Silicone cross-linked polyurethane materials for thrombus and biodegradation resistant small-diameter vascular grafts and coating of blood contacting devices

The aim of the SILCROTHANE project is to develop a new silicone based polyurethane (PU) material that can be used in biomedical applications whereas a polymer with suitable biocompatibility and biostability is required. In particular this new material, thanks to its silicone content, will be indicated for applications whereas the device needs to be in contact with blood. For this reason SILCROTHANE, in the shape of small diameter vascular grafts (SDVGs) or coating of preexisting implantable devices (polyester vascular grafts - DVGs, metallic vascular stents -MVSs), should be particularly useful in the cardiovascular field. The reaction conditions protocol to synthesise SILCROTHANE materials formulations containing up to a 1:1 ratio between PU and silicone was set up, then bulk and surface material characterisation analytical techniques were applied to identify the chemical interaction occurred between the SILCROTHANE components. In vitro and in vivo testing were performed on material samples in the form of films and porous membranes to evaluate cellular viability and growth, inflammatory tissue response, degree of tissue integration and biostability. The cytotoxicity tests, using the extraction method according to ISO 10993-5, revealed that SILCROTHANE material films with PDMS content up to 40% did not modify the viability and the proliferation rate of HUVEC and L929 fibroblasts. SILCROTHANE films containing silicone concentrations between 20-40% improved the biocompatibility and the tolerance of the implanted biomaterial. In long term, this biomaterial showed fibrous tissue infiltration. The biostability was estimated by histological examination, SEM and FT-IR that evidenced a absence of biodegradation for SILCROTHANE containing 30 and 40% of silicone regarding to the lower and higher percentages. Suitable material processing technologies and structural devices evaluation methods were investigated to realise SILCROTHANE devices. In particular, a spray technology (SPI) was employed to realise SILCROTHANE SDVGs and to coat DVGs and MVSs. Afterwards these devices were characterised: mechanical properties, in vitro biocompatibility through cytotoxicity tests and hemocompatibility were evaluated. Finally, the SILCROTHANE devices were implanted in suitable pre-clinical animal model to assess the effective performance of the material SILCROTHANE SDVGs with different layers in the wall thickness, hydraulic permeability and radial compliance were implanted in three animal model (acute experiments in pig and chronic experiments in sheep and minipig) as carotid artery by-pass. Moreover different surgical technique were used. The best results in terms of patency rate were obtained in sheep model (up to 24 months of implantation), however numerous problems concerning mechanical instability (non uniform dilatation) were observed. Several attempts to reinforce the graft were carried out for example using a semipermeable barrier or a Nitinol external stents, however the reduction of compliance produced thrombus formation on the luminal side and an outside layer partial detachments due to the pressure of the infiltrated blood that appeared as aneurismatic areas. SILCROTHANE coating of DVGs was realised both in the inner or outer surfaces by SPI. The composite grafts were interposed in sheep carotid and femoral artery animal model, as reference equine collagen coated DVGs and SDVGs were used. Post-implant morphological evaluation revealed that DVGs is a thrombogenic surface, moreover it determined great inflammatory response and fibrous tissue encapsulation around the composite graft (SILCROTHANE and polyester). Concerning the MVSs, a complete SILCROTHANE coating was realized by SPI combined with high temperature. The quality of coating was evaluated by light microscopy and by SEM technique, these revealed that SPI technique allowed to deposit the polymer in a thin and uniform way also in the areas where the distance between the stents curves is minimal. During the in vivo implant in sheep femoral artery and then in rabbit aorta, technical problems were found with MVSs platform. These problems affected their performances in terms of vessel damage during stent application and vanished all attempts to analyse the potential benefit of coating with a low thrombogenic SILCROTHANE film. This section of the project needs to be further explored with an other stent platform. However, because the SILCROTHANE material showed good tissue integration and mild foreign body reaction, therefore could represent a potential scaffold for tissue-engineering application in the more demanding area of "functional replacement of damaged vessels/organs".