Studies in the development of a novel side-branch stent

Lead Research Organisation: University of Leicester
Department Name: Cardiovascular Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Banning A (2017) DEVELOPMENT OF A NOVEL SIDE-BRANCH STENT: IN-VITRO STUDY in Journal of the American College of Cardiology

 
Description MRC DPFS Scheme - Studies in the development of a novel side-branch stent.
Amount £151,364 (GBP)
Funding ID MR/L00514X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2016 
End 12/2016
 
Title Development of bifurcation in vitro silicon models to test the bifurcation stent protocols 
Description There are no ideal models for bifurcation disease We have approached a commercial organisation who have made specific models for our research We ahve also developed micro CT proformas 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2014 
Provided To Others? Yes  
Impact As yet unknown 
 
Title Micro-CT evaluation of coronary stents 
Description Use of high resolution micro-CT to evaluate the structure of coronary stents following deployment in both silicone phantom bifurcation models and also in vivo deployment. The methodology has been extended to allow quantitative assessment of stent apposition using 3D multiplanar reconstructions as well as measurements of stent cell area. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact Allows the accurate assessment of stent deployment and apposition. 
 
Description Dr Douglas Fraser 
Organisation Manchester Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution 1. Development of the designs for the novel stent, with our collaborators in Promoted Labs Marseille, exploring the underlying concept of a side branch stent with a collapsible malleable end to cover the ostium of the side branch in a coronary bifurcation. 2. Performing computational modelling and finite element analysis of the novel stent to determine predicted performance and stent apposition characteristics, as well as predicted stress/strain on the stent during deployment. 3. In-vitro testing of the stent prototypes within silicone bifurcation models, with analysis of data using Micro-CT 4. Testing mechanical properties of the stent for recoil, foreshortening and radial strength. 5. Analysis of the data generated from the above studies.
Collaborator Contribution Dr Fraser is an interventional cardiologist who has extensive published expertise in coronary stent bench testing. We have entered into a collaboration with him to review the current and future design iterations for the stent under non-disclosure agreement. 1. Review of the current data on the prototype stents under non-disclosure confidentiality agreement 2. Opinion on the currently proposed design iterations for refinement of the stent prototypes to improve deployment characteristics.
Impact 1. Selection of further design iterations to take forward to the next round of computational modelling, finite element analysis and in-vitro testing.
Start Year 2016
 
Description JG, University of Sheffield. 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution AHG and the clinical reserach fellow have worked with Dr Julian Gunn from the University of Sheffield in the preparation of the grant proposal, and also as a co-investigator we have liaised with JG with regards to Phase 3 of the reserach project which will involve testing any of the developed prototypes within porcine bifurcations.
Collaborator Contribution JG has been involved in regular project management group meetings during the initial design phase of the project, and also brings his knowledge and expertise in stents and treatment of bifurcation disease. He will continue to be involved in the project, and in particular during phase 3 of the project where developed prototypes will be deployed within porcine bifurcations, which will take place in the labs at the university of Sheffield.
Impact Outputs include the development of 2 initial designs which will be taken towards manufacture and testing in coronary bifurcations, Development of study protocols for Phase 3 of the project.
Start Year 2011
 
