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Review

Surface Bio-Functionalization of Anti-Bacterial Titanium Implants: A Review

by
Junhao Sui
,
Shu Liu
,
Mengchen Chen
and
Hao Zhang
*
Department of Orthopedics, Changhai Hospital Affiliated to the Navy Military Medical University, Shanghai 200433, China
*
Author to whom correspondence should be addressed.
Coatings 2022, 12(8), 1125; https://doi.org/10.3390/coatings12081125
Submission received: 19 June 2022 / Revised: 21 July 2022 / Accepted: 1 August 2022 / Published: 5 August 2022
(This article belongs to the Special Issue Application of Coatings on Implants Surfaces)
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Abstract

:
Titanium (Ti) and titanium alloy have been widely used in orthopedics. However, the successful application of titanium implants is mainly limited due to implant-associated infections. The implant surface contributes to osseointegration, but also has the risk of accelerating the growth of bacterial colonies, and the implant surfaces infected with bacteria easily form biofilms that are resistant to antibiotics. Biofilm-related implant infections are a disastrous complication of trauma orthopedic surgery and occur when an implant is colonized by bacteria. Surface bio-functionalization has been extensively studied to better realize the inhibition of bacterial proliferation to further optimize the mechanical functions of implants. Recently, the surface bio-functionalization of titanium implants has been presented to improve osseointegration. However, there are still numerous clinical and non-clinical challenges. In this review, these aspects were highlighted to develop surface bio-functionalization strategies for enhancing the clinical application of titanium implants to eliminate implant-associated infections.

1. Introduction

Titanium implants have been well developed and adopted to restore the structures and functions of the skeletal system, e.g., fixation of fractures, correction of deformities, joint replacement, and bone void fillers. Orthopedic titanium implants include various prosthetic joints and osteosynthetic materials (wires, pins, screws, and plates). A growing body of evidence demonstrated that clinical challenges associated with implant failure in orthopedic surgery are mainly attributed to implant-associated infections and the lack of enough bone for implants [1]. The clinical application of orthopedic implants for a long time is inevitably associated with the possibility of infection [2]. To date, no effective treatment strategy has been presented for the successful eradication of bacterial infections or prevention of its recurrence. Once infection occurs, the most effective treatment is surgical excision of the implant and local debridement, accompanied by substantial social and economic burden. It was reported that implant-associated infections in surgical procedures occur in up to 5% of patients, and efficacious interventions are urgently required to prevent and treat implant-associated infections [3,4].
Despite the great advances in orthopedic surgical techniques and optimized designing of implants, infection is still a potential complication and has noticeably attracted clinicians’ attention [5]. According to surveys performed in the UK and USA, the annual infection rate after knee or hip arthroplasty was in the range of 1%–2% and has continued to increase in recent years [6]. Infections after internal fixation occur in 1%–2% of closed fractures and in up to 30% of open fractures [7]. The main pathogen causing infection in orthopedic surgery is Staphylococcus aureus (S. aureus), a Gram-positive bacterium. Once planktonic bacteria bind to the surfaces of the implant, they may proliferate rapidly and secrete extracellular matrices that are rich in lipopolysaccharides, teichoic acids and proteins, leading to the formation of sessile bacterial communities, namely biofilms, which are highly resistant to the host immune system and antibiotic therapy. The formation of biofilms results in device-associated infections, leading to the implant failure. Implants that have bactericidal properties which will minimize bacterial colonization and biofilm formation could timely eradicate them on the implant surface and prevent their invasion and harboring within the periprosthetic tissue environment. Therefore, their development remains to be the top priority in eradicating periprosthetic infections.
The systemic administration of antibiotics is a common strategy to treat postoperative implant-associated infections, while local antibiotics are preferred. A growing body of evidence demonstrated that the frequent use of locally applied antibiotic-loaded biomaterials, particularly antibiotic-loaded polymethyl methacrylate bone cement, has contributed to the problem of drug resistance in bone surgery [8]. Designing implants with antibacterial properties is one of the most effective strategies to prevent and treat implant-associated infections, and it is especially of use to reduce bacterial adhesion and inhibit biofilm formation. Surface coating and modification are the most commonly used methods for the modification of implants. In recent decades, a great number of studies have concentrated on the antibacterial coating, surface modifications, and antimicrobial agents for deposition onto the implant surface. To date, several materials with antibacterial properties have been developed, such as silver nanoparticles (AgNPs), cerium oxide nanoparticles (CeO2NPs), copper (Cu), polymers (e.g., chitosan), carbon nanostructures and antimicrobial peptides (AMPs). They have further been employed in combination with implants/biomaterials due to their good compatibility and a broad bactericidal spectrum.
The present review aimed to concentrate on titanium implants and their surface characteristics (See Table 1). Additionally, an attempt was made to summarize the latest advances in the bio-functionalization of titanium implants, discuss the main strategies to prevent implant-associated infections, and suggest the future perspectives to control implant-associated infections.

