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|
|Supervisor||Julian Chaudhuri (Supervisor) & Marianne Ellis (Supervisor)|
- bioartificial livers
- mathematical modelling