Clinical Application of Bioartificial Liver Support Systems

Kerkhove, M.-P. Van De; Hoekstra, Ruurdtje; Chamuleau, R. A. F. M.; Gulik, Thomas M. Van

doi:10.1097/01.sla.0000132986.75257.19

Cited by 164 publications

(90 citation statements)

References 115 publications

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“…However, animal models make extension to the human clinical scenario difficult due to, amongst other reasons, species differences in response to test substances, the degree of reversibility, the disease process duration and the degree of involvement of other organ systems [24,25]. The ¾-partial liver resection in rats is an attractive model in that it is welldescribed, technically feasible, highly reproducible, non-toxic yet severe, but reversible within a time period sufficient to enable study.…”

Section: Discussionmentioning

confidence: 99%

Non-toxicity of IV Injected Perfluorocarbon Oxygen Carrier in an Animal Model of Liver Regeneration Following Surgical Injury

Nieuwoudt

Engelbrecht

Sentle

et al. 2009

Artificial Cells, Blood Substitutes, and Biotechnology

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Lethal dose experiments in animals have demonstrated that second generation perfluorocarbon oxygen carriers are remarkably non-toxic. However, this non-toxicity has not previously been demonstrated in a liver failure scenario. A surgical liver damage and regeneration model in rats was selected using a well-controlled cross tabulated study design. A large number of physiological, biochemical and haematological parameters were measured. No indications were found that intravenously injected perfluorooctyl bromide emulsion was toxic at the concentrations employed, in either healthy or severe liver injury scenarios. Neither was there any significant impact on the rate of liver regeneration following the injuries. Bearing in mind prior human clinical studies, it is therefore safe to assume that perfluorocarbon emulsions are also non-toxic in bioartificial liver treatments.

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Section: Discussionmentioning

confidence: 99%

Non-toxicity of IV Injected Perfluorocarbon Oxygen Carrier in an Animal Model of Liver Regeneration Following Surgical Injury

Nieuwoudt

Engelbrecht

Sentle

et al. 2009

Artificial Cells, Blood Substitutes, and Biotechnology

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“…12), showed significant improvement of survival time in ALF animal models (13,14,33), and proved to be safe in a phase I clinical trial conducted in Italy (38)(39)(40). In this era of organ donor shortage, many acute liver failure (ALF) patients die on the liver transplantation Logistical problems may, however, affect the outcome of BAL treatment.…”

Section: Introductionmentioning

confidence: 99%

Subnormothermic Preservation Maintains Viability and Function in a Porcine Hepatocyte Culture Model Simulating Bioreactor Transport

et al. 2006

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Bioartificial liver (BAL) systems have been developed to bridge patients with acute liver failure (ALF) to liver transplantation or liver regeneration. Clinical application of BAL systems is dependent on the supportive quality of cells used and direct availability of the whole system. Reliable transport of BAL systems from the laboratory to remote treatment centers is therefore inevitable. Subsequently, preservation conditions play a crucial role during transport of a BAL, with temperature being one of the most determining factors. In this study, we assessed the effect of subnormothermic preservation on freshly isolated porcine hepatocytes cultured in monolayer under oxygenation. Additionally, the effect of the University of Wisconsin (UW) preservation solution was compared with Williams' E (WE) culture medium at 4°C. The control group was cultured for 3 days at 37°C, whereas the transport groups were cultured at 4°C, 15°C, 21°C, or 28°C for 24 h at day 2. All groups were tested each day for cell damage and hepatic functions. Subnormothermic culture (i.e., 15°C to 28°C) for a period of 24 h did not reduce any hepatic function and did not increase cellular damage. In contrast, culture of hepatocytes in WE medium and preservation in UW solution at 4°C significantly reduced hepatic function. In conclusion, freshly isolated porcine hepatocytes can be preserved for 24 h at subnormothermic temperatures as low as 15°C. Future research will focus on the implementation of the AMC-BAL in an oxygenated culture medium perfusion system for transport between the laboratory and the hospital.

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“…In addition the biotransformation capacity of the hepatocytes within the bioreactor was retained for at least a week, providing a good model for metabolite investigations from slowly metabolised drugs [35]. The activity of CYP3A4 was demonstrated in the 3D bioreactor system by monitoring the metabolism of atorvastatin acid (ATA) to its 2-and 4-hyroxylated metabolites [36], and for HepaRG cells in the 3D system by monitoring midazolam, which indicated that CYP3A4 activity was retained for up to 2 weeks [48]. This retention of CYP3A4 activity is longer than that currently available in other in vitro models.…”

Section: Use Of Bals In Dmpk Studiesmentioning

confidence: 99%

“…Blood is ultrafiltered and pumped through fibres, with plasma flowing through the ECS. This direct interaction allows cellular processes to occur before the ultrafiltrate is filtered by a dual membrane to remove cells and cellular debris and returned back into the blood stream [48].…”

Section: Device Designs and Functionalitymentioning

confidence: 99%

The use of bioreactors as in vitro models in pharmaceutical research

Ginai

Elsby

Hewitt

et al. 2013

Drug Discovery Today

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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.

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Clinical Application of Bioartificial Liver Support Systems

Cited by 164 publications

References 115 publications

Non-toxicity of IV Injected Perfluorocarbon Oxygen Carrier in an Animal Model of Liver Regeneration Following Surgical Injury

Non-toxicity of IV Injected Perfluorocarbon Oxygen Carrier in an Animal Model of Liver Regeneration Following Surgical Injury

Subnormothermic Preservation Maintains Viability and Function in a Porcine Hepatocyte Culture Model Simulating Bioreactor Transport

The use of bioreactors as in vitro models in pharmaceutical research

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