2. Research Highlights on Antibacterial Surface Treatment for Orthopedic Implants

2.1. Metal Coating

The chemical surface and structure of implants may vary according to changes in the surface layer of implants through physical or chemical reactions, such as oxidation or mechanical modifications. In addition, silver (Ag), gold (Au), zinc (Zn), Cu, and magnesium (Mg) were widely used as antibacterial coatings because of their excellent antimicrobial properties and effectively inhibiting a variety of microbes, including Gram-positive and Gram-negative bacteria [9,10,11,12,13,14]. Some of the synthesized samples are shown in Figure 1. Ionic substituted calcium phosphate coatings loaded with Ag and Zn could be prepared using the pulsed current electrochemical deposition technique, and they have shown superior antibacterial properties to the pure hydroxyapatite [15]. Sutha et al. [16] prepared Zn incorporated hydroxyapatite (HAP) coatings on the implants through the spin coating method and found that the antibacterial properties of the Zn-HAP coating were enhanced when Zn concentration exceeded 6 mol%. In order to achieve antibacterial ability, other metals, such as Mg, Cu, and Au, have been loaded onto implants. Excellent bioresorbable, osteoconductive, and antibacterial properties have been demonstrated for Mg and its alloys for bone repair in the osteosynthetic application [17]. Cu can kill the bacteria in a short time by closely contacting with them, while different from the main mechanisms, including cell membrane damage and reactive oxygen species (ROS) generation [18]. The antibacterial properties of Au have been confirmed, although Au ions have minimal ion release in vivo [19,20,21]. Besides, it was found that metal-organic frameworks, which are porous coordination materials composed of organic ligands and metal ions, can enhance the antibacterial properties of the implants because they can release large amounts of metal ions at the early-stage [22].
The antibacterial mechanisms of metal coating mainly involve several processes that were summarized as follows: (1) metals can lead to protein dysfunction; (2) additionally, they can result in the production of ROS and the depletion of antioxidants; (3) there is evidence that certain metals impair membrane function; (4) nutritional assimilation can be affected by certain metals; (5) it is also possible for them to be genotoxic [23]. It is noteworthy that the Ag ions can exert remarkable bactericidal effects even at very low concentrations, while those effects can be enhanced with increasing Ag concentrations, indicating the necessity of the study of cytotoxicity of Ag ions. Research also shows that no noticeable cytotoxic response for 2, 5, 7.5, and 10 mol% Ag-containing mesoporous silver-doped bio-ceramics (MBCs) exists [24]. There was a lack of consistent data to show the necessary dose of silver to lead to argyria in the literature. One of the studies demonstrated that a minimum amount of 1.8 g silver is necessary to cause argyria, but other authors quoted 4–6 g [25,26,27,28]. It is possible that silver absorbed into human tissues from implants will enter the systemic circulation as a protein complex. Silver overexposure can cause diarrhea, hypotension, stomach irritation, and bradypnea [29]. Argyrosis caused by fine deposits of silver metal could last long or be permanent, but it would not be life-threatening. Patients who are subject to long-term exposure to implants that would release high levels of silver have experienced Argyria-like symptoms [30]. It is known that Cu at high concentrations can be toxic [31,32]. There was no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) was related to a total Cu intake of 0.8 mg and 1.2 mg [33]. The first symptoms of poisoning were nausea and vomiting, followed by abdominal pain and diarrhea [34]. Chronic Cu toxicity is mainly influential on the liver. Typically, Cu toxicity could be manifested by the development of liver cirrhosis, which comes with episodes of hemolysis and damage to renal tubules, the brain, and other organs [32]. Besides, Cu toxicity is suspected to contribute to neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, and binding sites for Cu were identified in amyloid plaques [31,35]. Cu can also interfere with or influence many metabolic, regulatory, immunity and functional pathways in the body [31,36]. Many metals are toxic to all cell types at high doses. The studies have shown that Mg ions at a concentration of 3 mM can enhance human osteoblast activity, but a concentration of 5 mM will suppress it [37,38]. Gold NPs up to 250 mM were not toxic, while the ionic gold at 25 mM was cytotoxic [39]. The concentrations of zinc ions released from the Zn-Ti surface were estimated to be lower than the cytotoxic limit that inhibits the proliferation and differentiation of osteoblast [40]. Regarding the cytotoxicity of other metal particles, their concentrations should be controlled to prevent potential side effects. To reduce metal toxicity in cells, it is suggested to reduce the particle size of metals and to optimize their concentrations in biomaterials and their release profiles. Toxicity to the human body could be averted by changing the route of administration or confining these toxic substances to implant surfaces.

