Antibacterial coating of implants in orthopaedics and trauma: a classification proposal in an evolving panorama

Chemical and/or physical modifications of the surface layer of an existing biomaterial may result in a substantial change of its susceptibility to bacterial colonization.

Surface characteristics of implants, like surface roughness and chemistry, hydrophilicity, surface energy or potential and conductivity play in fact crucial roles in bacterial adhesion and subsequent biofilm formation. Surface physio-chemical modification of an implant is also relatively simple and economic to achieve and to industrialize.

Ultraviolet light irradiation, for example, is able to increase “spontaneous” wettability on titanium dioxide, which in turn can inhibit bacterial adhesion without compromising osteogenesis on titanium alloy implants [40, 41]. A bacterial anti-adhesive surface can also be achieved by modifying the crystalline structure of the surface oxide layer [42].

Some polymer coatings, like the hydrophilic polymethacrylic acid, polyethylene oxide, or protein-resistant polyethylene glycol can be applied to the surface of titanium implants and result in significant inhibition of bacterial adhesion [43‐45]. Even if some of these coatings may impair local osteoblast function, the use of additional bioactive molecules as sericin and RGD motif could restore and even improve the impaired cell function [46]. Hydrophobic and super-hydrophobic surface treatment technologies have also shown a great repellent antibacterial effect in preclinical studies [47, 48].

Other researchers have focused on controlling the biological response to biomaterials via alterations in surface structure and design [49, 50]. In this regard, changing the implant surface at a nanometric scale, at which bacterial adhesion does not simply follow the roughness of the surface but also is dependent on other variables like the quantity of adsorbed proteins, can in fact suppress bacteria adhesion [51].

Treating more specifically protein surfaces and/or protein–bacteria interactions may also be a successful strategy of inhibiting bacterial adhesion to a specific biomaterial [52, 53]. Friedman et al., using a rabbit model, demonstrated reduced bacterial adherence on pure titanium samples and decreased infection rates of implants coated with cross-linked albumin [54].

More recently, novel strategies include production of self-assembled mono- or multilayers, surface grafting or hydrogels, or the use of biosurfactants and microbial amphyphilic compounds with excellent anti-adhesive properties [55, 56].

In summary, a number of anti-adhesive surface modifications have been proposed for different purposes, but only a few will probably be suitable for clinical use. In particular, a strong anti-adhesive layer cannot be used for coating of fixation surfaces of joint arthroplasty since it could also interfere with implant osteointegration, leading to early mechanical failure [48, 49]. Another challenge of designing anti-adhesive technologies relates to the current inability to find a universal treatment that can be applied to all surfaces and biomaterials, all bacterial species and under all (ingrowth and noningrowth) implants. Moreover, passive coating methods should be preferred as long as their antibacterial ability is strong enough to prevent biofilm formation, but the ability of passive coatings to resist bacterial adhesion is generally limited and varies greatly depending on the bacterial species and loads [57]. In vivo efficacy and long-term effects of these new technologies both on host’s cells and on bacterial resistance are also poorly understood and need to be further investigated before clinical applications and market introduction.

Surface modifications may include pharmacologically active pre-incorporated antibacterial agents or compounds, like antibiotics, antiseptics, metal ions, or organic molecules. Such pharmacologically activated coatings may change the implant from a passive, pharmacologically inert medical device, to something more and more similar to a drug agent, with difficult to predict long-term effects and challenging regulatory issues.

Historically, two main strategies have been proposed for effective antibacterial surface treatment either “contact killing” or drug eluting, while in terms of durability, we can distinguish between degradable and non-degradable coatings. Killing of bacteria can be achieved by interfering with cell respiration or division, cell wall formation or bacterial signaling network as well as inhibition of the transition of planktonic phenotype of bacteria into a sessile type [58].

Antibacterial surface technologies can employ metals (silver, zinc, copper, etc.), non-metal elements (e.g., iodine, selenium), organic substances (antibiotics, anti-infective peptides, chitosan, other substances), and their combinations.

