Research On Biomedical Coating Materials With Anticoagulant And Antibacterial Dual-function

At present,blood contact medical devices have been widely used in clinical,which has saved countless patients,and the complications related to the devices have been paid more and more attention by researchers.Complications of blood contact medical devices mainly include coagulation and infection.It is worth noting that the two complications are related to each other.The occurrence of coagulation will promote the occurrence of infection,and the reverse is also true.The current clinical solutions of the two complications were use of anticoagulant drugs and antibiotics,however,anticoagulants easy to induce bleeding risk,antibiotics can induce drug-resistant bacteria,and for equipment related infections,especially the formation of biofilms,conventional antibiotics play the limited role,so the coating with dual-function of anticoagulation and antibacterial is an effective way to solve this problems.After the development of recent years,researchers have developed a variety of coating technologies,and achieved relatively effective results.However,these coatings mostly only have a single anticoagulant or antibacterial function,and the uniformity and stability of the coating are difficult to meet the requirements of clinical safety.Meanwhile,the function of the coating is hard to maintain for a long time,which limits the clinical application.To solve these problems,this study developed a variety of coating technology with anticoagulant and antibacterial dualfunctions at the same time,through combination of antifouling and bacteridical function as one to build dual-functional coating,coating design focuses on the safety and efficacy of clinical requirements,especially pay attention to the longterm stability and uniformity of the coating,to keep the dual-function of the coating can exist for a long time.Specific research results are as follows:(1)The cell-membrane-mimicking coating has excellent blood compatibility and has been applied in clinical practice.However,the coating lacks antibacterial properties and has good anti-biofilm performance in the short time,but the long-term anti-biofilm performance is not ideal.Quaternary ammonium salt(QAs)has excellent bactericidal properties and has been widely used.For the preparation of anticoagulant and antimicrobial coating material,we synthesized a series of QAs and phosphoryl choline(PC)containing copolymers,among them the content of the QAs is below 10 %,by simple dipcoating method,the coating were successfully formed in glass,polylactic acid and the PVC materials,and the coating could be stable in water at least one week.PC provides anticoagulation and antifouling functions of the coating,and QA chould kill the attached bacteria.The synergistic effect of the two compounts chould significantly reduce the adhesion and proliferation of bacteria on the surface.The bacterial experiment results show that the formation of biofilm can be significantly inhibited within one week when only 5 % QA is added to the coating.The results of in vitro blood test showed that the coating could reduce the adhesion and activation of platelets,and did not cause significant hemolysis even when the QA content was 10 %.The ex vivo blood circulation test showed that the coating had excellent anticoagulant ability.These results indicate that the synergistic effect of a small amount of QA and PC can effectively prevent the formation of bacterial biofilm without significantly reducing the original hemocompatibility of PC.(2)In order to prepare long-term stable antibacterial and anticoagulant surface coatings,we prepared a series of hydrogel coatings with different monomer ratios(acrylic acid/acrylamide)by surface-initiated polymerization.The hydrogel coating is uniform and stable on the surface of the substrate.The thickness of the coating is between 100 and 200 μm.The coating can withstand mechanical wear and is stable in the water environment for at least 4 weeks.By impregnation the hydrogel coating with antimicrobial agent,the hydrogel coating could possess good antibacterial propertiy.The loading and release behavior of antimicrobial agent can be adjusted by the ratio of monomers.The antibacterial hydrogel coating chould keep good antibacterial properties at least in 4 weeks as well as anti-bacteria adhesion properties,the experimental results show that the coating does not induce blood platelet activation and hemolysis,ex vivo experiments show that the coating has a good thrombosis resist ability in 2 hours blood circulation(3)Antimicrobial peptides(AMPs)has excellent antibacterial properties,which is considered to be the next generation of antibiotics,on the basis of research(2),we prepared a antimicrobial peptides(AMPs)embedded hydrogel coating,the hydrogel coating maintain the long-term stability,and the introduction of AMPs endow the coating with "contact killing" function,the coating has the antibacterial rate of 100 % on Escherichia coli and Staphylococcus aureus,and there is no obvious bacterial adhesion on the surface of coating,the bactericidal performance of SA-Bac2 A could prolonged at least4 weeks.The results of in vitro and ex vivo blood circulation experiments showed that the coating had good hemocompatibility.The results of in vivo antibacterial experiments also confirmed the anti-infective effect of AMPs embedded hydrogel coating,and the immunofluorescence data of tissues further indicated the anti-inflammatory effect of AMPs embedded hydrogel coating.Embedded AMPs endow hydrogel coating with good antibacterial properties,and "embedded" compared with the "fully cover" chould keep hydrogel coating with original antithrombotic and antifouling performance,at the same time,the hydrogel chould improve the stability of AMPs,so this kind of AMPs embedded hydrogel coating can achieve long-term antibacterial and anticoagulant function at the same time.(4)Dexamethasone(Dex)has a good anti-inflammatory effect,reducing the body’s inflammatory response to devices or to blood clots and bacteria releated infections.On the basis of research(2),anti-inflammatory drugs were grafted onto the surface of the hydrogel coating by chemical bonds(ketone thioacetal)which could be broken by reactive oxygen species(ROS).A hydrogel coating with ROS-responsive Dex release was prepared and loaded with nano-Ag particles by in situ reduction method.Drug release experiments showed that Dex have the response release behavior,in vitro cell experiments show the released Dex could inhibite macrophage activation,in vivo experiments showed that the coating chould reduce inflammation to the surrounding tissues.Both in vitro and in vivo antibacterial experiments show that the coating have excellent performance of anti-infection,in vitro blood experiments and ex vivo experiments show that the coating has good hemocompatibility.