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Back to Journal »International Journal of Nanomedicine» Volume 15

Progress of Cerium Oxide Nanoparticles in the Application of Orthopedic Biomedicine

Authors: Li H, Xia P, Pan S, Qi Z, Fu C, Yu Z, Kong W, Chang Y, Wang K, Wu D, Yang X

The 2020 volume will be published on September 29, 2020: 15 pages 7199-7214

DOI https://doi.org/10.2147/IJN.S270229

Single anonymous peer review

Editor approved for publication: Dr. Yan Shen

Li Hongru, Xia Peng, Pan Su, Qi Ping, Fu Chuan, Yu Ziyuan, Kong Weijian, Chang Yuxin, Wang Kai, Wu Dankai, Yang Xiaoyu, Department of Orthopedics, Second Hospital of Jilin University, Changchun 130041 China Correspondent: Dankai Wu; Xiaoyu Yang Jilin University Department of Orthopedics, Second Hospital, Changchun, TX 130041, People’s Republic of Nano-cerium oxides (CeO2-NPs) are of increasing interest. Their significant vacancy oxygen deficiency (VO) promotes the redox process and catalytic activity. The verification shows that CeO2-NPs is a kind of nano-enzyme based on inorganic nanoparticles, which has anti-inflammatory, anti-cancer and angiogenesis effects. In addition, they can complement other materials in tissue engineering (TE) well. Related to the properties of CeO2-NPs and practical biosynthetic methods, this review will emphasize the recent applications of CeO2-NPs in orthopedic biomedicine, especially bone tissue engineering (BTE). This review introduces, evaluates and prospects the orthopedic potential and shortcomings of CeO2-NPs, hoping to provide reference value for the future research and development of CeO2-NPs-based therapeutic drugs. Keywords: CeO2-NPs, green synthesis, ROS, bone tissue engineering, coating, orthopedic implants

Cerium is the first element with 4f electrons among 17 rare earth elements or lanthanides. The special 4f orbital with equal energy gives cerium its unique physical and chemical properties. 1 In addition, cerium has the highest content of rare earth elements. The application of cerium has a very broad space in the fields of light, electricity and magnetism. 2-5 At present, people are working hard to explore further applications of cerium. CeO2-NPs are nanocrystals derived from cerium. Cerium mostly exists in the form of cerium oxide and has a unique face-centered cubic fluorite lattice structure. Common sense believes that the rapid and convenient oxidation state transition from Ce3+ to Ce4+ contributes to the high redox activity of CeO2. 6 During the oxidation state transition, the alternate loss of oxygen and/or other electrons in CeO2 and CeO2-x-stoichiometric compounds) creates oxygen vacancies or defects in the lattice structure, as shown in Figure 1. The high oxygen storage capacity of the crystal lattice and the high oxygen mobility in the crystal lattice promote the wide application of cerium oxide in biological effects related to redox reactions. 8 Evidence shows that the higher surface area to volume ratio of CeO2-NPs makes the surface atomic lattice softer than the bulk. The nano effect has a significant influence on the catalytic activity of CeO2. Compared with the traditional block structure, nano-CeO2 can increase the catalytic activity by two orders of magnitude. 9 The reduced particle size and increased surface area to volume ratio result in the formation of more oxygen vacancies. Even the loss of one oxygen atom after size reduction will cause high lattice strain. 10 The stronger the catalytic activity, the higher the effect of CeO2-NPs in biomedical applications. Figure 1 The structural characterization of CeO2-NP and its self-storage stability and self-regeneration ability to play an anti-oxidant chemical reaction.

Figure 1 The structural characterization of CeO2-NP and its self-storage stability and self-regeneration ability to play an anti-oxidant chemical reaction.

The rapid development of nanotechnology has broadened the exploration path of nanoenzymes based on inorganic nanoparticles. The combination of computer simulation and theoretical calculation solved the possible catalytic mechanism of these nanoenzymes. CeO2-NPs is a typical nanoenzyme. The valence transition from Ce3+ to Ce4+ is similar to the mechanism of various oxidoreductases, and it can also catalyze reversible redox in cells and tissues. 11 The formation of Ce4+ and low surface vacancies is essential for oxidation, while Ce3+ and electronic reorganization in the lattice oxygen vacancies provide the power for reduction. Part of the specific catalytic mechanism mimicking enzymes is accurate, such as redox and automatic recovery after substrate binding, but some are still being studied. 12,13 The ability to simulate the activity of multiple enzymes provides excellent convenience for mainly biomedical applications that rely on redox activities, such as anti-inflammatory, antibacterial, and angiogenesis.

Excellent catalyst performance makes CeO2-NPs stand out in the multi-purpose industrial applications of photochemistry and electrochemistry, such as solid oxide batteries, 14 degradation of organic pollutants, 15 high-performance catalysts, 16 sensors, 17 abrasive particles, 18 coating materials, 19 and so on. The application of CeO2-NPs in bioinformatics and computational biology has attracted more and more attention. CeO2-NPs play an important role in tissue engineering and regenerative medicine, especially in orthopedic medical treatment, 20 because of their prospective antioxidant, antibacterial, anti-inflammatory, anti-cancer, non-toxic, and angiogenic properties , Drug/gene delivery, etc. 21,22

The application of CeO2-NPs in nano-biomedical technology is becoming more and more common. More and more electron microscopes and microscopes research on its atomic lattice model, lattice parameters, surface oxygen vacancies, etc., provide an experimental basis for its powerful catalytic mechanism. 23,24 Huang et al. 25 further discovered the highest reactivity of CeO2 surface (100) through transmission electron microscopy and first-principles calculations. After studying the electronic nanostructures of CeO2 and its related catalytic complexes through density functional theory (DFT), Bruix and Neyman8 elaborated on the reasons why CeO2-NPs of specific sizes exhibit higher reactivity, as well as the nanostructures and metal supports interaction between. The size also affects the enhanced electronic conductivity of CeO2-NPs, the pressure-induced phase transition, the size-induced lattice relaxation, and the blue shift of the ultraviolet absorption spectrum. 9,26 The size will limit or enhance the cell's absorption of CEO2-NPs and affect biological parameters such as biological half-life, diffusivity, immunogenicity, etc. 27,28 In addition, size also affects the toxicity of CEO2-NPs in the body and the internal environment. 29 In addition to catalytic performance, the suggestion is to continue to read more specific cerium oxide material physics and defect chemistry. 9,30

In nanomedicine, inorganic enzyme simulation of nanomaterials has become the latest research hotspot. In addition to simulating the structure and function of natural enzymes, enzyme-simulating nanomaterials are more stable, more controllable, more natural, and lower in preparation costs. CeO2-NPs are due to their various enzyme activities, 31,32, such as superoxide dismutase, 33 catalase, 7 phosphatase, 34,35 peroxidase, 36 oxidase, 37 and other mimic activities. One of the research objects. Although studies have shown that the mimic activities of phosphatase and catalase follow different chemical methods and involve different active sites, 38 more complex mechanisms are worthy of further study. Surprisingly, superoxide dismutase and catalase mimic activities are the two main methods to eliminate reactive oxygen species (ROS). It is well known that ROS is the initiator of oxidative stress in many diseases. The adaptability of various enzymes in the treatment system to 3D biomaterials directly or indirectly realizes the antibacterial, anti-inflammatory and anti-cancer effects of CeO2-NPs. 21,39

The temperature, concentration of reactants, pH, reaction environment and stabilizers during the synthesis of CeO2-NPs will affect the physical, chemical and biological properties of CeO2-NPs. 40 A well-designed synthesis method can fine-tune the surface properties of CeO2-NPs. Traditional chemical synthesis and mature green synthesis are the main synthetic methods of CeO2-NPs. The general view is that green synthesis that does not require harsh reaction conditions such as high temperature and high pressure is more conducive to biological applications, avoids potential chemical toxicity and maintains high biocompatibility. 41 However, the advantages of chemical synthesis indicate that it should continue. For example, the ability to control reaction conditions and reactant properties by changing capping agents and other measures, achievable large-scale production and reducing chemical toxicity is becoming more and more mature. 42 Recently there has been a lot of research on the synthesis method of CeO2-NPs. 21,43 This review summarizes some recently reported synthetic methods that are related to biomedical applications or have potential for biomedical applications. It is strongly recommended to continue reading the synthesis method and more detailed classification.