2.2. Nanocomposite Coating

In biotechnology, the nanoscale study has revealed the effective control rate achieved by manipulating the nanosurface properties of materials, which can control and guide protein adsorption, cell adhesion, and proliferation [41,49]. In recent years, several studies have employed nanotechnology to construct nanoscale surfaces in an attempt to manipulate and improve the antibacterial functions of implant surface materials, including physical, chemical, and mechanical properties [50]. It was reported that many researchers put forward various metal nanocomposite coatings [51,52,53,54,55,58,59,60], which have a higher antibacterial activity and lower cytotoxicity than metal coatings [56,57]. Some of the nanocomposite coatings are shown in Table 2. However, high concentrations of nanometals are cytotoxic, depending on their type, size, total surface area, and agglomeration [61,62]. The formation of chelates with the metal nanoparticles (NPs) can alter the metal release behavior of implant materials from burst to long-lasting. Nanoparticles have been demonstrated to be an effective carrier for controlled- or sustained-release formulations. Drug carriers effectively protect drugs against inactivation and achieve sustained, controlled, or even targeted release, resulting in increased therapeutic effectiveness and reduced toxic sideeffects [63]. The nano-Ag-epidermal growth factor (EGF) sustained-release carrier consisting of AgNPs exhibited a promising and sustained antibacterial activity by sustained, controlled releasing of nanoparticles, effectively promoted cell division and proliferation, and decreased cytotoxicity [64]. To eliminate the problem of nanometals toxicity, Nusret et al. [65] embedded AgNPs to design an Ag ions-doped calcium phosphate-based ceramic nanopowder, of which the active surface area was maximized while maintaining the total amount of Ag at a low level below the toxicity threshold for cells. However, further in vitro and/or in vivo animal investigations are warranted. And in this study, silver-coated implants also had a lower rate of colonization. All rabbits with implant colonization also had growth of bacteria on the culture of the swab used in the medullary canal. The presence of zinc oxide (ZnO) in the genipin-crosslinked chitosan (GC)/poly (ethylene glycol) (PEG) matrix inhibited the proliferation of bacteria effectively. Most of all, previous studies have demonstrated that ZnO exhibited antimicrobial activities on a broad spectrum of bacteria and is non-toxic [66,67,68]. Liu et al. [69] successfully prepared a novel nanocomposite of GC/PEG film through sol-cast transformation, in which various amounts of ZnO nanoparticles. A lubricated orthopedic implant surface (LOIS) was developed to prevent bacterial infections associate, meaning that there was a micro/nanostructured orthopedic implant surface tightly combined with a thin lubricant layer [70]. The in vivo femoral fracture model in rabbits demonstrated the superior antibacterial property and biocompatibility of LOIS. However, the infection-related inflammation remains problematic due to the anti-repellent properties of the lubricant layer infused in the hierarchical micro/nanostructured surface. Additionally, there are still unmet challenges for LOIS to be integrated with osteoinduction. To integrate the selective adhesion of osteoinductive cells or regenerative medicine with LOIS, further research is required to solve the problem.
To date, several mechanisms have been proposed to inhibit the growth and kill invading bacteria. First, NPs kill bacterial cells by damaging the cell membranes, which is similar to the bactericidal mechanism of AgNPs [18,71,72,73,74,75]. Second, another mechanism is inhibiting enzymatic activity and inducing oxidative stress and ROS generation [72,76,77]. It was suggested that copper nanoparticles (CuNPs) can interact with oxidative organelles or redox active protein to induce ROS generation in cells, while Cu ions produced by NPs can also induce ROS generation by different chemical reactions [78]. Third, metal ions directly interact with the functional group of proteins, inhibit cell wall synthesis and related cellular functions, directly bind to the bacterial genes and inhibit DNA replication, thereby hindering bacterial proliferation [79,80,81]. In addition, mechanisms, such as the inhibition of energy metabolism [82], increased membrane permeability [83,84,85], and physical penetration [86], may also be involved in antibacterial activity.
Table
Table 2. Composition and antibacterial mechanism of nanocomposite coating.
Table 2. Composition and antibacterial mechanism of nanocomposite coating.
Composition of Surface CoatingAnti-Bacteria PropertiesAnti-Bacteria Ingredients or MechanismsReferences
Ag/HA nanocomposite coatingInhibition of S aureus and E coli biofilm formationRelease of silver nanoparticles[58]
DLC surfaces containing silver nanoparticlesReduction the growth of S aureus and S epidermidisRelease of silver[59,60]
NanoAg-EGFStrong inhibitory actions against the five pathogenic organismsSustained release of nanosilver[64]
Silver ion-doped ceramic nanopowder coatingAn increase in resistance to bacterial colonizationControlled release of Ag+ ions; keep the total amount of silver low[65]
GC/PEG/ZnO/Ag nanocompositesHigh antibacterial activity toward E. coliRelease of ZnO and Ag nanoparticles[69]
Lubricated orthopedic implant surface (LOIS)Inhibition of P. aeruginosa and MRSA biofilm formationThe self-healing property of lubricants in micro/nanostructured surfaces; repel the adhesion of various liquids[70]

