Liver disease is an escalating global health issue. While liver transplantation is an effective mode of therapy, patient mortality has increased due to the shortage of donor organs. Developing renewable sources of human liver tissue is therefore attractive. Pluripotent stem cell-derived liver tissue represents a potential alternative to cadaver derived hepatocytes and whole organ transplant. At present, two-dimensional differentiation procedures deliver tissue lacking certain functions and long-term stability. Efforts to overcome these limiting factors have led to the building of three-dimensional (3D) cellular aggregates. Although enabling for the field, their widespread application is limited due to their reliance on variable biological components. Our studies focused on the development of 3D liver tissue under defined conditions. In vitro generated 3D tissues exhibited stable phenotype for over 1 year in culture, providing an attractive resource for long-term in vitro studies. Moreover, 3D derived tissue provided critical liver support in two animal models, including immunocompetent recipients. Therefore, we believe that our study provides stable human tissue to better model liver biology ‘in the dish’, and in the future may permit the support of compromised liver function in humans.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2280-2) contains supplementary material, which is available to authorized users.

Word TeaserThe development of dynamic 3D bioreactor based systems as in vitro models for use in DMPK studies. Author BiographiesMaaria Ginai graduated with a first Class Bachelors degree with honours in Biomedical Science from the University of Kent (UK) in 2010. She is currently studying a BBSRC CASEfunded PhD at the Centre for Biological Engineering at Loughborough University in the area of bioartificial device progression to in vitro models for use in the pharmaceutical industry. This project is supported by AstraZeneca.Christopher J. Hewitt has a first Class Bachelors degree in Biology from Royal Holloway College, University of London (UK) and a PhD in Chemical Engineering from the University of Birmingham (UK). He is Director of the £7.3M EPSRC Doctoral Training Centre in Regenerative Medicine and co-founder of the £2M Centre for Biological Engineering at Loughborough University (UK). He also leads the Cell Technologies research group whose work spans the Engineering/Life science interface seeking to understand the interaction of the organism with the engineering environment within such diverse areas as microbial fermentation, bio-transformation, cell culture and mostly recently regenerative medicine bioprocessing.Karen Coopman has a first Class Bachelors degree in Pharmacology from the University of Bristol (UK) and a PhD from the Department of Pharmacy and Pharmacology at the University of Bath (UK). She was appointed to a lectureship at Loughborough University, where she is the Operations Manager of the EPSRC-funded Doctoral Training Centre in Regenerative Medicine. She co-leads the Cell Technologies research group within University's Centre for Biological Engineering and is currently a member of the EPSRC's Early Career Forum in Manufacturing Research. The overarching themes of Karen's research are the manufacture of cellular therapies and the use of cells in the drug discovery process. AbstractBringing a new drug to market is costly in terms of capital and time investments, and any development issues encountered in late stage clinical trials may often be due to in vitro -in vivo extrapolations (IVIVE) not accurately reflecting clinical outcome. In the discipline of drug metabolism and pharmacokinetics (DMPK), current in vitro cellular methods do not provide the 3D structure and function of organs found in vivo, so new dynamic methods need to be established to aid improvement of IVIVE. This review will highlight the importance of model progression into dynamic systems for use within drug development, focussing on devices developed currently in the areas of the liver and blood-brain barrier, and the potential to develop models for other organ systems such as the kidney.

No abstract

No abstract