Antibacterial activity of the majority of metal coatings is closely linked to the ionic or nano form rather than to the bulk material [59]. Silver is the most prevalent metal used in biomedical applications. Dissolved silver cations are biochemically active agents that interfere with bacterial cell membrane permeability and cellular metabolism. Silver also contributes to formation of reactive oxygen species and other mechanisms that potentially influence prokaryotic cells [60]. There has been concern, however, about the toxicity of silver ions [61]. Research efforts have focused on the development of silver coating technologies that reduce or even eliminate toxicity while maintaining antibacterial effects [62, 63]. Despite demonstrated clinical efficacy and safety in recent comparative studies [64, 65], routine use of silver-coated implants remains rather limited. The main obstacle to a broader usage of such technology is cytotoxicity on bone cells, that prevented until now coating of the intra-medullary part of the prosthesis. In addition, cost issues and the inability to apply the technology to a variety of prosthetic implants and devices further reduces its application outside oncological or highly selected cases.

Copper and zinc also have potent antibacterial effects on a wide spectrum of bacterial species [66, 67]; however, potential toxic side effects of these metals remain a strong concern [68]. Proposed solutions include copper- and zinc-based nanomaterials or, alternatively, controlled release [69]. The risk of bacterial resistance to metallic coatings remains a potential limitation for their widespread use [70]. Concern also exists about the mechanical properties of implant nanocoatings since damage may occur during surgical implantation especially in cementless implants inserted via press-fit methods [71].

Another interesting technology is related to modification of commonly used alloys, like titanium. The anti-infective potential of titanium dioxide layers has been widely investigated and proven effective in vitro both alone [72] or in combination with other substances [73].

Non-metal elements like hydrogen, chlorine, iodine, or oxygen are commonly used in biomedicine for their anti-infective properties. Selenium bound covalently onto the surface of titanium or titanium alloy implant discs has been shown to prevent Staphylococcus aureus and Staphylococcus epidermidis attachment without affecting osteoblast viability [74]. Selenium catalyzes the formation of superoxide radicals and subsequently inhibits bacterial adhesion and viability. In addition, selenium nanoparticles can inhibit bacterial growth and biofilm formation [75].

Ongoing research is also directed to determine the clinical applicability of carbon substances like graphene or carbon nanotubes, that can be synthesized in multifunctional layers [76]; however, the most interesting technology today under study, related to non-metal elements, is probably iodine coating of titanium alloys, that has recently demonstrated clinical efficacy in a continuous series of 222 patients with excellent results [77].

Several organic compounds with antibacterial properties have the potential to be linked to the surface of implants conferring them anti-infective properties. A large number of studies have investigated the efficacy of surfaces coated with covalently linked antibiotics [78‐82]. Clinical effectiveness of such implants is most likely limited to infections caused by bacteria that are sensitive to the specific antibiotic that has been coupled. In addition, strong forces such as covalent binding are insufficiently sensitive to react to weak external stimuli [83]. In fact, despite the theoretical advantages for non-eluting systems, this concept is limited by the fragility of the coatings and killing activity potential of bacteria which might not be directly adjacent to the implant. To overcome these issues, combinations of antibiotics with other compounds have been proposed either alone or in association with a particular mechanism of controlled release [84]. Antibiotics such as gentamicin, vancomycin, and others have been loaded into porous hydroxyapatite (HA) coatings on titanium implants. The antibiotic-HA coatings exhibit significant improvement in preventing infection compared with standard HA coatings in vivo, but there are still many unresolved issues regarding the methodology of antibiotic incorporation into the HA coating and the optimal release kinetics and possible detachment of the coating at the time of press-fit insertion.

Biodegradable polymers and sol–gel coatings are also utilized to form controlled release antibiotic-laden coatings on titanium implants [85, 86]. Clinical applications of antibiotic-loaded D-poly-lactate acid/gentamycin intra-medullary coated nail have been recently reported with early positive results [87].

Some antiseptic agent such as chlorhexidine, chloroxylenol, or poly-hexamethylenebiguanide have demonstrated efficacy and might be an alternative to avoid the risk of drug resistance. Chlorhexidine can be adsorbed to the TiO2 layer on titanium surfaces and is released gradually over several days [88]. Its release pattern is similar to that of antibiotic-laden coatings with an initial rapid release rate followed by slower but sustained release [89].

Another promising approach involves coating implants with antimicrobial peptides, cytokines, or other molecules critical for host response to bacteria invasion. This heterogeneous group of substances has proven experimentally their efficacy against a wide range of pathogens [90]. Antimicrobial peptides, like antibiotics, function via damage of the cell wall and inhibition of key bacterial protein synthesis. In addition, they exert influence upon inflammation, tissue healing, and apoptotic events [91]; resistance to antimicrobial peptides has been reported less frequently than to antibiotics [92]. Initial experiments demonstrated that a thin layer of antimicrobial peptides affixed onto the surfaces of metal alloys exhibit excellent antibacterial effects against typical pathogens related to PJI [93].

