Dental implants occupies an important position in the field of tooth loss restoration. However, dental implants still have risk factors such as implant infection and imperfect osseointegration. In order to enhance the osseointegration and antibacterial properties of implants, researchers have done a lot of research on the modification of implant materials, and the modification of trace elements is one of the hot spots. Studies have shown that trace elements such as silver, zinc, fluorine, strontium, and manganese are closely related to oral health and have excellent performance in antibacterial and osteogenesis. Microelement modified implants are of great significance to improve the success rate of dental implants and improve the treatment effect.
1. Application technology of surface modification of titanium implants with trace elements
1.1 Plasma immersion ion implantation method
The traditional ion implantation method is to accelerate the charged ions into the surface of the material vertically to form a coating with special properties. The plasma immersion ion implantation (PIII) is an improvement of the ion implantation method. This method immerses the material in the plasma and performs ion implantation from multiple angles, which solves the problem that the ion implantation technology has harsh requirements for the implantation angle, and the technology does not affect the surface structure of the material, and is suitable for materials with complex structures such as implants.
"The composition of the surface film after injection can be the simple substance of the modifying element, the oxide of the modifying element, or the compound of the modifying element and the matrix element, depending on the material composition of the modifying element and the matrix and the conditions during injection. For example, when titanium implants are modified by non-metal elements, compounds such as TiN and TiF4 can be formed. When titanium implants are modified by metal elements, ZnO, MgO or pure metallic zinc or magnesium deposits can be formed.
1.2 Micro arc oxidation method
Micro arc oxidation (MAO) is to form a thick and stable oxide film on the metal surface by relying on the instantaneous high temperature generated by arc discharge in the electrolyte. The composition and performance of the film are mainly affected by the chemical composition of the electrolyte. The thickness, pore size and roughness of the oxide produced by this method are also easier to control than other methods. Similar to the PIII method, the MAO method can still form an oxide film with uniform properties, close adhesion and wear resistance on materials with complex surface structures.
The magnetron sputtering method uses particles to impact the surface of a target in a vacuum, sputtering particles on the surface of the target, allowing them to cool and deposit on the surface of the material to form a nano-coating structure. The coating is relatively thin, but the bond is tighter. The technical characteristics of magnetron sputtering are that the temperature of the substrate is low, the process parameters of the thin film are relatively easy to control, and it is suitable for large-area coating; the electrochemical deposition method is to place the material in the corresponding trace element solution or molten salt, and make the The surface of the cathode material is plated with a metal film. Combining this method with the PIII method is called plasma immersion ion implantation and deposition (PIII&D), which is widely used in the field of biomedicine. For the selection of modification methods, it is necessary to consider the nature of the material, the nature of the modified element, efficiency, energy consumption, etc., and for the same element, whether different modification methods will produce different biological effects can be compared the study.
2. Trace elements used for surface modification of titanium implants
Titanium is a biologically inert material and does not possess biological activities such as osteoinductive and antibacterial properties, and metal implants are subject to electrochemical corrosion in the oral cavity. Simple surface topography modification has limited effect on the biological performance of titanium implants, while trace element modification can give performances that traditional titanium implants do not possess.
Fluoride has a wide range of applications in the oral cavity. Lee et al. used hydrofluoric acid (HF) to etch the titanium disk after sandblasting. The fluoride on the surface of the titanium disk mainly appeared in the form of TiOF2. It was found through the culture experiment of osteoblast-like cells MG-63 on the surface of the titanium disk. Compared with the control group, more cells and more osteogenic-related gene Cbfα1 (Runx2) expression can be observed on the titanium disk etched by HF. The surface wettability of the titanium disc is also improved, which enhances the differentiation activity of the cells.
Wang et al. used the PIII method to inject fluorine into the surface of the titanium implant. The modified surface of the implant added a new surface layer mainly composed of TiF4. The fluorine-modified (F-Ti) implant was effective against Porphyromonas gingivalis. (Porphyromonas gingivalis, Pg) has a lytic effect, which weakens the proliferation of osteoblast-like cells MG-63 and the negative effect on alkaline phosphatase (ALP) activity. The interference of OPG/RANKL, an important pathway in osteoclasts, is related to some extent; in vivo experiments show that F-Ti implants have a stronger ability to chelate calcium ions, resulting in more bone deposits, compared with pure titanium implants in the control group The body has a high degree of implant osseointegration.
