Christopher McCormick

Modelling drug-eluting stents

In this study, we consider a family of mathematical models to describe the elution of drug from polymer-coated stents into the arterial wall. Our models include the polymer layer, the media, the adventitia, a possible topcoat polymer layer and atherosclerotic plaque. We investigate the relative importance of transmural convection, diffusion and drug-dependent parameters in drug delivery and deposition. Furthermore, we investigate how the release rate from the stent can be altered and examine the resulting effect on cellular drug concentrations.

Release mechanism and parameter estimation in drug-eluting stent systems : analytical solutions of drug release and tissue transport

Drug-eluting stents have significantly improved the treatment of coronary artery disease. They offer reduced rates of restenosis compared with their bare-metal predecessors and are the current gold standard in percutaneous coronary interventions. Drug-eluting stents have been approved for use in humans since 2002 and yet, despite the intensive research activity over the past decade, the drug release mechanism(s) and the uptake into the arterial wall are still poorly understood. While stent manufacturers have focussed primarily on empirical methods, several mathematical models have appeared in the literature considering the release problem, the uptake problem and also the coupled problem. However, two significant challenges that remain are in understanding the drug release mechanism(s) and also the determination of the various parameters characterizing the system. These include drug diffusion coefficients and dissolution constants in the stent polymer coating as well as drug diffusion coefficients, binding/uptake rates and the magnitude of the transmural convection in the arterial wall. In this paper we attempt to address these problems. We provide analytical solutions which, when compared with appropriate experiments, may allow the various parameters of the system to be estimated via the inverse problem. The analytical solutions which we provide here for drug release in vitro may thus be used as a tool for providing insights into the mechanism(s) of release.

Modeling Arterial Wall Drug Concentrations Following the Insertion of a Drug-Eluting Stent

A mathematical model of a drug-eluting stent is proposed. The model considers a polymer region, containing the drug initially, and a porous region, consisting of smooth muscle cells embedded in an extracellular matrix. An analytical solution is obtained for the drug concentration both in the target cells and the interstitial region of the tissue in terms of the drug release concentration at the interface between the polymer and the tissue. When the polymer region and the tissue region are considered as a coupled system, it can be shown, under certain assumptions, that the drug release concentration satisfies a Volterra integral equation which must be solved numerically in general. The drug concentrations, both in the cellular and extracellular regions, are then determined from the solution of this integral equation and used in deriving the mass of drug in the cells and extracellular space.

Prostacyclin analogues: the next drug-eluting stent?

Recent concern over existing drug-eluting stents, for the treatment of myocardial ischaemia, has led to the development of approaches that seek to inhibit restenosis while promoting the recovery of a functional endothelium. Prostacyclin analogues may be worthy candidates for use within a drug-eluting stent by virtue of their wide profile of vasoprotective effects. This article reviews recent developments in this area, and in so doing, reveals the future challenges for the further development of this technology.

Some design considerations for polymer-free drug-eluting stents: a mathematical approach

In this paper we provide the first model of drug elution from polymer-free arterial drug-eluting stents. The generalised model is capable of predicting drug release from a number of polymer-free systems including those that exhibit nanoporous, nanotubular and smooth surfaces. We derive analytical solutions which allow us to easily determine the important parameters that control drug release. Drug release profiles are provided, and we offer design recommendations so that the release profile may be tailored to achieve the desired outcome. The models presented here are not specific to drug-eluting stents and may also be applied to other biomedical implants that use nanoporous surfaces to release a drug.

Modelling the Impact of Atherosclerosis on Drug Release and Distribution from Coronary Stents

Although drug-eluting stents (DES) are now widely used for the treatment of coronary heart disease, there remains considerable scope for the development of enhanced designs which address some of the limitations of existing devices. The drug release profile is a key element governing the overall performance of DES. The use of in vitro, in vivo, ex vivo, in silico and mathematical models has enhanced understanding of the factors which govern drug uptake and distribution from DES. Such work has identified the physical phenomena determining the transport of drug from the stent and through tissue, and has highlighted the importance of stent coatings and drug physical properties to this process. However, there is limited information regarding the precise role that the atherosclerotic lesion has in determining the uptake and distribution of drug. In this review, we start by discussing the various models that have been used in this research area, highlighting the different types of information they can provide. We then go on to describe more recent methods that incorporate the impact of atherosclerotic lesions.