Chitosan (CS) is a polycationic polymer derived from chitin that exhibits antibacterial and antifungal activity. The exact mechanism of action remains poorly understood. There is some evidence that CS derivatives can be firmly anchored to titanium alloys and that they have a protective effect against some bacterial species either alone or in combination with other antimicrobial substances like antibiotics or antimicrobial peptides [94, 95]. CS derivatives secured to external fixator pins have been studied as a method of preventing pin tract infections [96]. However, we are not aware of a study to date reporting data from clinical setting.

Long-term impact of permanently coated implants with antibiotics and other organic compounds, never used before either for local or general administration, does raise concerns regarding possible induction of bacterial resistance, local, and general toxicity and possible detrimental effects on implant osteointegration, ultimately preventing clinical applications until now.

Still more complex approaches involve the development of multifunctional surface layers, like functional polymer brush coating, that combine anti-adhesive and antimicrobial substances and other compounds able to enhance tissue integration [97], while “smart coatings”, sensitive and responsive to a variety of stimuli, including the presence of bacteria [98], are another fascinating but futuristic research pathway that poses a number of open questions, like feasible coating manufacturing process, non-adverse reactions in vivo, mechanical resistance, or preservation of intended functionalities throughout the life of the device.

Instead of pre-manufactured surface modifications, either with or without pharmacologically active agents, a different approach to implant protection may be to provide a traditional implant with an antibacterial carrier or coating at the time of surgery. The separation of the protective solution from the implant until surgery may reduce the regulatory requirements and increase the applicability of a universal antibacterial coating to many different already existing implants and biomaterials.

Local administration of antibiotics historically attracted much attention in orthopaedics. Buchholz et at. first popularized the incorporation of antibiotics into polymethylmethacrylate (PMMA) bone cement for local antibiotic prophylaxis in cemented total joint arthroplasty [99]. Clinical studies have shown that antibiotic-loaded bone cement can decrease deep infection rates of cemented total hip arthroplasties and revision rates due to supposed “aseptic” loosening when combined with systemic antibiotic administration [100] and this solution has been found both effective and economically sound, especially in high-risk patients [101, 102]. However, PMMA was not designed as a local delivery carrier of antibiotics and may have some limits. Antibiotic-loaded PMMA may not overcome biofilm formation and may be associated with the development of antibiotic-resistant “small-colony variants” [103, 104], while the increasing use of cementless implants worldwide, especially at the hip site, make this a possible option only for a restricted number of patients.

Other porous materials for local antibiotic delivery like collagen sponges [105], cancellous bone [106], and calcium phosphate cements [107, 108] were not specifically designed to protect implanted biomaterials, and their use for routine infection prevention in joint prosthesis is limited by their insufficient in vitro, in vivo, and clinical evidence of efficacy in this specific application, their inability to be applied as a coating to all implants’ surfaces, and their relatively high costs and possible interference with primary implant fixation and long-term osteointegration.

Biocompatible hydrogels do represent a possible alternative solution, as they have demonstrated to be able to deliver local pharmacological agents and may be designed to meet the desired elution pattern [109]. Recently, a fast-resorbable hydrogel coating, that can be loaded intra-operatively with various antibacterials, has been introduced in the European market [110]. Based on the facts that bacterial colonization occurs within the very first hours after implant and that short-term systemic prophylaxis is equally effective as the long-term one to prevent PJIs [111], this novel coating technology introduced the “short-term local protection” of the implant. A short-term local delivery system may in fact meet the requirements needed to win the “run to the surface”, while limiting possible long-term unwanted side effects [112]. This novel fast-resorbable hydrogel coating, “Defensive Antibacterial Coating”, DAC® (Novagenit Srl, Mezzolombardo, Italy), composed of covalently linked hyaluronan and poly-D,L-lactide, (Fig. 1), is designed to undergo complete hydrolytic degradation in vivo within 48 to 72 h, being able to completely release a variety of different antibacterials, including glycopeptides, amynoglycosides, and fluoquinolones (Table 3), at concentrations ranging from 2 % to 10 %. The hydrogel showed a synergistic antibacterial activity with various antibiotics and antibiofilm agents in vitro [113], while in vivo it has been proven effective a rabbit model of highly contaminated implant both with [114] and without systemic prophylaxis [115]. An ongoing European multicenter clinical trial (Fig. 2) is currently investigating the safety and the efficacy of the device [116].