalable bioartificial liver module. Hepatocyte functionality (albumin, urea) was measured at days 10, 30, 60, and 90 and we observed stable albumin secretion and urea function throughout the culture period. In parallel, drug metabolizing enzyme biomarkers such as ethoxyresorufin-O-deethylase, the methylthiazol tetrazolium test, and the lactate dehydrogenase test were carried out at days 10, 30, 60, and 90. We noticed excellent mitochondrial status and membrane stability at 90 days of culture. Since alpha glutathione S-transferase (GST) is highly sensitive and a specific marker of hepatocyte injury, we observed significantly low alpha GST levels on all measured days (10, 30, 60, and 90). Finally, we performed the image analysis of mitochondria-cultured hepatocytes at day 90 in different biophysical parameters using confocal microscopy. We applied an automatic algorithm-based method for 3D visualization to show the classic representation of the mitochondrial distribution in double hepatocytes. An automated morphological measurement was conducted on the mitochondrial distribution in the cultured hepatocytes. Our proof of concept of a scalable bioartificial liver modular device meets FDA guidelines and may function as an alternative model of animal experimentation for pharmacological and toxicological studies involving drug metabolism, enzyme induction, transplantation, viral hepatitis, hepatocyte regeneration, and can also be used in other existing bioreactor modules for long-term culture for up to 90 days or more.

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Section: Long-tern Survivalmentioning

confidence: 99%

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Giri¹,

Braumann²,

Giri³

et al. 2013

IJN

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“…Similarly, our work using static oxygenating 2D bioreactor cultures showed that these activities were well preserved and inducible in porcine hepatocytes. Here, the importance of an adequate oxygenation for the Phase I metabolism is emphasized by the lack of an effective induction of Phase I enzymatic activities in the conventional plates which have been shown to force hepatocyte cultures into more anaerobic metabolic states (Jensen et al, 1976). The long-term maintenance and inducibility of biotransformation-involving enzymes in in vitro hepatic cultures are important aspects that are to be taken into account when determining drug metabolic pattern and predicting hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of a small-scale bioreactor based on a bioartificial hepatic culture model for predictive pharmacological in vitro screenings

Schmitmeier¹,

Langsch²,

Jasmund³

et al. 2006

Biotechnol. Bioeng.

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A vast majority of pharmacons are beset by possible interactions and side effects which have usually been tested in laboratory animals. However, better methods are needed to reduce the number of animal experiments and interspecies differences with respect to drug metabolism, as well as to provide a faster and more cost-effective way of analysis. These facts have led to the development of in vitro models based on isolated primary hepatocytes to better assess drug metabolism, interactions, and toxicity. A new small-scale bioreactor with the hepatic sandwich model and a gas-permeable membrane at the bottom allowing a definable oxygen exchange, has been constructed and compared with the conventional well plates. Compared to hepatocytes cultured in conventional systems, the cells exhibited a stronger liver-specific capacity and remained in a differentiated state in the small-scale bioreactor over a cultivation period of 17 days. This in vitro model could serve as a tool to predict the liver response to newly developed drugs.

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“…The diffusion coefficient is dependent on the molecular size, the solvent, and temperature [17,18], and as the molecular size increases, the diffusion coefficient decreases. The source term in Equation (9) is represented by a simple Michaelis-Menton relationship for nutrient metabolism, and is given as [4,19] qˇD Vˇ cell Km C C Á Cˇ (10) where Vˇ(mol/cell.s) is the maximum uptake rate, Km (mol/m 3 / is the concentration at which the half-maximum rate occurs, and cell (cell/m 3 / is the density of cell seeded in the scaffold.…”

Section: Mass Transfer In Porous Systemmentioning

confidence: 99%

“…It is also assumed that the cell density is uniform nthroughout the scaffold, and the cells have an equal rate of nutrient consumption. The material properties for the numerical simulation are given in Table I [4,8,18,25,26]. The total length of the fiber is taken as 0.30 cm, and at the inlet of the lumen, an average fluid velocity of 0.745 cm/s is prescribed with a free outlet flow region.…”

Section: Nutrient Distribution In a Hollow Fiber Membrane Bioreactormentioning

confidence: 99%

Finite element model for nutrient distribution analysis of a hollow fiber membrane bioreactor

Unnikrishnan

Reddy

2011

Numer Methods Biomed Eng

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Hollow fiber membrane bioreactors (HFMB) are extensively used for the development of tissue substitutes for bones and cartilages. In an HFMB, the nutrient transport is dependent on the material properties of the porous scaffold and fiber membrane and also on the fluid flow through the hollow fiber. The difficulty in obtaining real-time data along with the presence of large number of variables in experimental studies have lead to increased application of computational models for the performance analysis of bioreactors. A major difficulty in the computational analysis of HFMB is the modeling of the interactions at the fluid and porous scaffold interfaces, which has often been neglected or incorporated using specific boundary conditions. In this study, a new FEM is developed to analyze the fluid flow in the fluid-porous region with the interface coupled directly into the FEM. Distribution of nutrients in the bioreactor is studied by coupling mass transport equations to the fluid-porous finite element framework. The new model is implemented to study the influence of permeability, cell density, and flow rate on the nutrient concentration distribution in the HFMB. The developed computational framework is an ideal tool to study fluid flow through porous-open channels and can also be used for the design of bioreactors for optimal tissue growth.

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Diffusion in tissue cultures on gas-permeable and impermeable supports

Cited by 44 publications

References 10 publications

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Development and characterization of a small-scale bioreactor based on a bioartificial hepatic culture model for predictive pharmacological in vitro screenings

Finite element model for nutrient distribution analysis of a hollow fiber membrane bioreactor

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