Optimal Design of Drug Eluting Stents

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

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 coposition 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.

Planned Impact

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)

Publications

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McGinty S Drug delivery in biological tissues: a two-layer reaction-diffusion-convection model in Proceedings of the 18th European Conference on Mathematics for Industry 2014 (2014)

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McGinty S (2015) Does anisotropy promote spatial uniformity of stent-delivered drug distribution in arterial tissue? in International Journal of Heat and Mass Transfer

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McGinty S (2015) A general model of coupled drug release and tissue absorption for drug delivery devices. in Journal of controlled release : official journal of the Controlled Release Society

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Mcginty S (2015) On the influence of solid-liquid mass transfer in the modelling of drug release from stents in Journal of Coupled Systems and Multiscale Dynamics

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McGinty S (2016) On the role of specific drug binding in modelling arterial eluting stents in Journal of Mathematical Chemistry

 
Description 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.
Exploitation Route An important feature of the models that have been developed is that they can be easily applied to optimise the design of a wide number of different stent types, from traditional polymer coated devices, to polymer-free drug and fully bioresorbable versions. By applying our models as a complement to the empirical methods currently used, we hope to make the whole stent design process more efficient for industry, ultimately leading to more rapid development of a wider range of stents in the future.

Importantly, the modelling techniques can also be applied to the optimisation of drug release from other implantable devices, which are becoming an increasingly important aspect of medical technology in the 21st Century. We are now beginning to apply the knowledge developed in this project to the development of better implants across a range of areas, including orthopaedics, cardiac regeneration and abdominal aortic aneurysms.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our combination of mathematical modelling and in-vitro experimental work has helped to inform the design of a novel drug-eluting stent in collaboration with a UK SME. This stent has undegone a pre-clinical trial, with the data collected now being analysed ahead of publication in the coming months.
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description International Exchanges
Amount £8,400 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 03/2014 
End 03/2016
 
Title Characterisation of microporous stent surface topography and drug release profile 
Description The overall aim of the work was to mathematically model drug release from microporous stent surfaces. A series of models were developed for different conditions. Images of the microporous stent surfaces were obtained using Atomic Force Microscopy (AFM). These images were used to inform the model development. The model drug release predictions were then compared against stent drug release profiles that were determined experimentally. Microporous stent surface images were obtained using an Atomic Force Microscope (MFP 3D, Asylum Research, CA, USA). Scans were performed in intermittent contact mode in air, at a scan size of 5 and 20 micrometers. A rectangular silicon probe with an aluminium coating was used (160 TS, Olympus). The spring constant of this cantilever type was 26 N/m. Images were collected from 4 randomly selected points from three separate Yukon Choice stents (uncoated). For each location, an ortho projection and a 3D image were produced. The images produced are included in this dataset as separate JPEG files (48 in total). Drug release data were generated as follows. A single Yukon Choice stent was coated with rapamycin solution (10mg/ml in ethanol) using the Translumina dose-adjustable stent coating machine, according to manufacturer's instructions. The coated stent was then immersed in release medium (phosphate buffered saline:ethanol (90:10)) and the rapamycin release from the surface quantified over time using UV-spectroscopy (UV 2401 PC, Shimadzu Corporation). Raw data and processed data on drug release are included in this dataset within an MS Excel file, which also contains further experimental details. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Unknown 
 
Title Data for: "Combining mathematical modelling with in vitro experiments to predict in vivo drug-eluting stent performance" 
Description Drug-eluting stents are the preferred treatment for symptomatic coronary artery disease.However, despite rapid evolution of the stent design there remain limitations in their use and efficacy. The precise contribution of the drug dose and release kinetics from stents to device efficacy is unclear and existing models are limited in their capacity to fully evaluate this. This work developed a predictive computational model of drug release and tissue distribution from the stent into the artery wall tissue, using in vitro data and validating with in vivo data. The data used to inform and validate this model are contained within his repository, 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact
 
Description Collaboration with IAC-CNR 
Organisation National Research Council
Department Insititute of Applied Mathematics (IAC)
Country Italy 
Sector Public 
PI Contribution New mathematical models and experimental data
Collaborator Contribution New mathematical models
Impact New mathematical models, resulting in publications
Start Year 2013
 
Description Collaboration with Irish researchers (Martin Meere and Tuoi Vo) 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution Mathematical models of polymer-free stents
Collaborator Contribution New mathematical models and publications
Impact New mathematical models and publications
Start Year 2014
 
Description Collaboration with Irish researchers (Martin Meere and Tuoi Vo) 
Organisation University of Limerick
Department Mathematics in Science and Industry (MACSI)
Country Ireland 
Sector Academic/University 
PI Contribution Mathematical models of polymer-free stents
Collaborator Contribution New mathematical models and publications
Impact New mathematical models and publications
Start Year 2014
 
Description Industry collaboration with UK SME manufacturer 
Organisation Biomer Technology
Country United Kingdom 
Sector Private 
PI Contribution We applied the modelling techniques developed in the project to the design of a novel prototype drug-eluting stent.
Collaborator Contribution The industry partner contributed technical expertise and provided access to facilities and materials, thus enabling the coating to be applied to the prototype stent.
Impact Key output from the collaboration has been the production of a novel prototype drug-eluting stent. The first stage of pre-clinical trials of the device are complete and analysis of these findings is underway. One-post doctoral researcher has gained experience of working at the interface between academia and industry, through a series of short site visits and periods spent within the company's manufacturing facility.
Start Year 2014
 
Title New drug-eluting stent 
Description Development on new drug-eluting stent, informed by in-vitro experiments and mathematical modelling. Currently analysing pre-clinical data. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Notable impacts expected in the future 
 
Description Cardiovascular disease and treatment: mathematical modelling and clinical insights 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation workshop facilitator
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Talks followed by discussion with input from industrialists and clinicians

Collaborative activities
Year(s) Of Engagement Activity 2013
URL http://www.strath.ac.uk/code/codenews/
 
Description Cardiovascular implants: models, materials, monitoring and early life (Strathclyde) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Engage with Strathclyde event to showcase research to the public, industry and clinical attendees.
Year(s) Of Engagement Activity 2015
URL http://www.engage.strath.ac.uk/files/media/event_files/Cardiovascular_Implants_Approved.pdf
 
Description Images of Research Public Engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Entry to Images of Research Exhibition. Image toured the country, appearing in public spaces such as The Science Centre.
Year(s) Of Engagement Activity 2015
 
Description Mathematical modelling of drug delivery devices 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation workshop facilitator
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Mini-symposium comprising talks by experts in the field, attended by industrialists.

Collaborative activities
Year(s) Of Engagement Activity 2014
 
Description Next generation stents: scoping the future (Limerick, Ireland) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Stents workshop with industrial and clinical participation. Break-out group discussions
Year(s) Of Engagement Activity 2015
URL http://www.macsi.ul.ie/stentworkshop.html
 
Description Optimal Coronary Stent Design and the Role of Modelling 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talks and panel session on futre of research in the field

Company engagements and collaborations
Year(s) Of Engagement Activity 2014
URL http://www.macsi.ul.ie/stentworkshop.html