In Vitro And In Vivo Biocompatibility Study Of CuZn/ZnCu Alloy As Active Contraceptive Material

Unintended pregnancy is currently a global public health problem,as it often ends with induced abortion,which seriously affects the reproductive health of women of childbearing age,especially those who have repeated terminations of pregnancy.Taking appropriate contraceptive measures is an important way to protect women's reproductive health.Copper-containing intrauterine device(Cu-IUD)is one of the most widely used contraceptive method over the world,characterized by safe,long-term effective,reversive and economical.However,Cupric ion(Cu2+)burst release at the initial stage of implantation and rough corrosion surface are associated with several side effects of Cu-IUD such as lower abdominal discomfort,abnormal bleeding and pain.These side effects are main reasons for discontinuing the use of the Cu-IUD.Currently,research and development of intrauterine devices is mostly focused on copper-containing intrauterine device.In order to reduce the side effects of Cu-IUD,we proposed a new strategy by incorporating bioactive metallic zinc into copper matrix.Cu-38Zn(38 wt.%zinc)alloy was successfully prepared for Cu-IUD in this study,and industrial H62 alloy(Commercial brass)as a control.Zn,as the second most abundant trace element in human body,which is involved in numerous enzymatic catalysis and metabolic processes.Zinc ion has been found in the functions of contraceptive action,wound-healing and antimicrobial function.In addition,the combination of Cu2+and Zn2+has an antagonistic effect on cytotoxicity and a synergistic effect on antimicrobial activity.Therefore,zinc has great potential and broad application prospects in the reduction of side effects.As early as 1969,Zipper discovered that copper,zinc and other metal salts have contraceptive effects in animal experiments.With the rapid development of materials science and medicine,new breakthroughs in the development and research of biomedical zinc alloys,which have been reported in the fields of orthopedic materials and cardiovascular scaffolds.In this paper,Zn-0.5Cu(0.5 wt.%copper)and Zn-1Cu(1 wt.%copper)alloys were prepared for IUD.On the one hand,in order to assess the feasibility of zinc alloys as an active metal IUD material,and on the other hand,to broaden the options range of available active IUD materials.In this study,the corrosion degradation properties,ion release characteristics,biocompatibilities and contraceptive effects of copper-and zinc-based alloy materials were systematically investigated by in vitro long-term immersion experiment,cytotoxicity test and in vivo implantation experiments.1.The main research finding of Cu-Zn alloy are as follows:Investigation on ion release in the simulated uterine fluid showed that the initial Cu2+release rates were 38.91±4.24 ?g/day and 21.53±2.11 ?g/day for pure Cu and H62,and 12.24±0.56 ?g/day for Cu-38Zn.Compared to pure Cu and H62,Cu-38Zn significantly reduced the initial Cu2+burst release.Cu2+from the Cu-38Zn material could be continuously and steadily released at rate of 0.69±0.14 ?g/day in later stages of immersion.The release of Zn2+ accompanied with Cu2+ release and showed the similar trend of variations.In vitro and in vivo corrosion results showed that Cu-38Zn and H62 have better corrosion resistance than pure Cu in uterine microenvironment.Surface roughness of the three groups of materials was ranked as Cu-38Zn<H62<pure Cu.There are few corrosion products on the surface of Cu-38Zn and the peeling-off of corrosion products was not observed.In vitro cytotoxicity and histopathological of rat uterus results showed that significantly lower cytotoxicity,mild endometrial tissue stimulation and faster endometrial tissue repair in Cu-38Zn group compared to the pure Cu and H62 groups,showing good cytocompatibility and histocompatibility.The Anti-fertility experiments showed that the contraceptive efficacy of Cu-38Zn and H62 is as excellent as that of pure Cu.2.The main research finding of Zn-Cu alloy are as follows:The vitro immersion experiment found that the release rate of Zn2+of Zn-0.5 Cu and Zn-1Cu were significantly higher than that of pure Zn during the initial and later stage.Surface Observation of the sample immersed in simulate uterine fluid revealed that the visible corrosion products on the surfaces of the three materials gradually increased with prolonged immersion time,and there was some difference in corrosion morphology.Electrochemical test showed that the corrosion rate of Zn-0.5Cu and Zn-1Cu alloys were higher than pure Zn.In vitro cytotoxicity and histopathological of rat uterus results showed significantly differences in cell viability and uterine tissue reactivity between Zn-0.5Cu and Zn-1Cu.Zn-1Cu having better cytocompatibility and histocompatibility compared to pure Zn,while the opposite was true for Zn-0.5Cu.The Anti-fertility experiments showed that pure Zn,Zn-0.5Cu and Zn-1Cu materials all exhibit good contraceptive efficacy.The above studies indicated that Cu-38Zn alloy significantly reduced the initial Cu2+burst release and has a low material surface roughness.In addition,it can promote uterine tissue repair.Therefore,Cu-38Zn can greatly reduce the side effects of the traditional Cu-IUD and is expected to become a new type of IUD material with low side effects.Zn-1Cu alloy has the potential to become a new degradable IUD material with good biocompatibility and contraceptive efficacy.