Bioartificial livers: theoretical methods to improve and optimize design

Abstract

In this work, a mathematical modelling approach is taken to improve and optimize the designs of bioartificial liver (BAL) systems. BALs are an alternative therapy for the extremely serious condition of liver failure where liver transplant is currently the only viable option. As yet, large-scale clinical trials have not been successful enough in order for BALs to gain regulatory approval. Through the work in this report, it is envisaged that BAL design can be improved to the point where they can gain clinical acceptanceOne of the main issues in BAL design is the provision of adequate oxygen to the cell mass. To this end, a mathematical model to describe oxygen mass transport is developed based on the principle of Krogh cylinders. The results of this model are subsequently interpreted and presented in Operating Region charts, an image of a parameter space that corresponds to viable BAL designs. These charts allow several important design trends to be identified, e.g. numerous short and thin hollow fibres are favourable over fewer thicker, longer fibres. In addition, it is shown that a physiologically relevant cell number of more than 10% of the native liver cell mass can be supported in these devices under the right conditions. Subsequently the concept of the Operating Region is expanded to include zonation, a metabolic phenomenon where local oxygen tension is a primary modulator of liver cell function. It is found that zonation profiles can be well controlled and under standard conditions a plasma flow rate of 185 ml/min to the BAL would distribute the three metabolic zones evenly. Finally, the principles of the Operating Region charts and zonation are applied to three existing commercial BAL designs; the HepaMate, BLSS and ELAD systems. In each case it could be seen that the default designs of each system did not present ideal environments for liver cells. Through consideration of zonation profiles, each device design and operating parameters could be optimized to produce in vivo-like environments. In the case of the ELAD, reducing the plasma flow rate from 500 to 90 ml/min resulted in a balanced zonation profile. Overall, the work in this report has developed and detailed a series of tools that will assist a BAL designer in making judicious choices over bioreactor design and operating parameters. As a result, it is hoped that BALs can take a step forward towards clinical practice and ultimately saving lives.

Date of Award	1 Jun 2011
Original language	English
Awarding Institution	University of Bath
Supervisor	Julian Chaudhuri (Supervisor) & Marianne Ellis (Supervisor)