published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Thesis Ph. D.)(Chemical Engineering)--University of Pretoria, 2003. / Title from opening screen (viewed Oct. 06, 2004). Summaries in English and Afrikaans. Includes bibliographical references (leaves 144-151).

The purpose of the investigation was the design and development of an oxygen carrier system for oxygenation of liver cells (hepatocytes) in a bio-artificial liver support system. Acute liver failure is a devastating condition with higher than 80% mortality. Currently the only successful treatment is orthotopic liver transplantation. The high mortality rate could be reduced if a system could be developed that could bridge the patient either until recovery (due to the liver’s well-known regeneration ability) or until transplantation. Such a system requires a bioreactor with a high density of cultured cells. Sufficient oxygen delivery to the cells is critical to ensure efficient cell function. The CSIR and University of Pretoria (UP) have designed and developed a novel bio-artificial liver support system (BALSS) that utilizes perfluorooctyl bromide (PFOB) as artificial oxygen carrier. As the PFOB is not miscible with water, it needs to be emulsified. To enable the use of the PFOB emulsion in the UP-CSIR BALSS, a study was carried out to investigate relevant aspects relating to the PFOB emulsion, i.e. the formulation, manufacturing procedure, stability, rheology and mass transfer characteristics. The study results are reported in this dissertation, including a proposed mass transfer model for describing oxygen mass transfer to and from the PFOB emulsions. Emulsion stability can be improved through control of the droplet size and size distribution, limiting Ostwald ripening, and control of zeta potential of the dispersed phase droplets. PFOB emulsions with dispersed phase (PFOB) volume fractions between 0.4 and 0.5 and Sauter mean droplet diameter between 100 and 200 nm were found to be optimal for oxygen mass transfer in cell culture systems. The PFOB emulsion in the UP-CSIR BALSS can be concentrated and recirculated using ultrafiltration. Quantitative recovery of PFOB from its emulsions can be carried out using distillation with orthophosphoric acid. Experimental overall mass transfer coefficients for membrane oxygenators obtained without PFOB compared well with literature reported values of 2.5x10-5 m/s by Goerke et al. (2002) and 1 – 3x10-5 m/s by Schneider et al. (1995) for similar systems. The addition of 0.2 v/v PFOB leads to an increase in the membrane oxygenator mass transfer coefficient by a factor of about 30, and an increase in oxygen carrying capacity by a factor of about 4.5. It was also shown that suitable PFOB emulsions can have a significant impact on the growth and function of hepatocytes in a BALSS. / Thesis (PhD (Chemical Engineering))--University of Pretoria, 2005. / Chemical Engineering / unrestricted

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22302号 / 医博第4543号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 妹尾 浩, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Concerning potential immunological reaction in patients receiving multiple bioartificial liver treatments (with porcine hepatocytes bioreactor), the beneficial effect of sequential plasmapheresis-hemoadsorption-bio-liver treatment protocol was studied. The hypothesis was tested in a trichosanthin-induced anaphylaxis rat model. Fatal anaphylactic response upon antigen challenge was reduced in a previously trichosanthin sensitized rat prior with cross circulation. It was suggested that circulating antibodies responsible for immunological response were removed by the non cell-based treatment. The potential risk of hypersensitivity reaction of subsequent cell-based treatment was reduced. In the design of HBLSS, the sequential plasmapheresis-hemofiltration-bio-liver treatment was suggested to alleviate potential immunological consequences and allow multiple uses in single patient. / In addition to artificial liver research, pharmacological therapies are sought to treat ALF. Recent studies suggested that the local renin-angiotensin system (RAS) in the liver regulate the fibrogenic response. The possible involvement of RAS in acute liver injury was investigated in the present study. In the D-galactosamine induced rat liver failure model, angiotensin II type 1 receptors (AT1R) were detected by immunohistochemical staining in the centrilobular region after induction of acute liver injury which was not evident in normal liver. There were associated elevation of total bilirubin, alanine aminotransferase and tissue inhibitor of metalloproteinase type 1 (TIMP-1). Losartan treatment was able to reduce all these parameters. TIMP-1 protein was reduced by 1.5 fold (p<0.05) on day 1 and 1.56 fold (p<0.05) on day 3 in the losartan treatment group relative to the GalN group. The survival rate of the losartan treatment group was significantly higher than that without treatment (5-day survival, 85% vs 42.5%, p<0.05). This finding suggested the local renin-angiotensin system plays a role in the pathophysiological mechanism of acute liver injury. / In summary, the presence study addressed two approaches in treating liver failure. The HBLSS treatment protocol improved survival of acute-on-chronic liver failure patients. The protective effect of losartan in liver injury suggests AT1R blockade is a potential therapeutic strategy in acute liver injury. / The mainstay treatment of acute liver failure (ALF) is conservative medical therapy. In patients having acute liver insufficiency, the only proven life-saving procedure is liver transplantation. The concept of supportive care in liver failure is to optimize patient's clinical condition by replacing some of the essential functions of liver and allowing liver regeneration in order to compensate the loss of hepatocellular functions. / There was increasing evidence suggesting a role of artificial liver (extracorporeal system) in the treatment of liver failure. A retrospective study was performed in a group of acute-on-chronic liver failure (AoCLF) patients treated with hybrid bioartificial liver support system (HBLSS). From 2001-2004, there were 40 chronic liver disease patients presented with acute deterioration. Patients were treated either with conventional medical therapy (n=21) or integrated with HBLSS treatment (n=19). The 60-day survival rate was 30% and 68.5% respectively (P<0.05 log-rank test). Integration of hybrid bioartificial liver support system (HBLSS) in treating acute-on-chronic liver failure (AoCLF) patients improved the survival outcome. Univariate analysis of admission blood parameters revealed creatinine appeared to predict mortality in AoCLF patients with HBLSS treatment. / Chan Hoi Ming Herman. / "June 2006." / Adviser: Siu-cheung Michael Tam. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1547. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 104-116). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

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. / Thesis (PhD)--University of Pretoria, 2010. / Chemical Engineering / unrestricted