Constructing Multifunctional Cardiovascular Implant Surface Via Plasma Polymerization Technique

Cardiovascular diseases (CVDs) are responsible for more than 30% of all global deaths, making them the leading cause of mortality worldwide. Applying vascular stents to treat CVDs has been one of the most effective and rapidly adopted medical interventions. During the past three decades, several generations of stents have been designed with a growing knowledge of the interaction among stent, blood and endothelium. The first generation stent was named bare metal stent, which replaced the commonly invention method of percutaneous transluminal coronary angioplasty at that time. Afterward, Drug eluting stent, a revolutionary device to address the problem of in stent restenosis, developed by coating a drug-loaded polymer onto the bare metal substrate, obtained great success. Nowadays, novel concepts of stents are raised up such as the endothelial progenitor cell (EPC) capture stents, biodegradable metal stents, fully degradable polymer stents and endothelium mimicking functional stents, which are currently in clinical evaluation.The outcomes of these studies are highly expected.Plasma polymerization started in the 1960's, at which time rapid development of polymer science was achieved. Only up to recent decades, the advantages of plasma polymerization, for example the fact that pinhole-free, conformal thin films can be deposited on most substrates (polymers, glasses, metals, ceramics etc.), employment of a simple one-step coating procedure, and a wide range of compounds as alternative monomers for plasma polymerization, have been fully recognized. Together with the merit of good binding force and resistance of deformation, this technique is well-suited for surface modification of cardiovascular implant devices.In order to develop plasma polymerization technique applied in biofunctionalization of vascular implants, we first chose allylamine as precusor and nitrogen as assisted gas, with the nitrogen flow from 3 sccm to 6 sccm, to prepare plasma amine surfaces. These amine-rich films were characterized by GATR-FTIR and XPS, and the anticorrosion properties were demonstrated by electrochemical analysis. The results showed that the higher density of amine groups of the allylamine-nitrogen plasma polymerized film contributes to more serum protein adsorption which may enhance the adhesion and growth of cells on biomaterials. The in vitro and in vivo anti-inflammatory evaluation was performed and it has been confirmed that these nitrogen-rich surfaces could inhibit the activation of macrophages by down-regulation of the pro-inflammatory cytokines TNF-? and IL-6, and exhibit acceptable tissue-compatibility.Meanwhile, we employed a one-step solvent-free process to construct a plasma polymeric allylamine (PPAam) coating on biodegradable stent substrates (MgZnMn alloys and pure Fe). The resulting coating not only provided endothelium-friendly microenvironment but also exhibits corrosion resistance, and also the results revealed that the PPAam coating was sufficiently flexible to follow the deformation of the substrate during the balloon expansion without cracking or peeling from the struts.Furthermore, we tried to make a further step to explore the possibility of PPAam applied onto EPC capture stents. The processes involved as the first-step deposition of PPAam onto bare metal substrate to introduce amine groups, followed by the electrostatic adsorption of DNA aptamers that could specifically bind EPCs. It was demonstrated that about 175 ng/cm2 aptamers immobilized onto the PPAam surface could capture EPCs, and presented a cellular friendly surface for the proliferation of both EPCs and ECs but no effect on SMCs.Native endothelium monolayer could produce many functional molecules with anti-thrombotic and anti-hyperplasia properties including nitric oxide (NO), prostacyclin, thrombomodulin, heparin-like molecules. Therefore, we conceived that an ideal stent should simultaneously exhibit anticoagulant and antiproliferative properties and additionally promote the regeneration of healthy endothelium. Multifunction bilayer polymeric coatings were constructed based on PPAam surface followed by covalently immobilization of heparin and selenocystamine via carbodiimide chemistry, which presents glutathione peroxidase (GPx)-like catalytic activity to generate NO. More importantly, both of heparin and NO act as multifunctional biomolecules could promote the adhesion and growth of endothelial cells but inhibit proliferation of smooth muscle cells. The released NO could also enhance attachment, growth, and recruitment of EPCs, suggesting the great potential in endothelium repair ability.In summary, the research deals with the surface modification of a large variety of substrates used in vascular stents by plasma polymerization and the evaluation of their biocompatibility. In order to better realize and compare the different kinds of vascular stent, a systematically investigation of plasma functionalized different stents is carried out. These strategies may provide detailed information of constructing biocompatible physical microenvironment, and lay the foundation of developing next generation of cardiovascular implants.