Implant-associated infection is a major source of morbidity in orthopaedic surgery. There has been extensive research into the development of materials that prevent biofilm formation, and hence, reduce the risk of infection. Silver nanoparticle technology is receiving much interest in the field of orthopaedics for its antimicrobial properties, and the results of studies to date are encouraging. Antimicrobial effects have been seen when silver nanoparticles are used in trauma implants, tumour prostheses, bone cement, and also when combined with hydroxyapatite coatings. Although there are promising results with in vitro and in vivo studies, the number of clinical studies remains small. Future studies will be required to explore further the possible side effects associated with silver nanoparticles, to ensure their use in an effective and biocompatible manner. Here we present a review of the current literature relating to the production of nanosilver for medical use, and its orthopaedic applications.
Cite this article: Bone Joint J 2015; 97-B:582–9.
Silver is a soft, white, lustrous transition metal which is recognised to have antimicrobial properties and has assumed an important role in the treatment of infections.1-3 As a non-specific biocidal agent, in suitable doses silver is not toxic to mammalian cells and disinfects a broad spectrum of bacterial and fungal species, including antibiotic-resistant strains.1-3 Silver and silver nanoparticles are used as antimicrobials in a variety of industrial, healthcare and domestic applications.4,5 Silver has been incorporated into wound dressings, and as an antimicrobial coating on medical devices in order to prevent biofilm formation.6 The clinical potential of silver nanotechnology is of particular interest to the field of orthopaedics, where infection of implanted devices represents a persistent threat. In this paper we provide a review of the literature on the use of silver nanoparticles and their application in the field of orthopaedics. In addition, we review the potential for toxicity if silver is not used with caution.
Mechanism of action
Silver has well-documented broad-spectrum activity against Gram-positive and Gram-negative bacteria, fungi, protozoa and viruses.7 However, its mechanism of action has only recently been elucidated. In vitro studies have shown that silver releases biologically active ions from its surface. The released ions bind to a number of bacterial cell structures, including the peptidoglycan cell wall and plasma membrane, the bacterial DNA and bacterial proteins (Fig. 1).8 This creates three different mechanisms by which silver exerts its toxic effects. The binding of ions to the cell wall damages the outer cell layers, causing loss of cell contents and creating structural abnormalities.9 As Gram-positive bacteria have thicker cell walls, a higher concentration of silver is necessary to prevent bacterial growth than for Gram-negative bacteria.10 Interaction with sulfhydryl (SH) groups in bacterial proteins and enzymes impairs many key cell functions, such as respiration and permeability. Binding to nucleic acids in DNA prevents cell reproduction.11 A further mechanism of toxicity is through the production of reactive oxygen species (ROS) by silver ions. This generation of ROS probably acts in synergy with the SH group interaction mechanism. Evidence for this is the increased antimicrobial activity seen in aerobic versus anaerobic conditions.12 These mechanisms of action provide for de-constitution of surface species, such as proteins, cells and resultant biofilms, which in turn promotes long-term exposure of the surface silver nanoparticles and their associated antimicrobial effects.
The multimodal activity outlined above has major clinical significance, as there is far less potential for bacterial resistance to silver than with traditional antibiotic agents. When bacterial resistance to silver nanoparticles does occur, it develops more slowly than resistance to antibiotics.13 Some of this resistance appears to be related to genes that control the pumping of silver out of the cell.14 Taglietti et al15 showed that a self-assembled monolayer of silver nanoparticles on glass was obtained via amino-silanisation of the glass surface. They found that there was prolonged release of silver ions, whereas the silver nanoparticles remained attached to the underlying substrate, and strong antibiofilm activity against the biofilm-producer Staphylococcus epidermidis was detected. The structural make-up of silver has consequences for its antimicrobial efficacy. Choi et al16 conducted a comparative study of nanosilver, silver chloride and silver nitrate and concluded that nanosilver has greater efficacy against bacteria. This is thought to be because nanosilver has a secondary mechanism of action. Nanosilver particle size is another important factor that influences the level of antimicrobial activity. It has been shown that smaller particles (< 10 nm) are significantly more efficacious, as there is a greater surface area for the release of silver ions. Therefore, particle size may be of greater significance than concentration or mass.17 The period of activity has also been shown to be related to nanoparticle size and, when present, the type of nanoparticle functionalising element (i.e. a nanoparticle that has had a chemical functional group added to its surface). It is reported that ion concentrations for the best antibiotic effects range between 10 nM and 