Bioreactor — Bioartificial Liver

What is a Bioartificial Liver?

The treatment of end-stage liver disease by liver transplantation is limited to donor organ shortage. This has lead to the design of bioartificial liver devices, that bridge patients until they either recover or receive a transplant. In these devices, patient plasma is circulated extracorporally through a bioreactor. The bioreactor houses metabolically active liver cells (hepatocytes) sandwiched between artificial plates or capillaries.

The functions of the liver are principally carried out by hepatocytes. The goal is to develop bioartificial liver devices in which hepatocytes are optimally maintained so that they carry out as many activities as possible. The most important functions of hepatocytes are:

• synthesis of many proteins e.g. clotting factors
• production of bile and regulation of carbohydrate, fat and protein metabolism
• detoxification of ammonia
• break down alcolhol and drugs

Development of a Standardised Bioreactor with a 3D Capillary Membrane Structure

As all cells in bioreactors the hepatocytes have to live without the natural network of capillaries, arteries and veins. In single layer cell cultures the mass flow of gases and nutrients can be achieved by diffusion alone. If, however, a higher cell volume requires a three dimensional structure, transport by diffusion alone will not suffice. One needs to introduce a convective transport. The next best we have in comparison to natural capillaries carrying blood are artificial capillaries carrying an appropriate gas or fluid. These artificial capillary membranes have defined pores, which permit the passage of the molecules needed by the hepatocytes. As well they permit the passage of the waste products of the hepatocytes. Two kinds of capillary membrane are used: Oxyplus^® capillary membrane for gas transfer and the MicroPES^® TF10 capillary membrane for transfer of larger molecules. Both are fabricated by Membrana GmbH, Wuppertal. The company custom weaves the capillaries with a thread to specifications. This permits to define spacing between the capillary membranes. What the proper spacing is needs to be found out in the course of the development. The method to be used is the numerical simulation of convective diffusion of different species. Woven layers of different capillary membranes are mounted together. A proprietary way of forming the manifold permits the use of several different types of capillary membrane for different fluids and gases. Even optical fibers can be included. The capillary membrane layers are mounted on base plates. The gluing is done with an automatic gluing machine. It follows a defined path and leaves a line of glue, which forms the manifolds and connects the stacks. A short burst of ultraviolet light cures the glue and the next plate can be mounted. This method permits variable stacking and thus a variable cell volume the bioreactor is scalable. The perfusion system consists of a pump for the perfusion solution and a gas mixing device for three different gases.

This project is part of the Platform Cell Biology within the BMBF program Systems Biology .