Final Report Summary - REBIOSTENT (Reinforced Bioresorbable Biomaterials for Therapeutic Drug Eluting Stents) Executive Summary:Stents are tubular type implants that are deployed most commonly to recover the shape of narrowed arterial segments. Although their clinical use is widespread, current designs often cause adverse responses in patients. The ReBioStent project evaluated the production of biodegradable and biocompatible resorbable stents using highly innovative, novel, smart and multifunctional materials aiming to overcome these shortcomings through a consortium of 14 companies and universities from across Europe. Over a 3 year research and development programme, the consortium achieved significant progress towards developing a Bioresorbable Drug Eluting Stent. A range of biomaterials and surface treatments has been developed; synthetic and natural origin polymers and blends, reinforcing inorganic particulate fillers, drug delivery systems and surface treatments to enhance the healing process. In-vitro cytotoxicity testing ensured that the combination of materials, drugs and surface treatments were biocompatible. Additionally a novel biomechanoreactor to simulate in-vivo conditions was developed. In tandem, results of computer modelling and simulation studies of stent properties have informed selection of final scaffold geometry from several candidate designs. The final design was identified using the data generated and manufacturing methods selected with potential for mass production of stents at a commercially competitive cost. In-vivo testing verified the biocompatibility and biofunctionality of the implanted stents and analysis of the results led to clear measures to refine the stent design and processing for enhanced properties as well revisions to the implantation techniques to better suit the characteristics of the new stent. In parallel with the research activities ReBioStent has actively disseminated the project results. In addition to conference presentations, publications and the project web site, it has run three dedicated Science for Industry sessions at the international biomaterial conferences to raise awareness of the project activities. The project partners are now evaluating exploitation of the project outcomes through two routes; as stand-alone Intellectual Property Right (IPR) generated by the Work Packages and Tasks and as a finished device. Their aim is to build on the significant progress made in ReBioStent to bring this innovative technology to market. Project Context and Objectives:Stents are tubular type implants that are deployed most commonly to recover the shape of narrowed arterial segments. Although, the clinical use of stents is widespread, they cause adverse responses including inflammation, in-stent restenosis (recurrence of narrowing of the blood vessel) and thrombosis (formation of a blood clot inside the blood vessel). Endothelialisation (formation of the cells that line the blood vessel) in the area by the stent greatly reduces these adverse reactions. In contrast to permanent stents in recent years, development of a biodegradable stent that recovers and maintains arterial shape and then gradually disappears and avoids further complications, have been gaining momentum. The main concept of the ReBioStent project was the production of biodegradable and biocompatible resorbable stents using highly innovative, novel, smart and multifunctional materials (Figure 1) aiming to overcome all the shortcomings of the currently available stents. The stents produced within ReBioStent were made of novel bioresorbable, biocompatible materials with tailorable degradability meeting the requirement of long term stability for coronary artery stents. Other features targeted included controlled drug eluting capability, surface functionalisation to enable positive interaction at the cell-biomaterial interphase and radio-opacity. To achieve this aim of developing the next generation resorbable drug eluting stent, the following objectives were addressed over a three year programme by a consortium of 14 companies and universities from across Europe:Objective 1: Biomaterials development: Develop advanced functional biomaterials using both natural (polyhydroxyalkanoate, cellulose) and synthetic (PLLA based copolymer with ethylene glycol and caprolactone) polymers based on FDA approved materials with tailored mechanical, thermal, properties (glass transition temperature below body temperature), degradation rates (bioresorption in the body between 6-12 months) and improved biocompatibility, to form the base material for stent end product. Further improvement of the base material properties, by the development of composites using bioresorbable inorganic fillers (mesoporous silicate glasses and phosphate glasses) and organic material (bacterial cellulose). All the biomaterials developed must meet stringent requirements needed for the stent application and demonstrate scale-up capacity from lab to industrial level.Objective 2: Surface functionalisation of biomaterials: Develop advanced manufacturing technologies for the generation of tubular samples (stents) with a functionalised inner surface by applying physical and biochemical methods in order to improve the blood contacting characteristics of the stent luminal surface (anti-thrombogenic property), by promoting endothelial cell (EC) and endothelial progenitor cell (EPC) attachment, proliferation and alignment (stent endothelisation), preventing smooth muscle cell attachment and ensuring long term stability by preventing restenosis.Objective 3: Drug delivery: Develop an efficient drug delivery system that will be combined with the stent for controlled spatial and temporal release of the two FDA approved drugs (Tacrolimus and Sirolimus) to avoid the restenosis process. The drug delivery vehicles will be based on polymeric (PHA/PLLA) microspheres, bioabsorbable silicate or phosphate glasses and surface coating technology.Objective 4: Modelling and simulation to develop ideal multifunctional biomaterials and stent prototypes: Predictive models will be used for (1) enhancing the mechanical properties of the biomaterials and composite systems, (2) explore stent architecture by reviewing 5 design variations of strut architecture, (3) model