The goal of HeMiBio is to develop a hepatic microfluidic bioreactor from human iPSC-derived hepatocytes, hepatic sinusoidal endothelial cells (HSEC) and stellate cells (HSC), suitable for inclusion in a repeated dose toxicity testing strategy of pharmaceuticals/cosmetic ingredients. The successful creation of such a liver-device requires (a) homotypic and heterotypic interactions between the three cell types to induce and maintain their functional, differentiated state, and (b) optimisation of the matrix, oxygenation conditions, nutrient transport and physiological shear forces. The objectives are (1) to engineer the cellular components incorporated in the bioreactor to enable specific and spatially defined enrichment of the different cells from iPSC progeny, and, by gene editing, to allow non-invasive monitoring of the cellular state (differentiation and damage). (2) Aside from the molecular sensors, an array of electro-chemical sensors will be embedded in the reactors to assess liver-specific function and cellular health under repeated dose toxicity conditions, dynamically and in a high-throughput way. Cells and sensors will be built into (3) bioreactors that will be sequentially upgraded from 2D to 3D microfluidic reactors to ultimately allow full maintenance of mature functional hepatocytes, HSC and HSEC for >28 days. (4) As the ultimate goal is to use the device as a human-based alternative to rodent long-term hepatotoxicity studies, it will be of utmost importance to provide proof of concept that the 3D-devices reveal the hepatotoxicity of prototypical hepatotoxic compounds in vivo (5). “-Omics” and cell functionality studies will provide evidence that liver-like cells are present, exposed and affected by the selected toxic compounds. These ambitious objectives will be achieved by the excellent project team, composed of academic/industrial partners with unique and complementary biology, physiology, toxicology and technical skills from 7 EU Member States.
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FinanzierungsplanCP-IP - Large-scale integrating project