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BIOMAGSCAR Report Summary

Project ID: 278313
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 3 - BIOMAGSCAR (Biodegradable Magnetic Stent for Coronary Artery Luminal Regeneration)

Project Context and Objectives:
Project concept
Great progress has been made in treating cardiovascular disease by therapeutic interventions including drugs and devices, however, it still remains the number one killer. The coronary artery stent has revolutionised the management of patients with coronary artery disease and its use is on the increase across Europe. Although outcome for patients has improved, stents still fail because of restenosis and because of early and late thrombosis occurring at the site of the implantation. While drug eluting stents have helped to reduce the problem of restenosis, neointimal proliferation causing restenosis can still occur. Additionally, concern exists regarding the long-term safety of drug eluting stents as there appears to be a small but real increase in late and very late stent thrombosis, seen particularly after the discontinuation of antiplatelet therapy.

The concept we propose is use of a biodegradable magnetised stent (BMS) as a novel delivery device for regenerative medicine solutions that target the coronary artery vessel wall. Specifically we will develop the stent technology as a platform to attract cells through a technical concept known as magnetisation. Once redeployed into the patient, the endothelial cells will be attracted to the already implanted BMS and will proliferate to form a new endothelium. Over time the BMS will undergo a predictable degradation to leave a wholly biological artery through regeneration of native tissues.

Project objectives
Our objective, using the magnetic biodegradable stent as a tool, is to reduce the incidence of in stent restenosis and thrombosis. We have developed a detailed programme of work to deliver these strategies, culminating in clinical trials, and have defined a set of objectives that are initially scientific in focus following on to clinically/societally beneficial objectives. During the BIOMAGSCAR project our objectives are to:

• Complete a preclinical evaluation of the BIOMAGSCAR product (that is, a biodegradable and bio magentic stent) as a tool for delivery of regenerative therapies to the coronary artery wall;
• Optimise the magnetic characteristics of the stent and identify the optimum dosing for cells to enable a therapeutic benefit;
• Investigate the future possibility of enhancing the biodegradable and bio magnetic stent platform to accommodate delivery of advanced therapeutics such a gene therapy, with a common goal to protect the coronary artery vessel wall from restenosis and thrombosis.
Project Results:
During the first 18 months of the project we developed a number of novel magnesium stents. To determine optimal stent configuration we targeted different designs that were then characterised and their suitability for the application assessed. For stent magnetisation we selected a PLLA polymer that could be mixed with magnetisable particles and coated onto the stent to confer magnetism. Tests showed the magnetisable particles hold a magnetic field suitable for therapeutic applications.

A protocol for efficient isolation of CD34+ cells was established and demonstrated these cells can be differentiated into functional endothelial cells. To optimise the cell labelling with magnetic particles we quantified the number of surface AC133 and CD34 binding sites on isolated endothelial progenitor cells. In the second 18 months a redesign of the stent was made to reduce mechanical stress on struts and eliminate occurrence of stent fracture that had been observed during crimping and expansion.
QualiMed then manufactured and prepared for coating hundreds of stents according to the needs of the different study groups. Each stent was given a unique number to allow for assessment during the manufacturing process and retrospective analysis of performance during the studies. A meeting with German Notified Body DEKRA occurred in Sept 2014, during which the stent’s design features, their characteristics and an explanation of these features were presented and no concerns were raised against these or the planned toxicology and biocompatibility package. However, during the past 12 months the regulatory environment for advanced technologies continue to evolve it was advised that the Consortium evaluate the non-magnetisable stent first as this represents a new device that is not yet authorised for sale in the European Union. Following a successful evaluation of the non-magnetisable scaffold, the combined stent-stem cell combination can be evaluated in a clinical trial.

With the stent specification finalised, preclinical evaluation for safety and performance of the non-magnetisable platform is being evaluated by UEF. Separately, studies to establish efficacy and optimal dosing of stem cells for a therapeutic benefit are being completed. Data from these experiments will be used in future regulatory submissions.
Preliminary results indicate that the Mg120LA20 stent is performing similarly to the commercially available controls. Optical coherence tomography analysis at one, three, six and 12 months after stenting showed comparable rates of restenosis, an indicator of the stent's overall performance, and comparable results for the radial strength of the stents to controls. A key feature of our new non-magnetisable scaffold is that its biodegradation profile is thought to shorter than established controls; therefore we believe this platform is expected to be ideal for the stent-stem cell combination.

