Variant Creutzfeldt-Jakob Disease (vCJD) is linked to the transmission of Bovine Spongiform Encephalopathy (BSE) agent to human, presumably through the oral route. According to the initial projections, up to half a million of consumers could have developed this disease first identified in 1996 in United Kingdom. The number of undiagnosed contaminated bovine which entered into the human food chain has been estimated close to 2 millions. The human exposure to the risk has been very heterogeneous: cases reported up to now (over 215 cases worldwide) would correspond to the few ones exposed to the highest infectious doses. Besides them, ten- to hundred-thousands-fold more people would have been exposed to ten- to hundred-thousands-fold lower infectious loads, and their situation towards infection (healthy, carriers or under incubation) remains to be elucidated. In parallel to primary contamination through consumption of BSE-contaminated food products, secondary human-to-human transmission was rapidly suspected via contaminated surgical equipment, tissue transplantations as well as through blood or blood products, according to the presence of infectivity in peripheral organs of vCJD patients. Theoretical risk turned to real, since four likely vCJD transmissions via blood transfusion (red blood cell concentrate) were reported in the UK. For one of them, blood donation was performed three years before the donor developed clinical signs: this suggests that donors under incubation may present a risk for a long period before onset of disease without being suspected, since no blood diagnostic test is available up to now. In addition to these four cases, the Health Protection Agency in the United Kingdom (UK) reported in February 2009 the evidence of vCJD infection in a hemophiliac patient, suggesting that even after processing and dilution, plasma may also be infectious and constitute a potent source of contamination. This finding extends the risk to all plasmatic derivatives which were initially thought to be not concerned because of very low infectious doses theoretically involved. This concern was due to high dilution factors in the plasma batches and due to methods of purification used in the industrial processes. In this context, the current risk related to new cycles of infection by blood transfusion necessitates rapid implementation of measures to ensure that blood products are prion-free, notably by developing methods to eliminate infectivity when preparing these products in the absence of available diagnostic techniques for screening donors, as it has been recently recommended by a UK independent experts panel. In a previous RIB-2005 Project called PRIONSECUR, a device (P-CAPT filter) was validated to remove prion potentially present into red blood cell concentrate. The present project aims to enforce blood security by completing the validation of P-CAPT device on endogenous infectivity in a unique primate model of prion disease, which is considered as the most pertinent model of human situation towards prion. In parallel, we propose to develop and validate, according to the same strategy used for developing P-CAPT device, new devices to remove prions from plasma. Indeed, safety of plasma and derivatives towards prion is currently heterogeneous since it relies on various techniques. Moreover, we recently observed that, in a primate model of human prion disease, exposure to low doses of BSE induces, after extensive incubation periods, atypical forms of vCJD that would remain undiagnosed with current methods. These animals are modeling low doses-exposed consumers, suggesting a major health problem if similar situation in human exists. We proposed in the frame of this project to confirm or infirm the transmissibility of those new forms through blood, and evaluate the ability of the aforementioned devices to remove prions linked to those atypical forms.

The overall objective of this collaborative project is to develop, from chemistry to the device, a tissue-engineered vascular conduit that remains in-situ physiologically functional on the long term, containing the core elements of a vascular tissue. Such development will be carried out from in vitro building to in vivo evaluation in small animals. In our project, 5 partners from hospital department or academic research and 2 companies bring together their knowledge, know-how and expertise from macromolecular science, physico-chemistry of the elaboration of natural polymer systems, cellular and tissue biology, to in vivo implantation and evaluation. The material study and device design is the starting point of the project. The investigated systems result from the association of different chitosan-based hydrogels. Chitosan is a natural bioresorbable and biocompatible polysaccharide well suited for tissue engineering. Such hydrogel associations (the ChitoArts) will bring the combined mechanical and biological properties required for the application. The chitoart architectures are specifically designed as templates for tissue engineering, and in a second step will be bio-functionalized with the pertinent cell types to rebuild in a combined in vitro and in vivo approach, multilayered vascular conduits with a resulting tissue organization inspired from natural blood vessels. The methodology used here will rely on the optimization of each component of the ChitoArt architectures, in relation with coordinated in vitro and in vivo evaluations of their mechanical and biological properties.