Abstract :
[en] This work, entitled Innovative non-isocyanate polyurethanes for customized prosthetic heart valves, began with the primary goal of developing new polymeric heart valve prostheses, a need that has been identified over the past few years. Indeed, the effective treatment for most patients with heart valve disease is valve replacement by implantation of mechanical or biological prostheses. However, mechanical valves represent high risk of thromboembolism, and biological prostheses are prone to early degeneration. The emergence of a non-thrombogenic, durable, polymeric valve therefore appears as a promising solution. Polyurethanes (PUs) have adjustable mechanical properties which make them suitable for a wide range of applications, including in the biomedical field. Historically, these PUs have been synthesized from toxic isocyanates, representing a health threat. This has encouraged the search for safer and more environmental-friendly synthetic routes, leading today to the production of non-isocyanate polyurethanes (NIPUs).
In the first Chapter of this work, thermally-crosslinked polyhydroxyurethane (PHU) NIPU networks were synthesized via an isocyanate-free route, tested in vitro, and used to produce aortic valves. PHU elastomers reinforced with a polyester mesh showed mechanical properties similar to native valve leaflets. These NIPUs did not cause hemolysis and, interestingly, both platelet adhesion and contact activation-induced coagulation were strongly reduced on NIPU surfaces, indicating low thrombogenicity. Fibroblasts and endothelial cells maintained normal growth and shape after contact with these NIPUs, showing in vitro cytocompatibility. Simultaneously, fluid-structure interaction studies allowed the modeling of an ideal valve design, with minimal shear stress on the leaflets. Injection-molded NIPU valves were produced and tested in a ViVitro labs pulse duplicator, showing compliant hydrodynamic performances, comparable to bioprostheses used in clinics. Additionally, NIPU patches did not show any evidence of calcification over a period of 8 weeks, proving to be promising sustainable biomaterials for the manufacturing of prosthetic valves. The main limitation was linked to the lack of a “customizable” feature, since the production method (injection molding) renders the process of adapting valve geometries challenging, requiring repeated production of new molds. For that reason, different sorts of NIPUs, more adequate for easily adaptable manufacturing techniques (e.g. 3D printing), were explored subsequently.
In the second Chapter of this work, NIPU elastomers were designed by functionalizing PHU by a cyclic carbonate carrying a pendant unsaturation, enabling them to be post-photocrosslinked with polythiols. Elastomers with remarkable mechanical properties and tunable stiffness were obtained. Given the unique viscous properties of these PHU derivatives and their short gel times, formulations for light-based 3D printing were successfully developed and objects were printed by digital light processing (DLP) with a resolution down to the micrometer scale. In vitro tests confirmed cytocompatibility of these materials with human fibroblasts, while in vitro hemocompatibility tests revealed that they do not induce hemolysis, they do not increase platelet adhesion nor activate coagulation, also demonstrating their potential for future applications in the cardiovascular field. However, the production of a heart valve using these NIPUs was not envisaged, since the mechanical behavior revealed better suitability for other applications. In addition, DLP highlighted once again the need for a more readily tunable technique that would allow rapid prototyping. Consequently, a new class of NIPUs was developed, aiming to use heat-based additive manufacturing to process these biomaterials. In the third Chapter of this work, a new thermoplastic elastomer (TPE), specifically a poly(hydroxy-oxazolidone) (PHOx), was synthesized, processed by different manufacturing techniques, and evaluated biologically in vitro and in vivo. This work showed that this new PHOx can be successfully processed in diverse ways, including additive manufacturing, but also by hot pressing, extrusion, injection-molding and electrospinning. In vitro hemocompatibility tests demonstrated once more the low thrombogenicity of PHOx, with the absence of hemolysis or accelerated plasma coagulation, and a significant decrease of platelet adhesion on PHOx surfaces. Lower adhesion and proliferation of Staphylococcus epidermidis on PHOx revealed an interesting anti-adhesive effect, not present in PUs. No cytotoxicity was induced by PHOx, neither after contact with endothelial cells nor with fibroblasts. Additionally, subcutaneous implantation of PHOx in rabbits demonstrated in vivo biocompatibility through the absence of inflammation markers after one and four weeks. Hence, this PHOx represents a safer and greener alternative to conventional PU-based TPEs (synthesized from toxic isocyanates), being also hemo/biocompatible and suitable for various processing techniques, which shows its potential for the manufacturing of diverse blood-contacting devices, contributing for easily personalized medical care.
Other NIPU materials were further developed and are described in the Unpublished Results section of this work, namely dehydrated PHOx-derived networks (Nets), covalent adaptable networks (Cans), and NIPU fluorescent foams, which corroborated hemo/biocompatible features previously observed.
