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O2 Carrier Facilitated O2 Transport in a Hepatic Hollow Fiber Bioreactor

Chen, Guo
http://rave.ohiolink.edu/etdc/view?acc_num=osu1283207065

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Chemical and Biomolecular Engineering.
Bioartificial liver assist devices (BLADs) represent one of the most promising LAD systems in order to recapitulate a broad range of differentiated liver functions. It typically consists of hepatocytes that are cultured within an extracorporeal system (specifically, a hollow fiber (HF) bioreactor in this work). However, several challenges still need to be overcome in the realization of a viable BLAD, including provision of appropriate oxygenation to cultured hepatocytes in the device. Large scale cell culture in such a three dimensional construct often suffers from oxygen (O2) transport limitations. In addition, the maintenance of hepatocyte viability and its associated differentiated functions are highly dependent on appropriate O2 provision. The goal of this work is to investigate alternative strategies to improve the oxygenation of HF-based BLADs. I hypothesize in this dissertation that supplementation of O2 carriers in the hepatic HF bioreactor will improve O2 transport in the system and will lead to an improvement in cell proliferation and liver-specific functions. A series of mathematical models were developed in order to test this hypothesis. Steady state, two dimensional simulations were performed to describe O2 transport in a commercially available HF bioreactor with hepatocytes housed in the HF extracapillary space (ECS). Several conditions were simulated with the supplementation of HBOCs alone (four types of HBOCs with varying O2 affinity), PFCs alone, and mixtures of HBOC and PFC in the circulating cell culture medium. Experimental work were subsequently performed where bovine hemoglobin (BvHb) was supplemented in the circulating cell culture media of a commercially available hepatic HF bioreactor for the purpose of further testing the validity of the hypothesis. Hepatoma C3A cell line was cultured in the HF ECS for 2 weeks and differentiated liver functions were evaluated. Computational studies have demonstrated that O2 carriers can be used to improve O2 transport in a hepatic HF bioreactor. More specifically, HBOCs can dramatically improve O2 transport in the hepatic HF bioreactor and can be supplemented in the circulating cell culture media of the bioreactor in order to recapitulate the in vivo O2 spectrum in the device. PFCs were less efficient in oxygenating the HF bioreactor compared to HBOCs at physiological pO2 levels, but are expected to better oxygenate the bioreactor at higher pO2 levels. The use of a mixture of HBOCs and PFCs exhibited a synergistic effect in oxygenating the HF bioreactor. Our experiments indicated that supplementation of HBOCs (i.e. BvHb in this work) in the circulating cell culture media stream of a HF-based BLAD represents a feasible strategy to improve O2 transport and to dually conserve hepatocyte differentiated functions and cell mass within the device. Specifically, BvHb supplementation improved both cell proliferation and oxygenation in the HF bioreactor. BvHb supplemented bioreactors were more efficient in utilizing glucose and had a significantly lower ratio of lactate production to glucose consumption rate. Gene expression of genes involved in drug metabolism was generally higher for both phase I and phase II biotransformation activities, while albumin synthesis and ammonia detoxification functions were conserved for BvHb supplemented bioreactors.
Andre Palmer, Professor (Advisor)
Shang-Tian Yang, Professor (Committee Member)
Jeffrey Chalmers, Professor (Committee Member)
Jessica Winter, Professor (Committee Member)
Biomedical Research; Civil Engineering
Bioartificial liver assist device; liver failure; hollow fiber bioreactor; hemoglobin based O2 carriers; perfluorocarbon; oxygen transport; fluid motion; hepatoma cell line.

Recommended Citations

Citations

  • Chen, G. (2010). O2 Carrier Facilitated O2 Transport in a Hepatic Hollow Fiber Bioreactor [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283207065

    APA Style (7th edition)

  • Chen, Guo. O2 Carrier Facilitated O2 Transport in a Hepatic Hollow Fiber Bioreactor. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1283207065.

    MLA Style (8th edition)

  • Chen, Guo. "O2 Carrier Facilitated O2 Transport in a Hepatic Hollow Fiber Bioreactor." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283207065

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.