10 μM.18 A number of studies19,20 have investigated the use of silver nanoparticles in combination with antibiotics and have found a synergistic effect. Fayaz et al19 used Trichoderma viride for the biosynthesis of silver nanoparticles and also investigated the antimicrobial activity of these nanoparticles in the presence of antibiotics. They found that activity against Gram-positive and Gram-negative bacteria was increased for ampicillin, kanamycin, erythromycin and chloramphenicol. Dar, Ingle and Rai20 investigated the properties of nanosilver produced using the fungus Cryphonectria sp. The fungally produced nanosilver was found to have higher antibacterial activity against Escherichia coli,Salmonella typhi and Staphylococcus aureus than streptomycin and amphotericin. It also displayed antifungal activity against Candida albicans, and enhanced the effects of other antibiotics.20
Silver has been used medically in mineral and compound forms, such as silver zeolite and silver nitrate, and the advance of nanotechnology has enabled the production of nanosilver. Nanosilver constitutes minute structures of silver atoms measuring between 1 nm and 100 nm in diameter, metallically bonded together. Silver nanoparticles have been produced using a wide variety of methods, but the two main methods of production are chemical reduction and photoreduction. In these processes, negatively charged electrons are donated to the positively charged silver ions, causing them to return to their metallic form.21 A stabilising agent is usually added during production which prevents aggregation of the silver atoms, which could negatively affect the high antimicrobial activity associated with nanoscale dimensions.22 More recently, biological methods of producing nanosilver have been explored,23 which involve the use of organisms as reducing agents rather than as chemicals. This is an exciting development, as it eliminates the need for chemicals that may have added toxic effects, especially in clinical applications, thereby increasing the biocompatibility of the produced nanosilver. Multiple organisms have been used, including bacteria, fungi and plants. Unlike chemical reduction, which requires separate reducing and stabilising agents, the micro-organism used for biological synthesis provides both agents. Each produces silver nanoparticles that vary in size and shape, and which may be found intracellularly or extracellularly on the cell wall.23 A study involving the reduction of silver using S. aureus showed that the nanoparticles produced had high antimicrobial activity against methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidis (MRSE) and Streptococcus pyogenes.24 Nanoparticles produced chemically can aggregate in liquid, reducing the surface area available for high antimicrobial activity. One of the advantages of using biogenic silver is that it has been found to be more stable over longer periods of time in a liquid environment.25 Coating medical devices is the major use of silver nanoparticles, with the aim of preventing biofilm formation. A number of nanotechnology approaches to facilitate the adherence of silver to device surfaces, have been developed. These include vacuum-sputter coating and electrodeposition technologies, which fix vaporised silver on to the surface of the device.26
Peri-prosthetic infection is a significant problem in orthopaedic oncology, with infection rates of 9% to 29%.27-29 This patient group is at increased risk of infection compared with standard arthroplasty patients, because of immunosuppression related to their underlying disease, and also from adjuvant treatments such as chemotherapy and radiotherapy. Implant-related infection can result in amputation in these patients.28,30 Gosheger et al31 investigated the antimicrobial efficacy and possible side effects of a silver-coated mega-prosthesis in a rabbit model. They compared 15 titanium with 15 silver-coated MUTARS endoprostheses (Implantcast GmbH, Buxtehude, Germany), each of which had been inoculated with S. aureus. Rabbits in the silver group displayed significantly lower signs of inflammation as measured by C-reactive protein (CRP), neutrophil count and rectal temperature. The silver group also showed significantly lower rates of infection (7%) than the titanium group (47%), and no toxicological side effects were observed.31 The effect of silver coatings on infection rate was prospectively assessed in 51 sarcoma patients using a silver coating applied to the implanted mega-prostheses by galvanic deposition of elementary silver.30 The layer thickness ranged from 10 µm to 15 µm. No silver coating was applied at the articulating surfaces. The infection rate was compared with that of a historical control group of 74 patients who had undergone surgery using a non-silver-coated titanium mega-prosthesis and was found to be substantially reduced, from 17.6% in the titanium group to 5.6% in the silver group. A total of five patients out of 16 (38.5%) in the titanium group who developed a deep infection required amputation, but there were no amputations for infection in the silver-coated group.30 At present, silver-coated prostheses are indicated in the prophylaxis of infection in tumour cases and also in the setting of extensive trauma-related infection. However, there have been no clinical studies comparing silver-coated revision arthroplasty with non-coated implants, nor have there been any clinical studies using silver nanoparticle technology.
