Developing Immunomodulatory Materials for Vascular Applications

Abstract

The ever-increasing prevalence of cardiovascular disease (CVD) calls for interventions that rely on effective and safe materials to perform over the long term. Coronary artery disease (CAD), accounting for more than half the mortality caused by CAD, is mainly treated via coronary artery bypass grafting (CABG), which requires the use of vascular grafts to bypass the arterial blockage. While autologous vessels remain the gold standard for such treatment, their availability is often limited due to comorbidity or previous use, which generates a great need for synthetic vascular grafts that can perform well in coronary circulations. The performance of current clinically approved vascular materials, such as Dacron and Teflon, varies greatly according to the diameter of the vessels where they are employed. In small-diameter (< 6 mm) blood vessels, their long-term patency is generally poor due to three common mechanisms: thrombosis, poor endothelialisation and neointimal hyperplasia. Additionally, increasing evidence points to foreign body immune responses and the accompanying inflammation as a common biological driver behind these modes of failures. Incorporating immunomodulatory or anti-inflammatory properties into the design of vascular materials will thus be an important consideration in the future, while traditional graft design has been focused on mechanical strength. This thesis investigates the combination of several approaches that aim to improve the immunomodulatory properties of small-diameter vascular grafts. Chapter 2 examines plasma surface modification known as plasma immersion ion implantation (PIII) - a functionalisation method that is demonstrated to successfully immobilise macrophage colony stimulating factor (M-CSF) onto polylactic acid (PLLA) surfaces while retaining its immunomodulatory roles, driving the polarisation of M2 macrophages and changes in cytokines representing a shift towards a more anti-inflammatory environment. Chapter 3 examines the influences of distinct architectures of a well characterised biomaterial - silk, on the subsequent immune responses, with low porosity silk scaffolds leading to a more favourable inflammatory reaction than equivalent materials of higher porosity. This suggests biophysical cues to be an important tool for modulating immune responses. Chapter 4 combines the approaches from the previous chapters and evaluates the immunomodulatory performance of interleukin-10 (IL-10) functionalised low-porosity silk grafts, shown to lead to a favourable immune response, signified by lower macrophage infiltration and enhanced M2 polarisation, accompanied by improved functional outcomes, including more complete endothelialisation and a more rapid maturation of neointima. Collectively, this thesis demonstrates the feasibility of improving the performance of vascular materials via incorporating immunomodulatory properties into graft design.