ENGINEERING OXYGEN TRANSPORT FOR IMPROVING CELL PERFORMANCE IN HEPATIC DEVICES
The bioartificial liver (BAL) advancing medical technology aims to provide temporary liver substitution for patients in dire need of liver transplants and also for drug development. Yet despite nearly fifty years of development, the approval for this medical device from U.S. regulatory agencies (e.g., Food and Drug Administration) is still pending. The reasons for this have both clinical and fundamental aspects. Current clinical trial data does not convincingly demonstrate a higher survival rate of patients that received BAL treatment than non-BAL treated control. This issue may be attributed to the fundamental fact that, as a medical bioreactor, BALs still lack the effectiveness at the level of the natural liver. As oxygen (O2) is a key substance to determine efficiency of the hepatocytes housed in the BAL, intensifying the O2 conditions within the BAL cellular space will elevate overall BAL performance. This proposition has been substantiated by several studies. With higher efficiency the BAL may increase the liver patients' survival rate, benefit new drug development, and may ultimately attain the government approval in the U.S.The work of this doctoral study focuses on methods of enhancing O2 transport into three-dimensional (3D) customized hepatic devices. Firstly, enriched O2 conditions were established within customized hepatic systems by applying an inert organic compound - perfluorocarbon (PFC). The PFC-treated hepatic cells demonstrated high cytochrome P450 (CYP 450) function performance especially when 3D gelatin sponge were used as the scaffold. They also exhibited less glucose consumption. Next the 3Divgelatin sponge scaffold was then characterized in a computational fluid dynamics (CFD)-based simulation to clarify the reasons for the performance improvement. The results of this simulation also suggest that using the new 3D cellular scaffold is an effective method for addressing the O2 delivery problem previously reported for a novel BAL design, the four quadrant bioreactor (4QB) when using the 4QB for the support of larger cell numbers. Lastly, the effects of a previously custom designed flow device and the gelatin sponge scaffold, on the drug metabolism of rat primary hepatocytes (RPHs) were evaluated. The key results from the drug metabolism tests were confirmation of the benefits of combining the 3D gelatin sponge scaffold and flow condition in increasing the hepatocytes drug metabolism enzyme performance. Surprisingly, the results also demonstrated the suppression of the RPHs drug metabolizing ability in flow devices and relevant analysis to this phenomenon was also conducted.This doctoral study has thus provided valuable information on experimental and numerical approaches for improving the fundamental performance of future BAL designs. It mainly highlights that in BALs, the 3D cell cultures and efficient flow perfusion are key to O2 delivery for the scaffold interstitial region (extracellular space). The work thus helps moving toward their development one step closer to establish the future clinical trial and industrial application of BAL devices.