External fixator pins
Pin tract infection is the most common complication associated with the use of external fixators and has been reported to be present in up to 42% of inserted pins.32 Pin tract infection can result in loosening requiring removal or exchange, loss of fixation, fracture non-union and osteomyelitis.33 An in vitro study has examined the antimicrobial efficacy of surface-coated external fixator pins. Stainless steel pins were coated with a continuous layer of polymer in which nanoparticulate silver was embedded. These test specimens were compared against uncoated stainless steel, titanium and copper pins. The test pins were incubated with S. epidermidis for 20 hours to initiate a biofilm, following which the test pins were analysed for highly adherent bacteria. It was demonstrated that fixation pins with a coating of nanoparticulate silver showed a 3 log-step reduction in biofilm-forming bacteria compared with non-coated stainless steel or titanium implants.34 These findings are supported by in vitro work by Wassall et al,35 who examined the antimicrobial effect of conventional silver and showed a significant reduction in adhesion for E. coli, Pseudomonas aeriginosa and S. aureus when silver coated pins were compared with stainless steel pins. Collinge et al36 reported on the potential benefit of silver coating on external fixator pins inoculated with S. aureus inserted into the iliac crest of sheep. After two and a half weeks, the pin sites were examined for movement, inflammation and infection. A reduction in the rate of infection from 84% to 62% was demonstrated when comparing silver coated and stainless steel pins. In addition, silver-coated pins were less frequently found to be loose than stainless steel pins. The authors postulated that bacterial adherence to the surface of the silver-coated pins was prevented by inhibition of the formation of a bacterial glycocalyx membrane on the surface of the pin, rather than by local leaching of silver ions.36 Coester et al37 performed a prospective randomised study in patients to compare the effect of silver coating on pin tract infection. The study design involved a monolateral fixator with stainless steel pins and silver-coated pins being used in the same construct, allowing for direct comparison of the effects of silver coating within the same environment. The results from 33 external fixators showed that there was no difference in the rate of pin tract infection, torque to remove pins or radiographic lucency around the pins.37 The difference in outcome between the results of Collinge et al36and those of Coester et al37 may be explained by the lack of direct inoculation of bacteria into the pin tract in the latter.
Massè et al38 prospectively studied 24 men who were treated with monolateral external fixators for tibial or femoral diaphyseal fractures. A total of 50 screws were silver coated and were compared with 56 uncoated stainless steel screws. The coated screws resulted in a lower rate of positive culture (30.0%) than the uncoated screws (42.9%), but this did not reach statistical significance (p = 0.243). The clinical behaviour of the pins did not differ between the groups, with both showing similar inflammation and mechanical anchorage scores. Because of an increase in the serum silver levels the study was discontinued on ethical grounds. However, the development of nanoparticle coatings should reduce the systemic absorption of silver and allow similar studies to be conducted safely.
Osteomyelitis and infected nonunion
Electrically generated silver ions have been used to treat osteomyelitis and infected nonunions with variable success.39-42 Concerns regarding toxicity and the ability to overcome large bone defects have limited the application of silver iontophoresis; a physical process by which ions flow diffusively in a medium driven by an applied electric field. The insertion of autogenous bone graft or allograft in the presence of active infection is contraindicated because the graft may act as a nidus for infection,43 but a tissue-engineered graft that can control infection and promote bone regeneration would be advantageous. Zheng et al44 have developed a composite bone graft consisting of bone morphogenetic protein 2 (BMP-2) coupled with nanosilver polylactic-co-glycolic acid (PLGA). A critical defect measuring 6 mm was created in the femoral diaphysis of rats, and bone grafts containing variable quantities of nanosilver were implanted into the defects. The grafts were injected with ten colony-forming units (CFU) of vancomycin-resistant MRSA. No antibiotic was administered post-operatively. Radiographic and histological analysis 12 weeks after implantation showed defect fusion from new bone formation in the BMP-2-2% nanosilver–PLGA graft (Fig. 2). In contrast, there was loss of bone and regression of the proximal and distal cut bone ends of the femur in the control group, which had a BMP-2-PLGA graft without nanosilver. Elimination of bacteria in the defect by the 2% nanosilver graft composite resulted in considerably more stimulation of new bone formation than the control graft, with resultant union.
Hydroxyapatite (HA) coating
HA is often used to coat trauma implants as it stimulates osseo-integration. It does not, however, contain any antibacterial properties unless it is combined with zinc, copper, titanium (Ti) silver or other antibiotic agents. A number of studies have investigated the efficacy of silver-containing hydroxyapatite coatings (Ag-HA) as potential agents for reducing the rate of implant-associated infections. In an in vitro study comparing the differences in bacterial adhesion on Ti, HA and Ag-HA surfaces, Chen et al45 assessed the efficacy of co-sputtered silver-containing HA. There was significantly lower adhesion of S. aureus and S. epidermidis on the Ag-HA surfaces, indicating that these coatings were bactericidal.
