Bioartificial Supply for liver failure – SUPPLIVER

SUPPLIVER is positioned in the field of the hepatic functions substitution by an approach of tissue engineering. While hepatic failures constitute a major cause of mortality at the world level, the only effective treatment at the moment in case of massive deficiency is the hepatic transplantation. To overcome the shortage of available transplants, artificial or bioartificial organs are under development. The first purely artificial substitutes are henceforth marketed, but are not always effective in replacing the multiple functions of the liver. The bioartificial systems tested in hospital until now are not very widespread , for a certain number of limiting factors associated in particular with the use of animal cells or cell lines, the limited performances observed, and the logistic difficulties for implementation.

The originality of the project comes from the choice to encapsulate human liver cells in a spherical porous structure (alginate beads modified or not), instead of using more traditional techniques based on hollow fibers. Through this approach, it becomes possible to prepare a sufficient number of human hepatocytes encapsulated, ready to use, and cryopreserved for storage on the long-term. The encapsulated cells can then either be put in contact with the patient's plasma in a fluidized bed bioreactor, which optimizes the transfer of material and functions of the reconstructed tissue (extracorporeal), or implanted.
To carry out this project essentially multi-disciplinary, UMR CNRS 6600 at University of Technology of Compiègne (UTC), the coordinator, has contacted the Hepatobiliary Center, Villejuif (INSERM U785) to associate its bioengineering / biomaterials approaches and clinical experiences. The encapsulation of human hepatoytes (primary first, then stem cells) will be performed by the UTC in collaboration with INSERM U1040, located on the Institute for Research in Biotherapy of Montpellier, with SME Kaly-Cell and the Biobank of Picardy (WP2). In addition to the optimization of biomaterial and mass transfer phenomena taking place there, it is proposed to test the benefit of a cyto-protective protein, the HIP / PAP, very well studied for its effects on tissue regeneration by Inserm U785.
In parallel, the Biobank of Picardy is responsible for developing techniques and protocols of cryopreservation and thawing of encapsulated hepatocytes (WP3). A complete extracorporeal circuit will be designed and developed (WP4) by the research center of Gambro / Hospal, one of the world's leading company in the field of blood purification. This research center has developed the monitor PRISMAFLEX ® that is widely used in intensive care units, including various modules, such as artificial liver MARS ®. This new device will be tested ex vivo, and then in a large animal model at the Hepatobiliary Center, Villejuif (WP5). The trials of implantation of beads will be achieved in Montpellier U1040 (WP6) in a mice model. Finally, to ensure, throughout the project, the adequacy of methods and protocols with a future clinical use, the company Kaly-Cell, specialized in the collection and culture of primary hepatocytes, will draft protocols in accordance with production GMP (Good Manufacturing Practice) (WP7), to obtain the consent of regulatory agencies.


At the end of SUPPLIVER, the main deliverables will be :
- a large stock of cells encapsulated and cryopreserved,
- a complete extracorporeal device, including the bioreactor and the cells encapsulated, ready for Phase I clinical study
- a protocol for implantation of encapsulated cells in a pre-clinical large animal model.