Calcium predominantly accumulates in bones and teeth in the form of hydroxyapatite, serving as a fundamental constituent of bone tissue. Hydroxyapatite is also a crucial element in commercial materials used for bone substitutes, scaffolds, and coatings (Bayat et al., 2017). Ca²⁺ functions as a pivotal intracellular signaling ion, orchestrating biological processes by regulating the transcription of numerous genes and transcription factors in all cells within the human body (Karadjian et al., 2019). It not only initiates signal during events such as cell proliferation, mitosis, and differentiation but also governs the cell cycle and enhances cell adhesion. Throughout tissue remodeling, local fluctuations in Ca²⁺ concentration can impact cellular behavior. Studies have demonstrated that lower concentrations of Ca²⁺ facilitate the migration of human osteoblasts, while higher concentrations promote their differentiation, thereby facilitating cell spreading and focal adhesion contacts (Lei et al., 2018). A significant body of research has substantiated that Ca²⁺ can stimulate osteogenesis. The release of Ca²⁺ from biomaterial surfaces can activate calcium ion channel transport proteins and one or more downstream signaling pathways, including the MAPK, cAMP-PKA, and PI3K-AKT pathways, thereby fostering osteoblast differentiation (Liu et al., 2014). It has also been suggested that Ca²⁺ is involved in regulating osteoblast differentiation through the activation of the Wnt/β-catenin signaling pathway, inducing heightened expression of osteogenic differentiation markers in mesenchymal stem cells, and consequently fostering bone formation (Bolander et al., 2016). Thus, the introduction of Ca²⁺ into coatings applied to the surface of titanium and its alloys can modify their surface chemistry. The integration of Ca/P ions into titanium implants enhances their interaction with surrounding bone, directly influencing the expression of osteogenic-related genes and the entire process of bone integration, thereby augmenting bone cell responses to the implants (Li et al., 2004). Such surfaces containing calcium can regulate the cell cycle of bone cells, encouraging osteoblast adhesion, proliferation, and differentiation, thus having the potential to enhance bone integration. Calcium salts exhibit good solubility (under acidic conditions) and can dissolve in water without precipitating when in contact with various electrolytes, enabling calcium to be directly incorporated into titanium implant surface coatings through a single MAO technique (Li et al., 2004; Ribeiro et al., 2015; Huang et al., 2018c; Rokosz et al., 2018; Li Y. et al., 2020; Kuroda et al., 2023), as illustrated in Supplementary Table S2.

Strontium is a vital trace element present within the human skeletal system, belonging to the alkaline earth metal group alongside calcium. It holds close ties to bone metabolism and can substitute for calcium to create strontium hydroxyapatite, a compound that can coexist with calcium in biomaterials. Extensive research has indicated that strontium exerts a dual impact on bone cells, promoting osteoblast differentiation while inhibiting osteoclast activity (Finke et al., 2007; Pemmer et al., 2013). The recently developed drug strontium ranelate has emerged as a highly effective treatment for osteoporosis. Furthermore, stable strontium exhibits low toxicity, enabling its long-term administration at high doses (Dahl et al., 2001). Sr²⁺ significantly influences the equilibrium between osteoblasts and osteoclasts and aids in bone mineralization (see Figure 3). In tissues rich in osteoblasts, Sr²⁺ activates the classical Wnt/β-catenin signaling pathway, thereby boosting the synthesis of collagen and non-collagen proteins. This, in turn, stimulates osteoblast proliferation and elevates the expression of alkaline phosphatase (ALP) and bone sialoprotein (BSP), facilitating differentiation and mineralization (Yang F. et al., 2011; Cai et al., 2016). Consequently, Sr²⁺ contributes to osteoblast-mediated bone formation (Chen et al., 2021). Conversely, Sr²⁺ intervenes in the NF-κB pathway to regulate osteoclast differentiation through the RANK/RANKL axis (Zhu et al., 2016; Hu et al., 2017). This interference suppresses the expression of mRNA and genes linked to osteoclasts (Mi et al., 2017), thereby restraining osteoclast-driven bone resorption (Wu et al., 2022; Wu et al., 2023).