There have been several studies investigating various methods for the incorporation of silver into HA coatings. These include ion exchange, thermal decomposition, sol-gel technology, magnetron sputtering, ion beam-assisted deposition and electrochemical deposition.46-50 The goal is to achieve a uniform coating that produces an antibacterial effect without compromising the osteoconductive effect of HA. The results have been promising, with most studies concluding that silver can be added to HA coatings without affecting the mechanical properties of HA. A universal occurrence in all studies of silver coatings is the ‘peak effect’, whereby a large release of silver ions is seen in the initial period. This is because the ions lie on the surface of the coating. This large release of ions helps to protect against infection in the first few weeks, when the risk of peri-prosthetic infection is highest.51 However, after this period there is minimal antimicrobial efficacy. A recent study52 investigated the co-deposition of silver and HA by electrochemical means. It was found that this method gave a steady prolonged release of silver ions which the authors suggested was due to the release of silver as the HA dissolved (compared with a double coating, in which silver overlies the HA coating). Thus, co-deposition gives good long-term antimicrobial cover but with loss of the ‘peak effect’, as there is limited bactericidal effect in the initial period.52 Shimazaki et al53 conducted a study in which Ag-HA-coated titanium plates were implanted subcutaneously in the backs of Sprague–Dawley rats, comparing Ag-HA-coated plates with HA-coated plates in terms of their activity against MRSA. The results demonstrated significantly fewer MRSA CFUs on the Ag-HA-coated plates, showing promise for the use of such coatings clinically. Akiyama et al54 investigated the bactericidal activity of Ag-HA-coated titanium in the medullary cavities of rat tibias. Again, the effects of Ag-HA coatings were compared with those of HA coatings and their relative activity against MRSA. The reduction in the numbers of viable MRSA in the tibiae with Ag-HA-coated implants compared with the HA-coated implants was statistically significant when measured at 24, 48 and 72 hours post-operatively (p = 0.002, p = 0.008 and p = 0.041, respectively). They also found significant differences on radiological assessment at four weeks, suggesting a prolonged inhibitory effect of the silver ions on bacterial growth.54
Alt et al55 reported an in vitro study comparing nanosilver-loaded bone cement with gentamicin-loaded and plain cement. Each cement type was tested against S. epidermidis, MRSE and MRSA. Only the nanosilver cement had high antimicrobial efficacy against all bacterial strains. Prokopovich et al56 conducted a novel study using tiopronin (a thiol compound) as a stabilising agent, and encapsulating the produced nanosilver in bone cement. The tiopronin provided excellent stability to the nanosilver and the combination exhibited good antimicrobial efficacy without affecting the mechanics of the cement or producing cytotoxicity.
Silver has been used in wound dressings for some time, and more recently dressings containing nanosilver have become available. These are designed to provide a sustained release of silver ions over a number of days, taking effect via delivery into the wound and through their action on the exudate released from the wound. Studies have shown that dressings containing nanosilver have a higher antimicrobial effect than bulk silver, although little is known about the possibility of increased toxic effects.57
Coating of trauma implants
Silver coatings on trauma implants have generally proved effective in vitro, but in vivo studies have shown mixed results.58,59 In 2004, Sheehan et al60 investigated the effect of Ti, stainless steel and silver-coated implants against biofilm formation in rabbits. A Kirschner wire (silver-coated titanium, silver-coated stainless steel, and titanium and stainless steel controls) 2 mm in diameter was implanted into each of the distal femoral canals of the rabbits, and S. epidermidis and S. aureus were introduced by direct inoculation. There was no statistically significant difference in bacterial adhesion when comparing the control groups with the silver-coated implants. More recent in vivo work by Kose et al61used a more sophisticated method of silver coating. In their study, instead of directly coating the implants with metallic silver, a silver ion-doped calcium phosphate-based ceramic nanopowder was developed, the idea being that ionic silver is more biologically active. This coating was applied to 2.5 mm titanium alloy pins, which were implanted in the distal femoral canals of rabbits, similar to the study by Sheehan et al,60 and MRSA was inoculated. Colonisation of the silver-coated implants was compared with that of the uncoated and HA-coated implants. In the silver-coated group, the antimicrobial outcomes were more favourable, with a lower proportion of positive cultures and lower rates of osteomyelitis.61 Comparing the results of these two studies, it may be hypothesised that advances in the production of silver coatings have allowed for the manufacture of more biologically active models.
In addition to their use on orthopaedic implants, silver nanoparticles can be found in common consumer products as a result of their excellent antimicrobial properties.62-64 With the recent concerns relating to the effect of metal ion exposure as a result of metal-on-metal arthroplasty, surgeons are apprehensive about the potential toxic effect of silver nanoparticles.65 A cautionary note has been sounded elsewhere regarding the introduction of nanotechnology to medicine.66 A number of studies have been performed exploring the effect of sliver nanoparticles on a variety of cell types. These investigations have demonstrated that silver nanoparticles have the potential to induce developmental abnormalities in zebra fish embryos,67 disrupt the cell membrane,68 and induce genotoxic and cytotoxic damage to human lung fibroblast and glioblastoma cells,69 in addition to a system-wide suppression of the immune system.70 One of the difficulties of using silver nanoparticles in orthopaedics is controlling the release of the silver ions. These particles can be released from the connection sites on the implants to which they were attached, under the biodegrading effects of body fluid during medical treatment, and can harm the surrounding tissue.71 Considering that most patients into whom these implants have been inserted have undergone some bony procedure, the influence of the silver nanoparticles on bony metabolism is of critical importance. Pauksch et al72 recently explored this by investigating the effect of silver nanoparticles on primary human mesenchymal stem cells and osteoblasts. Their study demonstrated silver nanoparticle-mediated cytotoxicity at higher concentrations (10 μg/g) and suggested that a therapeutic window for the application of these particles in medical products might exist. Greulich et al73 also confirmed that silver nanoparticles were taken up by human mesenchymal stem cells and were found intracellularly in endolysosomal structures but not in the cell nuclei. A further study by Necula et al74 focused on the in vitro cytotoxicity of silver nanoparticles of various concentrations using a human osteoblastic cell line and evaluated their bactericidal activity against MRSA. The results showed that high concentrations of silver nanoparticles (3.0 Ag) were extremely cytotoxic, but lower concentrations (0.3 Ag) demonstrated optimum cell growth of osteoblasts as well as good antibacterial properties. It appears that the cytotoxicity is not only dose dependent but also particle size dependent. Albers et al75 demonstrated that the antibacterial effects of silver nanoparticles occurred at concentrations that were two to four times higher than those inducing cytotoxic effects. The authors stated that such adverse effects on osteoblast and osteoclast survival may have deleterious effects on the biocompatibility of orthopaedic implants.
