Optimal Design of Drug Eluting Stents

Coronary artery disease is the most common type of heart disease and the number one leading cause of death in Europe and North America. It is estimated to cost the public purse over £3.5 billion per annum in the UK alone. The disease arises from atherosclerosis, in which fatty deposits build up on the walls of the blood vessels (arteries) that supply the heart itself. These deposits can narrow the artery and reduce blood flow to the heart. This may lead to angina or a heart attack. Severely narrowed arteries are often treated by insertion of a stent which is an expandable metal meshwork tube that opens up the blocked artery. The performance of these stents is improved by covering them with a layer that gradually releases a drug to moderate the wound-healing reaction of the artery wall. Without the drug coating, many patients experience a growth of tissue around the stent that can narrow the artery again. The timing and extent of release of the drug from the stent into the artery wall is critical. If drug release is inadequate then tissue growth occurs and the artery becomes blocked; however if drug release is excessive then there is a problem for the repair of the important inner lining of the artery, called the endothelium. If there is endothelial damage this increases the risk of late thrombosis. Failure of endothelial regrowth is especially critical over the metal struts of the stent, where drug concentration is highest. Thus correct performance of the drug-eluting stent depends on accurate delivery of an effective, but non-toxic, drug profile. Drug-release profiles of currently available drug-eluting stents have been derived empirically; however the use of mathematical modelling principles will enable the design of improved release profiles and should lead to improved performance and fewer adverse effects.

In this project we will develop a mathematical model that will be more realistic than previous models. It will be based more closely on the structure and composition of a diseased artery such as would be present in patients who are receiving a drug-eluting stent. Moreover our mathematical model will be more sophisticated than previous models because it will incorporate information about the errors associated with the various measurements that need to be made. We shall make accurate determinations, using the actual drugs that are used to treat patients, to find out how they move through the artery wall. We shall show that our model works correctly by measuring the performance of a stent that we have designed. The current project will utilise the best available methods to create a much more accurate and predictive model that, for the first time, will allow a stent to be designed with the assistance of a model and not solely empirically.

Localised drug delivery using stents as the delivery platform holds many attractions including higher local tissue levels, lower risk of systemic toxicity and controlled release of the active agent over a prolonged period of time. However, there are significant challenges associated with combining optimal stent design, an appropriate therapeutic agent at an appropriate dose and a suitable polymer coating. Although successful drug-eluting stents have been developed and are widely used in cardiology today, there are limitations relating to late stent thrombosis, categories of patients for whom drug-eluting stents are not suitable, and uncertainties about optimizing dose profile for novel drugs currently in development.

As Burt and Hunter (2006) point out, meaningful progress on tackling this problem can only come from an interdisciplinary collaboration owing to the wide range of key issues involved: e.g. mechanical behaviour of the stent, diffusion of the drug through the tissue and blood flow within the artery lies within the regime of applied mathematics and engineering; application and deployment of stents and the long-term safety issues are the domain of the clinician; the design and testing of coatings and candidate drugs is the concern of pharmaceutical scientists. The present proposal assembles the necessary range of expertise in a project that will run the mathematical, drug delivery and biological streams together as a team. The result will be a mathematical model of drug delivery from a stent that is superior to any currently available. The model will be based on a biologically correct representation of a diseased artery, will have accurate measurement of diffusion and partition coefficients in artery wall and cells, will incorporate information about the errors associated with parameter estimates and will be validated by realistic biological testing.

The model will therefore for the first time have the capacity to be used to design a stent for optimal performance. This may involve an improved profile of drug release using the same drugs that are currently loaded on to stents, or a more individualized approach where the release profile matches the type of plaque in a particular patient. The model will be able to cope with newer drugs currently in development which may be more hydrophilic than currently used drugs, or with combinations of drugs.

The use of this improved model will benefit the academic community concerned with drug release and delivery to the artery wall. It will help to understand how drug release is affected by pathological changes in the artery wall. It will improve understanding of the relationship between drug profile, endothelium repair, restenosis and stent performance. Much of the benefit will be to the academic community working on mathematical modeling, drug release and biological activity of drug-eluting stents. However there will also be a real benefit to the industry that makes drug-eluting stents by improving performance, cutting development times and reducing costs. This has the potential to stimulate appropriate commercial development in the medical devices industry in the UK. Our work will enhance the opportunities for the establishment and expansion of smaller biotech companies in the UK to compete with the large multinationals that currently dominate world-wide supply of drug-eluting stents. These smaller companies may be able to offer specialist development programmes to optimize drug release profiles in collaboration with major stent manufacturers.

Burt HM, Hunter WL, Drug-eluting stents: A multidisciplinary success story, Advanced Drug Delivery Reviews, Volume 58, Issue 3, Page 350-357, (2006)