The main factors that cause implant placement failure are infection, microfracture, and surgery. Among them, bone resorption around the implant material is one of the main causes of implant failure. The most important cause of failure is currently considered to be aseptic loosening, which accounts for 20% of the failure rate. Aseptic loosening occurs when the bone at the implant-bone interface is destroyed, dissolved and resorbed, resulting in the loosening and loss of the implant. To date, the pathophysiological mechanisms underlying the occurrence of osteolysis in metal implants are not well understood. Many studies have shown that peri-implant bone resorption occurs due to increased osteoclast activity and decreased osteoblast bone formation capacity. Bauer and Purdue PE, among others, found that a large number of wear debris particles in the microenvironment around the bone-implant interface produced by long-term wear of the implant triggered a series of inflammatory responses and bone resorption, mainly due to the activation of macrophages that had phagocytosed the wear particles and produced a series of regulatory mediators leading to the production of mature osteoclasts. The phenomenon and mechanism of bone resorption due to wear particles is widely recognized, however, it has been suggested that, in addition to wear particles, metal ions released from the implant surface and from bioerosion of the wear particle surface play a potential role in aseptic loosening. Although the widely used titanium and its alloys have good biocompatibility and corrosion resistance, titanium is not absolutely safe for the human body. Immediately after implantation, the implant is surrounded by a layer of extracellular fluid and proteins, and is subjected to repeated wear and tear by external forces for a long time in the complex body fluid environment, resulting in the production of wear particles on the surface of the titanium implant and the release of titanium ions. Several studies have shown that high concentrations of titanium ions have been detected in the tissues surrounding titanium implants, even in the body fluids of patients after titanium arthroplasty, and in distant organs (including liver, spleen, lymph nodes). There is increasing evidence that the release of metal ions around implants is an important cause of aseptic loosening of implants. The release of titanium ions Although pure titanium has generally good mechanical properties and is highly resistant to corrosion, pigmentation and granulomas formed in the soft and hard tissues around the titanium implant can be found during secondary surgery due to the free flow of titanium ions, and titanium particles are widely found in the surrounding tissues under light and transmission electron microscopy, even in the liver, spleen, lymph nodes, bone marrow and even blood and urine of patients after knee and hip arthroplasty. More titanium ions are present in the urine, but the release of titanium after dental implant placement is low, and current studies have not found high concentrations of titanium ions in distant sites. In 1960 Ferguson first reported the release of titanium ions around titanium implants, and the concentration of titanium ions in the surrounding tissues was 20 times higher than in normal tissues 4-6 months after implantation, reaching 11.4 – 13.1 ppm. Ducheyne et al. compared the ability of titanium materials with different pore sizes on the surface to release ions, and they found that sparse porous titanium specimens, 12 months after implantation Bianco et al. investigated the release of titanium ions around titanium implants in the absence of wear particles and showed that there was a local accumulation of titanium ions and that the concentration of titanium ions increased with time. Bianco et al. investigated the release of titanium ions around titanium implants in the absence of wear particles and showed that there was localized accumulation of titanium ions and that the concentration of titanium ions increased with time, but there was no widespread distant propagation. In addition, Mu Y et al. pointed out that the release of titanium ions at 48 hours of implant placement is mainly due to surgical trauma and dissolution of wear particles. Even without the presence of wear particles, titanium ions are still released. Her-Hsiung Huang et al. found that the release of titanium ions from titanium implants with nitrided surfaces was significantly less than that from untreated ones, and affected the cell adhesion capacity. In general, the release of titanium ions from the tissues surrounding the titanium implants is related to the number of implants, alloy type, volume, size, surface morphology, treatment