Drug release from polymer coated stents

A problem presented at the UK MMSG Strathclyde 2004.

Presented by:
Simon Kennedy (Physiology and Pharmacology, University of Strathclyde)
Participants:
LR Band, JEF Green, A Grief, GW Jones, S Kennedy

Problem Description

An arterial stent is a contemporary medical device used to prevent ischemia (inadequate blood flow) caused by the growth of an atherosclerotic plaque inside an artery wall.

The insertion of a stent causes some damage to the vessel and often the endothelium is removed during the process and the stent contacts the smooth muscle cells of the artery's media layer. Until the endothelium grows back, over a period of about four weeks, the endothelium's ability to inhibit smooth muscle cell proliferation is lost and the vessel wall may thicken over the stent and reduce the lumenal area, a process called restenosis. The stent provokes an inflammatory response, which causes factors to be released which could also encourage tissue growth and restenosis.

To reduce restenosis, drugs such as paclitaxel and rapamycin can be mixed with a polymer and coated on to the stent. These drugs diffuse into the artery wall where they are taken up by the smooth muscle cells. The drugs interrupt their cell cycle and thus prevent their proliferation. The study group was asked to investigate mathematic models for the drug transport across the artery wall, the subsequent uptake by the cells, and the effect of this upon the tissue growth.

Study Group Report

In this report, we have described the development of models treating two problems related to the introduction of a stent into an artery. We considered at the release of a drug from a polymer coated stent. Simple scaling arguments suggest that the proportion of the drug which is absorbed by the artery wall is dependent on the precise contact area between each wire of the stent and the underlying tissue. Because the contact problem requires detailed knowledge of the local biomechanics of a diseased artery wall, and knowledge of the mechanical forces applied during stent insertion, it seems unlikely that mathematical modelling can provide satisfactory results for this contact problem. However, the transport of the drug within the artery wall is quite amenable to mathematical modelling.

We established a simple model describing the advection and diffusion of the drug and its uptake by cells in the media layer of the artery wall. We solved this model in a simplified one dimensional geometry. We found that the initial release of a drug from a drug coated stent, over times <2.5 days after stent insertion, is governed by the drug's cell binding properties. At later times, variation in the cellular drug concentration is largely accounted for by the transport of the drug to the outer layer of the artery wall. Future work could include the study of more complex geometries and more complex drug-cell binding kinetics.

We also treated the related problem of smooth muscle cell proliferation in a stented artery, which can lead to restenosis. We showed, using our simple model, that drug-eluting stents can slow the rate of restenosis, or possibly eliminate the problem altogether, if the drug is sufficiently effective (in practice, there will be issues of toxicity, which we have not considered here). One of the most significant limitations of this model was the assumption of a constant drug concentration on the surface of the stent.

Download the full report

Follow-Up Activities

The following funding for further work has been obtained to investigate aspects of this problem:

Drug Eluting Stents
S Wilson
Carnegie Trust, three-year scholarship, £45k.