Materials that incorporate strontium, such as strontium-doped titanium implants, bioactive glasses, bioactive ceramic hydroxyapatite/silicate, and strontium-doped calcium polyphosphate, have exhibited exceptional biocompatibility and osteogenic properties (Park et al., 2012; Yan et al., 2013; Zhang et al., 2016a; Sato et al., 2016; Shen et al., 2022). Nevertheless, animal experiments in this realm are still in their preliminary stages, and the precise mechanisms underlying Sr²⁺'s effects on precursor cells remain elusive, necessitating further comprehensive research. Most strontium salts display good solubility, with 2%–25% of strontium being able to be integrated into the surface coatings of titanium implants using a single MAO technique (Fonseca and Brandi, 2010; Yan et al., 2013; Sato et al., 2016; Zhao et al., 2019b; Wang Y. R. et al., 2023), as outlined in Supplementary Table S2.

Zinc, an essential trace element, plays a pivotal role in cellular development, DNA synthesis, enzyme activity, and biomineralization. It is integral to diverse metabolic and cellular signaling pathways, contributing to normal growth, immune function, and neural development (Storrie and Stupp, 2005). As a metal ion, zinc exhibits osteogenic and antibacterial properties. Adequate zinc levels on biomaterial surfaces have demonstrated the capacity to stimulate bone cells, initiating a cascade of in vivo responses including adhesion, diffusion, proliferation, osteogenic differentiation, and bone formation and mineralization. Zn²⁺ elevates ALP activity and fosters the expression of osteogenic-related genes, such as Runx2, thereby enhancing osteoblast proliferation and the extension of pseudopodia (Thian et al., 2013; Shen et al., 2014; Zhang R. et al., 2018). Furthermore, cellular and molecular evidence suggests that Zn²⁺ acts as a vital cofactor for ALP and collagenase. Supplementation with Zn²⁺ or its incorporation into biomaterials upregulates the expression of osteogenic-related genes (e.g., ALP, collagen type I (COL-I), osteocalcin (OCN), and osteopontin (OPN)), thereby inducing osteoblast differentiation, and subsequently enhancing collagen secretion and calcium deposition, leading to the formation of bone nodules (Hadley et al., 2010; Yusa et al., 2011).

Research has indicated that zinc’s antibacterial properties are stable, long-lasting, and less susceptible to resistance compared to antibiotics (Zackular et al., 2016). Zn²⁺ can disrupt bacterial cell membrane integrity, trigger protein denaturation, and cause cellular content leakage, thus exerting antibacterial effects (Jin et al., 2014). Additionally, Zn²⁺ can impede bacterial cell wall synthesis, hindering the growth and reproduction of bacteria (Ahmed et al., 2019). Some studies have also highlighted zinc’s potential to enhance macrophage phagocytic activity and the release of inflammatory cytokines in polymorphonuclear leukocytes (Wang et al., 2017). Despite its established roles in bone metabolism, the clinical viability of zinc-containing biomaterials hinges on several factors, particularly concerns regarding zinc content and release kinetics (Qiao et al., 2014).

Zinc-enriched titanium implants have the potential to boost bone formation by facilitating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) while concurrently deterring bacterial adhesion and growth, thus mitigating inflammation surrounding the implants (Hu et al., 2012; Ahmed et al., 2019). The integration of zinc onto titanium implant surfaces represents a trend in cationic surface modification, with the release of Zn²⁺ significantly influencing bone integration. Zinc salts, such as zinc acetate, possess good water solubility, and a single MAO technique can be employed to immobilize zinc onto the surface coatings of titanium implants (Hu et al., 2012; Du et al., 2018; Wang et al., 2018; Zhao et al., 2019b; Komarova et al., 2020; Sun H. et al., 2022), as illustrated in Supplementary Table S2.

