Mathematical Modeling and Simulation of Intravascular Drug Delivery from Drug-Eluting Stents with Biodegradable PLGA Coating

Drug-eluting stents (DES) are commonly used in coronary angioplasty procedures. A DES elutes drug compounds from a thin polymeric coating into the surrounding coronary artery tissue to reduce in-stent restenosis (a significant lumen loss due to growth of vascular tissue). Biodurable (non-erodible) polymers are often used in the current DES coatings, which stay permanently in the patients. While promising treatment results were obtained, in-stent restenosis remains an issue and late in-stent thrombosis, which is associated with hypersensitivities to the polymer coatings, is also reported. Increasing interests have been raised towards the design of a more biocompatible coating, in particular a poly(lactic acid-co-glycolic acid) (PLGA) coating, for DES applications to improve the drug delivery and reduce adverse outcomes in patients. This dissertation aims to develop a mathematical model for describing the process of drug release from a biodegradable PLGA stent coating, and subsequent drug transport, pharmacokinetics, and distribution in the arterial wall. A model framework is developed in the first part of the dissertation, where a biodurable stent coating is considered, and the intravascular delivery of a hydrophobic drug from an implanted DES in a coronary artery is mathematically modeled. The model integrates drug diffusion in the coating with drug diffusion and reversible drug binding in the arterial wall. The model was solved by the finite volume method. The drug diffusivities in the coating and in the arterial wall were investigated for the impact on the drug release and arterial drug uptake. In particular, anisotropic vascular drug diffusivities result in slightly different average arterial drug levels but can lead to very different spatial drug distributions, and is likely related to the reported non-uniform restenosis thickness distribution in the artery cross-section. The second part of the dissertation focuses on modeling drug transport in a biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) coating. A mathematical model for the PLGA degradation, erosion, and coupled drug release from PLGA stent coating is developed and validated. An analytical expression is derived for PLGA mass loss. The drug transport model incorporates simultaneous drug diffusion through both the polymer solid and the liquid-filled pores in the coating, where an effective drug diffusivity model is derived taking into account factors including polymer molecular weight change, stent coating porosity change, and drug partitioning between solid and aqueous phases. The model predicted in vitro sirolimus release from PLGA stent coating, and demonstrated