Collaert et al. implanted 125 fluoride-modified titanium implants into the mandibles of 25 edentulous mandibular patients. After two years of follow-up, they found that the average bone loss around 125 fluoride-modified implants was only 0.11mm, and there was no implant. Peripheral inflammation occurs, and the success rate can be considered 100%. Before this experiment (2011), the average bone loss of the TiOblast implant used in the clinical experiment with the same surgical operation reached 1.29mm after two years, and the 1-year success rate was 78%.
Strontium is a kind of osteogenic trace element, and the related drug strontium ranelate is used to promote osseointegration around implants. Strontium can stimulate the proliferation of osteoblasts, inhibit the differentiation of osteoclasts, and can inhibit the adipogenic and chondrogenic differentiation of mesenchymal stem cells. Strontium can also inhibit the response of immune inflammatory cells around the implant. Okuzu et al. used strontium to modify the surface of implants by alkaline heating method. Cell experiments showed that compared with the control group, strontium-modified titanium implants effectively increased the expression of osteoblast β-atenin and osteogenic differentiation genes (Runx2, The expression of ALP, OCN, OPN) has also been significantly improved; in vivo experiments show that compared with the control group, the strontium modified implant has better early osseointegration and less bone loss in the later period.
The rapid osseointegration performance of the strontium modified implant obtained by Zhang et al. through the MAO method within 6 weeks is equivalent to that of the commercially available Straumann implant, and is different from the new bone formation direction of the Straumann implant "growth from the implant surface". The osteogenesis direction of strontium-modified implants extends along the surface of the implant, indicating that the degree of osseointegration will further increase. Offermanns et al. obtained a nano-scale titanium-strontium-oxygen (Ti-Sr-O) coating through a magnetron sputtering process and applied it to the surface of the titanium implant, creating a continuous and controllable strontium ion release environment. In the osteoporosis mouse model, the bone formation and osseointegration around the implant were significantly higher than those in the control group. The amount of new bone formation was positively correlated with the amount of strontium ions released. The coating can also make the implant osseointegrate Reach the maximum in advance. Subsequent studies have shown that in normal organisms, Ti-Sr-O coatings are more capable of promoting osteoinductive and early osseointegration of implants than SLActive titanium implants and fluorine-modified implants that are widely used clinically.
Silver ion modified implant has excellent antibacterial and anti-inflammatory ability. Experiments show that silver nanoparticles (Ag-NPs) have inhibitory effects on a variety of oral pathogens. Qiao et al. used the PIII method to embed AgNPs on a titanium implant with a roughened surface. The modified implant not only obtained good antibacterial activity, but also promoted the proliferation of osteoblast-like cells MG-63. And the PIII method releases less free silver, reducing the toxic effects of AgNPs. The co-injection of silver and other elements into the implant surface is also the current research direction.
Zhao et al. used the PIII method to co-inject magnesium and silver into the surface of titanium implants and found that the antibacterial and osteoinductive effects of magnesium and silver co-injection implants are stronger than those modified by magnesium or silver alone, showing osteogenesis Cells have stronger ALP activity and higher expression levels of osteogenic related genes. In vivo experiments show that the amount of co-injected implants is greater and the implant osseointegration is stronger. The osteoinduction effect of co-injected implants may be related to the formation of magnesium-silver micro-battery. Magnesium acts as an anode in the micro-battery. This structure can promote the release of magnesium ions. At the same time, silver acts as a cathode, reducing the release of silver and further reducing the amount of free silver. The cytotoxicity.
In the field of dental implants, there are more studies on zinc in promoting osseointegration. The zinc injected by Zhu et al. through the PIII method is present as ZnO on the surface of the titanium implant, and in the form of elemental zinc in the deep part, and the biological effect of the zinc-modified titanium implant is related to the voltage during zinc injection. When the injection voltage is 15kV When it rises to 30kV, the ability of the implant to promote cell proliferation and antibacterial is improved. Zinc can be injected not only alone, but also in combination with other elements.
Yu et al. injected zinc ions and magnesium ions into the surface of titanium implants by the PIII method, and observed that the growth of a variety of oral anaerobes was inhibited. Compared with zinc or magnesium ions injected alone, implants co-injected with zinc and magnesium ions also have the activity of promoting angiogenesis, and can improve the expression of bone mesenchymal stem cells (BMMSCs) osteogenic genes, Improve cell adhesion and growth activity, promote rapid osteogenesis, maintain long-term osteogenesis, and improve the strength of osseointegration. This may be related to the synergistic effect of zinc and magnesium ions in the process of osteogenesis.
