"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."
"Coronary heart disease is the leading cause of death globally. In the United Kingdom, it accounts for just under one-in-five of all deaths and costs the NHS more than £3.5billion in treatment costs annually. It is a narrowing of one or more of the blood vessels that supply blood to the heart, which if left untreated can lead to a heart attack. To prevent this, the majority of patients are now treated by permanent insertion of a tiny metal mesh tube, known as a stent, which re-opens the vessel and restores blood flow. The most advanced stents are now coated with a drug, which releases slowly into the vessel wall to improve outcomes. The clinicians who treat this condition day in day out are clear that there are tremendous opportunities to further improve on the design of these drug-eluting stents, such that they perform even better and in a wider number of patients than is currently possible.
A key element of modern stent performance is the drug release profile - releasing too much drug too fast will result in toxicity; releasing it too slowly or in small amounts may result in no therapeutic effect. Optimising this aspect of stent performance currently relies on empirical approaches. As a result the development of new devices by industry is a slow and costly process, which ultimately inhibits effective innovation in this important area.
In this project, we have addressed this gap by developing a series of mathematical and computational models, which when allied to the use of enhanced in vitro experimental models, can be used to better understand the performance limitations of existing stent drug release profiles, thus helping inform the design of optimised future devices. Working with an industry partner in the United Kingdom, we applied our new modelling techniques to design and produce a prototype drug-eluting stent with optimised drug release kinetics.
The optimised device is now undergoing the first stage of pre-clinical trials. By using a new type of polymer, allied to the application of mathematical modelling to optimise the drug release kinetics, we hope that the prototype stent will produce better results than existing devices. Ultimately, such performance improvements are targeted at reducing the number of repeat procedures and extending the use of stents to many patients who are currently treated by a more invasive coronary artery bypass graft procedure. As well as representing an important improvement in the treatment for coronary heart disease sufferers, this would also help reduce the overall cost of treating this condition."