method, as well as the surrounding body fluids, body metabolism, external stress, etc., independent of the surface roughness, and the distant release and deposition in the distant organs is reflected in total joint replacement patients, but not in implant patients so far. The effect on osteogenesis Bone marrow stromal cells are stem cells with multi-directional differentiation potential. They can differentiate into osteoblasts under the induction of vitamin C, dexamethasone and β-glycerophosphate, and express osteoblast marker proteins such as alkaline phosphatase (ALP), type I collagen and osteocalcin (OCN). Thompson GJ et al. observed the effect of non-lethal doses of metal ions on bone marrow stromal cells and found that non-lethal doses of titanium ions did not affect cell proliferation, but almost completely inhibited OCN secretion and matrix mineralization, indicating that titanium ions interfered with the differentiation of bone marrow stromal cells to osteoblasts and thus bone formation. further studies, indicating that metal ions released from the implant surface play a role in the aseptic loosening of joints and implants, and that non-lethal doses of ions released from the Ti-6Al-4V alloy inhibited the expression of osteoblast phenotype and the deposition of mineralized matrix, significantly inhibiting osteocalcin synthesis, suggesting that the ions released from the implant may contribute to peri-implant bone resorption. Liao H [20] et al. reported the effect of titanium ions on mineralization and bone-like nodule formation in rabbit skull bone osteoblast cultures, and showed that a concentration of 10 ppm of titanium ions significantly inhibited cell proliferation, and concentrations less than 5 ppm had no significant effect on cell proliferation, and less than 5 ppm had no effect on the number of mineralized nodules, but mineral deposition was significantly inhibited by 5 ppm of ions, even if the titanium ions were removed at the beginning of mineralization, the deposition of calcium salts during the subsequent formation of mineralized nodules was also inhibited. At the same time, 5 ppm Ti significantly reduced osteonectin (OSN) and osteopontin (OPN), while OCN was reduced to a lesser extent, and titanium ions delayed the expression of ALP mRNA, which genetically altered the ratio of components required for bone synthesis, thus affecting osteogenesis. Osteoblasts undergo three stages of bone formation: osteoblast proliferation, extracellular matrix maturation, and extracellular matrix mineralization. oPN and OSN are important components of the extracellular matrix and are involved in the construction, proliferation, migration, differentiation, and adhesion of the extracellular matrix, promoting osteoblast-like cells to adhere to the extracellular matrix [21], and have important roles in cell signaling and regulation of cell function. ALP is an early marker of extracellular matrix maturation, and osteoblasts secrete ALP and calcium salt crystals into the extracellular matrix, where ALP increases the local phosphate content and contributes to matrix mineralization. OSN has a high affinity for type I collagen and hydroxyapatite and can regulate the mineralization of type I collagen in vitro. OSN is involved in the initiation of bone mineralization and can trigger Ca2+ and phosphate crystallization in sub-stable Ca2+ and phosphate solutions. Titanium ions inhibit the expression of ALP, OSN, OPN and OCN during the differentiation of bone marrow stromal cells into osteoblasts and the mineralization of osteoblast-secreted matrix. The specific molecular signaling mechanism is not yet clear. In addition, Norman C et al [22] studied the effect of Ti4+ and V5+ ions in the formation of hydroxyapatite (HA), and the release of titanium ions interfered with the normal osteoid mineralization and reconstruction. The mechanism is unknown, as titanium ions dose-dependently reduce HA formation, bind to the HA crystalline surface and disrupt the crystal growth sites. In short, titanium ions inhibit the osteogenic capacity of osteoblasts by inhibiting the differentiation of osteogenic precursor cells into mature functional osteoblasts, inhibiting the proliferation of mature osteoblasts, the secretion of mineralized matrix, mineralization and deposition of calcium salts. The main reasons for bone resorption at the implant-bone interface are: convergence of more osteoclast precursor cells, promotion of their differentiation and activation of the function of osteoclast precursor cells to become functional mature multinucleated osteoclast-like bone resorbing cells and prolonging the life span of osteoclasts. The release of these factors also further promotes osteolysis. Cadosch D [23] found