Nanopatterned Human Liver BioChips for Drug Hepatotoxicity Screening

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Conventional drug toxicity models use rodent hepatocytes or immortalized human cell lines, which rapidly lose polarity differentiated phenotype and are not representative of normal liver tissue. Primary human hepatocytes (PHHs) exhibit phenotypic variability and instability in culture, with intermittent supply and high costs. Hepatoxicity is a leading cause of drug attrition, suggesting current preclinical models of toxicity are not universally predictive of drug effects in humans. Therefore a sustainable and scalable human hepatic in vitro cell culture platform would help generate more physiologically-relevant preclinical data for drug hepatoxicity screening. Commercially available bioengineered liver models are based on heterologous hepatic co-cultures, which may be contraindicated for pre-clinical hepatotoxicity testing. We will utilize the human HepaRG bipotential hepatic progenitor cell line as a functional surrogate to PHHs and a unique co-culture system for high-throughput screening (HTS) of hepatotoxicity.
The significance of the proposed work is to develop and validate a prototype HTS-compatible HepaRG-based BioChip by directed nanopattern-guided differentiation. HepaRGs undergo a complete differentiation program, which we will exploit to assess effects of nanopattern-guided differentiation/ cellular reorganization. Thus our research will grant access to general mechanistics of external cues for the improved culture of other hepatic cell types.

We will determine the interplay between nanoengineered substrates and hepatic phenotypic function by assessing:
*Nanotopographical control of HepaRG differentiation on fabricated nanopatterned polymer slides
*Define optimal configuration most predictive of in vivo-like metabolism
*Perform rigorous hepatotoxicity testing interrogated with automated HTS-compatible CellProfiler
*Using the above criteria, integrate the system for HTS using a novel ubiquitous 'BioChip' HTS platform for hepatotoxicity testing

The global market for drug discovery technologies and products is expected to expand from $41.0 billion in 2012 to $79.0 billion in 2017. Indeed, the drug discovery industry is highly dependent on cell-based assays and high-throughput screening (HTS) tools and the latter sector is expected to expand from $11.5 billion in 2012 to $20.0 billion in 2017.

There are some commercially available liver models include from RegeneMed, Hepregen and LiverChip. These systems utilize either heterologous hepatic co-cultures using rodent, primate or primary human hepatocytes combining complex multi-step microfabrication manufacturing processes leading to significantly increase per unit costs.

Besides having direct academic impact, our proposed nanofabrication based high-throughput system will have significant industrial impact. The driving technology underpinning the project is extremely accurate and will provide no batch-to-batch variation between samples. Moreover, it will be based on well established multi-well formats already widely used in industry and pharma. Gadegaard has a number of industrial contacts in the area of plastic cell culture ware made by injection moulding and is experience discussing with industry on translation aspects of the research outputs.

The research to be carried out and the outcomes will also have an interest to the public. With an increasingly ageing population we are increasingly relying on the health services provided leading to increased costs. Thus technologies capable of reducing such costs and providing for a faster route from discovery to market for pharma companies will also be of the public's interest. This importance will be communicated to the public using well-established routes of public engagement available at but University of Glasgow and Edinburgh.