Description Medtronic 
Organisation Medtronic
Country United States 
Sector Private 
PI Contribution 1. Development of the designs for the novel stent, with our collaborators in Promoted Labs Marseille, exploring the underlying concept of a side branch stent with a collapsible malleable end to cover the ostium of the side branch in a coronary bifurcation. 2. Performing computational modelling and finite element analysis of the novel stent to determine predicted performance and stent apposition characteristics, as well as predicted stress/strain on the stent during deployment. 3. In-vitro testing of the stent prototypes within silicone bifurcation models, with analysis of data using Micro-CT 4. Testing mechanical properties of the stent for recoil, foreshortening and radial strength. 5. Analysis of the data generated from the above studies.
Collaborator Contribution This collaboration involves Prof Martin Rothman (VP Medtronic Vascular), Sean Ward (Senior R&D Manager) and Aram Jamous (Principal R&D engineer) as an industry collaborator within this project to develop a novel bifurcation stent to address the need for a solution to the problem of treating side-branch coronary disease with percutaneous coronary intervention. We have had numerous web conferences with our industrial partners in Medtronic under non-disclosure confidentiality agreements following the initial set of data from the in-vitro stent deployment experiments. There was initially a stent-balloon mismatch between the prototype stents and the low-profile balloon used, resulting in balloon micro-perforation during attempted stent deployment. The team at Medtronic (Prof Rothman, Sean Ward and Aram Jamous) performed further detailed crimping evaluation using thicker stent balloons to ascertain the optimal crimping force to allow stent deployment without perforation of the stent balloon. Force dislodgement tests were also performed ensure the stent can be delivered without risk of stent displacement from the balloon. This allowed the research team to proceed with the in-vitro evaluation of the current prototype designs. Following the successful in-vitro experiments with deployment of the prototype stents within silicone bifurcation models, the data from Micro-CT were reviewed with Medtronic through a web conference. The stent performed as intended, however there was evidence of a large cell area within the deployed malleable end of the stent, which from our collaborative review with Medtronic was felt to need resolving prior to proceeding with further in-vivo deployments and eventual "first-in-man" studies. This has lead the research team to review the current designs and perform successive design iterations to address the large cell area. The proposed design iterations have also been reviewed with Medtronic and this has lead us to select the 2 design iterations that we will take forward to the next round of computational modelling, finite element analysis and in-vitro testing of prototypes prior to the in-vivo studies. This industry collaboration is important to ensure that the novel stent concept can be developed and translated to a stent that can be used to treat human coronary disease.
Impact 1. Crimping evaluation studies to overcome initial stent-balloon mismatch. 2. Crimping of stents onto suitable stent-balloons for the in-vitro deployment studies with the prototype stents. 3. Engineering input from a world-leading stent manufacturing company in the development of this novel stent. 4. Review of the data from the in-vitro studies to inform further design iterations and refinement of the current design to achieve optimal performance of the novel stent.
Start Year 2015
 
Description ProtomedLabs 
Organisation Protomed Labs SAS
Country France 
Sector Private 
PI Contribution Protomed Labs are a medical devices design organisation that have been involved in collaboration with AHG and the Clinical Fellow in design refinement and conducting the finite element analysis on the novel stent design. They have brought their knowledge and expertise in stent design to the project, in particular working with the PI and the research fellow in taming forward the initial designs towards the development of an initial prototype for the bifurcation stent. AHG and the reserach fellow have worked with Protomed in determining the best characteristics of the novel stent, providing clinical information on the use of stents in bifurcation and the range of bifurcation angles that the stent would be used in based on angiographic analysis of coronary arteries. In addition, both AHG and the clinical research fellow have provided input on the refinements of stent design based on reviews of the CAD designs and also virtual performance of the stents through the results of the FEA.
Collaborator Contribution As above: Protomed have been working with Prof Gershlick and the reserach fellow in development of the novel bifurcation stent design. In addition, they have also been working with us to develop the CAD and, with the reserach fellow, have taken these design through use of finite element analysis to determine virtually how the stent will perform in a virtual coronary bifurcation, and also what effect the mechanism of stent deployment has on the structural integrity of the stent in terms of measurement of Von-Mises stress equivalent and stress repartition during deployment of the stent. The FEA was also used to determine other mechanical properties of the stent such as elastic recoil and foreshortening on deployment of the stent.
Impact Main outcomes from this collaboration to date are the development of 2 prototype designs that have proven succesful in FEA testing and are now being laser cut from cobalt chromium for physical testing within simulated coronary bifurcation models and also to perform evaluation of crimping process and further on, the mechanical properties of the stent, This collaboration is multidisciplinary springing together the fields of coronary anatomy, coronary intervention and also biomedical engineering, physics and material mechanics.
Start Year 2010
 
Title Bifurcation Stent 
Description A novel bifurcation stent that is easily deliverable, covers any bifurcation angle & is widely applicable. 
IP Reference GB2450085 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact None yet
 