Precipitation proved to be the simplest and most widely used synthetic method CeO2-NPs. The common precursor is cerium nitrate hexahydrate, and the reaction environment is alkaline (see Table 1). 44-48 Other precursors and capping agents are still under research and development. Table 1 CeO2-NPs synthesized by precipitation method for biological applications

Table 1 CeO2-NPs synthesized by precipitation method for biological applications

The hydrothermal method is a common synthesis method for heating CeO2-NPs in an autoclave with water as the solvent. The synthesis process of the hydrothermal method can be accomplished through the mediation of surfactants. The hydrothermal method can produce various forms of CeO2-NPs. Solvents, stabilizers and synthesis conditions will affect the biomedical properties of CeO2-NPs (see Table 2). 7,49–52 Table 2 CeO2-NPs synthesized by hydrothermal method for biological applications

Table 2 Hydrothermally synthesized CeO2-NPs for biological applications

The green synthesis of CeO2-NPs has attracted more and more attention. In addition to eliminating the adverse effects of chemicals and chemical methods on the synthesis environment, green synthesis is not harsh on reaction conditions and is very popular in biological applications, especially when biocompatibility is enhanced. Nutrients, fungi, plants, bacteria and biopolymers are known materials that can mediate the synthesis of CeO2-NPs (see Table 3). 27,43,53–59 For example, the primary and secondary metabolites in plant extracts can be used as 60. Most natural CeO2-NPs have antioxidant, antibacterial, and photocatalytic activities. 61-64 When the synthesis reactant is combined with biocompatible materials or other materials that are conducive to biological applications, better synthesis effects will be obtained, 65-67 such as biosensing properties. Table 3 CeO2-NPs synthesized by green synthesis method for biological applications

Table 3 CeO2-NPs synthesized by green synthesis method for biological applications

The synthesis method determines the configuration, physical and chemical properties, surface groups, zeta potential, etc. of CeO2-NPs, thereby determining the application behavior and therapeutic effects of CeO2-NPs. Recently, the solvothermal method, that is, the microwave-mediated end capping of alcohols such as ethylene glycol, can synthesize CeO2-NPs co-doped with Co2+ and La 3+, which have certain weak magnetic properties, different shapes and controllable sizes. 68 ,69 The application research of magnetic nanoparticles in drug delivery systems started very early. 70 The Alzheimer's disease model has witnessed the application of magnetic CeO2-NPs in the magnetic separation of amyloid β (A-β) peptides; in addition, the magnetic CeO2-NPs structure can enhance magnetic resonance imaging (MRI) in cerebral hemorrhage The role of treatment. 71,72 This review believes that CeO2-NPs co-doped with Co2+ and La 3+ have potential delivery areas in future magnetic drugs.

Spraying has also recently been applied to the synthesis of CeO2-NPs in cell biology. Vassie et al. 73 first studied the effect of particle size on the absorption and intracellular transport of CeO2-NPs (d = 7 and 94 nm) synthesized in human cancer cells by flame spray pyrolysis. The results of the study show that the larger CeO2-NPs are stronger than the smaller CeO2-NPs in removing intracellular ROS, and the longer the treatment time, the higher the intracellular ROS removal rate. At the same time, in colon cancer cells, CeO2-NPs functionalized with folic acid have a stronger regulatory effect on ROS than CeO2-NPs in the control group. 74 However, CeO2-NPs induce ROS in ovarian cancer cells, possibly because the uptake of CeO2-NPs increases nanoparticles produced by ovarian cancer cells. The experimental results suggest the application prospects of CeO2-NPs in the delivery of anticancer drugs.

The synthesis of CeO2-NPs by the sol-gel method is one of the classic and popular methods. Reverse micelle microemulsion is one of the general auxiliary technologies in the sol-gel process, which is easy to control the surface area, morphology and other properties of nanoparticles. Torres-Romero et al. used titanium butoxide and cerium nitrate hexahydrate as precursors to synthesize titanium dioxide-cerium dioxide composite materials of different sizes. 75 Three years later, Torres-Romero et al. 76 showed that the titanium dioxide-cerium dioxide composite material exhibits excellent biocompatibility and delivery efficiency in drugs. Daunorubicin (DNR) Delivery System (DDS) anticancer. Another exciting study showed that CeO2-NPs synthesized by a sol-gel process reduced cerebral edema, recruitment of microglia/macrophages around hemorrhage lesions, and inflammation after intravenous injection into a mouse model of cerebral hemorrhage Protein. 77

Reverse phase has been applied to the first study of liposomes as carriers of cerium oxide nanoparticles. 78 This system has the advantages of liposome targeting, protein scavenging protection, static stability, and CeO2-NPs catalytic activity, and powerful antioxidant capacity. In addition, the system exhibits excellent biocompatibility, tolerance and absorption efficiency in fibroblasts. In addition to the above methods, the oxidation method, ball milling method, thermal decomposition method, sonochemical method, etc. are of little value in biological applications and are beyond the scope of this article.

Bone defects caused by congenital deformities, natural disasters, and traffic accidents are common orthopedic diseases in clinical medicine. Traditional treatment methods, including autologous transplantation and allogeneic transplantation, have limitations. 79 The development of new bone graft substitutes has always been a hot research topic. Bone tissue engineering (BTE) provides a new solution to the above limitations. The choice of 80 BTE material is very important because the required properties are numerous and complex. The recognized properties do cover osteoconductivity, biocompatibility, degradability, mechanical properties, pore structure, and processability. 81

In addition, traditional treatment methods require adjustment capabilities in terms of shape, imaging, infection, healing, and immune response. 82 Currently, composite materials used in traditional treatments mainly include medical metals, bioceramics and biopolymer materials. 83 CeO2-NPs have begun to look for advantageous positions in these materials. Further explored the potential of CeO2-NPs in stem cells, scaffold materials and growth factors, namely the three important elements of BTE. These potentials cover the capabilities of CeO2-NPs and the properties of enhancing or resisting other materials. At the same time, as a component of the nano drug delivery system, CeO2-NPs will act as pro-oxidants or antioxidants depending on the complex extracellular environment of cancer cells, relying on oxidative stress to induce cancer cell apoptosis. 84,85 CeO2-NPs are also involved in the treatment of osteosarcoma. Therefore, this review aims to summarize the main data on CeO2-NPs in orthopedics.

Anti-cancer therapy has not yet witnessed the widespread application of CeO2-NPs. Interestingly, CeO2-NPs can exhibit antioxidant activity or oxidants at different pH levels of subcellular localization. 86 For example, in colorectal cancer cells, CeO2-NPs can induce DNA breaks by increasing the production of ROS, through the p53-dependent mitochondrial signaling pathway. 84 Yazici et al. 87, 88 found different degrees of positive effects on osteosarcoma when studying the cytotoxicity of 0.1 M and 0.01 M dextran-coated CeO2-NPs based on dose and time dependence. Later, it was found that at pH 6.0, CeO2-NPs had the greatest damage to bone cancer cells and the least damage to healthy bone cells. 89 In addition to ROS and other mechanisms related to redox reactions, activated cytotoxic CD8+ T cells (CTL) after treatment with CeO2-NPs release more effector molecules and cytokines, including interleukin 2 (IL-2) and Tumor necrosis factor-α (TNF-α), granzyme B and perforin, which may lead to better cancer immunotherapy. 90 The above studies have proved that CeO2-NPs are a promising nanoparticle for the treatment of bone cancer. The surface functionalization of CeO2-NPs and the tumor microenvironment will affect the activity of antioxidants or pro-oxidants. Cell type or cell microenvironment may also have different effects on cytotoxicity. However, the specific impact mechanism needs to be further explored.

Hydroxyapatite (HA) is the natural form of calcium apatite and is the main mineral component of bones and teeth. HA can combine with tissues at the interface through chemical bonds to release ions and participate in metabolism. 91 More notably, the new bone will regenerate along the surface of the HA as the implant where the bone is in direct contact with the implant. 92 HA has a wide range of applications in clinical and experimental fields in terms of biocompatibility, non-toxicity and osteoconductivity. However, the mechanical modulus and fracture toughness of HA are not ideal. 93 The two main composites between CeO2 and HA are the surface coatings of HA-based stents and other bone implants, namely the composite coating of CeO2 and HA.

Pandey et al. conducted further research on hydroxyapatite (HA-CeO2-Ag) reinforced with cerium oxide and silver. After obtaining hydroxyapatite with 5 wt% CeO2 NPs and 2.5 wt% Ag NPs (HA-5C-2.5Ag) through spark plasma sintering (SPS), they first tried to compensate for the low mechanical and low mechanical properties of HA alone through HA-CeO2 Tribological properties-Ag.94 fretting and scratch testing proved that CeO2/Ag enhances the protective friction film and oxide protection in hydroxyapatite. HA-CeO2-Ag effectively limits tribological damage on multiple length scales. They further improved the test of the bactericidal activity, antioxidant activity and biological activity of HA-CeO2-Ag. The results of 95 showed that the number of human osteoblasts (hFOBs) in the experimental group increased by 6.7 times compared with the control group. Filament extension (60-150 μm) and matrix-like deposition reflect the cell-matrix intimacy. Analysis suggests that increased protein hydrophobicity may enhance the absorption rate of HA-CeO2-Ag to cells. They also believe that HA-CeO2-Ag can not only be used as an independent porous scaffold for internal fixation through surgery, and become a reliable substrate with effective bearing capacity in orthopedic applications, but also as an antibacterial bioactive coating on the femur. Floor. Stems for total hip replacement surgery (during implant manufacturing).