Another area of concern with respect to toxicity is the effect that silver nanoparticles might have on DNA synthesis, which would be particularly relevant when implants coated with silver nanoparticles are used in women of childbearing age. Powers et al76 showed that silver nanoparticles compromised neurodevelopment in PC12 cells, a model used for neuronal differentiation and neurosecretion. Their study revealed that exposure to silver nanoparticles was dependent on size and the coating to which it was attached, indicating that the effects are not due simply to the release of silver ions into the environment. Subsequent work from this group explored the effect of embryonic exposure of silver nanoparticles on zebra fish. The results indicate that the silver nanoparticles act as a developmental neurotoxicant, which can cause persistent neurobehavioral effects, which is also highly dependent on particle coating and size.77,78 Kovvuru et al79 explored the effect of oral ingestion of silver nanoparticles on inducing DNA damage and permanent genome alterations in a mouse model. Their results revealed that silver nanoparticles induced large DNA deletions in developing embryos, irreversible chromosomal damage in bone marrow, and double-strand breaks and oxidative DNA damage in peripheral blood. These issues highlight the health concerns about ions released from silver nanoparticles, particularly at high concentrations, although it should be noted that none of these issues have so far been reported in humans. A further concern relates to the effect of circulating silver nanoparticles, which inevitably end up in contact with vascular endothelium and have the potential to induce cardiovascular damage. In an in vitro study Ucciferri et al80 demonstrated that silver nanoparticles have a toxic effect on primary human endothelial cells. Furthermore, endothelial cells were shown to be more susceptible when exposed to silver nanoparticles under flow conditions in a bioreactor. This study highlights the fact that although simple in vitro tests are useful to screen compounds and to identify the type of effect induced on cells, they may not be sufficient to define safe exposure limits. The authors contend that more physiologically relevant in vitro models need to be developed to understand better how nanomaterials can affect human health. With respect to nanosilver, particle size can be significant in terms of side effects. Martínez-Gutierrez et al81 conducted a study which showed that the optimum particle size in terms of antimicrobial efficacy is in the region of 20 nm to 25 nm. They also studied the cytotoxic effects associated with nanoparticles of this size and concluded that 24 nm particles of nanosilver had potent antimicrobial activity, but this size of nanosilver particle was cytotoxic to macrophages, causing a proinflammatory response and apoptosis. There are limited examples of toxic effects of silver in orthopaedic practice. Vik et al82 reported a neuropathy, resulting in grave muscle paralysis, in a patient in whom silver-impregnated cement was used at revision total hip arthroplasty. Intra-operative analysis of the fluid drawn from the hip joint revealed that the concentration of silver was 1000 times the normal serum reference value. Following removal of the prosthesis and cement, the serum concentration of silver decreased over a period of two years from more than 60 times to 20 times normal, and the patient partially recovered from her muscle paralysis.83 Gosheger et al,31 in a rabbit model, also explored the infection rates and toxicological effects of silver-coated mega-endoprostheses. Their study demonstrated that the concentration of silver in blood and organs was elevated with the use of silver-coated implants, although there were no pathological changes in laboratory parameters or histological changes of the organs.
In conclusion, the use of silver nanoparticle technology in orthopaedic devices has great potential as a means to reduce the incidence of implant infection. Whereas many of the early animal studies produced positive initial results, this area certainly warrants further research, especially to elucidate the potential harmful effects of circulating silver nanoparticles. Further development of silver nanoparticle technology in orthopaedics needs to focus on controlling the release of the nanoparticles from the implant so that it is not only bioactive in preventing infection but also biocompatible with the host.
