title: The application of engineered liver tissues for novel drug discovery.
abstract: BACKGROUND
  Drug-induced liver injury remains a major cause of drug attrition. Furthermore, novel drugs are being developed for treating liver diseases. However, differences between animals and humans in liver pathways necessitate the use of human-relevant liver models to complement live animal testing during preclinical drug development. Microfabrication tools and synthetic biomaterials now allow for the creation of tissue subunits that display more physiologically relevant and long-term liver functions than possible with declining monolayers.
  
  
  METHODS
  The authors discuss acellular enzyme platforms, two-dimensional micropatterned co-cultures, three-dimensional spheroidal cultures, microfluidic perfusion, liver slices and humanized rodent models. They also present the use of cell lines, primary liver cells and induced pluripotent stem cell-derived human hepatocyte-like cells in the creation of cell-based models and discuss in silico approaches that allow integration and modeling of the datasets from these models. Finally, the authors describe the application of liver models for the discovery of novel therapeutics for liver diseases.
  
  
  CONCLUSIONS
  Engineered liver models with varying levels of in vivo-like complexities provide investigators with the opportunity to develop assays with sufficient complexity and required throughput. Control over cell-cell interactions and co-culture with stromal cells in both two dimension and three dimension are critical for enabling stable liver models. The validation of liver models with diverse sets of compounds for different applications, coupled with an analysis of cost:benefit ratio, is important for model adoption for routine screening. Ultimately, engineered liver models could significantly reduce drug development costs and enable the development of more efficacious and safer therapeutics for liver diseases.
authors.affiliation: Colorado State University, School of Biomedical Engineering , 200 W. Lake St, 1301 Campus Delivery, Fort Collins, CO 80523-1374 , USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lin
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ballinger
authors.forename: Salman R
authors.initials: SR
authors.lastname: Khetani
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008107:Liver Diseases / Q000188:drug therapy*; D013045:Species Specificity; D023822:Tissue Engineering / Q000379:methods
keywords: hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; humanized rodents; induced pluripotent stem cells; liver fibrosis; malaria; microfabrication; microfluidics; micropatterned co-cultures; non alcoholic fatty liver disease; primary human hepatocytes