Development and Evaluation of a Multilayered Small-Diameter Vascular Graft for Limb Ischemia

Despite extensive research on tissue-engineered and artificial small-diameter vascular grafts, with the exception of the expanded polytetrafluoroethylene (ePTFE) and polyester (PET) artificial grafts no other newly engineered grafts have proved to be clinically viable. The ePTFE and PET grafts have been found to occlude within less than 5 years after implantation due to the formation of thrombosis and intimal hyperplasia. Intimal hyperplasia is triggered mainly by compliance mismatch between the native artery and the implanted artificial conduit as well as bio incompatibility of the graft surface. Therefore, in this study we aimed to fabricate a biostable, multilayered small-diameter vascular graft with optimised compliance and an antithrombotic luminal surface. Three polymers (polymethyl methacrylate (PMMA), polydimethyl siloxane (PDMS) and thermoplastic polyurethane (TPU)) were selected for the fabrication of the vascular graft utilising electrospinning, taking into consideration their biostability and biocompatibility. TPU and PDMS, well known for their elasticity, were selected to impart optimal mechanical properties while PMMA served as a carrier polymer to impart nonlinearity to the overall structure due to its brittleness. The first section of the study optimised the fabrication technique including polymer concentrations, solvent utilised and their combinations as well as selection of the most suitable electrospinning parameters. The developed nanofibers were then characterised in terms of the physical, morphological and mechanical properties. The optimal PMMA:PDMS ratio of 1:3 was selected and utilised throughout for all the remaining investigations. Coaxial electrospinning with TPU as the core was utilised to address the limited extensibility observed when using only PMMA and PDMS. The incorporation of TPU in the fibres resulted in enhanced elasticity and strength. These coaxially electrospun nanofibers were then used as the mechanically reinforcing layer of the vascular graft. TPU was further added as the outer layer to anchor the artificial conduit to the surrounding tissue. For the luminal layer MXene nanoparticles were added to the PMMA: PDMS fibres to enhance the wettability and impart radiopacity to the vascular graft. The effect of adding the nanoparticles were then investigated in terms of hemo and biocompatibility. To further enhance functionality of the luminal surface two strategies were then used aiming to deter protein and platelet adhesion and enhance the rate of endothelialisation. The PMMA:PDMS nanofibers were then functionalised with heparin using a polydopamine bridge, resulting in enhanced antithrombotic properties. The polymer 2-Methacryloyloxyethyl phosphorylcholine (MPC) was also grafted onto the nanofiber surface to deter protein and platelet adhesion. Results showed that the MPC successfully deterred both protein and platelet adhesion as well as endothelial cell adhesion. The final section of the study utilised simulations to better understand the effect of biomechanical mismatch between the vascular graft and the native artery. Variations in the elasticity of the vascular conduit were found to have profound effects on the wall stress of the native artery, mainly at the anastomosis. The successful development and fabrication of a highly elastic synthetic graft with nonlinear mechanical behaviour is a great advancement towards combating intimal hyperplasia in synthetic conduits. The ability to easily tune its elasticity by utilising the thickness of the artificial graft shows great potential in the fabrication of patient specific artificial grafts.