1 Agarwal A , WeisTL, SchurrMJ, et al.Surfaces modified with nanometer-thick silver-impregnated polymeric films that kill bacteria but support growth of mammalian cells. Biomaterials2010;31:680–690. Google Scholar
2 Sambhy V , MacBrideMM, PetersonBR, SenA. Silver bromide nanoparticle/polymer composites: dual action tunable antimicrobial materials. J Am Chem Soc2006;128:9798–9808. Google Scholar
3 Cao H , LiuX. Silver nanoparticles-modified films versus biomedical device-associated infections. Wiley Interdiscip Rev Nanomed Nanobiotechnol2010;2:670–684. Google Scholar
4 Ansari MA , KhanHM, KhanAA, et al.Interaction of silver nanoparticles with Escherichia coli and their cell envelope biomolecules. J Basic Microbiol2014;54:905–915. Google Scholar
5 Phillips PL , YangQ, DavisS, et al.Antimicrobial dressing efficacy against mature Pseudomonas aeruginosa biofilm on porcine skin explants. Int Wound J2013;(Epub ahead of print). Google Scholar
6 Phillips PL , YangQ, DavisS, et al.Antimicrobial dressing efficacy against mature Pseudomonas aeruginosa biofilm on porcine skin explants. Int Wound J2013;(Epub ahead of print).:. Google Scholar
7 Nair LS , LaurencinCT. Nanofibers and nanoparticles for orthopaedic surgery applications. J Bone Joint Surg [Am]2008;90-A(Supp l1):128–131. Google Scholar
8 Chaloupka K , MalamY, SeifalianAM. Nanosilver as a new generation of nanoproduct in biomedical applications. Trends Biotechnol2010;28:580–588. Google Scholar
9 Yamanaka M , HaraK, KudoJ. Bactericidal actions of a silver ion solution on Escherichia coli, studied by energy-filtering transmission electron microscopy and proteomic analysis. Appl Environ Microbiol2005;71:7589–7593. Google Scholar
10 Alt V , BechertT, SteinrückeP, et al.An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials2004;25:4383–4391. Google Scholar
11 Chaloupka K , MalamY, SeifalianAM. Nanosilver as a new generation of nanoproduct in biomedical applications. Trends Biotechnol2010;28:580–588. Google Scholar
12 Park HJ , KimJY, KimJ, et al.Silver-ion-mediated reactive oxygen species generation affecting bactericidal activity. Water Res2009;43:1027–1032. Google Scholar
13 Percival SL , BowlerPG, RussellD. Bacterial resistance to silver in wound care. J Hosp Infect2005;60:1–7. Google Scholar
14 Cuin A , MassabniAC, LeiteCQ, et al.Synthesis, X-ray structure and antimycobacterial activity of silver complexes with alpha-hydroxycarboxylic acids. J Inorg Biochem2007;101:291–296. Google Scholar
15 Taglietti A , ArciolaCR, D'AgostinoA, et al.Antibiofilm activity of a monolayer of silver nanoparticles anchored to an amino-silanized glass surface. Biomaterials2014;35:1779–1788. Google Scholar
16 Choi O , DengKK, KimNJ, et al.The inhibitory effects of silver nanoparticles, silver ions, and silver chloride colloids on microbial growth. Water Res2008;42:3066–3074. Google Scholar
17 Alt V , BechertT, SteinrückeP, et al.An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials2004;25:4383–4391. Google Scholar
18 Kim JS , KukE, YuKN, et al.Antimicrobial effects of silver nanoparticles. Nanomedicine2007;3:95–101. Google Scholar
19 Fayaz AM , BalajiK, GirilalM, et al.Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria. Nanomedicine2010;6:103–109. Google Scholar
20 Dar MA , IngleA, RaiM. Enhanced antimicrobial activity of silver nanoparticles synthesized by Cryphonectria sp. evaluated singly and in combination with antibiotics. Nanomedicine2013;9:105–110. Google Scholar
21 Chaloupka K , MalamY, SeifalianAM. Nanosilver as a new generation of nanoproduct in biomedical applications. Trends Biotechnol2010;28:580–588. Google Scholar
22 Travan A , MarsichE, DonatiI, et al.Silver-polysaccharide nanocomposite antimicrobial coatings for methacrylic thermosets. Acta Biomater2011;7:337–346. Google Scholar
23 Sintubin L , VerstraeteW, BoonN. Biologically produced nanosilver: current state and future perspectives. Biotechnol Bioeng2012;109:2422–2436. Google Scholar
24 Nanda A , SaravananM. Biosynthesis of silver nanoparticles from Staphylococcus aureus and its antimicrobial activity against MRSA and MRSE. Nanomedicine2009;5:452–456. Google Scholar
25 Bhainsa KC , D'SouzaSF. Extracellular biosynthesis of silver nanoparticles using the fungus Aspergillus fumigatus. Colloids Surf B Biointerfaces2006;47:160–164. Google Scholar