the dynamic response of the stent and to assess the fatigue life and (5) model blood flow through the stent.Objective 5: Cell-biomaterial interactions: Understand the interplay between the biomaterials developed (polymeric matrices, composite systems, drug delivery vehicles) and different cell types at in vitro level to assess the cytocompatibility of ALL stent materials and prototypes under static and dynamic cell culture conditions. Conception of a novel biomechanoreactor to carry out in vivo simulation experiments.Objective 6: Design, fabricate and optimise a new generation of stent: Biomaterials will be selected using stringent mechanical testing. Tooling designs will be generated for both forming the stent in the form of cylindrical tubes and as flat sheets that can be coiled into the final shapes. Laser cutting technique will be investigated for the cutting of the final pattern design in the polymeric tubes.Objective 7: In vivo studies: Assess the performance of the stent prototype developed in a clinically relevant animal model, both small and large, as proof of concept and preclinical validation.Objective 8: Scaled up production of the new generation of Reinforced Bioresorbable Therapeutic Drug Eluting Stents taking into account standards, regulatory affair and economic issues.Project Results:The consortium has successfully developed various biomaterials of both synthetic (PLLA based copolymer of ethylene glycol and caprolactone) and natural origin (PHA and cellulose) with predefined physicochemical properties for the development of stent base material. These materials have also been combined in the form of blends to develop novel materials for stent development. Depending on the stringent requirement of mechanical properties and biocompatibility assessment the consortium has selected the biomaterials for stent development. Up-scaling synthesis of these selected biomaterials has been achieved. Furthermore using the selected biomaterials, novel composite systems containing bioresorbable inorganic (mesoporous silica, functionalised mesoporous silica particles and phosphate glass) and organic fillers (bacterial cellulose) have also been developed. Composites containing Barium Sulphate powder to achieve radio-opacity for non-invasive monitoring have been demonstrated. Drug delivery vehicles based on organic and inorganic particles incorporating the target drug rapamycin has been successfully fabricated. A sustained release of the drug from these powders was observed for up to 30 days in phosphate buffer medium. The properties of the synthetic and natural polymer blends were enhanced to produce hybrid bio-composites, a newly developed technology. Inorganic fillers were added to reinforce the polymeric materials, increasing their strength and stiffness and making them malleable enough to be used in stent manufacture. Additionally controlled release properties were achieved by incorporating the target drug, Rapamycin, within the silica and organic fillers. Polymer-inorganic composites with well-distributed particulates were reproducibly made in newly developed, scalable processes again capable of meeting the project requirements. A range of materials with varied bioresorbable polymer and filler loadings were evaluated to assess chemical and physical properties, and biocompatibility through in-vitro cell studies. Successful strategies have also been applied to surface functionalise by physical (micro patterning) and biochemical methods (coupling of PEGylated REDV peptides onto plasma treated surfaces of biomaterials) to improve the blood contacting characteristics of the stent surface (lumen of the graft), enhance stent endothelialisation and ensure long term stability. Compositions were characterised for use in stents through measurement of properties, such as mechanical performance, thermal performance, biocompatibility and degradation behaviour. The drug release profile of the short-listed polymers was characterised with the best results from the synthetic composites incorporating drug loaded silica particles and drug added to the polymer. The stent processing operations had minimal effect on the drug release profile once the process parameters were optimised. The developed biomaterials, surface treatments and stent prototypes underwent in-vitro cytotoxicity testing to ensure that the combination of materials and drugs were biocompatible. Tests were according to DIN/EN ISO 10993-5 and beyond using various cell types. Additionally a novel biomechanoreactor to simulate in-vivo conditions and hence allow the identification of the most promising stent prototypes has been developed. It is a novel, custom-made, multifunctional biomechanoreactor (BMR) designed and built to enable testing of stent performance via in vivo simulation experiments.In tandem, results of computer modelling and simulation studies have informed selection of final stent scaffold geometry from several CAD designs. To assist with this evaluation, an automated geometry generation tool was developed giving efficient design exploration and optimisation. Further stent characteristics were modelled to compare the performance of the selected design alternatives. Recoil was calculated for the selected stents using measured stress-strain relationship for the two families of materials (natural polymers and synthetic polymers). Models of drug release, dynamics analysis and fatigue as well as radial compression tests were used compare the performance of two design alternatives.The final stent design was identified using the data generated by the project. Production methods were considered, selecting those that had the potential to be scaled up for mass production of stents and be commercially competitive. For example, the polymer synthesis processes were optimised to increase polymer yield and the selected grades were produced on a large scale, providing sufficient amounts of material to meet the project needs. Up-scaling of filler production was achieved effectively.Following the successful manufacture of a large number of stent prototypes for use in the project, a review of the production route confirmed that Good Manufacturing Practice (GMP) was adhered to and that the stent could be mass produced at a competitive cost. In-vivo testing