Tantalum can promote implant bone formation and inhibit bacterial proliferation. Shi et al. found that the promotion of osteogenesis by tantalum may be related to the activation of Wnt/β-atenin and TGF-β/Smad signaling pathways, and tantalum also has an inhibitory effect on osteoclasts. The performance of tantalum modified implants is closely related to the particle size of tantalum. Nano-tantalum has better osteoinductive properties than microporous tantalum. In vivo studies by Lee et al. have shown that the porous tantalum trabecular bone modified titanium implants (Trabecular metal? Dental Implants, TM) have better bone-promoting performance and performance than TSV (Tapered Screw-Vent? Because the amount of new bone formation is greater, the trabecular bone microstructure is better. Compared with traditional titanium implants, titanium implants modified with porous tantalum trabecular bone have a lower risk of bone loss.
Zhu et al. used a magnetron sputtering method to cover the surface of titanium implants with a micro/nano coating containing tantalum, and observed that it has a certain inhibitory effect on the adhesion of the main pathogenic bacteria in the oral cavity. The mechanism may be due to the effect of BMMSCs on tantalum. The high adhesion effect is specific, that is, it is not affected by bacteria, and the surface of this high cell adhesion implant reduces the chance of bacterial adhesion, thus showing a bacteriostatic effect.
Cobalt can inactivate hypoxia inducible factor (hypoxia inducible factor, HIF) specific prolyl hydroxylase, thereby stabilizing HIF-1, activating downstream genes, and achieving the effect of activating osteogenesis. Zhou et al. used the MAO method to cover the surface of titanium implants with cobalt-doped titanium dioxide/calcium phosphate coatings, and found that the incorporation of cobalt caused cells around the implants to express higher levels of cytokines related to blood vessels and bone formation, and blood vessels and The bone formation effect is positively related to the amount of cobalt incorporated.
The study also found that when strontium, cobalt, and fluorine were co-injected onto the surface of the implant through the MAO method, in vitro antibacterial experiments showed that the antibacterial rate of co-injected implants could reach 95%; and in terms of promoting angiogenesis and osteogenesis, co-injection implants The body is better than the three elements of strontium, cobalt and fluorine injected separately or in pairs. However, excessive cobalt element can easily lead to cytotoxicity, and repeated experiments are needed to determine its optimal concentration and long-term biological toxicity.
Manganese has been proved to play an important role in the process of osteogenesis. The lack of manganese may lead to problems such as slow bone formation and bone deformation. Yu et al. used PIII&D and MAO methods to cover the surface of titanium implants with a manganese-containing coating to construct an environment that can release manganese ions for a long time. The manganese coating has a certain inhibitory effect on E. coli and Pseudomonas aeruginosa. In terms of osteogenesis, manganese can enhance the differentiation of osteoblasts and increase the overall bone formation. The reason may be that manganese affects the parathyroid hormone signaling pathway, thereby regulating bone mineral density. However, excessive manganese has a toxic effect on osteoblasts. The manganese-containing coating prepared by the PIII&D method releases less manganese ions than the manganese ion prepared by the MAO method, and has better biological safety.
Heo et al. implanted gold nanoparticles into the surface of silanized titanium implants. The gold-modified implants can enhance osteoblast differentiation and increase the expression of osteogenic differentiation-specific genes (COL1, Runx2, OCN, BSP, etc.) in human adipose stem cells , Improve the activity of ALP, increase the deposition of calcium salt, and promote the formation of the implant osseointegration interface. Studies have found that gold nanoparticles can participate in signal pathways such as p38/MAPK and ERK/MAPK to promote osteogenesis. Li et al. used cerium (Ce) to modify the surface of titanium implants, and obtained nano-cerium oxide coatings with different Ce3+/Ce4+ ratios on the surface of titanium implants by magnetron sputtering. With the increase of Ce4+ content, the vitality of BMMSCs The formation and mineralization level of new bone around the implant also increases.
``In summary, different trace elements have their own advantages. For example, strontium, tantalum and other elements have obvious promoting effect on bone formation, and elements such as silver and zinc have better antibacterial effects. The joint use of two or more elements will achieve better results than the use of one element alone. At present, some element-modified implants have been used in clinics (fluorine, tantalum, etc.), and some implants even have better antibacterial and osteogenic effects than commercially available implants. One of the primary problems facing the modified implants of trace elements is how to find a suitable value in the low concentration range where the trace elements play a role. It is necessary to ensure that the trace elements can effectively perform their biological functions and to ensure their The body has the least potential side effects.