Periodic Reporting for period 4 - PV-COAT (PROSTHETIC VALVE BIOACTIVE SURFACE COATING TO REDUCE THE PREVALENCE OF THROMBOSIS) Okres sprawozdawczy: 2020-03-01 do 2021-02-28 Podsumowanie kontekstu i ogólnych celów projektu Valvular heart disease affects more than 100 million people worldwide, and the problem is growing because of the high incidence of rheumatic heart disease in developing countries and the increasing burden of degenerative valve disease in the ageing population. About 800 000 prosthetic heart valve replacements are implanted every year worldwide, and this remains the only treatment for the majority of patients with severe valvular heart disease. Heart valve prostheses are currently among the most widely used cardiovascular devices. Continuing advances in heart valve prosthesis design and in techniques for implantation have improved survival of patients who receive these devices. However, the ideal valve prosthesis does not exist. Mechanical valve prostheses, made of metallic and polymeric components, are prone to blood clotting (thrombosis) and therefore require permanent anticoagulation and monitoring, which often leads to adverse reactions, i.e. higher risks of thromboembolism or hemorrhage, and impacts patient's quality of life. The present project aims to reduce mechanical valve thrombosis to improve their long-term in vivo performance by using a novel bioactive coating.The ultimate scope is to reduce the need for anticoagulant treatment and its related risk of bleeding. As a final result, the number of revision surgeries performed each year due to valve thrombosis could be reduced. Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty By using innovative polymer chemistry, we succeeded to coat clinically used mechanical heart valve prosthesis with bioactive polymers.Several layers of polymeric nanoscale particles loaded with an antithrombotic drug, referred to as nano-reservoirs, could be attached on the surface of the entire valve prosthesis. In addition, an anti-fouling and anti-adhesive polymer bearing an anticoagulant could be grafted on top of this multilayer assembly of nano-reservoirs. This technology enabled us to achieve the expected antithrombotic effect. The coated valve prosthesis induced less thrombosis than non-coated ones. Moreover, our coating did not alter prosthetic valve hemodynamic performance.The antithrombotic activity of our coating was demonstrated during in vitro assays with human blood. The hemodynamic performance was verified in a pulse duplicator as a model of human heart. Coating durability on the long-term was assessed in a dedicated prosthetic valve durability tester producing accelerated cardiac cycles. We found that the coating remained unaltered for a period equivalent to two years of human life. Finally, and more importantly, the in vivo demonstration of our coating performance was obtained upon surgical implantation of coated and non-coated valve prosthesis in the pig. Even though none of the implanted animals received anticoagulation during 1-month follow-up, our coating led to impressive reduction of valve thrombosis. Almost no thrombi were observed on the surface of explanted coated valve, whereas massive thrombosis occurred on non-coated valve leaflets.In the course of this project, we also discovered that a widely used antithrombotic drug also possesses unforeseen antibacterial and anti-biofilm activity. We found that nano-reservoirs loaded with this drug exhibited dual antithrombotic and antibacterial properties. This discovery was of utmost importance since thrombosis and bacterial infection represent the two main clinical complications of prosthetic heart valves. Our team has then synthetized a series of new molecules with potent antibacterial and anti-biofilm activities against resistant staphylococci and enterococci. Hence, our bioactive coating could be used for the prevention of thrombosis and infection of prosthetic heart valves. In addition to prosthetic heart valves, this technology could be applied to any materials of implantable medical devices, including not only metals, plastics but also bioprostheses. The results of this project led to the publication of 5 patents and 3 peer-reviewed research articles. Several other research articles are in preparation. Communications have been made in national and international scientific congresses as well as in events for the general public. Our discovery about the new antibacterial activity of the antithrombotic drug has also been released in the media at both national and international levels.We recently created a spin-off company with the aim to bring our coating technology on the market. Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu) In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to evaluate a variety of valve materials. However, the ideal materials do not exist, and hemocompatibility problems persist.With the promising advances of our bioactive coating approach, the coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future.Due to thrombotic reactions that occur when blood comes in contact with foreign prosthetic materials, patients with mechanical heart valves require lifelong anticoagulant treatment, which makes them at risk of thromboembolic and bleeding events. Our project provides the first evidence that the clinical performance of mechanical heart valve prosthesis can be improved by using a bioactive coating. This innovative coating technology prevents prosthesis-associated thrombosis. Furthermore, we remarkably found that this coating can also protect from prosthesis bacterial infection, thereby potentially reducing the risk of infective endocarditis. To date, bioactive coating for mechanical heart valve do not exist. Although several coatings have been developed for the prevention of either thrombosis or infection of other blood-contacting devices, such as catheters, none of them combine our coating characteristics. Our bioactive coating shows unique features, which makes it novel and highly valuable. It is universal, i.e. it can be attached on any materials, e.g. plastics, metals, biological tissues It is modular, i.e. it could be applied to various medical devices or biomaterials by simply adapting the numbers of layers, and by loading or grafting appropriate drugs or bioactive molecules. Bioactive coating of mechanical prosthetic heart valve to prevent thrombosis and infection
