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Titanium (Ti) and its alloys have been extensively used as implant materials in clinical practice due to their high corrosion resistance, light weight and excellent biocompatibility. However, the insufficient intrinsic osteogenic capacity of Ti and its alloys impedes bone repair and regeneration, and implant-related infection or inflammation remains the leading cause of implant failure. Bacterial infections or inflammatory diseases constitute severe threats to human health. The physicochemical properties of the material are critical to the success of clinical procedures, and the doping of Cu into Ti implants has been confirmed to be capable of enhancing the bone repair/regeneration, angiogenesis and antibacterial capability.
- implant
- titanium and titanium alloys
- copper doping
- synthetic methods
1. Introduction
Titanium (Ti) and its alloys have been widely used in human implants, such as dental implants, hip and knee replacements, bone plates and screws, owing to their good mechanical properties, excellent corrosion resistance and optimal biocompatibility [1,2,3][1][2][3]. However, these materials are susceptible to bacterial infections because of their biological inertness, low osteogenic and insufficient antibacterial ability [4,5][4][5]. In orthopedic surgery, periprosthetic infections can lead to the loosening of the prosthesis, failure of joint fusion, amputation and even death.
For dental implants, inflammatory disease around the implants often leads to the loss of surrounding bones and consequently affects the longevity of the implants, which is the most common cause of implant failure. The average prevalence of peri-implantitis was 22%, with a positive correlation to the time of placement [6], whereas 5–11% of implants were failed and must be removed [7]. For orthopedic replacement, the risk of infection is around 0.4% to 16.1%, depending on the extent of fracture [8,9][8][9]. After total knee arthroplasty, the probabilities of periprosthetic joint infection at the knee, hip and ankle locations were 0.5–2% [10], 2–9% [11] and 0.3–1.7% [12], respectively.
In recent years, many pieces of research have shown that Cu-doped Ti implants are resistant to bacterial adhesion and biofilms due to the release of Cu ions from the coating surface. In addition to the antibacterial effects, Cu ions could also enhance the differentiation of bone marrow stem cells (BMSCs) to osteoblasts, which is associated with bone regeneration [17][13]. Therefore, introducing Cu can give Ti and its alloy implants improved osteogenesis ability without reducing the biocompatibility.
2. Preparation Techniques and Related Properties of Cu-Doped Ti Implants
2.1. Ion Implantation
Plasma immersion ion implantation (PIII) has been widely used for the modification of Ti surfaces. The PIII involves the implantion of target metal ions as dopants into a suitable substrate utilizing pulsed, high-voltage direct current or pure direct current [41[14][15],42], without changing the surface morphology of the substrate [19][16]. In addition, the technique also offers a high bond strength between the modified layer and the bulk material.
Compared to other methods, the PIII is highly reliable and reproducible [43][17] and is able to dope various elements, including Ag [43][17], Ca [44][18], Mg [45][19] and Zn [46][20] into Ti implants. More importantly, the amount of the dopants can be easily controlled by adjusting the plasma time, pressure, pulse duration and pulse frequency during the injection process [47][21], which provides a convenient and feasible way to tune the surface property.
It is now well established from various studies that the implantation of Cu ions into Ti by PIII technology has many advantages. Liu et al. [48][22] used the PIII technique to dope Cu into Ti implants and studied the effects of the Cu content on the bacterial and cellular behavior of Ti surface by adjusting the implantation time. They found that a shorter plasma treatment time (e.g., 1 h) resulted in a low Cu concentration and thus no significant antimicrobial effect on Escherichia coli (E. coli), while a longer plasma time (e.g., 2 or 3 h) led to an enhanced antimicrobial performance.
Dual ion implantation can effectively improve the mechanical properties and corrosion resistance of Ti and reduce the cellular toxicity following the implantation of Cu. C/Cu co-implantation can effectively improve the mechanical properties of the Ti surface, and the formed Cu/C galvanic corrosion pair can improve the corrosion resistance of the Ti surface [51][23]. In contrast, the Cu implantation can only slightly increase the nano-hardness value of the Ti surface, probably due to the presence of internal metallic Cu [52][24].
Overall, the co-implantation of multiple ions could become a promising direction to enhance the overall performance of Ti implants. For example, the co-implantation of copper ions with non-metallic ions can solve problems such as the reduced corrosion resistance of the material caused by the implantion of copper ions. While the co-implantation of copper ions with other metal ions (e.g., Sr, Ca and Mg) could also enhance the functionality, such as the antibacterial activity as well as osteogenic and angiogenic properties. Conventional ion implantation technology often suffers from complicated operations and expensive costs. Research on ion implanted copper is mainly focused on plasma immersion implantation, while research on other ion implants, such as ion assisted deposition, is very rare and needs to be further developed.