Magnesium, an essential element crucial for bone health, ranks as the second most abundant divalent cation within cells, exerting a vital role in regulating diverse cellular functions. Roughly 60% of the body’s magnesium is stored in the bone matrix, where it governs the transport of calcium and potassium ions, thereby maintaining structural integrity and functional equilibrium. Additionally, magnesium acts as a cofactor for enzyme activation and inhibition, influencing cellular processes such as cell cycle control, proliferation, and differentiation. Hence, magnesium deficiency can precipitate osteoporosis, making Mg²⁺ supplementation particularly beneficial for osteoporosis patients (Zhang Y. et al., 2016). Mg²⁺ exercises its influence on bone mineral and matrix metabolism via bone metabolism-associated hormones, growth factors, signaling pathway elements, as well as by direct interaction with bone tissue itself (Yan et al., 2019). The influence of magnesium on bone metabolism chiefly manifests in the activation of osteoblasts, fostering the proliferation, differentiation, and adhesion of osteoprogenitor cells. However, excessive Mg²⁺ levels can hinder these processes and extracellular matrix mineralization by competing with Ca²⁺ for calcium ion channels, ultimately promoting bone development.

Studies have indicated that Mg²⁺ enhances the initial biological response surrounding implants and augments the biomechanical strength of bone integration (Reis et al., 2020). Furthermore, as a biodegradable element, magnesium has attracted extensive research attention for its incorporation into biomaterials to facilitate stem cell differentiation into osteoblasts and amplify bone formation (Sun et al., 2013; Li X. et al., 2018; Nabiyouni et al., 2018; Zhao Z. et al., 2021). Capitalizing on the biological attributes of magnesium ions, surface modification techniques utilizing magnesium-containing cations have emerged as a focal point in biomedical exploration. In the realm of bone regeneration, research has unveiled the benefits of introducing magnesium to titanium implants, fostering improved bone integration (Wang et al., 2014; Li X. et al., 2020; Zhang R. et al., 2021), and integrating Mg²⁺ onto nano-porous titanium surfaces to enhance osteoblast maturation (Sul et al., 2005; Wang et al., 2014; Zhao et al., 2019a). The optimal concentration of Mg²⁺ can activate downstream target proteins by modulating Akt expression, thus influencing osteoblast proliferation and differentiation (McGonnell et al., 2012). Moreover, Mg²⁺ has been found to polarize macrophages toward an M2 phenotype, curbing macrophage inflammatory responses in vitro (Li X. et al., 2018). Elevated Mg²⁺ concentrations are linked to reduced production of reactive oxygen species (ROS) and nitric oxide (NO) in immune cells (Son et al., 2007). Additional investigations have demonstrated Mg^2+'s capability to foster vascular regeneration by activating the e-NOS signaling pathway (Vinten-Johansen et al., 2005; de Baaij et al., 2015).

Magnesium salts, such as magnesium acetate, exhibit favorable water solubility and can be integrated into the surface coatings of titanium implants through the single technique of micro-arc oxidation (MAO) (Li X. et al., 2018; Li X. et al., 2020; Zhang R. et al., 2021), as illustrated in Supplementary Table S2.

Copper is an essential trace element within the human body, renowned for its involvement in bone metabolism and antimicrobial properties (Hoppe et al., 2011; Burghardt et al., 2015). In vitro investigations have demonstrated that external Cu²⁺ stimulates ALP activity, augments the synthesis of COL-I, OCN, and OPN, enhances in vitro mineralization, and encourages osteogenic differentiation of mesenchymal stem cells (MSCs) within an osteogenic culture medium (Burghardt et al., 2015). Studies have further indicated that the integration of Cu²⁺ into biomaterial surfaces can induce the generation of ROS, leading to potential damage to lipids, proteins, membranes, and DNA (Borkow and Gabbay, 2005; Nandakumar et al., 2011; Huang et al., 2018a). Furthermore, surfaces containing copper have been shown to enhance macrophage-mediated bacterial phagocytosis and augment bacterial eradication, suggesting an improved bactericidal capacity of macrophages in the presence of copper (Huang et al., 2018b; Huang et al., 2019). Another investigation exhibited that copper nanoparticle coatings, applied to biomaterial surfaces, manifest remarkable antibacterial effects. Even at low concentrations, these copper nanoparticles exhibit favorable biocompatibility, fostering osteoblast proliferation and adhesion, as well as heightening extracellular matrix mineralization (Zhang X. et al., 2018). Moreover, both low and high concentrations of copper nanoparticles are demonstrated to be non-toxic to endothelial cells and to stimulate the release of nitric oxide and vascular endothelial growth factor (Zhang X. et al., 2018). Numerous studies have corroborated the interaction of Cu²⁺ with various angiogenesis-related growth factors, including vascular endothelial growth factor (VEGF), angiogenin (ANG), and matrix metalloproteinases (MMPs) (Jacobs et al., 2020). The addition of Cu²⁺ to bone regenerative materials can significantly elevate the expression of hypoxia-inducible factor-1α (Hif-1α), consequently upregulating the expression of genes and proteins associated with angiogenesis (Gerard et al., 2010; Wu et al., 2013).