Li et al. 96-98 prepared CeO2-HA composite coating by plasma spraying technology, and conducted a lot of research to verify the application of the coating. Due to the antioxidant properties of CeO2, the increase of CeO2 content in the coating can increase cell viability and reduce cell apoptosis, but the chemical stability is slightly reduced. The up-regulation of Wnt/β-catenin signal transduction can better protect BMSC from H2O2-induced osteoblast differentiation damage. In addition, the CeO2-HA composite coating can protect BMSCs induced by H2O2 from producing osteoclasts, which is reflected in the increase in the OPG/RANKL ratio. The above research results provide a theoretical basis for osteoporotic bone regeneration materials. 96 In the inflammatory response study, it was found that the increase of CeO2 content in the HA coating enhanced the osteogenic activity of BMSCs through Smad-dependent BMP. 97 The addition of CeO2 also gave the HA coating an anti-inflammatory effect. HA-30Ce has an ideal effect on the polarization of macrophages by inducing the drift to the M2 phenotype. These results indicate that the composite coating has osteogenic and anti-inflammatory properties. In addition to the above experiments, a set of results found that a higher Ce4+ concentration up-regulated the expression of anti-inflammatory cytokines (IL-10 and IL-1RA) and osteoinductive molecules (BMP2 and TGF-1) in macrophages, which means The adjustment of cerium value may be an important strategy to improve osteogenic properties and reduce inflammation. 99

Another application is the attachment of CeO2 and HA composites to other materials with specific mechanical stability, such as AZ91 magnesium alloy. 100 Researchers have developed AZ91 magnesium alloy coatings with manganese (Mn) and strontium (Sr) substituted hydroxyapatite (Mn, Sr-HAP) coatings on CeO2, which enhances the corrosion resistance of the entire material and is beneficial to AZ91 Clinical application of magnesium alloy. Sanyal et al. 101 prepared ceria-stabilized zirconia (CSZ) in fluorohydroxyapatite (FHA) by a sol-gel method. As a hard material, CSZ has been verified for toughness and bone conduction. In addition, the HA-CNT-CeO2-Ag composite material, that is, the plasma sprayed HA coating Ti-6A1-4V,102 is 2.3 times, 1.6 times and 3.1 times the Vickers hardness, estimated modulus and fracture toughness, respectively. Separate HA. At the same time, the HA-CNT-CeO2-Ag complex also exhibits cell adhesion and bactericidal activities. There is a similar effect in the composite material of cerium-doped glass reinforced hydroxyapatite (GR-HA). 103

In 2004, a mesoporous bioactive glass (MBG) based on the SiO2-CaO-P2O5 composition was prepared by combining the sol-gel method and the supramolecular chemical method. 104 Subsequently, Shruti et al. 105 synthesized a mesoporous bioactive glass scaffold (MBG_Scs) based on 80% SiO2 (MBG_Scs) -15% CaO-5% P2O5 (molar ratio) mesoporous sol-gel glass, which was replaced by Ce2O3, Ga2O3 and ZnO . This composite material contains super pores interconnected by blood vessels suitable for nutrient supply and normal cell growth, as shown in Figure 2. Figure 2 Schematic diagram of possible biological properties of Ce3+, Ga3+ and Zn2+ substituted MBG_Scs prepared by rapid prototyping: 3-D printing. Note: Reprinted from Acta Biomaterialia, 9(1), Shruti S, Salinas AJ, Lusvardi G, Malavasi G, Menabue L, Vallet-Regi M. Mesoporous bioactive scaffolds made of glass containing cerium, gallium and zinc. 4836–4844, Copyright 2013, with permission from Elsevier.105

Figure 2 Schematic diagram of possible biological properties of Ce3+, Ga3+ and Zn2+ substituted MBG_Scs prepared by rapid prototyping: 3-D printing. Note: Reprinted from Acta Biomaterialia, 9(1), Shruti S, Salinas AJ, Lusvardi G, Malavasi G, Menabue L, Vallet-Regi M. Mesoporous bioactive scaffolds made of glass containing cerium, gallium and zinc. 4836–4844, Copyright 2013, with permission from Elsevier.105

Adding cerium oxide directly to HA will generate cerium phosphate, which affects the biocompatibility to a certain extent. 106 Therefore, Nicolini et al.107 doped CeO2-NPs with different molar ratios of Ce 3+ and Ce 4+ into MBGs with 80% SiO 2–15 %CaO-5%P2O5. These high surface area MBGs will form HA when immersed in simulated body fluid (SBF). Tests have shown that Ce-MGB can reduce catalase and superoxide dismutase mimics (SOD). Catalase activity is best found in 45S5 bioglass containing cerium, and the highest cerium content can reach 5.3%. Both infrared spectroscopy and X-ray diffraction analysis confirmed the presence of HA in certain types of Ce-MGB. The above-mentioned tests, including the biological activity test, show the feasibility of MBG with non-oxidability and synthetic enzyme mimic activity. Atkinson et al. synthesized Ce-MBGs by evaporation-induced self-assembly (EISA) and performed the above test. They verified the biocompatibility with mouse fibroblasts. The antibacterial and biological activity of 50% SiO2-(45-x)% CaO-5% P2O5 MBG with a molar content of 1,5% CeO2-NPs has also been verified. 109,110 Recently, 45S5 bioglass containing cerium oxide has been developed to have a polyhedral shape and large size, and has demonstrated cell absorption, survival and proliferation capabilities. 111 CeO2-NPs doped in MBG containing MgO can reduce the degradation rate and improve chemical durability. At the same time, tests confirmed that the "sol-gel" synthesis technology increased the growth rate of hydroxyapatite compared to the traditional "melt quenching" route. 106

The above experiments provide preliminary evidence for the application of CeO2-NPs doped in MBG in bone regeneration materials. Future research may focus on MBG based on 3D bioactive scaffolds and in vivo experiments. Recently, Lu et al. 112 used hollow Ce-BG microspheres and chitosan (CTS) to construct CeO2-NPs-modified Ce-BG scaffolds through freeze-drying procedures. The CeO2-NPs in the scaffold can quickly promote the proliferation and osteogenic differentiation of hBMSC through osteocalcin (OCN), alkaline phosphatase (ALP), type I collagen (COL-1), and others. The enhancement of bone induction of Ce-MBG scaffold is mainly related to the activated ERK pathway, which can be prevented by adding a selective ERK1/2 inhibitor (SCH772984). In vivo experiments on a rat skull defect model show that, compared with a single MBG scaffold, Ce-MBG scaffold can promote collagen deposition, osteoblast formation and bone regeneration.

Metal-free dental zirconia implants have attracted much attention. Due to excellent mechanical properties, stable physical and chemical properties, and excellent biocompatibility, metal-free dental zirconia implants can avoid the gray appearance of the gums and the potential hypersensitivity reactions of titanium implants. 113 The durability of traditional materials has caused problems. Yttria-stabilized zirconia (3Y-TZP) is aging or low-temperature degradation (LTD), which basically involves phase changes that cause microcracks, leading to catastrophic failure; 114 high-purity alumina (Al2O3) has weaker toughness. The emergence of a new type of zirconia substrate overcomes the significant shortcomings of 3Y-TZP.115

At present, the mainstream adopts zirconia polycrystalline (CE-TZP) with stable ceria as the second phase to improve the toughness of alumina composites, and finally form CE-TZP/Al2O3 composites. The macro and micro mechanisms that increase toughness have been proven. 116 Scientists have previously proved that CE-CE-TZP/Al2O3 can promote HA formation and osteoblast proliferation and differentiation. 117 This study compared the biomechanical and histological behavior of Ce-TZP/Al2O3. And 3Y-TZP. 118 Ce-TZP/Al2O3 shows stronger shear strength, but the average surface roughness is slightly lower. There was no significant difference in the thickness of the new bone around the bone marrow area and the bone-implant contact (BIC) implant. Osteoclasts were not observed at any time in the CE-TZP/Al2O3 experiment, but in the 3Y-TZP group, it shows that Ce-TZP/Al2O3 has better biocompatibility. The surface roughness can be treated with hydrofluoric acid, and the nano form can significantly enhance bone formation and osseointegration in the body. 119 In addition to rats, studies in dogs have also proved that CE-TZP/Al2O3 is an excellent dental implant, including excellent bone resorption and soft tissue attachment. 120,121

Based on CE-TZP/Al2O3 to continue to solve the problem of hydrothermal aging, Altmann et al. developed a new and stable zirconia-alumina-aluminate composite ceramic (ZA 8 Sr 8-Ce11). The results found the most significant long-term attachment of primary osteoblasts and mineralized deposition of extracellular matrix (ECM). ZA8 Sr8-Ce11 with microporous shape is one of the best materials for clinical application. 122 3D printed Ce-TZP/Al2O3 shows a compressive strength similar to that of leather bone, close to 200 MPa. In addition, the viability and differentiation ability of cultured cells are also very strong. Generally speaking, such composite materials have excellent aesthetic properties, chemical stability, negligible corrosion and wear, and excellent mechanical and biological properties.