verified the biocompatibility and biofunctionality of the implanted stents. In large animal assays, pigs were randomly implanted, in Left Anterior Descendent artery (LAD), Right Coronary Artery (RCA) and Left Circumflex artery (LCX) with two prototypes of stents (natural and synthetic) compared to a commercial bare metal stent control. After a 30 days follow up, the animals were sacrificed and their coronary arteries submitted to histological protocol in order to obtain histological preparations. All the samples were observed with an optical microscope, photographed and measured to obtain qualitative and quantitative data reported on the stent evaluation forms. The analysis led to clear measures to refine the stent design and processing for enhanced properties as well revisions to the implantation techniques to better suit the characteristics of the new stent. The consortium has therefore achieved significant progress towards developing a Bioresorbable Drug Eluting Stent and is developing plans to take this innovative technology further.Potential Impact:Coronary artery disease (CAD) remains the main contributor towards the mortality and economic burden associated with cardiovascular disease (CVDs). CAD is caused by the deposition of plaque in the coronary artery resulting in obstructed blood and nutrient supply to the heart, leading to myocardial infarction (Choudhury RP, Lee JM and Greaves DR. Nat Clin Pract Cardiovasc Med (2005);2(6):309-15) . The societal cost of CAD is estimated as 27% of the total cost of all CVDs (Tardif J-C. European Heart Journal Supplements (2010);12:C2–C10 doi:10.1093/eurheartj/suq014). Currently, approximately 3.8 million men and 3.4 million women worldwide die each year from CAD (WHO. The global burden of disease: 2004 update. www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html) . The cost of CAD to the healthcare system of the European Union was estimated at 23 billion Euros in 2003 ( Leal J, Luengo-Fernández R, Gray A et al. Eur Heart J (2006);27:1610–1619.); however, more recent studies suggest that this has increased to over 49 billion Euros. Over 678,000 people provide care to CAD patients, representing 702 million hours of care, which was estimated to cost the European Union 6.8 billion Euros. Approximately one million working years were lost because of CAD mortality, accounting for 44% of all working years lost because of cardiovascular deaths, with a cost of 11.7 billion Euros. The most promising treatment for CAD is a procedure known as angioplasty which involves mechanical widening of narrowed blood vessel supported by cardiovascular implants called stents. However, the most widely used stents (bare metal stents and drug eluting stents) once implanted typically remain in the patient’s body as a foreign body, which often leads to short and long-term complications including inflammation, in-stent restenosis and thrombosis. A third type of stent based on bioresorbable polymers is currently only commercially manufactured by Abbott, a US based company. The product is still in its infancy and although available in the market, does not have FDA approval for the technology and evidence suggests that it has several limitations (limited expansion up to 3 mm diameter, fracture problem when inflated above 3-4.5 mm diameter, cannot withstand hard and calcified lesions, lower radial strength when compared to metallic stents and high cost, $2500 per stent).It is in this context that the ReBioStent consortium has focused on and made great progress in developing the next generation bioabsorbable vascular stent aiming to overcome all the shortcomings of the currently available stents.DisseminationDissemination was through conference presentations, journal publications, special dissemination events, publicity materials (flyers and posters), a project web site, press releases and presentations to the Medical Advisory Board. A total of 46 individual dissemination items were created during the course of the project.Three dedicated ReBioStent Science for Industry sessions were held at the following biomaterial conferences:– Bioresorbable Materials for Medical Applications, 27th Meeting of the European Society for Biomaterials (Krakow, September 2015)– Biological Substitutes and Biodegradable Implants: A Promising Approach for Innovative Surgery, 10th World Biomaterials Congress (Montreal, May 2016)– ReBioStent Session, Meeting of the UK Society for Biomaterials (London, June 2016)These “Science for Industry” sessions disseminated the project results to the wider scientific community through speakers from the project consortium members to raise awareness of the project results. They also included keynote speakers from outside the project to increase interest outside the consortiumDissemination has continued after project completion with members presenting to industry and interest group meetings and several project partners presenting on ReBioStent developments to 28th Meeting of the European Society for Biomaterials in September 2017 in Athens.Exploitation of the Project ResultsThe project partners are aiming to exploit the project outcomes through two routes:− Exploitation of stand-alone Intellectual Property Right (IPR) generated by the Work Packages and TasksThese can be classified as 10 innovations in materials, products and services, 6 advances in scientific and process know-how, and 3 items of information to support the exploitation of the new stent. − Exploitation of a finished device i.e. a bioresorbable drug-eluting stentFor commercial exploitation of a finished device, further work is required. The consortium is considering the possibility of forming a spin-out company to perform the design and development work and to commercialise the finished coronary stent device. The initial tasks of the company will be to prepare the business plan, analyse the market and explore funding routes.List of Websites:The project website was set up as an early project milestone with the addresshttps://rebiostent.eu/ Contacts:Dr Xiang Zhang (Project Co-ordinator) - xiang.zhang@lucideon.comProf Ipsita Roy (Scientific Co-ordinator) - i.roy01@westminster.ac.ukStuart MacLachlan (Project Manager) - stuart.maclachlan@lucideon.com Related documents final1-rebiostent-final-report-figure-1.pdf