2.3. Antibiotic Coating

The locally sustained-release antibiotic delivery strategy is considered as a promising alternative to systemic antibiotic delivery, which targets antibiotics to the selected sites and releases them at high concentrations over a long period of time [87,88,89]. First, high local doses that do not cause systemic toxicity can lead to high efficacy at the specific local site. Additionally, antibiotics can be delivered locally to target specific peri-implantitis pathogens and prevent potential antibiotic resistance. The drugs included conventional antibiotics, such as gentamicin, amoxicillin, carbenicillin, vancomycin, and cephalothin, which were incorporated in sustained-release antibiotic delivery devices [4]. The two most important factors, the strategy of drug incorporation into the coatings and the drug release rates from coatings, can highly influence the effectiveness of antibiotics [90]. Zhang et al. [91] prepared vancomycin-coated titanium implants by electrospinning, which exerted antibacterial properties in vitro and in vivo. There are several limitations: (1) the effect on other bacterial strains was unknown; (2) the longer-term efficacy of the vancomycin-loaded coating was also unknown. It is well-known that gentamicin is an effective antimicrobial agent for the treatment of bone infections because of its antimicrobial activity [92,93]. Gentamicin is an aminoglycoside, water-soluble antibiotic commonly used to prevent and treat bacterial infections in orthopedics [94]. A previous study utilized the electrophoretic deposition process (EPD) to produce bioactive hydroxyapatite/chitosan (HAP/CS) and hydroxyapatite/chitosan/gentamicin (HAP/CS/Gent) coatings on titanium, in which favorable osteopromotive and antibacterial properties could be achieved [95].