Activation of prostanoid EP receptors by prostacyclin analogues in rabbit iliac artery: implications for anti-restenotic potential.

Prostacyclin analogues have the potential to be effective agents in a new generation of drug-eluting stents by virtue of prostanoid IP receptor mediated anti-proliferative effects on smooth muscle cells. However, prostanoid IP receptor mediated vessel relaxation is reduced at elevated analogue concentrations. The mechanisms underlying this loss of activity are unclear, and its influence on the anti-proliferative potential of these compounds remains to be determined. A classical organ bath approach was used to examine the functional response of the rabbit iliac artery to the prostacyclin analogues, AFP-07 and cicaprost. Selective receptor antagonists for prostanoid IP (RO-1138452), EP(1) (SC-51322) and EP(3) (L-798106) receptors were used to characterise the receptors involved. The effects of these agents on proliferation ([(3)H]-thymidine incorporation) of rabbit iliac artery smooth muscle cells stimulated by foetal calf serum were then studied. AFP-07 gave a bell-shaped log concentration-response curve consisting of prostanoid IP receptor mediated relaxation followed by reversal at higher concentrations. SC-51322 and L-798106 potentiated this relaxation, although only L-798106 completely removed the contractile element. The prostanoid EP(3) receptor agonist, sulprostone, produced constriction, which was attenuated by L-798106. RO-1138452 blocked the inhibitory action of AFP-07 and cicaprost on proliferation, implicating an involvement of prostanoid IP receptors. L-798106 had no effect on the anti-proliferative effect of cicaprost, but reduced the effect of AFP-07. Non-selective activation of prostanoid EP(3) receptors (and possibly prostanoid EP(1) receptors) compromises the relaxant activity of prostacyclin analogues, although it does not reduce the anti-proliferative capacity of these compounds in the model studied.

Succinobucol-eluting stents increase neointimal thickening and peri-strut inflammation in a porcine coronary model.

The aim of this study was to assess the efficacy of stent‐based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model. Background: Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti‐inflammatory properties.

Minimally Invasive Sensing

The key causes of mortality today include cardiovascular disease, infectious diseases, cancer and diabetes. Figure 1, from the World Health Organisation’s Global Burden of Disease Report (World Health Organisation [WHO], 2006), illustrates the proportion of deaths due to the major causes. When these statistics are taken together with the age at death data as shown in Figure 2 (WHO, 2006) it can be seen that in the higher income countries, the burden of caring for the ageing population with chronic conditions will dominate healthcare needs and budgets. In the lower income countries there are still significant problems with childhood illness and infectious diseases and the challenge here is to protect the health of their younger populations.

Overview of cardiovascular stent designs

Coronary heart disease (CHD) is the leading cause of death globally. Research over recent decades has greatly increased understanding of the pathophysiology of this condition and revealed potential targets for therapeutic intervention. Revascularization procedures are used to treat more advanced stages of the disease to restore blood to the affected tissue. For many years, this was achieved through the use of a coronary artery bypass graft (CABG). This remains a very effective treatment that is still widely used, particularly in patients with multivessel disease or complex lesions in major vessels. However, in recent decades it has been overtaken by the use of a less invasive procedure, percutaneous coronary intervention (PCI). There have been various technology developments that have helped drive this increased use of PCI, with the introduction of stents being particularly significant. The permanent implantation of a stent, a tube-like metal device, immediately following traditional balloon angioplasty provides ongoing mechanical support to the vessel wall. As its name implies, this chapter will provide an overview of cardiovascular stent designs, with particular focus given to drug-eluting stents. The chapter closes with a discussion on the current state of the art in stent design and future perspectives.