Fabrication And Properties Of Functional Polycarbonate Coatings On Biodegradable Metal Vascular Stents

A vascular stent consists is used in the treatment of coronary artery diseases as a reliable device,which is implanted to reopen the occluded arteries after expansion.In the last two decades,a new generation of biodegradable stents has emerged,which are expected to provide the initial necessary mechanical strength while spontaneously degrading and being absorbed along with the vascular repair process.Both Magnesium（Mg）alloys and zinc（Zn）alloys have been considered a promising material for biodegradable stents due to their biodegradability,favorable biocompatibility,and superior mechanical property.However,Mg alloys possess a fast corrosion rate,poor corrosion resistance,and inhomogeneous corrosion behavior.The rapid and inhomogeneous degradation behavior of an implanted Mg-alloy stent would lead to premature loss of mechanical scaffolding support before full vascular repair.In contrast,Zn alloys possessed slower corrosion rates.However due to the initial excessive release of Zn²⁺,Zn alloys present obvious cytotoxicity in vitro,indicating a potential risk of a delayed reendothelialization process and inflammatory reaction in vivo.Therefore,how to regulate the degradation rate and degradation behavior of degradable metals,improve the surface bioactivity of degradable metals,and match the service life and surface bioactivity of stents with the repair process of surrounding damaged vascular tissue has become a huge challenge for clinical application of degradable metal stents.In addition,the stent coating also requere biological functions in clinic,such as anticoagulant,anti-inflammatory,promoting endothelialization,inhibiting neointimal hyperplasia and preventing in stent restenosis,which are benefit to the repair process of blood vessels.Biodegradable polymeric coating has been demonstrated as a more versatile approach to control the corrosion behavior and improve surface biocompatibility for biodegradable stents,due to the good biocompatibility,design versatility,cost-effectiveness,and ease of process.biodegradable aliphatic polycarbonates（APCs）,especially poly（trimethylene carbonate）（PTMC）and its derivatives,could be coating candidates for Mg implants as they present as a unique surface-erosion behavior the degradation from surface to the interior,which can provide sufficient protection of the Mg implants from the corrosive media until their full biodegradation.In addition,PTMC has been approved by the US Food and Drug Administration（FDA）and forms neutral degradation products which reduced the inflammatory tissue response.Considering the mentioned advantages,APCs are almost tailored coating materials for Mg-alloy stents.Unfortunately,the tiny and complex mesh tube structure poses a considerable challenge for constructing smooth,uniform,thickness controllable,and defect-free polymeric coatings on Mg-alloy stents by conventional coating methods such as dipping,spraying,and layer-by-layer assembly.To address these limitations and break through the bottleneck,this study aims to develop a biodegradable polymer functional coating system that can control the degradation behavior of biodegradble stents and exhibit therapeutic functions to match the vascular tissue repair process.This proposal is based on the homogeneous surface-eroding degradation behavior of aliphatic polycarbonate coatings and multi-technology cross over the polymer design and synthesis,macromolecular self-assembly,electrophoretic deposition and photo-crosslinking.The proposal is designed to explore the effects of coating composition,structure and function on the degradation behavior of biodegradable stents and tissue healing process,to reveal the relationship between the structures and properties and the time-sequential mechanism of functional coating,as well as to explore a new strategy for the development of biodegradable metal implants with precise biological functions.The specific research contents are as follows:1.Thiol-ene photo-crosslinked biodegradable polycarbonate coating on Mg alloyThe photo-crosslinked polycarbonate coatings with surface-erosion behavior were fabricated for enhancement of corrosion resistance of Mg alloy.First,allyl-functional poly[（5-methyl-5-allyloxycarbonyl-1,3-propanediol carbonate）-co-（trimethylene carbonate）][P（MAC-co-TMC）,（PMT）]were synthesized through ring opening copolymerization at first.The PMT copolymers together with pentaerythritol tetrakis（3-mercaptopropionate）and photoinitiator Irgacure I2959 were then applied on AZ31 Mg alloy.Afterward,the coating was cured by photo-initiated thiol-ene crosslinking reaction.The Poly（L-lactide）（PLLA）and poly（1,3-trimethylene carbonate）（PTMC）coatings without crosslinking were prepared and used as control.Our results show that the crosslinked PMT coatings showed superior mechanical properties compared with PLLA and PTMC coatings.Meanwhile,the surface-erosion behavior of the crosslinked PMT coatings was kept as confirmed by scanning electron microscopy analysis.As a result,the crosslinked PMT-coated Mg alloy showed lower corrosion rates,better in vitro corrosion resistance,and much lower cytotoxicity,compared with bare Mg and ones coated by PLLA