3. Surface Topography Modification

By loading or diffusing substances on the surface of implants, the coating forms an additional layer. Surface modification refers to the modification of the thin layer on the surface of implants at the atomic, molecular, or geomorphological level [96]. According to a previous study, it was shown that the physicochemical properties of implant surface, including topography, stiffness, surface charge, hydrophilicity, and hydrophobicity, can selectively promote or prevent the adhesion of bacteria [97,98]. Surface properties of implant materials, such as surface roughness and surface nano-micro-hierarchical structure, can be altered by surface morphology modifications [99,100]. A variety of surface modification techniques, such as anodization [90,101], layer-by-layer modification [102,103], electrodeposition [104], etc., have been used in orthopedic implants. Some of these are shown in Table 3. See Figure 2, it was demonstrated by our research group that the interconnected micro-patterned structured titanium rods loaded with vancomycin could be applied for preventing titanium implant-associated infections [105]. Some material surfaces with nanostructured topographic features have successfully reduced bacterial adhesion [106,107,108]. Colon et al. [109] employed methods, such as cold compaction, compression, calcination, etc., to produce ZnO and titanium dioxide (TiO2), and then, implanted them on titanium, which led to the reduction of S. epidermidis adhesion and increased osteoblast functions necessary to promote the efficacy of orthopedic implants. There are several techniques (e.g., photolithography, femtosecond laser, electron beam radiation, chemical etching, anodization, etc.) for synthesizing nanostructures [110], of which, the laser surface modification is associated with high levels of controllability and flexibility. A growing body of evidence has demonstrated the potential of laser for altering the surface properties of biomaterials to improve their biological and tribological functions [111]. It is well-known that the topographic features of the surface are essential for bacterial adhesion. It was found that bacteria (e.g., Pseudomonas aeruginosa, S. aureus, Escherichia coli (E. coli), and Helicobacter pylori) are sensitive to the space between adjacent pillars [112,113]. Xu et al. [107] confirmed that nanostructured polyurethane urea (PUU), with two sizes of square arranged nanopillars, can reduce adherence to staphylococci and inhibit biofilm formation. The surface nanostructures that rupture and physically deform bacterial cells may be achieved by mechanical stress [114,115]. It was reported that bacteria can be killed by the antibacterial nanoarrays fabricated on titanium surfaces using a simple hydrothermal etching process, and the nano-wire arrays were found to be strikingly similar to the natural bacterial nano-patterns found on dragonfly wings [116,117]. It was suggested that the surface modification technique could not only increase the bactericidal properties of the surface, but also enhance the ability of the substrate to adhere human cells [116]. In addition, materials with nanopatterned surfaces appeared to have significant antibacterial effects against antibiotic-resistant bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) [118].
In order to improve the antibacterial ability and corrosion resistance of titanium implants, various modification techniques have been presented, such as fabricating nanotubes via loading of nanopolymer coatings and the incorporation of metals. The fabrication of nanotubes on titanium surfaces was reported as an efficient approach to improving the bioactivity of titanium. Besides, as shown in Figure 3, the size of titanium-nanotube (Ti-NT) particles should be controlled to effectively load antibiotics, enabling immobilization of titanium nanotubes with polydopamine and hyaluronic acid to control the drug release [119]. Titanium-based coatings have high biocompatibility, making them attractive in the field of biomedicine. Wu et al. [120] reported an N-halamine polymeric coating on the titanium surface that simultaneously has long-lasting renewable antibacterial efficacy with good stability and biocompatibility. Through the combination of electrospinning and atomic layer deposition, a bilayer system consisted of an acrylic polymeric coating containing synthesized zinc oxide nanotubes on a polyethylene substrate was successfully developed. Compared with active materials containing commercial zinc oxide nanoparticles (ZnONPs), higher microbial inhibition against Gram-negative bacteria was achieved [121].
Table
Table 3. Composition and antibacterial mechanism of surface topography structure.
Table 3. Composition and antibacterial mechanism of surface topography structure.
Composition of Surface Topography StructureAnti-Bacteria PropertiesAnti-Bacteria Ingredients or MechanismsReference
Vancomycin-loaded Ti coatings with interconnected micro-patterned structureProphylaxis against MRSA infectionMicro-patterned structure inhibit bacterial adhesion and biofilm formation
Bactericidal effect of vancomycin		[105]
Nanophase ZnO and TiO2Reduce S. epidermidis adhesionROS generation; release of Zinc ion; bacterial cell membrane damage[109]
Micro-to nano-scale patterning mimicked the surface architecture of dragonfly wingsReduce almost 50% of Pseudomonas aeruginosa cells and 20% of the Staphylococcus aureus cells adhesionNano-wire arrays make the surface moderately bactericidal[116]
Micro-grooved surfacesPrevent bacterial colonizationThe formation of a biological seal[117]
Hydrothermally grown oxide layers composed of nanoflowers, nanopetals and nanofibersAntibacterial properties against Staphylococcus aureus and methicillin resistant Staphylococcus aureusThe interaction of bacterial cells with the nano-sized pointed morphologies[118]
Polydopamine and hyaluronic acid immobilisation on vancomycin-loaded titanium nanotubeAntibacterial ability against S. aureus
Inhibit the formation of bacterial biofilms		Titanium nanotubes inhibit the bacterial biofilms
Bactericidal effect of vancomycin
Dopamine can control drug release		[119]
N-halamine polymeric coatingLong-lasting renewable antibacterial efficacyTi-PAA-NCl can kill the key bacteria and prevent the formation of bacterial biofilm[120]
An antimicrobial polymeric bilayer structure containing hollow zinc oxide nanotubesPresent the highest activity against Gram-negative bacteriaAntimicrobial effectiveness is dependent on zinc oxide concentration[121]

4. Covalently Grafted Bioactive Agents to the Titanium Surfaces

Grafting and coating are the most important and frequently utilized membrane surface modification methods [122]. Some scholars have engineered the surface of implants by introducing additional superficial functionalities, in which several surface characteristics, such as hydrophilicity, antibacterial properties, and pH-dependent solubility could be modulated and regulated to a certain extent [123,124,125,126,127,128]. By incorporating antibiotics, proteins, and AMPs with different functions into implant design, bioactive surfaces have been synthesized to facilitate specific biological responses [129,130,131]. It was reported that ionic polymer models, such as poly (sodium styrene sulfonate) (polyNaSS), were directly grafted onto titanium and titanium alloy surfaces by a two-step reaction. A study on bacterial adhesion showed that titanium and titanium alloy surfaces grafted with polyNaSS exhibited a high level (>70%) of inhibition of S. aureus adhesion compared with non-grafted titanium and titanium alloy surfaces [132,133,134]. Chen et al. [135] grafted Melimine, a synthetic AMP, onto titanium surfaces by various groups and chemical bonds, and Melimine coating significantly reduced in vitro adhesion and biofilm formation of P. aeruginosa (up to 62%) and S. aureus (up to 84%) on titanium substrates compared with blank surfaces, while ensuring good biocompatibility [136]. It has also been shown that grafting polyNaSS onto titanium surfaces by dopamine anchor exhibited antimicrobial effects against S. aureus [137]. DJK-5, a cationic peptide, was developed and considered as a promising candidate to covalent modification of antibacterial titanium [138]. Magainin I (Mag I) remarkably reduced the bacterial adhesion and inhibited the growth of the remaining adherent bacteria [139]. In order to achieve a controlled, “smart”, local delivery of antibiotics, a novel, biodegradable coating using branched poly (ethylene glycol)-poly (propylene sulfide) (PEG-PPS) polymer was designed to deliver vancomycin and tigecycline both passively and actively. This polymer is novel because it combines the passive elution of antibiotics with an active-release mechanism that targets bacteria to prevent postoperative implant-associated infections [140]. Covalent grafting with an AMP on the titanium surface is an excellent approach to fabricating antibacterial titanium. This approach could fabricate a contact-kill antibacterial surface and decrease bacterial resistance.
Although coatings with a single function have been extensively developed, there is a lack of an easy and reliable method to produce clinically applicable implants with dual and multiple functions. As shown in Figure 4, Yang et al. [141] used 3-glycidyloxypropyltrimethoxysilane (GPTMS), as a coupling agent, to covalently immobilize hyperbranched poly-L-lysine (HBPL) polymers on the alkali-heat treated titanium substrates and implants, accompanying by promising antibacterial activities against S. aureus and E. coli, with in vitro antibacterial efficiencies as high as 89.4% and 92.2%, respectively. A previous study confirmed that the HBPL-modified implants had good antibacterial and anti-inflammatory abilities at the early-stage of implantation, as well as a better osseointegration. To achieve antibacterial, osteogenic properties, and reduction of macrophage inflammation, a study demonstrated that bacitracin was successfully covalently immobilized to the titanium surface through bonding of the amino group of its C-terminal carboxyl on the surface [142,143].