Titanium and its alloys have been widely used in orthopedics and dental implants. 123 The three key factors for the long-term clinical success of implants are the stability of antibacterial, anti-inflammatory and osseointegration, which have been resolved in a variety of ways. 124,125 CeO2-NPs is undoubtedly a suitable potential material. Li et al.126 developed a new type of Ti surface modified with CeO2-NPs (nanorods, nanocubes and nanooctahedrons) of different shapes. They also tested the antibacterial and anti-inflammatory responses of different CeO2-NPs composites deposited in Ti. The results showed that the three kinds of CeO2 modified Ti showed the same strong antibacterial properties. Nano-octahedral CeO2 modified Ti has the best anti-inflammatory effect (Figure 3). Zhao et al.127 used APS to deposit TiO2 coatings doped with different percentages of CeO2 on cp-TI substrates. The results show that the dose dependence of CeO2 determines the corrosion resistance, cell compatibility and antibacterial properties. Doping below 20% will not affect the crystal structure. Figure 3 Schematic diagram of the antibacterial and anti-inflammatory properties of CeO2-NPs (rod-CeO2, cube-CeO2, octa-CeO2) modified implant surface. Note: Reprinted from Acta Biomaterialia, 94, Li X, Qi M, Sun X, etc., surface treatment of titanium implants with nano-structured cerium oxide to improve antibacterial and anti-inflammatory capabilities. 627-643. Copyright 2019, with permission from Elsevier.126

Figure 3 Schematic diagram of the antibacterial and anti-inflammatory properties of CeO2-NPs (rod-CeO2, cube-CeO2, octa-CeO2) modified implant surface. Note: Reprinted from Acta Biomaterialia, 94, Li X, Qi M, Sun X, etc., surface treatment of titanium implants with nano-structured cerium oxide to improve antibacterial and anti-inflammatory capabilities. 627-643. Copyright 2019, with permission from Elsevier.126

Like the composite with HA, the effect of CeO2-NPs as a titanium-based implant coating on the valence of cerium was also studied. The results showed that at high Ce4+ concentrations, the expression of osteogenic genes and proteins was significantly up-regulated, and the macrophages expressed a highly polarized M2 phenotype. An increase in the percentage of M2 can increase the production of anti-inflammatory cytokines. 128 In addition, high Ce4+ shows higher catalase activity, but lower peroxidase activity. The results of protein adsorption and conformation showed that the cell binding site exposed by fibronectin and the subsequent cell morphology were related to the Ce valence. 80 In general, adjusting the cerium valence may be a good strategy for designing orthopedic/dental implant coatings with beneficial immunity. Response.

To further understand the biomaterial potential of CeO2, Ball et al. produced porous cerium oxide by direct foaming. Tests of cytotoxicity, inflammatory response and reactive oxygen species found that CeO2 is similar to commercially available bioglass. Another study found that when CeO2-NPs were doped into 3D nanocomposite scaffolds, cultured HMSCs increased osteogenic differentiation and collagen production. 130 There is evidence that cerium oxide promotes the migration and osteogenic differentiation of bone marrow stromal cells through the Smad1/5/8 signaling pathway. 131 An important finding showed that CeO2-NPs can induce stem cells to grow in PLGA scaffolds. The formed PLGA/nano-CeO2-NPs scaffold can adjust the roughness, thereby increasing the sensitivity of the cells to the surface characteristics of the host. 132

Insufficient angiogenesis hinders the clinical application of bone tissue engineering materials. The current mainstream solution is that bone tissue materials carry endogenous angiogenic factors to promote the proliferation, migration, differentiation and angiogenesis of endothelial cells (EC) and/or endothelial progenitor cells (EPC). 133,134 Nethi et al.135 demonstrated functional angiogenic properties. Organosilane functionalized CeO2-NPs (nanospheres) nanoconjugates, and indicated that the expression of p38 MAPK/HIF-1α may be a reasonable signal transduction mechanism for its angiogenic properties. In another study, CNPs promoted the full hypertrophy and differentiation of BMSCs by activating the DHX15-p38 MAPK signaling pathway, thereby accelerating the process of endochondral ossification, which can better overcome the lack of vascularization and related hypoxia at the initial stage of implantation. 136 CeO2- NPs can also activate calcium channels in mesenchymal stem cells, and ultimately lead to the proliferation, migration and differentiation of EPC through a chain reaction137 (see Figure 4). The scheme in Figure 4 illustrates the mechanism by which CNPs promote angiogenesis in EPCs. Note: Reprinted with permission from Xiang J, Li J, He J, et al. Cerium oxide nanoparticles modify the interface of the scaffold to enhance the vascularization of bone grafts by activating the calcium channels of mesenchymal stem cells. ACS applied materials and interfaces. 2016; 8(7): 4489-4499. Copyright © 2016 American Chemical Society. 137

The scheme in Figure 4 illustrates the mechanism by which CNPs promote angiogenesis in EPCs. Note: Reprinted with permission from Xiang J, Li J, He J, et al. Cerium oxide nanoparticles modify the interface of the scaffold to enhance the vascularization of bone grafts by activating the calcium channels of mesenchymal stem cells. ACS applied materials and interfaces. 2016; 8(7): 4489-4499. Copyright © 2016 American Chemical Society. 137

The research of CeO2-NPs as nanoenzymes based on inorganic nanoparticles has just started. At present, the activity and specificity of nanoenzymes are still lower than that of natural enzymes, and the influence of pH is crucial. 31,32 It is worth noting that the in vivo biocompatibility is evaluated by protein corona. Hard and soft protein corona affects the biologically active interface, including availability, stability and ecotoxicity. The hapten formed by the adsorbed protein can also cause abnormal immune homeostasis. 138 The conversion of anti-oxidation and pro-oxidation is a double-edged sword. It is necessary to fully control the external environmental conditions to ensure that the conversion can achieve the expected effect instead of the opposite effect. For example, CeO2-NPs promote angiogenesis and anti-vascularization The production characteristics are affected by microenvironmental parameters, including pH, production of reactive oxygen species, and intracellular oxygen concentration. 134 The same translation problem that led to conflicting toxicology reports constitutes a challenge for future supervision and environmental risk assessment of the application of CeO2-NPs. 29 In addition, Ce3+ enhances the expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) in bone metabolism, thereby increasing the level of ROS, thereby activating RANKL-139. The latest research shows that CeO2 -The genotoxicity of NPs is a function of in vitro concentration and particle size. 140 In vivo experiments have shown that short-term exposure to uncoated CeO2-NPs in rats can induce lung inflammation and dose-independent DNA da mage.141 ​​It increases the difficulty of modification and synthesis. In summary, the establishment of long-term clinical safety and ecological environment safety evaluation still requires a long-term research process.

CeO2-NPs have found a wide range of potential in the field of biomedicine. This review discusses the latest advances in the orthopedic biomedical application of CeO2-NPs. Green synthetic methods using biocompatible stabilizers are becoming more and more important in the production of CeO2-NPs and their orthopedic biomedical applications. The surface chemistry, particle size, and physical and chemical properties of CeO2-NPs need to be reasonably controlled. CeO2-NPs doped with metal element substitutes, such as graphene, PLGA and other thermal materials, have made progress in the application of bone implant materials. In addition, in imaging, such as reducing the harmful effects of Gd and enhancing the contrast of MRI are very attractive; 28 In terms of drug carriers, CeO2-NPs are used as encapsulated in liposomes or PEGylated in combination with other materials. Carrier; a magnetic nanoconjugate delivery system with a core-shell structure is under study. 27,142 In clinical applications, the ability of CeO2-NPs to promote angiogenesis and development has become critical. Despite the above-mentioned challenges, it is expected that in the future, CeO2-NPs will overcome their limitations, play a good role in 3D tissue engineering materials, and flourish in interdisciplinary nanomedicine.

We would like to thank all authors for their help in writing and revising the manuscript. This work was funded by the Jilin Province Science and Technology Development Plan Project 20180101308JC.

The authors report no conflicts of interest in this work.

1. Smiles DE, Batista ER, Booth CH, etc. The duality of electronic positioning and covalent in lanthanide and actinide metallocenes. Chemical science. 2020; 11(10): 2796-2809. doi:10.1039/C9SC06114B

2. Bazhukova IN, Sokovnin SY, Ilves VG, etc. Luminescence and optical properties of cerium oxide nanoparticles. Opt Mater (Amst). 2019; 92: 136-142. doi:10.1016/j.optmat.2019.04.021

3. Naderi H, Sobati H, Sobhani-Nasab A, etc. Synthesis of cerium tungstate nanostructures and application chemistry selection of supercapacitors. 2019;4(10):2862–2867. doi:10.1002/slct.201803753

4. Jung HK, Kim CH, Hong AR, etc. Luminescence and magnetic properties of cerium-doped yttrium aluminum garnet and yttrium iron garnet composite materials. Ceramics International 2019; 45(8): 9846-9851. doi:10.1016/j.ceramint.2019.02.023

5. Bhuvanesh N, Suresh S, Velmurugan K, Thamilselvan A, Nandhakumar R. Quinoline-based probes: large blue shift fluorescence and electrochemical sensing of cerium ions and their biological applications. J Photochem Photobiol A-Chem. 2020;386:112103. doi:10.1016/j.jphotochem.2019.112103

6. Mohd Fadzil NA, Ab Rahim MH, Pragas Maniam G. A brief review of ceria and modified ceria: synthesis and applications. Material express. 2018;5(8):085019. doi:10.1088/2053-1591/aad2b5