3.2. Alloy
2.2. Alloy
The main methods of alloy preparation include ingot metallurgy, powder metallurgy, selective laser melting etc. [56][25] Among them, arc melting [57,58,59][26][27][28] and powder metallurgy are the common methods for preparing alloys. The arc melting method involves introducing a certain percentage of the metal material into a clamp and then, after repeated evacuations, filling the vacuum furnace with protective argon gas. Afterwards, the plasma arc of the electrodes is heated to melt the elements completely, and then the entire melt is solidified into an alloy using rapid cooling with water.
The arc melting process is simple and has a wide range of applications, but the castings have disadvantages, such as component segregation, coarse structure and internal shrinkage. The powder metallurgy method uses metal powder as raw material and prepares the alloys by ball milling, mixing, extruding and sintering, which results in a more uniform alloy composition; however, the toughness of the casting is relatively poor.
However, the hardness, strength and corrosion resistance of the samples were improved after thermal treatment (900 °C for 2 h), which had little effect on the antibacterial properties. The treatment of 900 °C/2 h + 400 °C/12 h further improved the hardness, corrosion resistance and mechanical strength and significantly improved the antibacterial effect. The Ti-Cu alloy prepared by the sintering process, on the other hand, had better corrosion resistance and hardness than the as-cast Ti-Cu alloy, as well as a better yield strength.
Compared to pure Ti, the Ti-Cu alloy had significantly higher hardness, yield strength and compressive strength [15,18][29][30], which can be explained by the solid solution strengthening of Ti and the fine precipitation of intra-metallic compounds that may be similar to dental silver amalgam [61,62][31][32]. Unlike the Cu-doped Ti surface prepared by ion implantation [50][33], the Ti-Cu alloy had improved corrosion resistance [15][29].
2.3. Electrochemical Techniques
Common electrochemical treatment techniques include electrodeposition, anodic oxidation, micro-arc oxidation etc. The electrodeposition method is used for electroplating. Typically, two metal electrodes are immersed in a specific electrolyte and an external electric field is applied to deposit the required metal on the working electrode. Electrodeposition has proven to be one of the most versatile methods for preparing nanostructured coatings [74][34], with features that are superior to conventional deposition techniques (e.g., low processing temperatures, low-cost equipment, possibility of fabrication on porous substrates with complex shapes and simple control of coating properties) [75,76][35][36]. Micro-arc oxidation (MAO), also known as plasma electrolytic oxidation (PEO), was derived from anodic oxidation technology. It uses arc discharge to enhance and activate the reaction occurring on the anode to form a high quality reinforced ceramic film on the surface of metal substrate. The micro-arc oxidation film has the characteristics of strong adhesion with matrix, compact structure, high toughness, good wear resistance and corrosion resistance. MAO produces a hard and thick porous TiO2 coating and, as the voltage rises during the generation of the TiO2 film, a large number of micro-arc discharges break through the oxide film. The target ions and oxygen within the electrolyte then enter the inner regions of the coating through these discharge channels, resulting in a coating doped with bio-functional ions (e.g., Zn, Ca, Cu, P, Ag and Bi) [77,78,79,80][37][38][39][40]. Many studies have demonstrated the superiority of MAO technology for treating Ti-based materials for medical devices. MAO coatings doped with calcium (Ca) and phosphorus (P) can improve the biocompatibility of Ti substrates [81,82,83,84][41][42][43][44]. Due to the good properties of Cu ions, such as the antibacterial properties exhibited at low concentrations with low cytotoxicity [85][45], many researchers have used the MAO technique to incorporate Cu ions together with other bio-functional ions onto Ti surfaces in one step to prepare antibacterial coatings, and the effectiveness of this approach has already been proven. Appropriate doses of Cu can promote the up-regulation of osteogenic-related proteins, such as ALP, OCP and OCN in osteoblasts and bone mesenchymal stem cells [33][46].3.4. Sputtering
2.4. Sputtering
Magnetron sputtering is a process where atoms or molecules are ejected from a target by bombardment of high-energy plasma, which then travel through the vacuum environment and deposit onto a substrate. During the sputtering process, the electrons on the target surface are accelerated under the action of an electric field and collide with the sputtering gas Ar to produce argon ions and secondary electrons [104][47]. The magnetron sputtering technique is capable of preparing thin films with strong bonding to the substrate, and the preparation conditions are simple and controllable, which can avoid the defects and adverse effects caused by chemical methods during the preparation process [105][48]. The formation and growth of thin films are strongly influenced by the plasma parameters and energy (particle) flux [106,107][49][50]. Conventional direct current magnetron sputtering (dc-MS) is typically characterized by low ionization and ion flux [108,109][51][52]. The main features of high-power pulsed magnetron sputtering (HiPIMS) operating at low frequencies (~100 Hz) and short pulse widths are higher ionization of sputtered particles and higher ion fluxes [110,111][53][54]. Dual sputter source high power pulsed magnetron sputtering (dual-HiPIMS) can be used for the deposition of multicomponent films and alloys [112][55]. Stranak et al. [113][56] applied the above three different techniques to deposit Cu-containing films with different chemical compositions on Ti6Al4V substrates. Generally, these films are composed of Ti and Cu metals; however, a few oxides are also formed on the surface of the films. The films with different releases of Cu ions could be achieved by Dulbecco’s Modified Eagle’s Medium (DMEM), where the dual-HiPIMS technique produces films with higher Cu content and density and can be completely released in DMEM [113][56]. Among these films, only the films prepared by dual-HiPIMS technique showed antibacterial effects against the planktonic bacteria S.S. epidermidis epidermidis and S. aureus, which may be related to the rapid release of Cu ions.3.5. Sol-Gel