Title Novel patent protected stent 
Description The stent under development is a novel stent that could be deployed within the side-branch of a coronary bifurcation lesion which would completely appose the side branch with no ingress of stent material within the lumen of the main branch or side branch. The design of the stent still requires some refinement to achieve its optimum performance. Following on from work undertaken previously on an NIHR grant, the current phase of development has led to refinement of the inItial designs leading to new prototype designs that have performed well with computer modelling in terms of succesful simulated deployment within a virtual bifurcation using FEA with good mechanical properties (stress/strain profile, foreshortening and recoil post deployment of the stent). Following the successful FEA work, the stent prototypes were laser-cut from cobalt chromium and crimped onto stent-balloons following a through crimping evaluation process including determination of nominal pressure for deployment and force-dislodgement tests. The stents were then deployed in silicone bifurcation models of different shape and angle of bifurcation, and scanned with Micro-CT. The results of this showed that while the stent prototypes can be deployed as intended, there is an unexpected issue with the size of the stent cell area following deployment. Following review of the data with our industry partners and collaborators we have developed with Promoted Labs 2 further design iterations that aim to address this issue, and are proceeding with further round of FEA and in-vitro testing, prior to in-vivo deployment within porcine arterial bifurcations (coronary, renal and iliofemoral) to assess deployment characteristics and also tissue healing responses and platelet deposition studies. This current work is funded by a research grant awarded by the MRC DPFS funding scheme (MR/L00514X/1). This MRC funding commenced in January 2014, and we have recently been awarded additional funding to continue the work on the novel stent until December 2016. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact Development of this novel stent could allow treatment of true coronary bifurcation lesions which would include coverage of the side branch ostial disease, regardless of the angle subtended by the bifurcation, with a standard stent within the main branch, The aim is to improve treatment of this challenging subset of coronary disease. 
 
Description British Cardiovascular Intervention Society Advanced Cardiovascular Intervention 2017 conference - moderated poster presentation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A presentation of data from in-vivo studies on the novel bifurcation side-branch stent. This was given as part of the Young Investigator Award moderated poster sessions at the annual BCIS Advanced Cardiovascular Intervention conference, to an audience of researchers, interventional cardiologists (the intended user of this novel technology), industry representatives, and interventional cardiology trainees.
Year(s) Of Engagement Activity 2017
 
Description British Cardiovascular Interventional Society Advanced Cardiovascular Intervention 2016: Moderated Poster Presentation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of stent concept, computational modelling and finite element analysis and results of the in-vitro deployment experiments as a poster presentation at the annual flagship interventional cardiology conference in London. This allowed for presentation of the stent to interventional cardiologists (primary potential users of the technology) as well as industry. The content of the presentation was protected by recently filed patent to cover the stent design and future concepts for design iteration.
The feedback from the presentation was useful in informing future direction in the development of the novel stent, with many questions asked by the moderators and audience regarding use of the stent and potential drawbacks such as positioning of the stent. This presentation increased general awareness of the development of a novel stent concept to address a continuing clinical problem in the management of coronary bifurcation disease within the interventional cardiology community.
Year(s) Of Engagement Activity 2016
 
Description Presentation at National Conference - Bifurcation Lesion Treatment 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation entitled "How to develop a novel side-branch stent" presented by Professor Anthony H Gershlick at a national course for interventional cardiologists, cardiology trainees and industry on treatment of bifurcation coronary artery disease (Bifurcation Lesion Treatment 2018), The talk emphasised the steps towards the development of the novel stent, including exploring concepts for design, computational modelling, in-vitro and in-vivo testing and also showcased the results of the project not only as an example of how the process of industry interaction and design/development of novel technology, but also how the prototype stent can address an unmet clinical need.
Year(s) Of Engagement Activity 2018
 
Description Presentation of research poster at American College of Cardiology Meeting 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of a poster at the scientific ACC 2017 meeting, with audience consisting of researchers, clinicians in the field of cardiology and also industry representatives, indicating concept of the novel stent and key findings from the research.
Year(s) Of Engagement Activity 2017
 
Description Presentation of research study at Departmental meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Part of the Intervention research group within the department of cardiovascular sciences seminar to update other researchers and members of the department with regards to the research conducted within the project and the key findings of the project.
Year(s) Of Engagement Activity 2017