Nanofiber covered stent for vascular diseases

Abstract

A covered stent is one whose length and circumference is enclosed with a membrane or fabric like material. When implanted in an artery, the covering of the stent acts as a mechanical barrier to prevent contact between the vessel wall and the components of blood. Current covered stents have been proposed for the intervention of failed saphenous vein grafts (SVG), in the hope of reducing embolism and in-stent restenosis. However, clinical trials failed to demonstrate such benefits. The deficiencies of existing covered stent include thick stent design, non-degradable PTFE membrane with poor endothelialization, high deployment pressure and no drug loading capacity. The objective of my PhD study was to develop a new type of covered stent, nanofiber covered stent (NCS), which is thinner in wall thickness, more flexible and more biocompatible than the commercial design. Electrospinning techniques were proposed to deposit a nanofibrous membrane onto bare metal stents. The advantages of electrospun nanofiber include ease of fabrication, biomimic structure and flexibility. <br><br>At a first step, Polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA) and poly(L-lactic acid)-co-poly(N5-caprolactone) [P(LLA-CL)] were electrospun into nanofibrous mesh with various electrospinning conditions. Optimized concentrations of PGA, PLGA and P(LLA-CL) electrospinning using different solvents were determined. Hexafluoroisopropanol (HFIP) was found to be a proper solvent which could be used to electrospin all three polymers while maintaining good mechanical strength of the resultant nanofibrous mesh. The electrospun nanofibers using HFIP can be controlled to have consistent fiber diameter and porosity.<br><br>Secondly, porcine coronary artery smooth muscle cells (PCASMC) were cultured on three different polymeric nanofibers for up to 15 weeks. Cellular behaviors and nanofiber degradation were evaluated. Although PGA supported initial PCASMC growth, the rapid degradation of PGA nanofibers may limit its function as a physical barrier in NCS application. PLGA nanofibers facilitated cell growth during the first 30 days after seeding but the cell growth was slow thereafter. P(LLA-CL) facilitated long term (1-3 months) cell growth although the initial cell growth was slower than that of PLGA nanofiber. We found that cell culture significantly increased the degradation of PGA nanofibers while this effect was minor on PLGA and P(LLA-CL) nanofibers, although accelerated surface erosion was observed. The molecular weight of P(LLA-CL) and PLGA nanofibers decreased linearly during the degradation period for up to 100 days.<br><br>A separate study was made to evaluate the degradation effect of UV irradiation on nanofibers. It was demonstrated that normal dosage UV sterilization induced significant damage on PLGA and P(LLA-CL) nanofiber, reducing the molecular weights and mechanical strengths, but with no obvious effects on cell proliferation. The effect of UV-induced degradation could be utilized to accelerate nanofiber degradation and 3D nanofibrous scaffold can be fabricated with controlled degradation for tissue engineering applications. <br><br>Based on the biocompatibility and degradation results of the three polymeric nanofibers, P(LLA-CL) was selected for NCS fabrication. Direct electrospinning, double-disk and single-disk methods were developed to fabricate P(LLA-CL) nanofiber covered stents and single-disk method showed best performance in terms of mechanical property. Longitudinally aligned NCS fabricated by single-disk could be deployed in vitro without creating any defects on the nanofibrous cover. Paclitaxel was loaded onto P(LLA-CL) nanofiber with sustainable release kinetics and bioactivity. Paclitaxel was loaded onto NCS without affecting its mechanical property. Paclitaxel loaded NCS could potentially minimize the in-stent restenosis by providing both anti-proliferative agent and physical barrier.<br>