26 Chen W , LiuY, CourtneyHS, et al.In vitro anti-bacterial and biological properties of magnetron co-sputtered silver-containing hydroxyapatite coating. Biomaterials2006;27:5512–5517. Google Scholar
27 Pala E , TrovarelliG, CalabròT, et al.Survival of modern knee tumor megaprostheses: failures, functional results, and a comparative statistical analysis. Clin Orthop Relat Res2015;473:891–899. Google Scholar
28 Angelini A , DragoG, TrovarelliG, CalabròT, RuggieriP. Infection after surgical resection for pelvic bone tumors: an analysis of 270 patients from one institution. Clin Orthop Relat Res2014;472:349–359. Google Scholar
29 Angelini A , HendersonE, TrovarelliG, RuggieriP. Is there a role for knee arthrodesis with modular endoprostheses for tumor and revision of failed endoprostheses?Clin Orthop Relat Res2013;471:3326–3335. Google Scholar
30 Hardes J , von EiffC, StreitbuergerA, et al.Reduction of periprosthetic infection with silver-coated megaprostheses in patients with bone sarcoma. J Surg Oncol2010;101:389–395. Google Scholar
31 Gosheger G , HardesJ, AhrensH, et al.Silver-coated megaendoprostheses in a rabbit model-an analysis of the infection rate and toxicological side effects. Biomaterials2004;25:5547–5556. Google Scholar
32 Mahan J , SeligsonD, HenrySL, HynesP, DobbinsJ. Factors in pin tract infections. Orthopedics1991;14:305–308. Google Scholar
33 Jennison T , McNallyM, PanditH. Prevention of infection in external fixator pin sites. Acta Biomater2014;10:595–603. Google Scholar
34 Furkert FH , SörensenJH, ArnoldiJ, RobioneckB, SteckelH. Antimicrobial efficacy of surface-coated external fixation pins. Curr Microbiol2011;62:1743–1751. Google Scholar
35 Wassall MA , SantinM, IsalbertiC, CannasM, DenyerSP. Adhesion of bacteria to stainless steel and silver-coated orthopedic external fixation pins. J Biomed Mater Res1997;36:325–330. Google Scholar
36 Collinge CA , GollG, SeligsonD, EasleyKJ. Pin tract infections: silver vs uncoated pins. Orthopedics1994;17:445–448. Google Scholar
37 Coester LM , NepolaJV, AllenJ, MarshJL. The effects of silver coated external fixation pins. Iowa Orthop J2006;26:48–53. Google Scholar
38 Massè A , BrunoA, BosettiM, et al.Prevention of pin track infection in external fixation with silver coated pins: clinical and microbiological results. J Biomed Mater Res2000;53:600–604. Google Scholar
39 Tamura K . Some effects of weak direct current and silver ions on experimental osteomyelitis and their clinical application. Nihon Seikeigeka Gakkai Zasshi1983;57:187–197. Google Scholar
40 Webster DA , SpadaroJA, BeckerRO, KramerS. Silver anode treatment of chronic osteomyelitis. Clin Orthop Relat Res1981;161:105–114. Google Scholar
41 Nand S , SengarGK, NandS, JainVK, GuptaTD. Dual use of silver for management of chronic bone infections and infected non-unions. J Indian Med Assoc1996;94:91–95. Google Scholar
42 Becker RO , SpadaroJA. Treatment of orthopaedic infections with electrically generated silver ions. A preliminary report. J Bone Joint Surg [Am]1978;60-A:871–881. Google Scholar
43 Journeaux SF , JohnsonN, BryceSL, et al.Bacterial contamination rates during bone allograft retrieval. J Arthroplasty1999;14:677–681. Google Scholar
44 Zheng Z , YinW, ZaraJN, et al.The use of BMP-2 coupled - Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects. Biomaterials2010;31:9293–9300. Google Scholar
45 Chen W , LiuY, CourtneyHS, et al.In vitro anti-bacterial and biological properties of magnetron co-sputtered silver-containing hydroxyapatite coating. Biomaterials2006;27:5512–5517. Google Scholar
46 Journeaux SF , JohnsonN, BryceSL, et al.Bacterial contamination rates during bone allograft retrieval. J Arthroplasty1999;14:677–681. Google Scholar
47 Suwanprateeb J , ThammarakcharoenF, WasoontararatK, ChokevivatW, PhanphiriyaP. Single step preparation of nanosilver loaded calcium phosphate by low temperature co-conversion process. J Mater Sci Mater Med2012;23:2091–2100. Google Scholar
48 Sahni G , GopinathP, JeevanandamP. A novel thermal decomposition approach to synthesize hydroxyapatite-silver nanocomposites and their antibacterial action against GFP-expressing antibiotic resistant E. coli. Colloids Surf B Biointerfaces2013;103:441–447. Google Scholar
