Thromboresistant Polymers for Implantants
Development and Study on Thromboresistant Polymers and Coverings for Implantants and Miscellaneous Medical Articles
Tech Area / Field
- CHE-POL/Polymer Chemistry/Chemistry
8 Project completed
Senior Project Manager
Mitina L M
The Scientific Centre of Radiation Medicine and Burns, Armenia, Yerevan
- Yerevan Institute "Plastpolymer", Armenia, Yerevan\nState Engineering University of Armenia, Armenia, Yerevan
- Universita di Pisa / Dipartamento di Patologia Sperimentale, Biotecnologie Medicine, Infettivologia ed Epidemiologia, Italy, Pisa\nUniversidade de Coimbra, Portugal, Coimbra\nUniversity of Lund / Center for Chemistry and Chemical Engineering, Sweden, Lund\nKarl-Winnacker Institut, Germany, Frankfurt am Main
Project summaryProject goals: To develop synthetic polymer coverings for biomedical devices having short- or long-term contact with blood, in particular, to develop new thromboresistant polymer coverings for metal stents, cardio coronary valves, and cardiostimulators.
Amongst the various requirements set to polymers of medical indications there is one general and highly important requirement: in case an immediate contact with blood is supposed, the materials should be hemocompatible. The challenge of developing polymers specially intended to have contact with biological media has emerged since late 1950s. It was conditioned by the demands of biology and medicine for synthetic polymer materials intended for preparation of various endoprosthesis. Generation of a thrombus in case of contact of blood with a heterologous surface poses the highest danger during implantation. In cardiosurgery there are widely applied coronary stents, and the thromboresistance thereof is of prime importance. Stents were introduced into clinical practice in 1986 to treat abrupt closure and to prevent restenosis after angioplasty. The undisputed superiority of stents (tubular, coiled) over conventional balloon angioplasty has resulted in a plethora of stents in clinical use. At present, treatment of patients with ischemic heart disease with the use of coronary stents is the most commonly used mode worldwide. Unfortunately, after installation of a stent, there are registered complications, which in 10-20% cases cause expressed thrombogenesis on the surface of the stent, as well as complete closure of a lumen of coronary artery by a thrombus. One of the ways to reduce the frequency of developing complications is indication of anticoagulants of direct action. Another method of handling the complications is application of different coverings to the stent. In order to decrease the sedimentation of thrombocytes and fibrin, different coverings are applied to the surface of a stent, including polymer ones. Thus, with this aim inorganic coverings were developed by means of plasma spraying. According to the opinion of some researchers, coated stainless steel stents with gold, carbide, phosphorylcholine or heparin do not appear to confer any additional benefit, compared with bare metal stents. The compare of Carbofilm-coated and pure stainless steel stents with regard to early and late adverse effects (from March 2000 to June 2002 at 18 centers in Canada and Europe, 420 patients were randomized) has demonstrated that the carbon-coated Carbofilm-stents do not provide improvement in angiographic results or reduction of restenosis rate and major adverse cardiac events (myocardial infarction, reintervention, and death). At present, there is an urgent problem to develop new polymer coverings for steel coronary stents applying an available and cheap technique. The search for polymers possessing thromboresistant properties is dictated by both a necessity to replace expensive heparin and a demand to develop hemocompatible materials. Apart the polymer anticoagulants of direct action, thromboresistant polymer coverings are of even higher significance for medicine.
Amongst the great number of tested synthetic biomaterials polyorganosilicates, polyurethanes and polyesterurethanes were selected as the most suitable ones from the point of view of hemocompatability. However, even these materials are characterized by thrombogenicity and their surface is modified by grafting radiation polymerization. Therefore, development of new polymer materials possessing such characteristics as antimicrobial action and hemocompatibility still remains to be one of the urgent challenges for chemists. One of the known modes of obtaining anti-thrombogenic materials is modifying the surface of polymers by radiation graft polymerization introducing carboxylic groups to the surface layers of polymers and inducing the negative charge on the polymer surfaces. Radiation-chemical mode of obtaining polymer biomaterials has a number of advantages: purity of resulting materials, low temperature, and easily-handled regulation of the process rates by changing the power of radiation doses. However, this method is expensive and not readily available. In the proposed project we present electrosynthesis of polymers, electrochemical deposition and electrochemical formation of thromboresistant polymer coverings as easily available procedures, which might have practical application in coverings for stents.
In presented Project Proposal for the purpose of developing new polymer coverings it is supposed to perform synthesis of vinylazoles and electrochemically initiated polymerization thereof. The selection of monomers was conditioned by biological activity of compounds containing tri- and tetrazole cycles. Development and improvement of a method for electrical deposition of developed vinyl copolymers would allow obtaining coverings which are homogenous in thickness, as deposition automatically ceases on achieving the layer, which ensures isolation of the metallic electrode. Of scientific interest is the study on mechanisms of carboxylate polymers of vinyl acetate. The advantages of a method of electrodeposition out of water solutions or aqueous latexes are as follows: cost effectiveness; no environmental pollution; fire- safety, as well as possibility to apply the covering to the sites of devices with complex configuration, e.g. steel stents.
