The main outcome of the project is documented in three patent applications. The first patent already granted in Germany (Verfahren zur Erzeugung, zum Transport und zur Eliminierung von biochemischen Stoffen mittels aktiver biologischer Zellen. DE 199 43 205.8-41 European patent application EP 1090 984 A2) describes a method and device for production, transport and elimination of substances with the help of living cells in a so-called fibre-in-fibre bioreactor where tissue- and blood-compatible membranes can be combined. This bioreactor was successfully applied for kidney epithelial cells with the hollow fibre membranes described in the second patent. An up-scaling of the initial bioreactor prototype having only 4 fibre-in-fibre pairs was done with a bioreactor containing 16 units that was tested with hepatoblastoma cells. A more up-scaled fibre-in-fibre device was developed based on the Fresenius standard modules which has a great capacity to be used in biomedical applications. A project for the development of a biohybrid kidney based on this bioreactor type is under preparation. Experiments at GKSS and FU-IP are under work to investigate the application of the bioreactor for the production of monoclonal antibodies by hybridoma cells.
In a second patent (Membranes made from P(AN/NVP)-copolymers with both haemo- and tissue-compatibility and their application in medical field. German patent application DE 100 30 307.2 European patent application 01115145.3-2113) a bulk polymer composition is described that possesses both blood- and tissue-compatibility. Membranes made of theses polymers can be used in BHOs with fibre-in-fibre design, especially for kidney assist or replacement.
The third patent submitted deals with a new group of acrylonitrile copolymers that possess high tissue-compatibility especially for primary hepatocytes. Membranes made of these polymers will be used for the engineering of liver epithelial tissues in biohybrid liver systems.
The methods for surface modification of flat membranes and hollow fibres developed by Holland Biomaterials Group in close co-operation with GKSS supplying membranes with functionalities for a simple wet chemistry were successfully applied for creating membranes with higher blood- or tissue-compatibility. For HBG, the project has also resulted in a successful spin-off. Surface modification procedures that were initially developed in the project have evolved in spin-off activities and lead to products that are now commercialised.
Objectives and content
Biohybrid organs (BHOs) for the replacement of essential
functions of injured kidney, liver and pancreas for long
term use are still not available because primary organ
cells loose their function in-vitro within a few days.
Immobilisation of these cells is currently performed on
membranes that are mainly developed for other purposes
and do not support the specific function of organ cells.
An improved treatment of the diseases mentioned above by
BHOs would result in a decreased morbidity and mortality
of patients with a reduction of the overall costs for the
European health care system. Hence, it can be assumed
that there is a remarkable need for improved membranes
that can be used in BHOs. The development of membranes
(see work programme 2.1.6.M) with biospecific
functionality (see 2.1.4.M) and high biocompatibility
(see 2.1.4.M) within the European Community could improve
the competitiveness of European medical industry. It is
therefore the main objective of this project to develop
membranes with sufficient transport properties that
specifically support the attachment and function of
kidney epithelial cells and hepatocytes by the covalent
immobilisation of biogenic ligands, such as extracellular
matrix proteins, growth factor, and saccharide moieties.
Flat membranes and hollow fibres based on
polyacrylonitrile and polysulfone will be prepared with a
cut-off up to 300 kDa to allow the transport of ions,
nutrients, waste products, protein-bound toxins, etc. and
to protect xeno/allogenic cells from the host immune
system. The membranes will be functionalised and
modified by wet and dry surface chemistry. Biospecific
ligands will be covalently bound to support attachment
and function of kidney epithelial cells or primary
hepatocytes on one side of the membrane and to achieve a
good hemocompatibility on the blood contacting side of
the membrane. If both properties cannot be combined in
one membrane, replacement can be achieved by the
application of a specific fibre-in-fibre design for
hollow fibres. Knowledge on the production and
modification of suitable membranes on a lab-scale will be
used for upscaling to allow the production of those
membranes in larger quantities.
The consortium comprises a research institute with long
experience in polymer synthesis and membrane formation, a
company (SME) dealing with different surface modification
techniques for improved biocompatibility of polymers,
three different research institutes from universities
with expertise in haemo and tissue compatibility, and
artificial organs and one company producing membranes and
equipment for haemodialysis. The composition of the
consortium does not only ensure a qualified processing of
the proposed work, but guarantees also an exploitation of
results for an improved competitiveness of European
biomedical industry and better medical care.
Funding SchemeCSC - Cost-sharing contracts
66606 St Wendel
7522 NB Enschede
G4 0NW Glasgow