7. Wu L, Liu G, Wang W, et al. CeO2 nanoparticles modified with cyclodextrin are used as multifunctional nanoenzymes for the combined treatment of psoriasis. International J Nanomedicine. 2020; 15: 2515-2527. doi:10.2147/IJN.S246783

8. Bruix A, Neyman KM. Modeling of cerium oxide-based nanomaterials for catalysis and related applications. Catalan alphabet. 2016;146(10):2053-2080. doi:10.1007/s10562-016-1799-1

9. Sun C, Li H, Chen L. Nanostructured cerium oxide-based materials: synthesis, properties and applications. Energy and Environmental Science. 2012; 5(9): 8475-8505. doi:10.1039/c2ee22310d

10. Deshpande S, Patil S, Kuchibhatla SVNT, Seal S. Size-dependent changes of lattice parameters and valence states in nanocrystalline cerium oxide. Appl Phys Lett. 2005;87(13):133113. doi:10.1063/1.2061873

11. Celardo I, Pedersen JZ, Traversa E, Ghibelli L. Pharmacological potential of cerium oxide nanoparticles. nanoscale. 2011; 3(4): 1411-1420. doi:10.1039/c0nr00875c

12. Wei H, Wang E. Nanomaterials with enzyme-like properties (nanoenzymes): the next generation of artificial enzymes. Chem Soc Rev. 2013;42(14):6060–6093. doi:10.1039/c3cs35486e

13. Pirmohamed T, Dowding JM, Singh S, etc. Nanoceria exhibits redox state-dependent catalase mimetic activity. Chemical Commune. 2010;46(16):2736-2738. doi:10.1039/b922024k

14. Vibhu V, Flura A, Rougier A, etc. Electrochemical aging study of mixed lanthanum/praseodymium nickelate La2-xPrxNiO4+delta as solid oxide fuel or oxygen electrode of electrolysis cell. J Energy Chemistry. 2020; 46: 62-70. doi:10.1016/j.jechem.2019.10.012

15. Khan SA, Khan N, Irum U, etc. Cellulose acetate-Ce/[email protection] catalyst for degradation of organic pollutants. Int J Biol Macromol. 2020; 153: 806-816. doi:10.1016/j.ijbiomac.2020.03.013

16. Li S, Zhang Y, Wang Z, Du W, Zhu G. The effect of CeO2 catalyst morphology on the catalytic performance of lean methane combustion. Chemical Wright. 2020;49(5):461-464. doi:10.1246/cl.200049

17. Zito CA, Perfecto TM, Dippel AC, Volanti DP, Koziej D. Low temperature carbon dioxide gas sensor based on egg yolk shell ceria nanospheres. ACS application program interface. 2020; 12(15): 17757-17763. doi:10.1021/acsami.0c01641

18. Chen Y, Mu Z, Wang W, Chen A. Development of mesoporous SiO2/CeO2 core/shell nanoparticles with tunable structure for non-destructive and efficient polishing. Ceramic International 2020; 46(4): 4670-4678. doi:10.1016/j.ceramint.2019.10.198

19. Wen J, Song C, Liu TK, et al. Preparation of dense gadolinium-doped cerium oxide coating by ultra-low pressure plasma spraying and plasma spraying-physical vapor deposition process. coating. 2019;9(11):7. doi: 10.3390/coating 9110717

20. Xu C, Qu X. Cerium oxide nanoparticles: a multifunctional rare earth nanomaterial for biological applications. NPG Asian alma mater. 2014;6(3):e90. doi:10.1038/am.2013.88

21. Thakur N, Manna P, Das J. Synthesis and biomedical applications of nano-redox active nanoparticles nano-cerium oxide. J Nano Biotechnology. 2019;17(1):84. doi:10.1186/s12951-019-0516-9

22. Kargozar S, Baino F, Hoseini SJ, etc. Biomedical applications of nanocellulose: a new role for old players. Nanomedicine. 2018;13(23):3051-3069. doi:10.2217/nnm-2018-0189

23. Sinitsyn AV, Gracheva ME. Atomic model of cerium oxide nanoparticles with Ce3+ and Ce4+ atoms. nanotechnology. 2020;31(31):315708. doi:10.1088/1361-6528/ab87c8

24. Passacantando M, Santucci S. Surface electronic and structural properties of CeO2 nanoparticles: research conducted through core-level photoemission and peak diffraction. J Nanopart Res. 2013;15(8):1785. doi:10.1007/s11051-013-1785-0

25. Huang J, Yu Y, Zhu J, Yu R. Oxygen adsorption atoms and vacancies on the surface of CeO2 (110). Sci China Technology Science. 2018;61(1):135–139. doi:10.1007/s11431-017-9154-9

26. Castano CE, O'Keefe MJ, Fahrenholtz WG. Cerium-based oxide coating. Curr Opin Solid State Mater Sci. 2015;19(2):69–76. doi:10.1016/j.cossms.2014.11.005

27. Singh S, Ly A, Das S, Sakthivel TS, Barkam S, Seal S. Cerium Oxide Nanoparticles on the Nanobiological Interface: Size-dependent cellular uptake. Artif Cell Nanomedicine Biotechnology. 2018;46(sup3):S956–S963. doi:10.1080/21691401.2018.1521818

28. Eriksson P, Tal AA, Skallberg A, etc. Cerium oxide nanoparticles with antioxidant capacity and gadolinium integration are used for MRI contrast enhancement. Sci Rep. 2018;8(1):6999. doi:10.1038/s41598-018-25390-z

29. Dahle JT, Arai Y. Environmental Geochemistry of Cerium: Application and Toxicology of Cerium Oxide Nanoparticles. Int J Environ Res Public Health. 2015;12(2):1253-1278. doi:10.3390/ijerph120201253

30. Wu K, Sun LD, Yan CH. Recent progress in the controllable synthesis of cerium oxide nanocatalysts to improve catalytic performance. Adv energy materials. 2016;6(17):1600501. doi:10.1002/aenm.201600501

31. Ragg R, Tahir MN, Tremel W. Solids go bio: Inorganic nanoparticles as enzyme mimics. Euro J Inorg Chemistry. 2016;2016(13-14):1906-1915. doi:10.1002/ejic.201501237

32. Kang T, Kim YG, Kim D, Hyeon T. Inorganic nanoparticles with enzyme mimic activity for biomedical applications. Coord Chem Rev. 2020; 403:213092. doi:10.1016/j.ccr.2019.213092

33. Sozarukova MM, Shestakova MA, Teplonogova MA, Izmailov DY, Proskurnina EV, Ivanov VK. Quantify the free radical scavenging properties and SOD-like activity of ceria nanoparticles in the biochemical model. Russ J Inorg Chemistry. 2020;65(4):597-605. doi:10.1134/S0036023620040208

34. Yao T, Tian Z, Zhang Y, Qu Y. The phosphatase-like activity of CeO2 porous nanorods is used for highly stable dephosphorylation under interference. ACS application program interface. 2019;11(1):195–201. doi:10.1021/acsami.8b17086

35. Liu H, Liu J. Self-limiting phosphatase mimics CeO2 nanozyme. Chemical nano. 2020.

36. Yang Wei, Li Jie, Yang Jie, etc. Biomass-derived layered porous CoFe-LDH/CeO2 hybrid with peroxidase-like activity for colorimetric sensing of H2O2 and glucose. J alloy compound. 2020;815:152276. doi:10.1016/j.jallcom.2019.152276

37. Estevez AY, Ganesana M, Trentini JF, etc. The antioxidant enzyme mimic activity and neuroprotective effects of cerium oxide nanoparticles stabilized with different ratios of citric acid and EDTA. Biomolecules. 2019;9(10):562. doi:10.3390/biom9100562

38. Dhall A, Burns A, Dowding J, Das S, Seal S, Self W. Characterize the phosphatase mimic activity of cerium oxide nanoparticles, and distinguish its active site from the catalase mimic active site using an anionic inhibitor. Environmental Science Nano. 2017;4(8):1742-1749.

