Title page for ETD etd-06112010-130329


Document Type Doctoral Thesis
Author Nieuwoudt, Martin J
Email martin.nieuwoudt@up.ac.za
URN etd-06112010-130329
Document Title Bio-artificial liver support system : an evaluation of models used in demonstrating or improving metabolic and clinical efficacy
Degree PhD
Department Chemical Engineering
Supervisor
Advisor Name Title
Prof S W van der Merwe Co-Supervisor
Prof P de Vaal Supervisor
Keywords
  • bioprocess monitoring
  • state estimator
  • acute liver failure
  • hepatocyte bioreactor cell biology
  • animal models
  • compartmental pharmacokinetic models
  • bio-artificial liver
  • prognosis modeling
Date 2010-04-16
Availability unrestricted
Abstract
Acute liver failure (ALF) is a rare but devastating clinical syndrome with multiple causes and a variable course. The mortality rate is high. Orthotopic liver transplantation is the only therapy of proven survival benefit but the limited supply of donor organs, the rapidity of progression and the variable course of ALF limit its use. A need therefore exists for a method to ‘bridge’ patients, that is, provide temporary support, to either the spontaneous regeneration of the innate liver or transplantation. One possibility includes bio-artificial liver support systems (BALSS). This technology is composed of an extracorporeal circulation system incorporating a bioreactor that contains parenchymal liver cells (hepatocytes) to perform the detoxifying, transforming and synthetic properties of a liver. However, the development of a BALSS holds particular challenges. Despite approximately four decades of research, bio-artificial liver (BAL) technology globally remains in a pre-commercial stage. The University of Pretoria (UP) and the Council for Scientific and Industrial Research (CSIR) have developed a BALSS with novel characteristics. These include a computationally optimized radial-flow primary porcine hepatocyte bioreactor perfused with blood plasma, and a perfluorocarbon oxygen carrier which replaces hemoglobin. There are also novel design properties in the circulation system itself. Demonstrating the metabolic and clinical efficacy of a BAL device requires implementing, in vitro (cell biology), in vivo (animal) and mathematical modeling studies. These studies are a formal necessity but are inherently ‘models’ of the in vivo human clinical circumstance. That is, they are limited by their experimentally controlled configuration/s. In investigating these, this thesis firstly provides a foundation by reviewing the clinical and biological context of ALF and BAL technology, then presents and evaluates particular studies/models that have been implemented over several years in the course of the UP-CSIR BAL project. For each section, thoughts and recommendations regarding future work that will facilitate the development of BAL technology are discussed in detail. The thesis is concluded with an evaluation of success and the consensus-agreed requirement of continued research and innovation in the field.

© 2009, University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria.

Please cite as follows:

Nieuwoudt, M 2009, Bio-artificial liver support system : an evaluation of models used in demonstrating or improving metabolic and clinical efficacy, PhD thesis, University of Pretoria, Pretoria, viewed yymmdd < http://upetd.up.ac.za/thesis/available/etd-06112010-130329/ >

D10/441/ag

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