and PTMC coatings.Results indicate that the crosslinked PMT coatings with unique surface-erosion behavior and good cytocompatibility might be promising to improve the safety and success rate of Mg-based devices and implants.2.Preparation of biodegradable polycarbonate coatings on magnesium-alloy stents by electrophoretic depositionThe biodegradable polycarbonate coating was prepared by electrophoretic deposition and subsequent photo-crosslinking to achieve corrosion resistance and surface biocompatibility enhancement of Mg-alloy stents.First,the cationic polycarbonate[P（MAC-DEAET-co-MAC-co-TMC）,（PMDMT）]was synthesized by post-polymerization modification.Afterward,colloidal PMDMT particles loaded with the crosslinker pentaerythritol tetrakis（3-mercaptopropionate）（PETMP）were obtained by a macromolecular self-assembly method.Finally,the colloidal particles were deposited on AZ31 Mg substrates（including sheets and stents）by cathodic EPD,and the crosslinked APC networks were formed after UV irradiation.The results show that a uniform coating with controllable thickness can be prepared on AZ31Mg stents due to the inherent superiority of EPD in comparison to other coating methods.The results of the balloon expansion test indicated excellent mechanical property and adhesion strength of the coating on AZ31 Mg stents.Significantly,the coating presented surface-erosion degradation behavior with a predictable constant erosion rate of 1.9μm per month and 1.4μm per month in vitro and in vivo,respectively.Our results indicated that the combination of photo-crosslinked PMDMT polycarbonate and EPD method provided the employed Mg alloy with excellent corrosion resistance,which could lead to slow and homogeneous degradation behavior of Mg-alloy stents.In addition,coating modification on Mg substrate resulted in reduced hemolysis rate,enhancement of the adhesion and proliferation of endothelial cells,and reduction in tissue inflammation.This versatile strategy presents a potential application to avoid premature loss of mechanical integrity and improve the surface bioactivity of Mg-alloy stents.3.Fabrication of biodegradable endothelium-mimicking coatings with catalytic nitric oxide（NO）generation functionBased on the coating preparation strategy established by previous chapter and bionic design concept,hybrid coatings of polycarbonate,TA,and copper were fabricated by one-step EPD to enhance the corrosion resistance of Zn-alloy stents and provide an endothelium-mimicking bioactive surface.Specifically,colloidal particles of the hybrid material were first prepared by co-assembly of synthesized amino-functionalized aliphatic polycarbonate,tannic acid（TA）,and Cu²⁺.The colloids were used in a controlled cathodic EPD process to obtain phenolic-copper-amine crosslinked biodegradable coatings on Zn-alloy stents.the synthesized amino-functionalized aliphatic polycarbonates endowed the hybrid coating with specific surface-erosion properties,resulting in superior corrosion resistance and long-term stability in degradation tests both in vitro and in vivo.The durable TA-Cu²⁺immobilization and unique surface-erosion behavior of the hybrid coatings resulted in excellent and effective long-term corrosion resistance and catalytic activity for continuous NO-generation,as demonstrated in long-term dynamic/static immersion tests.These advantageous properties of the coated Zn-alloys resulted in the improvement of hemocompatibility,growth and proliferation for endothelial cells,and anti-bacterial and anti-inflammatory properties,which proves their great potential for practical applications.4.Zinc ion-crosslinked polycarbonate/heparin composite anticoagulant coatingsHerein,the Zn ion-crosslinked polycarbonate/heparin composite coating on Zn-alloy stent was fabricated by electrophoretic deposition（EPD）for enhancing the corrosion resistance,improving vascular compatibility and providing anticoagulant properties.Briefly,Carboxyl-functionalized PTMC[P（MAC-CA-co-TMC）,（PMCT）]was first synthesized by ring-opening polymerization and was subsequently modified by thiomalic acid via a“thiol-ene”click reaction.To enhanced the coordination between Zn ions and heparin,dopamine-conjugated heparin（Hep-DA）was synthesized and self-assembled with PMMST induced by Zn ions under the driving force of electrostatic interactions and chelation of catechol and zinc ions.This afforded a colloidal solution of PMMST/Hep-DA@Zn,which was deposited on the surface of Zn-alloy sheets and stents by anodic electrophoretic deposition（EPD）.The water resistance and mechanical property of coating were effectively improved owing to the formation of cross-linking based on the non-toxicity Zn-ligand coordination chemistry.The composite coating effectively suppressed the adhesion and activation of platelets due to the loaded heparin,the content of Hep-DA was 10 wt%.Owing to surface-erosion behavior,the coating would retain the integrity heparin immobilization surface,and meanwhile resulted in the uniform release of heparin,which may endow the coated Zn-alloy stents with a long-term anticoagulant function.The coating can effectively decrease the release rate of Zn ions due to its superior anti-corrosion property,and thereby promoted the adhesion and proliferation of ECs.