39. Jeong HG, Cha BG, Kang DW, etc. Cerium oxide nanoparticles made of 6-aminocaproic acid can overcome systemic inflammatory response syndrome. Adv healthcare materials. 2019;8(9):1801548. doi:10.1002/adhm.201801548

40. Dhall A, Self W. Cerium oxide nanoparticles: a brief review of their synthesis methods and biomedical applications. Antioxidants. 2018;7(8):97. doi:10.3390/antiox7080097

41. Charbgoo F, Bin Ahmad M, Darroudi M. Cerium oxide nanoparticles: green synthesis and biological applications. International J Nanomedicine. 2017; 12: 1401-1413. doi:10.2147/IJN.S124855

42. Ge J, Zhong L, Zhao L, Tang B, Song W. Layered nanoporous cerium oxide nanoparticles with high surface area: synthesis, characterization and catalytic activity. J Nanosci Nanotechnology. 2011;11(1):125–130. doi:10.1166/jnn.2011.2999

43. Nyoka M, Choonara YE, Kumar P, Kondiah PPD, Pillay V. Using various methods to synthesize cerium oxide nanoparticles: impact on biomedical applications. Nanomaterials (Basel). 2020;10(2):242. doi:10.3390/nano10020242

44. Morlando A, Chaki Borrás M, Rehman Y, etc. The development of CeO2 nanodots coated TiO2 nanoparticles has reduced photocatalytic activity and increased biocompatibility to human keratinocyte cell lines. J Mater Chem B. 2020;8(18):4016-4028. doi:10.1039/D0TB00629G

45. Lin YH, Shen LJ, Chou TH, Shih YH. Synthesis, stability and cytotoxicity of novel cerium oxide nanoparticles for biomedical applications. J Cluster Science. 2020.doi:10.1007/s10876-020-01798-4

46. ​​Jyothi PSP, Anitha B, Smitha S, Vibitha BV, Krishna PGA, Tharayil NJ. DNA-assisted synthesis of nano-cerium oxide, the size of which depends on the structure and optical properties of optoelectronic applications. Bull female science. 2020; 43(1):119. doi:10.1007/s12034-020-02102-w

47. Zhao X, Suo H, Zhang Z, Guo C. Upconverting CeO2: yb3+/Tm3+ hollow nanospheres are used for photothermal sterilization and deep tissue imaging in the first biological window. Ceramics International 2019; 45 (17, Part A): 21910–21916. doi:10.1016/j.ceramint.2019.07.202

48. Rahdar A, Aliahmad M, Hajinezhad MR, Samani M. Xanthan gum-stabilized nano-cerium oxide: Synthesis, characterization, and study of biochemical changes caused by nanoparticles in rat peritoneum based on green chemistry. J Mol structure. 2018; 1173: 166-172. doi:10.1016/j.molstruc.2018.06.092

49. Pujar MS, Hunagund SM, Barretto DA, etc. The synthesis of cerium oxide nanoparticles and the effect of surface morphology on biological activity. Bull female science. 2020; 43(1). doi: 10.1007/s12034-019-1962-6.

50. Balaji S, Mandal BK, Vinod Kumar Reddy L, Sen D. Biological cerium oxide nanoparticles (CeO2 NPs) with effective photocatalytic and cytotoxic activities. Biological Engineering. 2020; 7(1):26. doi:10.3390/bioengineering7010026

51. Nithya P, Sundrarajan M. Ag-Au bimetallic CeO2 nanoparticle functionalized biosynthesis of Ag-Au from Justicia adhatoda for pharmaceutical applications: antibacterial and anticancer activity. J Photochem Photobiol B-Biol. 2020;202:111706. doi:10.1016/j.jphotobiol.2019.111706

52. Ahamed M, Akhtar MJ, Khan MAM, Alaizeri ZM, Alhadlaq HA. To evaluate the cytotoxicity and oxidative stress response of CeO2-RGO nanocomposites in human lung epithelial A549 cells. nanomaterials. 2019;9(12):1709. doi:10.3390/nano9121709

53. Ayodhya D, Veerabhadram G. Green synthesis and stability of garlic extract [email protection] composite material, used for the photocatalytic and sonocatalytic degradation of mixed dyes and antibacterial research. J Mol structure. 2020;1205:127611. doi:10.1016/j.molstruc.2019.127611

54. Miri A, Akbarpour Birjandi S, Sarani M. Investigation of the cytotoxicity and UV protection of biosynthetic cerium oxide nanoparticles. J Biochem Mol Toxicol. 2020;34(6):e22475. doi:10.1002/jbt.22475

55. Kaygusuz H, Erim FB. Biopolymers of functional cerium oxide nanoparticles assist green synthesis. Chemical Papp. 2020;74(7):2357-2363. doi:10.1007/s11696-020-01084-7

56. Miri A, Darroudi M, Sarani M. Investigation of the biosynthesis of cerium oxide nanoparticles and their cytotoxicity to colon cancer cell lines. Applied organic chemistry. 2020; 34(1). doi:10.1002/aoc.5308

57. Elahi B, Mirzaee M, Darroudi M, Sadri K, Oskuee RK. Bio-based synthesis of nano-cerium oxide and evaluation of its biodistribution and biological characteristics. Colloidal surfing B biological interface. 2019;181:830-836. doi:10.1016/j.colsurfb.2019.06.045

58. Kargar H, Ghazavi H, Darroudi M. The size control and bio-directed synthesis of ceria nanopowders and its cytotoxic effect in vitro. Ceramics International 2015; 41(3): 4123-4128. doi:10.1016/j.ceramint.2014.11.108

59. Patil SN, Paradeshi JS, Chaudhari PB, Mishra SJ, Chaudhari BL. Evaluation of biotherapeutic potential and cytotoxicity of pectin-mediated synthesis of nanostructured cerium oxide. Applied biochemical biotechnology. 2016;180(4):638–654. doi:10.1007/s12010-016-2121-9

60. Senthilkumar RP, Bhuvaneshwari V, Malayaman V, etc. The biological method of using golden silk grass (Sida acuta Burm.f.) to synthesize cerium oxide nanoparticles and its antibacterial activity against Escherichia coli. Material express. 2019;6(10):105026. doi:10.1088/2053-1591/ab37b9

61. Fereydouni N, Sadeghnia HR, Mobarhan MG, etc. Nanoceria: Based on the green synthesis and formation mechanism of polyphenols, and evaluation of their cytotoxicity to L929 and HFFF2 cells. J Mol structure. 2019; 1186: 23-30.

62. Gunasekaran S, Dinesh A, Silambarasu A, Thirumurugan V, Shankar S. Rare earth element (REE) Nd3+ doped CeO2 nanoparticles doped with aloe leaf extract: structure, optical and antibacterial activity. J Nanosci Nanotechnology. 2019;19(7):3964–3970. doi:10.1166/jnn.2019.16307

63. Irshad MS, Aziz MH, Fatima M, etc. Green synthesis, cytotoxicity, antioxidant and photocatalytic activity of CeO2 nanoparticles mediated by orange peel extract (OPE). Material express. 2019; 6(9): 0950a4. doi:10.1088/2053-1591/ab3326

64. Sharmila G, Muthukumaran C, Saraswathi H, Sangeetha E, Soundarya S, Kumar NM. Green synthesis, characterization and biological activity of nano-cerium oxide. Ceramics International 2019; 45(9): 12382-12386. doi:10.1016/j.ceramint.2019.03.164

65. Du Xu, Jiang De, Chen S, et al. CeO2 nanocrystals integrated nitrogen-doped graphene nanocomposites: one-pot method, rapid synthesis and excellent electrocatalytic activity for enzymatic biosensing. Biosens Bioelectronics. 2017; 89: 681-688. doi:10.1016/j.bios.2015.11.054

66. Senthilkumar RP, Bhuvaneshwari V, Ranjithkumar R, Sathiyavimal S, Malayaman V, Chandarshekar B. Synthesis, characterization and antibacterial activity of mixed chitosan-cerium oxide nanoparticles: as biological nanomaterials. Int J Biol Macromol. 2017; 104: 1746-1752. doi:10.1016/j.ijbiomac.2017.03.139

67. Shen C, Pang K, Du L, Luo G. Green synthesis and enhanced photocatalytic activity of Ce-doped TiO2 nanoparticles supported on porous glass. Micronology. 2017; 34: 103-109.

68. Yang Zhi, Yin Zhi, Zhao Zhi, etc. The morphology and magnetic properties of La-doped CeO2 nanoparticles were studied by solvothermal method in a low magnetic field. Material chemistry and physics. 2020;240:122148. doi:10.1016/j.matchemphys.2019.122148

69. Yang Zhi, Zhao Zhi, Yu Jie, etc. The effect of Co substitution and magnetic field on the morphology and magnetic properties of CeO2 nanoparticles. Ceramics International 2019; 45(9): 11927-11933. doi:10.1016/j.ceramint.2019.03.081

70. Byrappa K, Ohara S, Adschiri T. Using supercritical fluid technology to synthesize nanoparticles-toward biomedical applications. Adv Drug Deliv Rev. 2008;60(3):299-327. doi:10.1016/j.addr.2007.09.001

71. Cha BG, Jeong HG, Kang DW, etc. Customized lipid-coated magnetic mesoporous silica nanoparticles doped with ceria nanoparticles are used to diagnose cerebral hemorrhage. Nano Resources 2018; 11(7): 3582-3592. doi:10.1007/s12274-017-1924-5

72. Kim D, Kwon HJ, Hyeon T. Magnetite/Ceria nanoparticle assembly for in vitro cleaning of amyloid-β in Alzheimer's disease. Adv Mater. 2019;31(19):1807965. doi:10.1002/adma.201807965

73. Lord Vassie JA, Whitelock JM, MS. The endocytosis of cerium oxide nanoparticles and the regulation of reactive oxygen species in human ovarian and colon cancer cells. Journal of Biomaterials. 2017; 50: 127-141. doi:10.1016/j.actbio.2016.12.010

74. Lord Vassie JA, Whitelock JM, MS. Targeted delivery and redox activity of folic acid functionalized nanocellulose in tumor cells. Moore Pharmaceuticals. 2018;15(3):994-1004. doi:10.1021/acs.molpharmaceut.7b00920

75. Torres-Romero A, Cajero-Juarez M, Contreras-Garcia ME. Titanium dioxide-ceria surfactant assisted sol-gel synthesis and characterization. Epitoanyag J is a silicate-based composite material. 2017;69(1):8-11.

