Understanding how anti–proliferative drug modulates arterial healing following stent deployment

McQueen, Alistair K. (2022) Understanding how anti–proliferative drug modulates arterial healing following stent deployment. PhD thesis, University of Glasgow.

Abstract

The treatment of coronary artery disease (CAD) was revolutionized following the advent of drug–eluting stents (DES). Since their adoption, patient outcome has significantly improved over earlier systems devoid of drug, where notable indices such as in–stent restenosis (ISR) and repeat revascularisations were reduced. However, such indices remain stubbornly high despite this technological innovation, with patients often returning after one–year for a follow–up procedure.
In an attempt to better understand the physical mechanisms that give rise to ISR, many computational models have emerged in recent years. Chapter 1 discusses these in more depth, where the literature is neatly separable into three distinct categories: (i) structural mechanics and computational fluid dynamics, (ii) drug transport models and (iii) mechano–biological models of restenosis. Although the first category is important, it is limitations in (ii) and (iii) that are more pressing. Firstly, drug transport models assume static arteries, where the effect of drug on cell function is ignored, and the artery does not change in response to the growing population of cells. As such, Chapter 2 explores this simplification in depth through a variety of different models describing the effectiveness of drug. Results allude to possible issues with current state–of–the–art drug transport models, such that when coupled to cell function, they are unable to capture the dose–dependent effect of drug on cell growth in vitro. In an attempt to better understand these issues, Chapter 3 explores the efficacy of these drugs when their cell cycle specificity is accounted for, discussing the possible implications of this, particularly in vivo.
Moreover, mechano–biological models of restenosis often neglect the delivery of drug, with the devices considered emulating earlier bare metal stents (BMS). Those which do account for the anti–proliferative nature of drug do so through inadequate means, where key findings from (ii) are ignored. Thus, building on the efforts of Chapter 2, Chapters 4–6 explore the spatiot-meporal effect of drug on restenosis, emulating drug delivery in vivo. Key conclusions from Chapter 5 reveals an intricate interplay between stent drug dose and release rate; simultaneously illustrating the impact of stent design on performance. The model is then built upon in Chapter 6, with the implications of delayed arterial healing analysed, a recurring issues associated with DES. The model is the first of its kind to explore the explicit role of anti–proliferative drug on multiple cell types (endothelial and smooth muscle cells), further highlighting the need for optimal drug release strategies to ensure the drug is both efficacious and safe.

• Item Type: Thesis (PhD)
• Subjects: R Medicine > R Medicine (General); R Medicine > RM Therapeutics. Pharmacology; T Technology > T Technology (General)
• Colleges/Schools: College of Science and Engineering > School of Engineering
• Supervisor's Name: Mcginty, Dr. Sean, Aggarwal, Dr. Ankush and Kennedy, Professor Simon
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-83277
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Nov 2022 10:26
• Last Modified: 13 Dec 2022 12:29
• Thesis DOI: 10.5525/gla.thesis.83277
• URI: https://theses.gla.ac.uk/id/eprint/83277

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