Research On Biocompatibility Of Metal-doped Zirconia-toughened Alumina

Artificial joint replacement is one of the most important methods for treating joint diseases such as advanced arthritis and loss of joint function.Zirconia-toughened alumina（ZTA）ceramics have been used in the manufacture of artificial hip joints because of their high hardness,good biocompatibility,high corrosion resistance and chemical stability,which can significantly reduce the incidence of complications such as osteolysis,prosthesis loosening and infection.However,due to the insufficient mechanical properties and poor lubrication status of the friction interface of ZTA ceramics,ceramic joints still suffer from complications such as wearing,squeaking,and fracturing in clinical applications.In order to reduce the incidence of complications such as wearing,squeaking,and fracturing,and to further improve the service performance of ZTA ceramic joints during application,it is necessary to improve the mechanical properties of ZTA ceramic materials and the lubrication properties of the friction interface.Metal doping,such as Cu doping and Fe doping,has been shown to improve the mechanical properties of ceramic materials,and the metal ions released during wear can catalyze the denaturation and decomposition of proteins in the joint cavity,prompting the production of a lubrication layer at the friction interface and improving the lubrication state.Therefore,Cu or Fe doped ceramics have a good prospect of application in artificial hip manufacturing.However,excessive Cu or Fe ions may lead to the release of reactive oxygen species,causing cell damage and cell death,which ultimately affects the biocompatibility of ceramic materials.Therefore,in order to promote the application of Cu or Fe metal-doped ceramics in the field of artificial hip joints,the biocompatibility of Cu or Fe doped ceramics needs to be investigated.In this study,copper-doped zirconia-toughened alumina（Cu:ZTA）ceramics with different Cu doping contents（0,0.2,0.7,and 1.1 wt%）and Fe-doped zirconia-toughened alumina ceramics（Fe:ZTA）with different Fe doping contents（0,1.5,3,and 5 wt%）were sintered using a fast hot pressed sinter（FHPS）system.The effects of metal doping on the surface morphology,hydrophobicity,surface energy,surface protein adsorption and ion release of the materials were investigated;The biocompatibility of Me:ZTA was evaluated by studying the level of cytocompatibility and inflammatory.After that,based on the cytocompatibility study,Me:ZTA ceramics with good cytocompatibility were selected and the wear debris was prepared,and the particle size distribution,microscopic morphology,composition and surface Zeta potential of the wear debris were analyzed.The cytotoxicity and inflammatory levels of Me:ZTA wear debris were studied using osteoblasts and macrophages to evaluate its biocompatibility.The results show that the monoclinic phase Zr O₂ gradually increases in the sintered ZTA with the increase of Cu doping.The phase change of Zr O₂ and the loss of Cu during the sintering process leaded to the increase of pores on the surface of ZTA.Compared with the ZTA ceramics without Cu addition,the hydrophobicity of Cu:ZTA increases,the surface energy decreases,and the amount of protein adsorption also increased significantly.The cytocompatibility evaluation showed that Cu doping significantly increased the early adhesion of osteoblasts（24 h）.Cu:ZTA with Cu doping of 0.2 and 0.7 wt%did not inhibit the cellular viability on the surface.Cu:ZTA with Cu doping of 0.7 wt%exhibiting the best cytocompatibility.The inflammatory response results indicate that Cu doping can stimulate macrophage morphology and induce M1-type polarization of macrophages,leading to increased release of pro-inflammatory factors and increasing the level of inflammatory.In addition,Cu:doping can significantly improve the antibacterial properties of Cu:ZTA.Cytotoxicity studies of Cu:ZTA debris also showed that Cu:ZTA debris could affect osteoblasts viability;low concentrations（50μg/m L）of Cu:ZTA debris showed low cytotoxicity;However,when osteoblasts were co-cultured with high concentrations（200,400,1000μg/m L）of Cu:ZTA debris,osteoblast viability was significantly inhibited and normal cell morphology was disrupted,indicating that high concentrations of Cu:ZTA debris exhibited significant cytotoxicity.The study on the inflammatory response of the debris also showed that the macrophage density gradually decreased and the morphology was gradually activated as the concentration of Cu:ZTA debris increased.The release of antitumor factorαwas also significantly elevated,indicating that the inflammatory of Cu:ZTA debris showed a typical concentration-dependent trend.After the concentration reached 200μg/m L,Cu:ZTA debris promoted the inflammatory.The combined results showed that Cu:ZTA with Cu doping of 0.2 and 0.7 wt%had better cytocompatibility and antibacterial properties than ZTA ceramics,but the level of inflammatory increased with increasing Cu doping.In addition,the concentration of debris in the joint cavity of ZTA ceramic prosthetic joints is about 50-400μg/m L per million revolutions of wear.During the development process,consideration should be given to improving the wear resistance of the material and reducing the wear of ceramic materials（debris concentration less than 50μg/m L）to avoid serious cytotoxic and inflammatory reactions caused by high concentration of debris.In Fe:ZTA,Fe reacts with Al₂O₃ in the matrix to form Fe Al₂O₄,resulting in a low ion release concentration of Fe:ZTA in the dielectric service environment.Fe doping reduces the hydrophilicity and surface energy of the ZTA ceramic surface and increases the protein adsorption on the ZTA surface.Cytocompatibility evaluation showed that after 72 h incubation,osteoblast viability was higher in the Fe:ZTA sample group than in the undoped ZTA ceramics,with Fe:ZTA with Fe doping of 1.5 wt%exhibiting the best cytocompatibility.Meanwhile,the inflammatory response showed that Fe doping did not induce changes in macrophage morphology.Fe:ZTA with Fe doping of 1.5 and 3 wt%also inhibited M1-type polarization of macrophages and reduced the release of interleukin 6,showing some anti-inflammatory effects.The cytotoxicity study of Fe:ZTA debris showed that co-culture with50,200,400 and 1000μg/m L of Fe:ZTA debris for 24 and 72 h did not significantly inhibit osteoblast viability and proliferation,indicating that the cytotoxicity level of Fe:ZTA debris was low.The level of inflammatory to Fe:ZTA debris was mainly influenced by the concentration of debris.Macrophage morphology was activated and released more interleukin6 when the concentration of debris reached 400μg/m L,indicating that Fe:ZTA debris induced inflammatory of macrophages at high concentrations.Thus,the above study shows that Fe:ZTA ceramics have better cytocompatibility than ZTA ceramics and can effectively inhibit the inflammatory response of macrophages,with Fe:ZTA with Fe doping of 1.5 wt%showing the best biocompatibility.Also,Fe:ZTA debris exhibited lower cytotoxicity and promoted the inflammatory response of macrophages only at high concentrations（400,1000μg/m L）.In this study,we systematically investigated the biocompatibility of metal-doped（Cu,Fe）ZTA ceramic materials and evaluated the cytotoxicity and inflammatory levels of two kinds of metal-doped ZTA ceramic debris for the application of metal-doped ceramic materials in the field of artificial joints.