In vitro toxicology in hepatocyte bioreactors-extracellular acidification rate (EAR) in a target cell line indicates hepato-activated transformation of substrates

Koebe, H.G.; Deglmann, Claus J.; Metzger, Robert P.; Hoerrlein, S.; Schildberg, F. W.

doi:10.1016/s0300-483x(00)00270-5

Cited by 16 publications

(4 citation statements)

References 49 publications

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“…9 In another study, a hepatocyte-bioreactor was developed to assess hepato-activated transformation of substrates. 10 These systems successfully demonstrated in vitro observation of metabolism-dependent drug toxicity. However, they are still far from the faithful reproduction of in vivo situation, since they do not capture the true dynamics of drug exposure to the human body.…”

Section: Introductionmentioning

confidence: 99%

A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

2010

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Drug discovery is often impeded by the poor predictability of in vitro assays for drug toxicity. One primary reason for this observation is the inability to reproduce the pharmacokinetics (PK) of drugs in vitro. Mathematical models to predict the pharmacokinetics-pharmacodynamics (PK-PD) of drugs are available, but have several limitations, preventing broader application. A microscale cell culture analog (microCCA) is a microfluidic device based on a PK-PD model, where multiple cell culture chambers are connected with fluidic channels to mimic multi-organ interactions and test drug toxicity in a pharmacokinetic-based manner. One critical issue with microfluidics, including the microCCA, is that specialized techniques are required for assembly and operation, limiting its usability to non-experts. Here, we describe a novel design, with enhanced usability while allowing hydrogel-cell cultures of multiple types. Gravity-induced flow enables pumpless operation and prevents bubble formation. Three cell lines representing the liver, tumor and marrow were cultured in the three-chamber microCCA to test the toxicity of an anticancer drug, 5-fluorouracil. The result was analyzed with a PK-PD model of the device, and compared with the result in static conditions. Each cell type exhibited differential responses to 5-FU, and the responses in the microfluidic environment were different from those in static environment. Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.

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Section: Introductionmentioning

confidence: 99%

A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

2010

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“…In an effort to combine a conventional perfusion bioreactor with a microscale cell culture device, a hepatocyte-bioreactor coupled was developed to assess hepatoactivated transformation of substrates [60]. In this device, primary pig hepatocytes were cultured in a recirculating 50 ml perfusion bioreactor, which was connected to a commercially available cell culture chamber called microphysiometer at a flow rate of 150 ll/min.…”

Section: Microscale Systems For Metabolism-dependent Toxicity Studymentioning

confidence: 99%

In vitro microscale systems for systematic drug toxicity study

Sung

Shuler

2009

Bioprocess Biosyst Eng

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After administration, drugs go through a complex, dynamic process of absorption, distribution, metabolism and excretion. The resulting time-dependent concentration, termed pharmacokinetics (PK), is critical to the pharmacological response from patients. An in vitro system that can test the dynamics of drug effects in a more systematic way would save time and costs in drug development. Integration of microfabrication and cell culture techniques has resulted in 'cells-on-a-chip' technology, which is showing promise for high-throughput drug screening in physiologically relevant manner. In this review, we summarize current research efforts which ultimately lead to in vitro systems for testing drug's effect in PK-based manner. In particular, we highlight the contribution of microscale systems towards this goal. We envision that the 'cells-on-a-chip' technology will serve as a valuable link between in vitro and in vivo studies, reducing the demand for animal studies, and making clinical trials more effective.

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“…Most systems discussed so far do not fulfi ll this requirement; rather, they are mostly applicable for a specifi c tissue construct of a desired size, to provide a controlled environment, and to enable a continuous supply of nutrients and oxygen as well as the removal of metabolites. Some systems were successfully applied for in-vitro drug studies [45,55,67,74,75], but these proved mostly to be unsuitable for handling a magnitude of culture units in parallel, as the need for additional devices such as pumps, tubes, medium reservoirs and aeration units ballooned.…”

Section: D Systems Used For Drug Testingmentioning

confidence: 99%

An Overview on Bioreactor Design, Prototyping and Process Control for Reproducible Three‐Dimensional Tissue Culture

Pörtner

Giese²

2006

Drug Testing in Vitro

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Bioreactor systems play an important role in tissue engineering, as they enable reproducible and controlled changes to be made in specifi c environmental factors. They can also provide the technical means to perform controlled studies aimed at understanding specifi c biological, chemical, or physical effects. Furthermore, bioreactors allow for a safe and reproducible production of tissue constructs. For later clinical applications, the bioreactor system should be an advantageous method in terms of low contamination risk, ease of handling, and scalability. With respect to drug screening, the main challenge is the effi cient, reproducible handling of a large quantity of tissue constructs in parallel (high-throughput screening). To date, the goals and expectations of bioreactor development have been fulfi lled only to some extent, as bioreactor design in tissue engineering is very complex and still at an early stage of development, especially for use in drug screening. In this chapter, important aspects of bioreactor design are summarized, and an overview of existing concepts is provided. An artifi cial immunosystem will be used as an example to demonstrate how an increased fundamental understanding of biological, biochemical, and engineering aspects can signifi cantly improve the properties of 3D tissue constructs.

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In vitro toxicology in hepatocyte bioreactors-extracellular acidification rate (EAR) in a target cell line indicates hepato-activated transformation of substrates

Cited by 16 publications

References 49 publications

A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

In vitro microscale systems for systematic drug toxicity study

An Overview on Bioreactor Design, Prototyping and Process Control for Reproducible Three‐Dimensional Tissue Culture

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