5. Multicomponent Coating

Applying the multifunctional coating is an appealing approach, especially in recent years, for the surface treatment to develop biologically inspired surfaces of Ti biomaterials. Therefore, increasing investigations have been seen in the new multicomponent polymer-based coatings with capabilities for both strengthening the bioactivity and antimicrobial activity of Ti biomaterials [144,145]. Due to the advantages, such as high biocompatibility, low toxicity, biodegradability, hydrophilicity, and relatively low cost, sodium alginate (NaC6H7O6) is a promising polymeric coating matrix for bioactive and antibacterial particles. However, the limited stability, poor mechanical properties, and lack of bioactivity and antibacterial properties are its major drawbacks [146,147,148,149,150]. Hydroxyapatite (HAP) with osteoinductive and osteoconductive capabilities has great potential for orthopedic applications [151]. The addition of HAP into alginate improves its mechanical stability and induces bioactivity and cytocompatibility [152]. Graphene oxide (GO) nanosheets have a large surface area, superior strength, and antibacterial properties against a wide range of bacteria [153]. Multicomponent sodium alginate-based coatings reinforced with HAP nanoparticles and graphite oxide (GtO) nanosheets consisting of GO packages were electrophoretically deposited on CP-Ti and Ti-13Nb-13Zr alloy [154]. Nevertheless, the multi-component coating lacks animal experiments to verify its biological function. Ballarre et al. [155] presented a new coating approach developing a multifunctional and dual surface coating system for titanium orthopedic implants by applying two different coating technologies (spray and electrophoretic deposition). The sol-gel sprayed bioactive glass particles (BG) layer combined with electrophoretic deposited chitosan/gelatin/silica (Si)-gentamicin (Ge) nanoparticles presents a suitable approach to generate bioactive and antibacterial surfaces to enhance Ti implant performance. In this study, silica nanoparticles were selected as carriers for the antibacterial agent, which are suitable to promote a controlled drug release simultaneously with their decomposition [156]. A diffusion-controlled mechanism, in which the radial gentamicin concentration inside the particle causes a gradient that becomes the driving force for its own release, is used by nanohybrids [157]. To evaluate the potential adverse long-term effects related to gentamicin release on cell adhesion and proliferation, further investigation is necessary. According to another study, nano-calcium phosphate/chitosan lactate multifunctional coatings on titanium with advanced corrosion resistance, bioactivity, and antibacterial properties have been successfully synthesized by the in-situ method of simultaneous anodization of the Ti substrate and anaphoretic deposition of calcium phosphate-based coatings [158].