2.5. Sol-Gel
The Sol-gel method uses compounds that contain highly chemically active components as precursors, which are uniformly mixed under the liquid phase and then undergo hydrolysis and condensation chemical reactions to form a stable and transparent sol system in solution. The solute is slowly polymerized between the aged gel particles to create a three-dimensional network structure of the gel, and the gel network is filled with a solvent that loses its fluidity to form the gel. The gels are dried, sintered and cured to prepare molecular or nanostructured materials. Cu-doped TiO2 monolayer and multilayer coatings on Ti6Al4V alloy substrates and CuO/TiO2 composite nanofibers were obtained using the sol-gel method [124,125][57][58]. In the former, titanium isopropoxide was used as the Ti precursor, copper (II) acetate hydrate and Cu powder as the Cu precursor [124][57]. The latter results in nanofibers with good morphology, while the former has a negative effect on the morphology of the nanofibers, and the one-dimensional structure of the coating was completely destroyed after calcination [124][57]. The CuO/TiO2 nanofibers prepared with Cu powder have anatase and rutile phases, while the CuO present in the Cu-containing nanofibers has excellent crystallinity. CuO/TiO2 nanofibers showed good antibacterial activity against Klebsiella pneumoniae, and the inhibitory effect on Klebsiella pneumoniae was enhanced with the increase of nanofiber concentration [124][57]. Higher concentrations of CuO/TiO2 nanofibers showed excellent toxicity against the tested pathogenic strain [124][57]. The latter used copper nitrate and titanium isopropoxide as the precursors of CuO and TiO2, respectively, to prepare CuO/TiO2 nanorods using the electrostatic spinning process [125][58].3. Conclusions
Pros and cons of different surface modification:- (1) The process of ion implantation is more complex and thus difficult to operate but results in little damage to the material surface and does not change the original size and roughness of the implants. Therefore, it is very suitable for the processing of precision substrates. Due to its high strength and corrosion resistance, titanium alloy has been widely used in clinical applications. However, its wear resistance is poor, and the corrosion products of particles entering human tissue after wear may lead to implant failure. The ion implantation technology can effectively strengthen its surface wear resistance.
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The process of ion implantation is more complex and thus difficult to operate but results in little damage to the material surface and does not change the original size and roughness of the implants. Therefore, it is very suitable for the processing of precision substrates. Due to its high strength and corrosion resistance, titanium alloy has been widely used in clinical applications. However, its wear resistance is poor, and the corrosion products of particles entering human tissue after wear may lead to implant failure. The ion implantation technology can effectively strengthen its surface wear resistance.
- (2) The MAO technology has the advantages of simple and fast processing process; however, its high energy consumption leads to high commercialization costs.
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The MAO technology has the advantages of simple and fast processing process; however, its high energy consumption leads to high commercialization costs.
- (3) The magnetron sputtering coatings have a superior bond with the substrate, the coating thickness can be tuned by adjusting the process parameters, and the co-sputtering of different metals can be realized, which is suitable for industrialization. However, it faces problems, including low target utilization and difficulty in sputtering magnetic targets.
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The magnetron sputtering coatings have a superior bond with the substrate, the coating thickness can be tuned by adjusting the process parameters, and the co-sputtering of different metals can be realized, which is suitable for industrialization. However, it faces problems, including low target utilization and difficulty in sputtering magnetic targets.
- (4)
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Although sol-gel methods easily achieve doping at the molecular level, they are expensive in principle and time consuming, which will increase the cost of commercialization. Overall, there is a trend to use different surface modification methods simultaneously to achieve better antibacterial effects and to promote osseointegration—for example, Ti-Cu alloys with combined sandblasting and acid etching technology and Ti-Cu alloys with combined anodic oxidation technology, magnetron sputtering and ion implantation technology.
- Although sol-gel methods easily achieve doping at the molecular level, they are expensive in principle and time consuming, which will increase the cost of commercialization. Overall, there is a trend to use different surface modification methods simultaneously to achieve better antibacterial effects and to promote osseointegration—for example, Ti-Cu alloys with combined sandblasting and acid etching technology and Ti-Cu alloys with combined anodic oxidation technology, magnetron sputtering and ion implantation technology.