While the optimal concentration of Cu²⁺ within diverse biomaterials has been extensively explored, some literature has indicated that elevated Cu²⁺ concentrations might induce cytotoxic effects and inhibit cellular activity (Zhang et al., 2016b). Hence, it is imperative to ensure the safety of copper-containing biomaterials. An optimal strategy to achieve this safety entails maximizing osteogenic rates both in vitro and in vivo while minimizing the copper content. Copper salts, such as copper sulfate, possess notable water solubility under acidic conditions, allowing the incorporation of copper ions (Huang et al., 2018a; Huang et al., 2019; Shimabukuro et al., 2020) or copper nanoparticles (Zhang X. et al., 2018) into surface coatings of titanium implants through the utilization of the single MAO technique, as illustrated in Supplementary Table S2.

Cobalt is an essential trace element and functions as a cofactor for numerous metalloproteins within the human body (Fraga, 2005). Co²⁺ has been demonstrated to modulate the expression of various genes associated with cytokine, chemokine, and regulatory molecule production, which play crucial roles in osteoblast functionality. In the realm of osteogenesis, mesoporous bioactive silicate glass scaffolds containing low concentrations of Co²⁺ have been observed to amplify the osteogenic response of bone marrow stromal cells (Wu et al., 2012). Furthermore, Co²⁺ can stabilize Hif-1α and subsequently activate downstream target genes like VEGF, making it a common choice for in vitro simulation of hypoxic environments (Wu et al., 2012). Nevertheless, excessive doses or prolonged exposure to Co²⁺ can impede cell growth, provoke cellular damage, and even induce apoptosis, potentially stemming from heightened oxidative stress (Lee et al., 2013). Research suggests that this cellular impairment is instigated by the generation of reactive oxygen species through the activation of Erk1/2 and NF-κB signaling pathways (Yang C. et al., 2011). Notably, elevated Co²⁺ levels have the potential to induce cytotoxic effects, underscoring the critical importance of ascertaining optimal and safe dosages when integrating it into implant surfaces (Zhou and Zhao, 2016b).

Extensive investigations have illustrated that cobalt can be incorporated into titanium alloy scaffolds through the utilization of MAO techniques. In vitro studies employing mesenchymal stem cell (MSC) culture models have indicated that titanium alloy scaffolds containing cobalt exhibit favorable cell compatibility, heightened angiogenesis, and osteogenic attributess (Wu et al., 2012; Perez et al., 2015; Zhou and Zhao, 2016a). Cobalt salts (e.g., cobalt acetate) possess good water solubility and can be integrated into the surface coatings of titanium implants using a singular MAO approach (Zhou and Zhao, 2016a; Zhou and Zhao, 2016b; Zhao Q. M. et al., 2021), as outlined in Supplementary Table S2.