6. The Evaluation of Antibacterial Coating

To inhibit the colonization of bacteria, a majority of current technics in the marketplace are based on the release of antimicrobial agents by a coating, such as antibiotics. The locally sustained-release antibiotic delivery is a potential approach for delivering high doses of drugs at a specific local site while minimizing systemic exposure [87,88,89]. However, each drug delivery method has its inherent limitations, including the unsustainability of drugs, the local toxicity problem, antibiotic resistance, and the lack of osteoinduction capacity, which could be the major drawback of this approach. Since the drug elution is finite, the positive effect of this approach will eventually disappear. Further investigation is required for the local toxicity on surrounding tissues while applying this approach. In vivo toxicity of antimicrobial agents and antibiotic resistance would largely limit the clinical usage of the antibiotic coating. Furthermore, the functionality of the antibiotic coating is relatively unitary due to the lack of osteogenesis and osteoinduction capacity. Therefore, implants fail to integrate with living bones, which may lead to aseptic loosening.
Metal and metal NPs are also extensively applied to antimicrobial coating in recent years. Metals, such as Ag, Cu, and Mg, loaded onto implants have been confirmed to kill the bacteria in a short time due to different mechanisms while avoiding the development of resistance to the drug. Apart from antimicrobial activities, some metals also exhibited excellent bioresorbable and osteoconductive properties [17]. Additionally, the metal coating is low-cost and easy to carry out. However, it is generally known that metals could be toxic at high doses to all types of cells and affect many metabolic, regulatory, immunity, and functional pathways.
The nanoscale study has controlled and guided protein adsorption, cell adhesion, and proliferation by manipulating the nanosurface properties of materials [41,49]. Nanoparticles can manipulate the release of drugs to achieve sustained and targeted release. However, further studies are necessary to conclusively determine the clinical applications and the significance of these results. Moreover, nanocomposite coating is of high requirement for the production process.
The surface of implant materials could have multiple functional properties with surface morphology modifications. However, it is worth noting that the topography and geometry of surface texturing also appear to affect cell adhesion and growth. Similarly, the successful design of biomaterials suitable for long-term implantation remains challenging in the treatment of infections related to implants. Clinical applications and the effects of these results still require further investigations.
Similarly, some studies have engineered the surface of implants by introducing additional superficial functionalities to make them multifunctional. However, problems, such as in vivo enzymatic degradation and the high cost of biomolecules, could be limitations for its industrial application. Besides the difficulty of the accessibility to active sites, the stability of biomolecules binding to implant surfaces could be challenging. Additionally, although small-animal models could simplify the experimental procedure, the findings cannot be assumed to be the same as those obtained from larger animals or humans. There is still a lack of research on the host immune response to such infections.
The multicomponent coating is a strategy that integrates a variety of biological functions, but some limitations should be noted, such as limited stability, poor mechanical properties, and lack of bioactivity. Although the coatings can be considered as an appealing potential material for medical implant application, further animal testing in vivo remains necessary.

