Preparation And Properties Of Sustained-released Chitosan Based Antibacterial Composite Microspheres

Indwelling medical devices play an important role in diagnosing and treating diseases.However,due to its long-term use of several days or even weeks,it is prone to hospital-acquired infections(HAI).Therefore,the development of long-lasting antibacterial materials is of great significance for improving medical treatment and people’s health.Chlorhexidine(CHX)is a broad-spectrum antibacterial agent with excellent antibacterial activity.However,with the extension of use time,its antibacterial ability will gradually weaken or even losed.It is necessary to continuously add chlorhexidine during use to exert its long-term antibacterial performance.Chitosan(CS)is a natural macromolecule with good biocompatibility.Its molecular chain contains a large number of amino groups and hydroxyl groups with modifiability and reactivity,and can be widely used in medical,packaging and other fields.In order to achieve the long-term antibacterial activity of chlorhexidine,chitosan/chlorhexidine acetate(CS/CHXA)composite microspheres were prepared by emulsification crosslinking method.The size,the degree of crosslinking,the drug loading of CHXA and the sustained release property of CS/CHXA composite microspheres were controlled by changing the composite ratio of CS and CHXA,cross-linking agent dosage and cross-linking time,etc.By adding CS/CHXA composite microspheres to the vinyl acetate-ethylene copolymer emulsion(VAE),a uniformly dispersed emulsion is prepared and coated on the surface of the rubber hose,promoting the long-term slow release of CHXA is finally expected to realize the long-term antibacterial effect of the rubber tube,and reduce the occurrence of secondary infections caused by medical devices.1.Chlorhexidine acetate(CHXA),which is easily soluble in water,is used as an antibacterial molecule.Chitosan/Chlorhexidine acetate(CS/CHXA)composite microspheres could be obtained by adding CHXA into chitosan(CS)by emulsification method,and then cross-linked to obtain stable.By adjusting the weights of acetic acid and chitosan,the ratio of oil to water,the dosage of chlorhexidine acetate,the amount of cross-linking agent,the cross-linking time,prepared CS/CHXA composite microspheres with different sizes and dispersibilities.Size and stability of the CS/CHXA composite microspheres were observed and calculated by SEM.The release properties of CHXA,the antibacterial properties and cell compatibility of CS/CHXA were investigated.The results showed that CS/CHXA composite microspheres with well dispersion and particle size of about 460 nm could be prepared under the conditions of acetic acid concentration of 3%,CS 60 mg,oil-water ratio of 8,CHXA 25 mg,stirring rate of 650 rpm,emulsifying time of 4 h,dosage of crosslinking agent of 10 m L,crosslinking time of 4 h and crosslinking temperature of 40℃.CHXA can be slowly released from the CS/CHXA composite microspheres for 14 days and the CS/CHXA composite microspheres show well antibacterial properties,up to 99%,and have good biocompatibility.Furthermore,the CS/CHXA composite microspheres were added to the vinyl acetate-ethylene copolymer emulsion(VAE)to prepare a uniformly dispersed emulsion and coated on the surface of the rubber hose,and the formed coating surface is uniform.Adjust the different addition amounts of microspheres could be obtained antibacterial coatings with different dispersibility.The results show that when the added amount of CS/CHXA composite microspheres is 2%,and the dispersion of CS/CHXA composite microspheres in the coating is the best.CHXA can be slowly released from the coating for 14 days,and it has well antibacterial properties within 14 days,up to 91%,and has good biocompatibility.2.In order to further improve the antibacterial performance of the rubber hose coating,silver nanoparticles were tried to be introduced on the surface of CS/CHXA.First,by the photoreduction method,Ag nanoparticles(Ag NPs)were introduced on the surface of CS/CHXA microspheres,and change the loading amount of Ag particles to prepare a series of(CS/CHXA)_a@(Ag)_b composite microspheres.The influence of the concentration of Ag~+solution on the microspheres during the preparation process was explored.When the concentration ratio of the CS/CHXA dispersion to the Ag~+solution is 3:1,the silver nanoparticles on the surface of the CS/CHXA microspheres are uniformly distributed without obvious agglomeration.The number of silver nanoparticles increased with the increase of Ag~+concentration during the preparation process.The(CS/CHXA)_a@(Ag)_b composite microspheres have the ability to slowly release CHXA,which can be released continuously for14 days.The antibacterial rate of the(CS/CHXA)_a@(Ag)_b composite microspheres against E.coli and S.aureus can reach 100%.Moreover,it has good biocompatibility.Furthermore,the(CS/CHXA)_a@(Ag)_b composite microspheres were added to the VAE to prepare a uniformly dispersed emulsion and coated on the surface of the rubber tube,and the formed coating surface was uniform.Adjust the different addition amounts of the(CS/CHXA)_a@(Ag)_b composite microspheres canobtain antibacterial coatings with different dispersibilities.The results show that the dispersion of the(CS/CHXA)_a@(Ag)_b composite microspheres in the coating is the best and the coating can continuously release CHXA for at least 14 days with well antibacterial properties to above 98%when the added amounts of the(CS/CHXA)_a@(Ag)_b composite microspheres is 2%.It shows that the synergistic antibacterial effect of Ag and CHXA improves the antibacterial performance of the composite material.In summary,the CS/CHXA composite microspheres were successfully prepared by the emulsion cross-linking method.By changing the reaction conditions,the size,stability and release performance of the composite microspheres can be controlled.After mixed it with the VAE emulsion,the resulting coating has well antibacterial properties and can maintain antibacterial properties for at least 14 d.After loading silver nanoparticles,its antibacterial performance becomes better because of the synergistic effect of silver nanoparticles.