A microfluidically perfused three dimensional human liver model

Rennert, Knut; Steinborn, Sandra; Gröger, Marko; Ungerböck, Birgit; Jank, A; Ehgartner, Josef; Nietzsche, Sándor; Dinger, J. E.; Kiehntopf, Michael; Funke, Harald; Peters, Frank T.; Lupp, Amelie; Gärtner, Claudia; Mayr, Torsten; Bauer, Michael; Huber, Otmar; Mosig, Alexander S.

doi:10.1016/j.biomaterials.2015.08.043

Cited by 201 publications

(181 citation statements)

References 73 publications

(63 reference statements)

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“…A shift from oxidative mitochondrial respiration to glycolysis was then shown after treatment with two hepatotoxins. Rennert et al established a liver biochip consisting of human umbilical vein endothelial cells and monocyte-derived macrophages in the vascular plane that was separated from the hepatic plane containing HepaRG and LX-2 cells with a membrane mimicking the space of Disse [57]. Luminescent-based sensor spots were integrated in the chip for real-time measurement of oxygen consumption.…”

Section: Engineered Liver Co-culturesmentioning

confidence: 99%

Engineered Liver Platforms for Different Phases of Drug Development

Ware

Khetani

2017

Trends in Biotechnology

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Drug-induced liver injury (DILI) remains a leading cause of drug withdrawal from human clinical trials or the marketplace. Due to species-specific differences in liver pathways, predicting human-relevant DILI using in vitro human liver models is critical. Microfabrication tools allow precise control over the cellular microenvironment towards stabilizing liver functions for weeks. These tools are used to engineer human liver models with different complexities and throughput using cell lines, primary cells, and stem cell-derived hepatocytes. Including multiple human liver cell types can mimic cell-cell interactions in specific types of DILI. Finally, organ-on-a-chip models demonstrate how drug metabolism in the liver affects multi-organ toxicities. In this review, we survey engineered human liver platforms within the needs of different phases of drug development.

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Section: Engineered Liver Co-culturesmentioning

confidence: 99%

Engineered Liver Platforms for Different Phases of Drug Development

Ware

Khetani

2017

Trends in Biotechnology

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“…18 HepaRG cells do express ASGPR, a specific receptor at the surface of hepatocytes, receptor of Ga and lactosyl. 37 A differential uptake of functionalized versus unfunctionalized micelles and nanoparticles was qualitatively observed in vitro by confocal imaging. To do so, nanocarriers were loaded with the fluorescent probe DilC 18 instead of BM.…”

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confidence: 99%

Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel

Paolini

Poul

Berjaud

et al. 2017

IJN

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Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of bio-compatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic- co -glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55).

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“…These membranes create an interface that allows cellular crosstalk of, in other words, endothelial and epithelial cell layers [3]. Several groups have established organ models of the kidney [4,5], intestine [6,7], lung [8,9], heart [10] or the blood–brain barrier [11,12] based on this concept.…”

mentioning

confidence: 99%

“…Several groups have established organ models of the kidney [4,5], intestine [6,7], lung [8,9], heart [10] or the blood–brain barrier [11,12] based on this concept. In a 3D model of the human liver it has been shown that the co-culture of different organ-specific cell types (hepatocytes with endothelial cells, macrophages and stellate cells) creates a microenvironment that stabilizes individual differentiation and functionality of individual cell types [3]. A unilateral perfusion protocol triggers alignment and polarization of hepatocytes, thereby prohibiting dedifferentiation as a prerequisite for preserved long-term function in vitro [3,13].…”

mentioning

confidence: 99%

“…In a 3D model of the human liver it has been shown that the co-culture of different organ-specific cell types (hepatocytes with endothelial cells, macrophages and stellate cells) creates a microenvironment that stabilizes individual differentiation and functionality of individual cell types [3]. A unilateral perfusion protocol triggers alignment and polarization of hepatocytes, thereby prohibiting dedifferentiation as a prerequisite for preserved long-term function in vitro [3,13]. Biochips also allow the integration of circulating immune cells and monitoring of their interaction under flow conditions with the biochip-embedded tissue.…”

mentioning

confidence: 99%

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