76. Torres-Romero A, Cajero-Juarez M, Nunez-Anita RE, Contreras-Garcia ME. Titanium dioxide nanoparticles doped with ceria are used as a drug delivery system. J Nanosci Nanotechnology. 2020;20(7):3971–3980. doi:10.1166/jnn.2020.17206

77. Kang DW, Kim CK, Jeong HG, etc. Customized cerium oxide nanoparticles for the biocompatibility of reactive oxygen species can solve the acute inflammatory response after cerebral hemorrhage. Nano Resources 2017;10(8):2743–2760.

78. Grillone A, Li T, Battaglini M, etc. Preparation, characterization and preliminary in vitro testing of nano-cerium oxide liposomes. nanomaterials. 2017;7(9):276. doi:10.3390/nano7090276

79. Pryjmakova J, Kaimlova M, Hubacek T, Svorcik V, Siegel J. Nanostructured materials for artificial tissue replacement. International J Molecular Science. 2020; 21(7).

80. Shao De, Li Ke, You Mei, etc. Macrophage polarization of plasma sprayed cerium dioxide coating on titanium-based implants: cerium valence is important. Applied surfing science. 2020;504:144070.

81. Li HR, Pan S, Xia P, et al. Application progress of gold nanoparticles in bone tissue engineering[J]. J Bioengineering. 2020; 14(1). doi: 10.1186/s13036-020-00236-3.

82. Crisan L, Crisan BV, Bran S, etc. Carbon-based nanomaterials are used as bone regeneration scaffolds. Part of science and technology. 2019:1-10. doi:10.1080/02726351.2019.1637382

83. Bow A, Anderson DE, Dhar M. Commercial bone graft substitutes: the influence of origin and processing on graft function. Drug Metabolism Revised Edition 2019; 51(4): 533–544. doi:10.1080/03602532.2019.1671860

84. Datta A, Mishra S, Manna K, Das Saha K, Mukherjee S, Roy S. The pro-oxidative therapeutic activity of cerium oxide nanoparticles in colorectal cancer cells. Omega. 2020; 5(17): 9714-9723. doi:10.1021/acsomega.9b04006

85. Abid SA, Taha AA, Ismail RA, Mohsin MH. Antibacterial and cytotoxic activity of cerium oxide nanoparticles prepared by laser ablation in liquid. Environ Sci Pollut Res Int. 2020;27(24):30479-30489. doi:10.1007/s11356-020-09332-9

86. De Marzi L, Monaco A, De Lapuente J, etc. The cytotoxicity and genotoxicity of ceria nanoparticles to different cell lines in vitro. International J Molecular Science. 2013;14(2):3065-3077.

87. Alpaslan E, Yazici H, Golshan N, Ziemer KS, Webster TJ. Dextran-coated cerium oxide nanoparticles for inhibiting the function of bone cancer cells. In: Narayan R, Bose S, Bandyopadhyay A, editors. Biomaterials Science: Processing, Characteristics and Applications V. Vol. 254; 2015:187-196.

88. Yazici H, Alpaslan E, Webster TJ. The effect of dextran coating on the cytotoxicity of cerium oxide nanoparticles on bone cancer cells. Chaom. 2015; 67(4): 804–810. doi:10.1007/s11837-015-1336-5

89. Alpaslan E, Yazici H, Golshan NH, Ziemer KS, Webster TJ. Dextran-coated cerium oxide nanoparticles inhibit the pH-dependent activity of osteosarcoma cell proliferation. Acs Biomater Sci Eng. 2015;1(11):1096–1103. doi:10.1021/acsbiomaterials.5b00194

90. Tang Sheng, Zhou Li, Liu Zhong, etc. Cerium dioxide nanoparticles promote the cytotoxic activity of CD8(+) T cells by activating NF-κB signaling. Biomaterials Science. 2019; 7(6): 2533-2544. doi:10.1039/C9BM00113A

91. Wong TW, Behl M, Yusoff NISM, etc. Bio-based composite material derived from plant-based precursors and hydroxyapatite with shape memory capabilities. Compound science and technology. 2020;194:108138. doi:10.1016/j.compscitech.2020.108138

92. Han SH, Lee J, Lee KM, etc. Using 3D printed calcium-deficient hydroxyapatite/collagen/bone morphogenetic protein 2 scaffolds to enhance the healing of rat skull defects. J Mech Behav Biomedical materials. 2020; 108: 103782. doi:10.1016/j.jmbbm.2020.103782

93. Avila JD, Alrawahi Z, Bose S, Bandyopadhyay A. Additively manufactured Ti6Al4V-Si-hydroxyapatite composite material for the joint surface of load-bearing implants. Add manufacturing. 2020;34:101241. doi:10.1016/j.addma.2020.101241

94. Pandey A, Nigam VK, Balani K. Multi-scale tribology of hydroxyapatite reinforced with cerium oxide and silver. Put on. 2018; 404-405: 12-21. doi:10.1016/j.wear.2018.01.006

95. Pandey A, Midha S, Sharma RK, etc. Antioxidant and antibacterial hydroxyapatite biocomposite for orthopedic applications. Mater Sci Eng C. 2018; 88: 13-24. doi:10.1016/j.msec.2018.02.014

96. Li K, Shen Q, Xie Y, You M, Huang L, Zheng X. The incorporation of cerium oxide into the hydroxyapatite coating protects bone marrow stromal cells from the inhibition of osteogenic differentiation induced by H2O2. Biological trace element reservoir. 2018;182(1):91–104. doi:10.1007/s12011-017-1066-3

97. Li K, Shen Q, Xie Y, You M, Huang L, Zheng X. Incorporation of cerium oxide into the hydroxyapatite coating regulates the osteogenic activity of mesenchymal stem cells and the polarization of macrophages. J Biomaterials application. 2017;31(7):1062-1076. doi:10.1177/0885328216682362

98. Li K, Xie Y, You M, Huang L, Zheng X. Plasma sprayed cerium oxide coating inhibits H2O2 induced oxidative stress and supports cell viability. J Mater Sci Mater Med. 2016;27(6):100.

99. You M, Li K, Xie Y, Huang L, Zheng X. The effect of cerium valence in cerium oxide coating on the response of bone mesenchymal stem cells and macrophages. Biological trace element reservoir. 2017;179(2):259-270. doi:10.1007/s12011-017-0968-4

100. Gopi D, Murugan N, Ramya S, Shinyjoy E, Kavitha L. AZ91 magnesium alloy with bulbous manganese, strontium substituted hydroxyapatite/cerium oxide double coating, with improved biological activity and corrosion resistance, Suitable for implant applications. RSC Advanced 2015;5(35):27402–27411. doi:10.1039/C5RA03432A

101. Sanyal V, Kesavamoorthi R, Ramachandra Raja C. The mechanical behavior and biological activity of fluorohydroxyapatite toughened by adding zirconium-cerium ions. Today's alma mater program. 2016;3(6):1923-1932.

102. Pandey A, Patel AK, Kumar V, etc. The use of hydroxyapatite bio-coating doped with cerium oxide and silver enhances the tribological and bacterial resistance of carbon nanotubes. nanomaterials. 2018;8(6):363. doi:10.3390/nano8060363

103. Morais DS, Fernandes S, Gomes PS, etc. The new cerium-doped glass reinforced hydroxyapatite has antibacterial and osteoconducting properties and can be used for bone tissue regeneration. Biomedical materials. 2015;10(5):055008. doi: 10.1088/1748-6041/10/5/055008

104. Yan X, Yu C, Zhou X, Tang J, Zhao D. Highly ordered mesoporous bioactive glass with excellent in vitro osteogenic bioactivity. Angew Chem Int Ed. 2004;43(44):5980–5984. doi:10.1002/anie.200460598

105. Shruti S, Salinas AJ, Lusvardi G, Malavasi G, Menabue L, Vallet-Regi M. Mesoporous bioactive scaffolds made of glass containing cerium, gallium and zinc. Journal of Biomaterials. 2013; 9(1): 4836-4844. doi:10.1016/j.actbio.2012.09.024

106. Kaur P, Singh KJ, Yadav AK, Kaur S, Kaur R, Kaur S. CeO2 doped CaO-P2O5-MgO-SiO2 bioceramic hydroxyapatite and other bone growth and cell viability research. Material chemistry and physics. 2020;243:122352. doi:10.1016/j.matchemphys.2019.122352

107. Nicolini V, Malavasi G, Lusvardi G, etc. Cerium-doped mesoporous bioactive glass: research on enzyme-like mimic activity and biological activity. Ceramic International 2019;45(16):20910–20920. doi:10.1016/j.ceramint.2019.07.080

108. Atkinson I, Anghel EM, Petrescu S, etc. Cerium-containing mesoporous bioactive glass: material characterization, in vitro biological activity, biocompatibility and cytotoxicity evaluation. Micropor Mesopor material. 2019;276:76-88. doi:10.1016/j.micromeso.2018.09.029

