Date of Award
Doctor of Philosophy (PhD)
Olin T Mefford
The use of stents in the treatment of atherosclerosis leads to a potential risk of restenosis, caused by neointimal hyperplasia. Neointimal hyperplasia is mainly caused by an injury to the endothelial layer of the blood vessel followed by the proliferation of smooth muscle cells into the lumen of the blood vessel. To address this, we designed a magnetically-guided drug delivery system to locally deliver heparin to a stented artery. The nanoparticles were synthesized, characterized, and tested on relevant human cell lines.
The particles were non-toxic to human smooth muscle cells, endothelial cells, and fibroblasts. They reduced the proliferation of the smooth muscle cells and increased the proliferation of endothelial cells at concentrations as low as 10 μg/mL. The particles also shifted the smooth muscle cells from their synthetic phenotype to their contractile phenotype.
The capture of the nanoparticles by the stent struts, under relevant magnetic field and blood velocity was modeled using COMSOL Multiphysics. The coronary artery was modeled using a 2D axisymmetric model with stainless steel stent struts. A Magnetic field of 1 T was applied to magnetize the stent struts. Three different strut geometries were compared for their effect of the capture efficiency. The model had a capture efficiency 0f 34-42%, which is comparable to models using the same particle sizes.
Ex vivo organ culture studies using porcine right coronary arteries were performed. The arteries were conditioned either statically in cell culture flasks or dynamically in an organ culture bioreactor. Nanoparticles reduced intimal thickening in and expressed contractile properties in the treated arteries compared to the controls.
We were successfully able to synthesize heparin-coated magnetic nanoparticles and achieve high heparin loading. Particle capture efficiency around the stent in the ex vivo porcine artery model was found to be similar to that predicted by the computational model. Consistent with the prior results of systemic heparin delivery, the nanoparticles reduce the proliferation and dedifferentiation of vascular smooth muscle cells while promoting endothelialization, both in vitro and ex vivo. Thus, these particles may be a promising treatment option for neointimal hyperplasia.
Ghobrial, Nardine M., "Using Heparin-Coated Nanoparticles in the Treatment of Neointimal Hyperplasia" (2020). All Dissertations. 2674.