that titanium ions can chemotacticize monocytes and induce their differentiation into mature functional osteoclasts, leading to osteolysis. It was found that titanium ions induced the differentiation of human monocytes into functional osteoclasts in 20% of the population, while titanium ions had no significant effect on the function of osteoclasts that had already differentiated in the presence of M-CSF and RANK-L, but only slightly inhibited it. In terms of molecular expression, they found that the expression of tartrate resistant acid phosphatase (TRAP) and histone proteinase K (CATK) increased significantly, TRAP staining positive cells increased, and the expression of chemokines 17 and 22 (CCL17 and 22) The expression and secretion of chemokines 17 and 22 (CCL17 and 22) were significantly increased. Titanium ions induce the differentiation of monocytes into mature functional osteoclasts, activate the expression of a series of genes specific to mature osteoclasts and the secretion of related proteins, recruit osteoclastic precursor cells in the circulation and induce their differentiation into mature osteoclasts may be one of the important mechanisms of aseptic loosening. cathepsin K is expressed at low levels in osteoclastic precursor cells, but is highly expressed in the process of osteoclast formation. Titanium ions may bind to phosphorylated proteins, lipids, adenosine, etc. Titanium ions may bind to certain phosphorylated proteins, thus inducing a series of signal transduction pathways unknown to us, activating cathepsin K expression, and binding to specific nucleotides to produce expression of some genes, thus promoting monocytes to mature osteoclasts. differentiation. K.G. Nichols [26] et al. suggested that titanium ions do not enhance or even slightly diminish the activity of differentiated mature osteoclasts, and that titanium ions cause osteolysis not by promoting bone resorption but by interfering with osteogenesis. There is a reciprocal regulatory mechanism between osteoblasts and osteoclasts, in which osteoblasts or bone marrow stromal cells express the receptor activator of NF-kB ligand (RANKL) and macrophage colony stimulating factor (M-CSF), which are associated with osteolysis. factor (M-CSF) are associated with osteoclast formation, and the binding of RANKL on the surface of osteoblasts and RANK on the surface of osteoclast precursor cells triggers a series of reactions that promote the differentiation and maturation of osteoclast precursor cells into functional osteoclasts and inhibit the apoptosis of osteoclasts. Osteoblasts and bone marrow stromal cells simultaneously secrete and express osteoprotegerin (OPG), which binds competitively with RANKL, preventing the binding between RANKL and RANK and preventing excessive bone resorption [27]. Therefore,the ratio of RANKL to OPG is crucial to maintain the local bone metabolic homeostasis. Titanium ions may disrupt the communication between osteoclasts and osteoblasts, act directly on osteoclastic precursor cells and disconnect them from osteogenic derivatives such as M-CSF and RANKL, or disrupt the balance between RANK and OPG, leading to dysregulation of osteogenesis and osteolysis and causing bone resorption. Therefore, the effect of titanium ions on osteoclasts is mainly reflected in these aspects: 1, chemotaxis and promote the differentiation of osteoclastic precursor cells into mature and functional osteoclasts, 2, low concentrations of non-lethal doses of titanium ions have little effect on mature osteoclasts, while high concentrations of titanium ions significantly inhibit their bone resorption capacity, 3, titanium ions interfere with the link between osteoclasts and osteoblasts, disrupting their mutual regulatory mechanisms, resulting in the imbalance of bone metabolism. leading to the imbalance of bone metabolism. In conclusion, titanium ions reduce bone formation, mineralization and repair by inhibiting the differentiation of osteogenic precursor cells into mature osteoblasts and inhibiting the expression of a series of cytokines, chemotaxis of osteoclastic precursor cells and promoting their differentiation into mature osteoblasts without inhibiting the function of osteoclasts, leading to bone resorption, and possibly interfering with the coupling between osteogenesis and osteolysis, resulting in an imbalance between osteogenesis and osteolysis. The molecular mechanism and the possible signaling mechanism However, the molecular mechanism and the possible signal transduction pathway need to be further investigated. Meanwhile, to further prevent aseptic loosening and reduce the failure rate, the material and surface of the implant should be reasonably treated to reduce the release of metal ions.