7. Conclusions and the Future Perspectives

In this review, various approaches related to the surface modification of antibacterial titanium implants were described. Postoperative infections are challenging complications following orthopedic surgery. Therefore, numerous novel surface materials and surface modification strategies were investigated to prevent and treat infections after orthopedic surgery. Each strategy is dependent of different situations, such as the type of bacteria, the desired effect, etc. In addition, a great number of potential limitations, such as the cytotoxicity of implant materials, quality, the cost of synthetic implant materials, and implant lifetime, should be eliminated. The existence of complex chemical materials and design methods, combined with inspiration from nature, may provide great future perspectives for the invention of biomaterials, which may overcome the ongoing limitations and challenges. Several studies have recently concentrated on loading natural antibacterial compounds with good biocompatibility onto orthopedic implants and exploited the antibacterial effects elicited by the released ions. It is suggested to further concentrate on the multi-functionalization of titanium implant materials and their clinical applications, including being biodegradable, biocompatible, supporting tissue attachment, tissue regeneration, cell proliferation, and good integration with the host tissue. Future research will advance the surface modification of antibacterial orthopedic implants.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81702666), the National Natural Science Foundation of China (Grant No. 81872171) and Shanghai Science and Technology Innovation Action Plan (Grant No. 22S31900400).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The scanning electron microscope (SEM) micrographs of all the synthesized samples. (a) HAP, (b) ZnHAP2, (c) CuHAP1, (d) CuHAP. All the samples consist of similar agglomerates, which are composed of fine crystallites. Because of the exceptionally small size, the crystallites cannot be seen individually in microphotographs. In addition, the fine agglomerates of particles interconnected variously into structures of different forms, morphology, and distribution were illustrated in the micrographs. Reprinted with permission from ref. [12]. Copyright 2010 Elsevier.
Figure 1. The scanning electron microscope (SEM) micrographs of all the synthesized samples. (a) HAP, (b) ZnHAP2, (c) CuHAP1, (d) CuHAP. All the samples consist of similar agglomerates, which are composed of fine crystallites. Because of the exceptionally small size, the crystallites cannot be seen individually in microphotographs. In addition, the fine agglomerates of particles interconnected variously into structures of different forms, morphology, and distribution were illustrated in the micrographs. Reprinted with permission from ref. [12]. Copyright 2010 Elsevier.
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Figure 2. Ti rod surface coated with a Ti coating through a hole-structure pattern: (A) structure diagram; (B) SEM before drug loading; (C) SEM after drug loading. Ti coating spray (pure Ti coating), plasma spray with the placeholder filler metal etching method, and spraying preparation solution (with a through hole design Ti coating) were utilized. Vancomycin was loading through the hole pattern structures between the Ti coating [105].
Figure 2. Ti rod surface coated with a Ti coating through a hole-structure pattern: (A) structure diagram; (B) SEM before drug loading; (C) SEM after drug loading. Ti coating spray (pure Ti coating), plasma spray with the placeholder filler metal etching method, and spraying preparation solution (with a through hole design Ti coating) were utilized. Vancomycin was loading through the hole pattern structures between the Ti coating [105].
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Figure 3. Immobilisation of polydopamine and hyaluronic acid on vancomycin-loaded titanium nanotube. Ti-NT bio-functionalized with polydopamine and hyaluronic acid to overcome the limitations of Ti-NT via improving drug loading, antibacterial activity, and osteogenic ability. It exhibited better antibacterial ability and promoted the osteogenic differentiation of rat bone marrow stem cells. Reprinted with permission from ref. [119]. Copyright 2022 Elsevier.
Figure 3. Immobilisation of polydopamine and hyaluronic acid on vancomycin-loaded titanium nanotube. Ti-NT bio-functionalized with polydopamine and hyaluronic acid to overcome the limitations of Ti-NT via improving drug loading, antibacterial activity, and osteogenic ability. It exhibited better antibacterial ability and promoted the osteogenic differentiation of rat bone marrow stem cells. Reprinted with permission from ref. [119]. Copyright 2022 Elsevier.
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Figure 4. Schematic diagram showing the structure of the HBPL-modified implant rod, which combines the anti-infection and promoted osteogenesis in vivo. Hyperbranched poly-L-lysine (HBPL) polymers were covalently immobilized onto the alkali-heat treated titanium (Ti) substrates and implants by using 3-glycidyloxypropyltrimethoxysilane (GPTMS) as the coupling agent, which displayed outstanding anti-infection activity and better osseointegration in vivo. Reprinted with permission from ref. [141]. Copyright 2021 Elsevier.
Figure 4. Schematic diagram showing the structure of the HBPL-modified implant rod, which combines the anti-infection and promoted osteogenesis in vivo. Hyperbranched poly-L-lysine (HBPL) polymers were covalently immobilized onto the alkali-heat treated titanium (Ti) substrates and implants by using 3-glycidyloxypropyltrimethoxysilane (GPTMS) as the coupling agent, which displayed outstanding anti-infection activity and better osseointegration in vivo. Reprinted with permission from ref. [141]. Copyright 2021 Elsevier.
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Table
Table 1. Antibacterial strategies and preparation technologies.
Table 1. Antibacterial strategies and preparation technologies.
Antibacterial StrategiesPreparation TechnologiesReferences
Metal coatingMetal coating could be prepared using the pulsed current electro-chemical deposition technique, the spin coating method, etc.[9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40]
Nanocomposite coatingSeveral studies have employed nanotechnology (plasma immersion ion implantation (PIII), the electrospray method, sol-cast transformation and so on) to construct nanoscale surfaces.[41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]
Antibiotic coatingThe drugs included conventional antibiotics, such as gentamicin, amoxicillin, carbeni-cillin, vancomycin, and cephalothin, which were incorporated in sustained-release an-tibiotic delivery devices by the electrospinning and the elec-trophoretic deposition process (EPD).[87,88,89,90,91,92,93,94,95]
Surface topography modificationsurface modification refers to the modification of the thin layer on the surface of implants at the atomic, molecular, or geomorphological level by anodiza-tion, layer-by-layer modification, electrodeposition, etc.[96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121]
Covalently grafted bioactive agents to the titanium surfacesWith incorporating antibiotics, proteins, and AMPs with different functions into implant design, bioactive surfaces have been synthesized to facilitate specific biological responses.[122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143]
Multicomponent coatingEPD, which is a coating technology, makes it possible for the co-deposition of different types of materials to develop multicomponent coatings on metallic substrates.[144,145,146,147,148,149,150,151,152,153,154,155,156,157,158]
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Sui, J.; Liu, S.; Chen, M.; Zhang, H. Surface Bio-Functionalization of Anti-Bacterial Titanium Implants: A Review. Coatings 2022, 12, 1125. https://doi.org/10.3390/coatings12081125

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Sui J, Liu S, Chen M, Zhang H. Surface Bio-Functionalization of Anti-Bacterial Titanium Implants: A Review. Coatings. 2022; 12(8):1125. https://doi.org/10.3390/coatings12081125

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Sui, Junhao, Shu Liu, Mengchen Chen, and Hao Zhang. 2022. "Surface Bio-Functionalization of Anti-Bacterial Titanium Implants: A Review" Coatings 12, no. 8: 1125. https://doi.org/10.3390/coatings12081125

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