Silver is one of the trace elements present in human tissues and has been utilized for thousands of years as a natural antibacterial material due to its extensive antibacterial spectrum and reduced propensity for generating resistance. In recent times, silver nanoparticles (AgNPs) have garnered significant interest as a classical antibacterial agent in the realm of antibacterial activity (Zhang Y. Y. et al., 2021; Wang H. et al., 2023; Wang Y. R. et al., 2023; Maj et al., 2023). The appeal of AgNPs can be attributed to various factors. Firstly, silver particles possess a substantial surface area-to-volume ratio and robust penetrability. Secondly, AgNPs exhibit remarkable bactericidal properties, ensuring prolonged resilience against bacteria. Additionally, they boast high-temperature stability and low volatility, yielding enduring antibacterial effects. The antibacterial mechanisms of silver are widely acknowledged through two modalities: contact-based eradication and ion-mediated eradication. AgNPs can attach to bacterial cell walls, inducing membrane damage that leads to leakage of intracellular contents and bacterial demise. The release of Ag⁺ ions from AgNPs also assumes a pivotal role in displaying antibacterial efficacy. The antibacterial potential of Ag⁺ ions has been substantiated (Calabrese et al., 2021); however, it may impose adverse effects on cells, underscoring the significance of controlled Ag⁺ release to mitigate unwanted outcomes.

Silver has additionally exhibited anti-inflammatory attributes and the capacity to induce the differentiation of stem cells into osteoblasts. Consequently, the incorporation of Ag⁺ ions onto the surface of titanium implants using MAO techniques can augment the initial adherence of BMSCs. Ag⁺ ions collaborate with the MAPK/ERK signaling cascade to activate osteogenic markers, enhance ALP activity and mineralization levels, and upregulate the expression of osteogenic genes, culminating in enhanced bone integration (Shimabukuro et al., 2019). Hence, incorporating silver into the surface of titanium and its alloys can enhance the antibacterial, anti-inflammatory, and osteogenic properties of titanium implants. Silver salts (such as silver nitrate) exhibit good water solubility and can be incorporated into the surface coatings of titanium implants using a single MAO technique. Thus, the integration of silver onto the surfaces of titanium and its alloys can heighten the antibacterial, anti-inflammatory, and osteogenic properties of titanium implants. Silver salts (e.g., silver nitrate), with favorable water solubility, can be seamlessly incorporated into the surface coatings of titanium implants through a singular MAO technique (Jia et al., 2016; Shimabukuro et al., 2019; Zhang L. et al., 2020; Zhang Y. Y. et al., 2021; Sun H. et al., 2022; Maj et al., 2023), as depicted in Supplementary Table S2.

There are several other metal cations that can be incorporated onto the surface of titanium implants using MAO technology, including manganese (Mn), iron (Fe), lithium (Li), vanadium (V), aluminum (Al), gold (Au), and others (refer to Supplementary Table S2). Among these, the absence of manganese (Mn) may lead to issues such as delayed bone formation and bone deformities. Coatings containing manganese, produced through MAO technology on the surface of titanium implants, exhibit remarkable corrosion resistance and can release Mn²⁺ over an extended duration, thereby exerting inhibitory effects on Escherichia coli and Pseudomonas aeruginosa. Concerning osteogenesis, Mn-doped titanium implants have demonstrated significant contributions to bone formation (Kang et al., 2018). Manganese can enhance osteoblast differentiation by influencing the parathyroid hormone signaling pathway, regulating bone mineral density, and augmenting overall bone formation (Zhang X. et al., 2020). However, excessive levels of manganese can have toxic effects on osteoblasts. Regarding iron (Fe), studies have demonstrated that Fe²⁺ incorporated within titanium dioxide coatings can chemically disrupt cell membranes and notably enhance the antibacterial activity of MC3T3-E1 cells (Tian et al., 2014). Increasing Fe²⁺ concentration can enhance fibroblast responses, encompassing proliferation, phenotype, and extracellular collagen secretion (Li K. et al., 2019), while also promoting osteoblast proliferation, expression of osteogenic genes, and extracellular matrix mineralization (Li K. et al., 2018). Recent research concerning lithium (Li) has indicated that employing MAO technology can generate titanium scaffolds with lithium-containing nano-porous coatings. In both in vitro and in vivo experiments, Li⁺ has shown to significantly enhance the biocompatibility and osteogenic potential of bone repair materials. Additionally, it has been demonstrated to stimulate the expression of ALP and osteogenic genes in osteoblasts through activation of the classical Wnt/β-catenin signaling pathway (Liu et al., 2018).