Engineered Liver Platforms for Different Phases of Drug Development

Ware, Brenton R.; Khetani, Salman R.

doi:10.1016/j.tibtech.2016.08.001

Cited by 73 publications

(75 citation statements)

References 75 publications

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“…Drug-induced liver injury remains a significant source of clinical attrition, restrictive drug labeling, and post-market withdrawal of therapeutics [93,94]. Because of the ability to mimic in vivo physiological parameters, organ-on-a-chip devices enhance hepatocyte functions to assess the cellular behavior responses to drugs, which offer an alternative to animal experimentation [94].…”

Section: Drug Screening and Toxicity Testingmentioning

confidence: 99%

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

et al. 2019

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Hepatology and drug development for liver diseases require in vitro liver models. Typical models include 2D planar primary hepatocytes, hepatocyte spheroids, hepatocyte organoids, and liver-on-a-chip. Liver-on-a-chip has emerged as the mainstream model for drug development because it recapitulates the liver microenvironment and has good assay robustness such as reproducibility. Liver-on-a-chip with human primary cells can potentially correlate clinical testing. Liver-on-a-chip can not only predict drug hepatotoxicity and drug metabolism, but also connect other artificial organs on the chip for a human-on-a-chip, which can reflect the overall effect of a drug. Engineering an effective liver-on-a-chip device requires knowledge of multiple disciplines including chemistry, fluidic mechanics, cell biology, electrics, and optics. This review first introduces the physiological microenvironments in the liver, especially the cell composition and its specialized roles, and then summarizes the strategies to build a liver-on-a-chip via microfluidic technologies and its biomedical applications. In addition, the latest advancements of liver-on-a-chip technologies are discussed, which serve as a basis for further liver-on-a-chip research.

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Section: Drug Screening and Toxicity Testingmentioning

confidence: 99%

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

et al. 2019

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“…In addition, human hepatoma cell lines (e.g., HepG2) show attractive profiles such as good availability, high proliferation capacity, and easy manipulation. However, the hepatic functions such as the gene expression levels and enzyme activities of HepG2 cells are significantly lower than those of primary hepatocytes (Ware & Khetani, 2017). Thus, there is a need for more faithful in vitro culture systems to maintain the proliferation ability of primary hepatocytes and restore the liver‐specific functions of HepG2 cells (Bell et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Glucose and lipid metabolism screening models of hepatocyte spheroids after culture with injectable fiber fragments

Wei

Xia²,

Chen

et al. 2020

J Tissue Eng Regen Med

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With the rise of obesity, diabetes, and other metabolic diseases, in vitro hepatic cell and tissue models play an essential role in the identification of active pharmaceutical ingredients. Up to now, three-dimensional (3D) culture models have rarely focused on hepatic glucose and lipid metabolism. In addition, primary human liver cells suffer from limited availability and interdonor difference for establishing reproducible models. Thus, in the current study, the most available human liver cancer cell line (HepG2) and primary hepatocytes from rats (rPH) were proposed to construct 3D spheroids using injectable fiber fragments with galactose grafts (gSF) as the substrate. rPH and HepG2 spheroids show strong cell-cell and cell-fiber fragment interactions to promote the cell viability, albumin, and urea syntheses. Compared with HepG2 spheroids, rPH spheroids indicate stronger glucose metabolism abilities in terms of glucose consumption, intracellular glycogen content, gluconeogenesis rate, and sensitivity to glucose modulator hormones like insulin and glucagon. On the other hand, HepG2 spheroids display strong lipid metabolism abilities in producing significantly higher levels of total cholesterol and triglyceride. Compared with those without fiber fragments, the gSF-supported 3D culture establishes effective models for in vitro glucose (rPH spheroids) and lipid metabolisms (HepG2 spheroids). The screening models are confirmed from the respective enzyme activities and gene expressions and show significantly higher sensitivity and clinically related responses to hypoglycemic and lipid-lowering drugs. Thus, the culture configuration demonstrates a predictable in vitro platform for defining glucose and lipid metabolism profiles and screening therapeutic agents for metabolism disorders like diabetes and obesity. K E Y W O R D S glucose metabolism model, high-throughput drug screening, injectable fiber fragment, lipid metabolism model, metabolism disorder, spheroid culture 1 | INTRODUCTION An epidemic of metabolic diseases such as diabetes and obesity is rising dramatically. Diabetes is a group of metabolic disorders of blood sugar and may cause serious long-term complications including cardiovascular diseases, foot ulcers, and damage to the eyes. It is estimated that over 420 million people have diabetes worldwide, and the case rate continues to rise especially in young people. Obesity is resulted from excessive and unbalanced food intake, unhealthy lifestyle, and lipid metabolism disorders, increasing the likelihood of cardiovascular Jiaojun Wei and Tian Xia , contributed equally to the work.

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“…Several sources of hepatic cells have been used, with each model having its own qualities: primary adult hepatocytes, oval cells (potential adult liver stem cells), mesenchymal stem cells, fetal liver progenitor cells, hiPSCs, and immortalized cell lines to name a few. 7,8 However, one of the main challenges remaining in tissue engineering consists of the organspecific organization of the tissue to promote improved functionality. The periportal area, rich in oxygen, is specialized in glucose metabolism, and the perivenous area, poor in oxygen, is specialized in xenobiotic detoxification.…”

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confidence: 99%

Characterization of liver zonation‐like transcriptomic patterns in HLCs derived from hiPSCs in a microfluidic biochip environment

Danoy

Poulain

Lereau-Bernier

et al. 2020

Biotechnology Progress

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The liver zonation is an important phenomenon characterized by a gradient of several functions along the liver acinus. However, this gradient remains difficult to reproduce in in-vitro conditions, making the obtention of an in-vitro method to recapitulate the liver zonation a challenging issue. In this study, we evaluated the spatial evolution of the transcriptome profile of human induced pluripotent stem cells (hiPSCs) differentiated toward hepatocytes-like cells (HLCs) phenotype in a microfluidic biochip environment. Cells collected at the inlet of the biochip, where the oxygen concentration is higher, were identified by the expression of genes involved in metabolic pathways related to cellular reorganization and cell proliferation. Cells collected in the middle and at the outlet of the biochips, where oxygen concentrations are lower, were characterized by the upregulation of genes involved in cellular detoxification processes (CYP450), PPAR signaling or arginine biosynthesis. A subset of 16 transcription factors (TFs) was extracted and identified as upstream regulators to HNF1A and PPARA. These TFs are also known as regulators to target genes engaged in the Wnt/βcatenin pathway, in the TGFβ/BMP/SMAD signaling, in the transition between epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET), in the homeostasis of lipids, bile acids and carbohydrates homeostasis, in drug metabolism, in the estrogen processing and in the oxidative stress response. Overall, the analysis allowed to confirm a partial zonation-like pattern in hiPSCs-derived HLCs in the microfluidic biochip environment. These results provide important insights into the reproduction of liver zonation in-vitro for a better understanding of the phenomenon.

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Engineered Liver Platforms for Different Phases of Drug Development

Cited by 73 publications

References 75 publications

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

Glucose and lipid metabolism screening models of hepatocyte spheroids after culture with injectable fiber fragments

Characterization of liver zonation‐like transcriptomic patterns in HLCs derived from hiPSCs in a microfluidic biochip environment

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