Hepatic Tissue Engineering: Development of Critical Technologies

Yarmush, Martin L.; Toner, Mehmet; Dunn, James C.Y.; Rotem, Avi; Hubel, Allison; Tompkins, Ronald G.

doi:10.1111/j.1749-6632.1992.tb42588.x

Cited by 135 publications

(95 citation statements)

References 26 publications

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“…These cocultures seeded under high oxygen tension showed a similar ability to predict in vivo hepatic clearance of both rapid and slow clearing drugs with an R 2 of 0.92 compared to 0.91 for hepatocytes in suspension, although we note that the actual value of such in vitro vs. in vivo comparison is uncertain. Moreover, as function in oxygenated co-cultures does not require 7 to 10 days to stabilize (6,14), this culture technique significantly reduces overall labor and cost. During this work we identified no clear .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, micropatterns of hepatocytes and 3T3-J2 were shown to acquire high levels of CYP450 gene transcription and metabolic activity following 11 days of culture (14). While these culture configurations offer significant metabolic competence, they do so only after a long adaptation period of between 7 to 10 days of culture during which the primary cells slowly adapt their metabolic activity to the in vitro microenvironment (6,14).…”

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confidence: 99%

“…However, the inherent difficulties in evaluating the metabolism of slow-clearing drugs under such short time periods bars many promising compounds from clinical validation (4). An alternative approach developed by several groups, including ours, is to support the long-term function of primary hepatocytes using specialized tissue culture configurations (6)(7)(8).…”

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confidence: 99%

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Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Kidambi

Yarmush

Novik³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

147

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The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R 2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures. drug discovery ͉ liver metabolism ͉ tissue engineering

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Kidambi

Yarmush

Novik³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

147

View full text Add to dashboard Cite

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“…42,43 Use of primary hepatocytes combined with a change of cell culture format to 3D and, more importantly, co-cultivation with non-parenchymal liver cells, such as endothelial cells, hepatic stellate cells or Kupffer cells, might improve their cellular and metabolic functions towards in vivo-like levels. 22,18,44,45 Induced stem cell technologies, recently awarded with the Nobel Prize in Medicine, [46][47][48][49] might provide new solutions to the well described but restricted access to human liver tissue. 50,51 Random dynamic monocultures A number of microfluidic liver culture devices exposing hepatocytes in random 3D culture at a lower organisational level have been engineered and will be discussed in this section.…”

Section: Relevance Of Cell Sourcesmentioning

confidence: 99%

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

2013

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Drug-induced liver toxicity dominates the reasons for pharmaceutical product ban, withdrawal or nonapproval since the thalidomide disaster in the late-1950s. Hopes to finally solve the liver toxicity test dilemma have recently risen to a historic level based on the latest progress in human microfluidic tissue culture devices. Chip-based human liver equivalents are envisaged to identify liver toxic agents regularly undiscovered by current test procedures at industrial throughput. In this review, we focus on advanced microfluidic microscale liver equivalents, appraising them against the level of architectural and, consequently, functional identity with their human counterpart in vivo. We emphasise the inherent relationship between human liver architecture and its drug-induced injury. Furthermore, we plot the current socio-economic drug development environment against the possible value such systems may add.Finally, we try to sketch a forecast for translational innovations in the field.

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“…MPS II has not responded to enzyme replacement ther apy, and bone marrow transplants have not been effec tive. Previous studies have shown the potential for using genetically modified lymphocytes to treat MPS II (4,34,45).…”

Section: Mucopolysaccharidosis Type II (Mps Ii)mentioning

confidence: 99%

Freezing Characteristics of Genetically Modified Lymphocytes for the Treatment of MPS II

1999

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The freezing characteristics of genetically modified lymphocytes obtained from a donor with mucopolysac charidosis type II (MPS II) were determined using cryomicroscopy and controlled rate freezing studies to determine postthaw viability. The cells from a donor with MPS II used in this investigation were cultured and transduced with a retroviral vector for the iduronate-2-sulfatase (IDS) enzyme for clinical studies for human gene therapy. The water transport and intracellular ice formation (IIF) characteristics of the cells were determined after completion of the culture and transduction protocol. The water transport parameters, L m and £, p , for the cultured and transduced cells were determined to be 4.4 ± 1.3 x 10~1 4 m 3 /Ns and 173 ± 25 kJ/mol, respectively. The IIF nucleation parameters, K and Q, were 5.5 x 10 10 K 5 and 3.5 x 10" (1/m 2 s), respectively. The postthaw viability of the genetically modified cells was less than the viability of the freshly isolated cells from the same donor. The postthaw viability of the cultured and transduced cells from a donor with MPS II was also less than that observed with cells from a normal donor that were frozen and thawed under the same conditions. These studies are essential in understanding the biophysical changes resulting from the ex vivo culture of cells and the manner in which these changes influence the ability of the cells to be cryopreserved.

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Hepatic Tissue Engineering: Development of Critical Technologies

Cited by 135 publications

References 26 publications

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

Freezing Characteristics of Genetically Modified Lymphocytes for the Treatment of MPS II

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