Présentation
The goals of this project are to build an external bioartificial liver, a liver-on-chip as well as a bioengineered liver. In the present project, bioconstruction of the liver will be performed by the assembly of building blocks –liver organoids, vascular networks and biliary networks- built separately and then integrated into a scaffold. Vascular and biliary networks will be produced by a mix of technologies comprising organotypic culture, micropatterning and stereolithography. Liver organoids will be produced by bioprinting as sheets or spheroids, involving–hepatocytes, endothelial cells and cholangiocytes-, or as liver buds obtained from stem cells. We will focus particularly on producing a functional biliary network which has been a missing element in all previous studies. The integration step should lead to a functional complete vascularized transplantable liver with a bile duct. The different steps of bioconstruction will be modeled in silico. Function of the different constructs will be assessed in vitro by functional assays and in vivo after implantation in animal models, which will also favor a complete maturation of the construct. Taking into account the poor yield of mature human liver cells, most cells will be obtained from differentiation of pluripotent stem cells, either embryonic or induced, which are now well mastered by our teams. Final assessment of the liver will be performed in an immunodeficient rat model of acute liver insufficiency. Progress in the construction of functional liver organoids will be transposed to the construction of an external bioartificial liver for the temporary treatment of acute liver failure and in liver-on-chip microfluidic devices for the study of drug metabolism and predictive toxicology. Studies in microfluidic devices should also allow us to improve maturation of the liver bioconstruction thanks to fluid pressure and flow. By the end of the 5-year project, we aim to provide a prototype of an external bioartificial liver to be used for phase I and II clinical studies as well as a prototype liver-on-chip device ready for use by pharmaceutical companies producing new drugs. All steps in the project will take into consideration GMP procedures. These goals can be reached by an interdisciplinary approach bringing together researcher from several Universities, Research Institute and small companies who master innovative technologies of bio-construction.