During the past 12 months, the Consortium have developed a prototype of the stent-stem cell combination. Preliminary biocompatibility and mechanical testing results suggest that this prototype performs as well as a biodegradable stent with respect to deployment and implantation features. Additionally, data on the toxicity of the magnetic polymer has been completed as part of the regulatory package. The prototype stent-stem cell combination was evaluated in an in vitro bioreactor using conditions that would mirror the clinical setting. The stent-stem cell combination were fixed and endothelial progenitor cells were tagged with iron (CliniMacs system) and injected into the bioreactor in short repeat intervals. After each interval the number of cells captured were measured with fluorescent labelling. The prototype stent stem-cell combination showed increasing cell capture with subsequent cell injections, and this suggests that our prototype has the ability to attract and retain stem cells in a clinical setting. Separately, cell viability did not show any significant decrease below 100% viability until concentrations significantly higher than will be observed during stent degradation. A clinical trial evaluation of the non-magnetisable stent will be undertaken in 2016.
Potential Impact:
BIOMAGSCAR aims to reduce the incidence of restenosis and late stent thrombosis by 50% by developing two key elements:

1) A biodegradable stent technology;
2) Using magnetism to support the delivery of advanced biological therapeutics to increase endothelialisation of vessel walls.

Longer term/wider impacts
Demonstration that magnetism can be used to deliver advanced biological therapeutics such cell therapy to a stent in the coronary artery could imply its application in other vessels, such as peripheral and renal arteries. This project will define the conditions necessary for the expansion of magnetic direction of cells in a wide number of therapeutic applications.

If we are able to show proof of concept that the attraction of biological cells to an implanted device is successful, then this methodology could be applied to the treatment of cancers or other diseases such as rheumatoid arthritis where there is anatomical access to the diseased organ that would allow delivery of cell therapy to encourage regeneration of diseased or damaged tissues.

The BIOMAGSCAR product is therefore a pivotal study which will open the way to the treatment of several diseases by biological cells. Later the methodology could be applied to advanced therapies such gene therapy and nucleotides.

Socio-economic impact
Stenting is the only revascularization procedure to have stood the test of time and matured to become the default technique. It was predicted that by 2010 1.5 million stents per year would be deployed in Europe. The prevalence of late in-stent thrombosis is 0.8%, hence approximately 12,000 European Citizens per year will have suffered a late in stent thrombosis. With the knowledge and technologies developed through the BIOMAGSCAR project our long term aim is to halve this number and save 6,000 people from unnecessary suffering.

With bare metal stent restenosis rates at nearly 16% at 1 year, if half of the 1.5M stents implanted by 2010 had been bare metal then there was potential for 120,000 instances of restenosis, costing €4000 for each repeat PCI. Following successful completion of the BIOMAGSCAR project, and introduction of the refined technique as a primary treatment option, we aim to reduce this number by half to only 60,000 a year. Given our target objectives to halve the number of patients suffering restenosis or a thrombotic event we believe that the BIOMAGSCAR project can save the European healthcare system €274.8 million p.a. in direct costs. This cost saving is increased further when we consider the wider associated social cost of the procedures (i.e. patient productivity & work related losses, outpatient care, medications, primary care, social support and care costs) which would increase this direct cost by at least a factor of ten. Consequently, we conservatively forecast that the return on investment on the initial grant funding for the BIOMAGSCAR project will be over €2.7 billion per annum.

Commercial impact
The European share of the global market for bare metal coronary stents is expected to be 35% by 2017. Core to our strategy is to improve the market share of the absorbable stent having demonstrated anti-restenotic and anti-thrombotic efficacy of our stent-cell combination. Once the BIOMAGSCAR project’s regenerative medicine strategy becomes available as a primary method of preventing restenosis and in-stent thrombosis we will be able to generate significant sales growth. Therefore the objective of this consortium is to realise the full impact of this technology, not only in solving a major clinical problem, but also establishing commercial success and generating jobs and wealth within European industry.
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