109. Goh YF, Alshemary AZ, Akram M, Abdul Kadir MR, Hussain R. In vitro characterization of antibacterial bioactive glass containing cerium oxide. Ceramics International 2014; 40 (1, part A): 729–737. doi:10.1016/j.ceramint.2013.06.062

110. Youness RA, Taha MA, El-Kheshen AA, El-Faramawy N, Ibrahim M. In vitro biological activity evaluation, antibacterial behavior and mechanical properties of cerium-containing phosphate glass. Material express. 2019;6(7):075212. doi:10.1088/2053-1591/ab15b5

111. Anesi A, Malavasi G, Chiarini L, Salvatori R, Lusvardi G. Cell proliferation is preliminarily evaluated for the existence of long-lasting self-regenerating antioxidant activity in cerium-doped bioactive glass. Material. 2020;13(10):2297. doi:10.3390/ma13102297

112. Lu B, Zhu DY, Yin JH, et al. Incorporation of cerium oxide into hollow mesoporous bioglass scaffolds enhances bone regeneration by activating the ERK signaling pathway. Biological manufacturing. 2019;11(2):025012. doi:10.1088/1758-5090/ab0676

113. Takemoto M, Fujibayashi S, Neo M, Suzuki J, Kokubo T, Nakamura T. Bone bonding ability of hydroxyapatite coated zirconia-alumina nanocomposite with microporous surface. J Biomed Mater Res A. 2006;78A(4):693-701. doi:10.1002/jbm.a.30748

114. Sivaraman K, Chopra A, Narayan AI, Balakrishnan D. Is zirconia a viable substitute for titanium? Critical review. J Prosthodont Res. 2018;62(2):121–133. doi:10.1016/j.jpor.2017.07.003

115. Apratim A, Eachempati P, Krishnappa Salian KK, Singh V, Chhabra S, Shah S. Zirconia in dental implantology: a review. J Int Soc Prev Community Dent. 2015; 5(3): 147–156. doi:10.4103/2231-0762.158014

116. Nawa M, Yamada K, Pezzotti G. The micro-mechanism behind the toughening behavior of cerium oxide stabilized tetragonal zirconia/alumina nanocomposites for biomedical applications. Key project. 2008;361-363:813-816. doi:10.4028/www.scientific.net/KEM.361-363.813

117. Pandey AK, Pati F, Mandal D, Dhara S, Biswas K. In vitro evaluation of the osteoconductivity and cellular response of zirconia and alumina-based ceramics. Mater Sci Eng C. 2013;33(7):3923–3930. doi:10.1016/j.msec.2013.05.032

118. Han JM, Hong G, Lin H, et al. Biomechanical and histological evaluation of osseointegration of two zirconia implants. International J Nanomedicine. 2016; 11: 6507-6516. doi:10.2147/IJN.S119519

119. Oshima Y, Iwasa F, Tachi K, Baba K. The effect of nano-featured topography on osteogenesis and osseointegration of ceria-stabilized zirconia/alumina nanocomposites. Int J Oral Maxillofac Implants. 2017;32(1):81–91. doi:10.11607/jomi.4366

120. Lopez-Píriz R, Fernández A, Goyos-Ball L, etc. The performance of the new Al2O3/Ce-TZP ceramic nanocomposite dental implants: a preliminary study on dogs. Material (Basel). 2017;10(6):614. doi:10.3390/ma10060614

121. Igarashi K, Nakahara K, Haga-Tsujimura M, Kobayashi E, Watanabe F. The dog model responds to the hard and soft tissues of three different implant materials. Dent Mater J. 2015;34(5):692-701. doi:10.4012/dmj.2014-361

122. Altmann B, Karygianni L, Al-Ahmad A, etc. Evaluate new long-acting ceria-stabilized zirconia-based ceramics with different surface morphologies as implant materials. Advanced functional materials. 2017;27(40):1702512.

123. Putra NE, Mirzaali MJ, Apachitei I, Zhou J, Zadpoor ​​AA. Multi-material additive manufacturing technology of titanium, magnesium and iron-based biomaterials for bone replacement. Journal of Biomaterials. 2020; 109:1-20. doi:10.1016/j.actbio.2020.03.037

124. Ding Y, Yuan Z, Liu P, Cai K, Liu R. Prepare strontium-doped protein supramolecular nanomembrane on a titanium substrate to promote osteogenesis. Mat Sci Eng C-Mater Biol Appl. 2020;111:110851. doi:10.1016/j.msec.2020.110851

125. Prakash C, Singh S, Ramakrishna S, Krolczyk G, Le CH. Microwave sintering of porous Ti-Nb-HA composites with high strength and enhanced biological activity for implant applications. J alloy compound. 2020;824.

126. Li X, Qi Min, Sun X, etc. Nano-structured cerium oxide is used for surface treatment of titanium implants to improve antibacterial and anti-inflammatory capabilities. Journal of Biomaterials. 2019; 94: 627-643. doi:10.1016/j.actbio.2019.06.023

127. Zhao X, Liu G, Zheng H, Cao H, Liu X. The dose-dependent effect of CeO2 on the microstructure and antibacterial properties of plasma sprayed TiO2 coatings for orthopedics applications. J Thermal spray technology. 2015;24(3):401–409. doi:10.1007/s11666-014-0179-x

128. Li J, Wen J, Li B, et al. Valence manipulation of cerium oxide nanoparticles on titanium surface to regulate cell fate and bone formation. Adv Sci. 2018;5(2):1700678. doi:10.1002/advs.201700678

129. Ball JP, Mound BA, Monsalve AG, Nino JC, Allen JB. Evaluation of the biocompatibility of porous cerium oxide foam for orthopedic tissue engineering. J Biomed Mater Res A. 2015;103(1):8-15. doi:10.1002/jbm.a.35137

130. Karakoti AS, Tsigkou O, Yue S, etc. Rare earth oxides are used as nano additives in 3-D nanocomposite scaffolds for bone regeneration. J Material Chemistry. 2010;20(40):8912–8919. doi:10.1039/c0jm01072c

131. Hu Y, Du Y, Jiang H, Jiang GS. Cerium promotes the migration and osteogenic differentiation of bone marrow stromal cells through the Smad1/5/8 signaling pathway. Int J Clin Exp Pathol. 2014; 7(8): 5369-5378.

132. Mandoli C, Pagliari F, Pagliari S, etc. CeO2 nanoparticles induce stem cell growth in the PLGA scaffold, which has improved biological activity of regenerative medicine. Advanced functional materials. 2010;20(10):1617-1624. doi:10.1002/adfm.200902363

133. Bal Z, Kushioka J, Kodama J, etc. The use and release of BMP and TGFSS in bone regeneration. Turkey J Medical Science. 2020.

134. Chen M, Zhang Y, Zhang W, Li J. The incorporation of polyhedral oligomeric silsesquioxane into gelatin hydrogel promotes angiogenesis in the process of vascularized bone regeneration. ACS application program interface. 2020;12(20):22410–22425. doi:10.1021/acsami.0c00714

135. Nethi SK, Nanda HS, Steele TWJ, Patra CR. Functionalized nano-cerium oxide exhibits improved angiogenesis properties. J Mater Chem B. 2017; 5(47): 9371–9383. doi:10.1039/C7TB01957B

136. Li Jie, Kang Fei, Gong Xiao, etc. Cerium dioxide nanoparticles promote the hypertrophy and differentiation of BMSCs through DHX15 activation, thereby enhancing the regeneration of critical-size bone defects based on endochondral ossification. FASEB J. 2019;33(5):6378-6389. doi:10.1096/fj.201802187R

137. Xiang Jie, Li Jie, He Jie, etc. The scaffold interface modified by cerium oxide nanoparticles enhances the vascularization of bone grafts by activating the calcium channels of mesenchymal stem cells. ACS application program interface. 2016; 8(7): 4489-4499. doi:10.1021/acsami.6b00158

138. Walkey C, Das S, Seal S, etc. Catalytic properties and biomedical applications of cerium oxide nanoparticles. Environmental Science Nano. 2015;2(1):33-53. doi:10.1039/C4EN00138A

139. Zhou Li, Tang Shun, Yang Li, etc. Cerium ions promote osteoclast formation by inducing reactive oxygen species. J Trace Elem Med Biol. 2019;52:126-135. doi:10.1016/j.jtemb.2018.12.006

140. Arslan K, Akbaba GB. In vitro genotoxicity evaluation and comparison of cerium(IV) microparticles and nanoparticles. Toxicology Industrial Health. 2020;36(2):76–83. doi:10.1177/0748233720913349

141. Aimonen K, Catalan J, Suhonen S, etc. Genotoxic and inflammatory effects of uncoated and coated CeO2 NPs in mice. Toxicology Wright. 2016;258:S276. doi:10.1016/j.toxlet.2016.06.1965

142. Turin-Moleavin IA, Fifere A, Lungoci AL, etc. Antioxidant activity in vitro and in vivo of novel magnetic cerium oxide nanocomposite. nanomaterials. 2019;9(11):1565. doi:10.3390/nano9111565

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