Abstract : Prion diseases are neurodegenerative, fatal and transmissible diseases, with no effective treatment. The risk of transmission of bovine spongiform encephalopathy to humans is now under control ; however the risk of human-to-human transmission of variant Creutzfeldt-Jakob disease via medical treatments (notably through blood transfusion) remains. Thus, understanding cellular and molecular mechanisms responsible for Prion replication and dissemination is critical to efficiently control Prion transmission. The mechanisms of Prion replication are poorly characterised and occur at time and size scale achieved experimentally with difficulty. Thus, mathematical models can help us understand prion multiplication by testing which mechanisms best fit to experimental data. Therefore the objectives of our study are to complete existing mathematical model in order to investigate the size-dependent replicative properties of prion aggregates and the cellular heterogeneity. Firstly, we have extended a previous study of the nucleated polymerization model to take into account size dependent replicative properties of prion aggregates. This is achieved by a choice of coefficients in the model that are not constant. Our results suggest that the size distribution of prion aggregates could be one of the most informative experimental data to study elementary replication mechanisms and to investigate strain phenomenon. Secondly, we have modelled the multicellular dynamics of prion replication by integrating intracellular replication (by nucleated polymerization) into a continuous and stochastic cellular automaton. The model formulation is based on an experimental characterisation of cellular heterogeneity. From an applicative point of view, this theoretical study has allowed us to propose several protocols to increase cell culture sensitivity to prion infection.