In this project, it is proposed to use electrochemical methods to form the thromboresistant coverings with immobilized drug substances on the basis of polyvinyl alcohol, which as a non-toxic polymer is widely used in pharmacology and might be applied for working-out coverings for medical and biological properties, randomized trials have demonstrated that drug-eluting stents coated with various anti-proliferative drugs, with or without a carrier polymer, afford unparalleled restenosis rates compared with non-drug-eluting stents. Drug-eluting stents, however, are expensive, and their long-term durability and safety remain undefined. Notwithstanding these unresolved issues, it is likely that the majority of percutaneous coronary interventions will involve the use of drug-eluting stents once a more attractive balance between their cost and clinical effects is reached.
In the course of Project implementation it would be of interest to evaluate the synthesized water-soluble polymers as blood anticoagulants of direct action. The results of activity within the frames of a proposed project will ensure further progress of researches performed earlier by the same research team in the area of thromboresistant polymer coverings for medical application. Revealing a correlation of structure, physical and mechanical properties with medical and biological characteristics of promising thromboresistant materials will allow for targeted synthesis of polymers with the required medical and biological properties.
On project fulfillment, the prototype polymer-covered biomedical devices will undergo clinical trials and then will be used for the development of high-technological products of commercial significance and medical indication.
The achievement of project goals presupposes activity aimed at the solution of the main tasks: synthesis of polymers, development of polymer coverings, medical and biological studies, processing and monitoring of obtained data for giving recommendations for clinical application.
The following scope of activity is pre-planned for project fulfillment: study on electrochemical (co-)polymerization on metal surface; synthesis of polymers and electrochemical precipitation out of solutions and dispersions of copolymers; electroformation of coverings based on polyvinyl alcohol; comparison of coverings obtained by different modes; study on physical and mechanic properties of polymers and coverings; selection of the most informative indices to characterize the response of a whole blood to sample coverings in vitro; in vivo animal experiments; obtaining and medical-biological evaluation of thromboresistant coverings for metallic stents, electro non-conductive polymer coverings for cardiostimulants, direct action polymer anticoagulants of blood, polymer coverings for coal hemosorbents.
The goal of the project will be achieved by the joint efforts of a united team of highly professional scientists of the 3 leading research institutions of Armenia: Sector of Radiation Medicine and Burns of the CTOBR (WHO Collaborating Centre of Radiation Medicine and Burns), State Engineering University, and Yerevan Institute “Plastpolymer”, which in accordance with their main activity profile have a positive experience in the frames of scientific and technical collaboration with ISTC in allied fields of chemical and technological, analytical and medical problems and possess a good command of methods for synthesis and processing of new materials for medical application (ISTC A-361 and A-948 Projects).
The chemists participating in this Project have a long-term experience in development, synthesis and implementation of polymers on the basis of vinyl monomers. The developers are authors of numerous inventions on obtaining thromboresistant coverings by means of electrochemical procedure.
The Sector of Radiation Medicine and Burns is selected to be the main basis for carrying out researches, as the scientific personnel of this Centre has significant traditions to study blood clotting system and the thrombocytopoiesis. At the Sector the required scientific and technical basis is available for medical and biological studies; there is an appropriate vivarium. During a long period of time the thematic scope of the Centre involved studies on blood clotting system in case of combined radiation/ thermal injuries of wartime as a part of a Plan of United Problem Commission of the USSR Ministry of Defense and Ministry of Health at the institute of Medical Radiology (Obninsk, Russia). The Centre has the required equipment, adjusted methods, and great experience of experimental and clinical activity, as well as trained staff of hematologists, immunologists, bacteriologists, etc. the work experience of which will be used in peaceful purposes.
Project methodology involves both known methods and techniques developed by project participants for evaluation of biocompatibility, determination of blood clotting indices, as well as high-tech methods of synthesis and modern physical and chemical methods of analysis. The researches will be performed in sample of normal blood and samples taken from irradiated animals in experiments in vivo. Methods of optic/light and electron microscopy will be applied for evaluation of coverings surfaces and functional properties of thrombocytes.
In accordance with ISTC goals the following tasks will be realized on performing the Project presented: re-orientation of the activity of scientists engaged previously in defense/weapon sector to solution of Public Health problems; integration of the researchers from Armenia into the International scientific community; support to the researches in the sphere of Public Health and Natural Sciences; rendering assistance in solution of national and international problems related to human health protection in case of treatment of cardio-vascular diseases.
The role of Foreign Collaborators might embrace methodical recommendations on evaluation of the quality of obtained coverings and possibility of their use in medical practice.
The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.
ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.