Studies in the development of a novel side-branch stent

Coronary artery disease is common. It occurs due to build-up of fatty deposits in the wall of the coronary arteries which supply blood to the heart muscle. This results in inadequate blood supply and therefore insufficient oxygen getting to the heart muscle causing cramp like sensation in the chest - angina. The commonest way of treating this is with stents; small wire mesh devices that keep the artery open. 4 million stents are placed in patients worldwide each year. In about 15% of patients the narrowings occur at a branch point which may then require the deployment of 2 stents at that point -one in the main artery and a second one abutting it in the side branch. If the angle between the main branch and the side branch is narrow (ie less than 90 degrees) and as stents have square ends, accommodating the angle between the main branch and the side branch is impossible - there is either a gap or an overlap, both of which can cause problems. A gap will result incomplete coverage of the disease while overlap of stents canresult in re-narrowing of the blood vessel and sometimes can lead to clot forming at this point, which can in turn lead to blocking of the artery and hence lead to a heart attack. The aim of this project is to develop a novel stent that can be placed in the side branch (with a specially designed end that can be modified by a balloon in the main branch) but without the side branch stent collapsing into the side branch artery lumen and obstructing blood flow. A second standard stent could then be placed in the main artery.
We have worked extensively with a prototype design company (Protomed, Marseilles) to produce such a stent. Preliminary work involved computer modelling, simulation experiment, and computer assessment to see how a proposed stent design would behave when it is deployed in the artery. Using this method, stent designs with good mechanical properties (virtual radial strength, deliverability and recoil) were refined and 2 early prototypes were produced and tested in videoed side branch models to see how they performed. The prototypes were also placed in 2 pigs and the results assessed with a special X ray technique- micro CT. This work showed that the concept of producing a stent with a modifiable end was viable, however these experiments also showed that modifications are required to produce stents that completely cover the vessel side branch with good mechanical properties.
The proposed research will take this preliminary work forward. We have liaised with our collaborators at Protomed Labs to determine how the initial designs to the modifiable end of the stent need to be changed to overcome some of the problems seen within the initial prototypes. We will then test these new designs virtually using computer modelling, to see how the stents would behave when they are deployed at various angles. This is an important stage, as any problems will require further modifications to the design and retesting.
We will then laser-cut the stents from cobalt chromium and test these by deploying them within silicone models of bifurcations (2 models representing different angles). The deployment of the stent will be filmed and analysed to see how the modifiable end of the stent behaved. We will look to ensure that none of the stent struts impinge into the lumen of the bifurcation model. Mechanical properties of the stent will also be assessed. Any problems with be addressed with further design modification.
Once the prototypes are successful, we will test them again in pigs to see how they perform in actual blood vessel branch points, and also in 28 day experiments which will give important information regarding the degree of healing around the stent, and to ensure no early complications of such a stent arise, such as formation of blood clot around the stent.
The aim of this research is to produce a stent that can be used safely, effectively and with ease to treat this difficult aspect of coronary disease.

Coronary artery disease (CAD) remains a major cause of mortality and morbidity. Percutaneous Coronary Intervention (PCI)-balloon inflation at the site of the narrowing with stent placed to keep the artery open-has become the dominant treatment for CAD. While PCI is a safe procedure with high success it can be more difficult and less predictable when disease occurs at branch points (bifurcation) as the angle between main and side branch can result in either a gap or overlap between the 2 stents used to treat each branch, due to the cylindrical stent ends being straight. Our aim is to develop a novel stent with a balloon modifiable proximal end conformed once placed in the bifurcation side arm allowing the end to accommodate the side branch/main branch angle. The main branch would then be stented with conventional stents for complete coverage of the bifurcation with no overlap/gap between the stents and no intrusion into the side branch stent. Initial work (previous NIHR grant) resulted in 2 early prototypes. The current proposal aims to build upon this work to allow the device to translate to clinical trials and practice
We have specific plans to refine the design of our prototypes using computer modelling, Finite Element Analysis, and to laser cut improved prototypes to test in latex bifurcation models (stent behaviour under direct vision). After any needed re re-design, for stent prototypes to be successfully, repeatedly and reliably conformed in-vitro, an appropriately numbered pig bifurcation study will be undertaken. Assessment of in-vivo performance will use micro-CT to assess stent remodelling/relationships with the main vessel stent and histological studies early and at 28 days for tissue reaction to the implanted stent at bifurcation site (to ensure there are no downsides to the concept of in-vivo conformability eg a nidus for in-stent intimal hyperplasia or stent thrombosis) The ultimate aim is to develop a side branch stent for CE mark and testing in man.

The following will benefit from the research undertaken with this grant:
1) Interventional Cardiologists: Bifurcation stenting is a challenging aspect of interventional cardiology, with current solutions to treat the side branch disease being suboptimal. The novel stent that would be developed would provide interventional cardiologists with an easy, effective and robust method of treating side branch disease. It has the potential to reduce procedure times, and hence radiation exposure to both patient and operators. This will enhance the effectiveness of such procedures, with incumbent effect on efficiency with which such bifurcation lesions are treated and hence overall cost reductions to NHS trusts in terms of time spent per patient in the catheter lab.

2) Patients with Bifurcation disease: This is the target group who will derive the most benefit from this novel stent. The stent would allow complete coverage of bifurcation lesions, hence improving patient quality of life and incumbent reduction in economic health costs through continued angina that would otherwise be caused by untreated side branch lesions.

3) Academic impact: The approach adopted for a modifiable stent end is novel and innovative. This will garner academic interest within the interventional cardiology community, as well as enhancing our knowledge of behaviour of the stent struts and how modifications in design of the stents can alter their behaviour. In addition, clinical members of the research team, the research fellow in particular, will have close interaction with scientists from other disciplines (bioengineering such as our collaborators in Protomed), hence enhancing knowledge and skills in terms of benchwork and translational research. It will form the basis of his MD Generic research skills, including planning and time management skills, communication between different research organisations and within different disciplines of research, data analysis skills, histological preparation skills, presentation skills and scientific writing skills will be developed by the clinical research fellow during the course of the research. These are generic skills that the research fellow will use in regular medical practice and throughout their career.

4) Industrial Impact: The novel stent, once developed from this research, will go on to "first-in-man" testing. If successful, we will continue and develop our discussions with any one or more of the major stent companies to collaborate in evolving the stent and bringing it to market. A competitive attractive aspect of this stent is that manufacture would involve currently used techniques of laser cutting. We anticipate global economic benefit from production of the stent for disseminated used, with additional impact on employment of individuals within the stent company for longer term manufacture, sales and further development of this stent.