49 Samani S , HossainalipourSM, TamizifarM, RezaieHR. In vitro antibacterial evaluation of sol-gel-derived Zn-, Ag-, and (Zn + Ag)-doped hydroxyapatite coatings against methicillin-resistant Staphylococcus aureus. J Biomed Mater Res A2013;101:222–230. Google Scholar
50 Sandukas S , YamamotoA, RabieiA. Osteoblast adhesion to functionally graded hydroxyapatite coatings doped with silver. J Biomed Mater Res A2011;97:490–497. Google Scholar
51 Pulido L , GhanemE, JoshiA, PurtillJJ, ParviziJ. Periprosthetic Joint Infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res2008; 466:1710–1715. Google Scholar
52 Ghani Y , CoathupMJ, HingKA, BlunnGW. Development of a hydroxyapatite coating containing silver for the prevention of peri-prosthetic infection. J Orthop Res2012;30:356–363. Google Scholar
53 Shimazaki T , MiyamotoH, AndoY, et al.In vivo antibacterial and silver-releasing properties of novel thermal sprayed silver-containing hydroxyapatite coating. J Biomed Mater Res B Appl Biomater2010;92:386–389. Google Scholar
54 Akiyama T , MiyamotoH, YonekuraY, et al.Silver oxide-containing hydroxyapatite coating has in vivo antibacterial activity in the rat tibia. J Orthop Res2013;31:1195–1200. Google Scholar
55 Alt V , BechertT, SteinrückeP, et al.An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials2004;25:4383–4391. Google Scholar
56 Prokopovich P , LeechR, CarmaltCJ, ParkinIP, PerniS. A novel bone cement impregnated with silver-tiopronin nanoparticles: its antimicrobial, cytotoxic, and mechanical properties. Int J Nanomedicine2013;8:2227–2237. Google Scholar
57 Wilkinson LJ , WhiteRJ, ChipmanJK. Silver and nanoparticles of silver in wound dressings: a review of efficacy and safety. J Wound Care2011;20:543–549. Google Scholar
58 Ewald A , GlückermannSK, ThullR, GbureckU. Antimicrobial titanium/silver PVD coatings on titanium. Biomed Eng Online2006;5:22. Google Scholar
59 Das K , BoseS, BandyopadhyayA, KarandikarB, GibbinsBL. Surface coatings for improvement of bone cell materials and antimicrobial activities of Ti implants. J Biomed Mater Res B Appl Biomater2008;87:455–460. Google Scholar
60 Sheehan E , McKennaJ, MulhallKJ, MarksP, McCormackD. Adhesion of Staphylococcus to orthopaedic metals, an in vivo study. J Orthop Res2004;22:39–43. Google Scholar
61 Kose N , OtuzbirA, PekşenC, KiremitçiA, DoğanA. A silver ion-doped calcium phosphate-based ceramic nanopowder-coated prosthesis increased infection resistance. Clin Orthop Relat Res2013;471:2532–2539. Google Scholar
62 Yuan X , SetyawatiMI, TanAS, et al.Highly luminescent silver nanoclusters with tunable emissions: cyclic reduction-decomposition synthesis and antimicrobial property. NPG Asia Mat2013;5:39. Google Scholar
63 Prucek R , TučekJ, KilianováM, et al.The targeted antibacterial and antifungal properties of magnetic nanocomposite of iron oxide and silver nanoparticles. Biomaterials2011;32:4704–4713. Google Scholar
64 Gray JE , NortonPR, AlnounoR, et al.Biological efficacy of electroless-deposited silver on plasma activated polyurethane. Biomaterials2003;24:2759–2765. Google Scholar
65 Hasegawa M , YoshidaK, WakabayashiH, SudoA. Prevalence of adverse reactions to metal debris following metal-on-metal THA. Orthopedics2013;36:606–612. Google Scholar
66 Sullivan MP , McHaleKJ, ParviziJ, MehtaS. Nanotechnology: current concepts in orthopaedic surgery and future directions. Bone Joint J2014;96-B:569–573. Google Scholar
67 Lee KJ , NallathambyPD, BrowningLM, OsgoodCJ, XuXH. In vivo imaging of transport and biocompatibility of single silver nanoparticles in early development of zebrafish embryos. ACS Nano2007;1:133–143. Google Scholar
68 Cheng X , ZhangW, JiY, et al.Revealing silver cytotoxicity using Au nanorods/Ag shell nanostructures: disrupting cell membrane and causing apoptosis through oxidative damage. RSC Adv2013;3:2296–2305. Google Scholar
69 AshaRani PV , Low Kah MunG, HandeMP, ValiyaveettilS. Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano2009;3:279–290. Google Scholar
70 De Jong WH , Van Der VenLT, SleijffersA, et al.Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats. Biomaterials2013;34:8333–8343. Google Scholar
71 Wang Z , SunY, WangD, LiuH, BoughtonRI. In situ fabrication of silver nanoparticle-filled hydrogen titanate nanotube layer on metallic titanium surface for bacteriostatic and biocompatible implantation. Int J Nanomedicine2013;8:2903–2916. Google Scholar
72 Pauksch L , HartmannS, RohnkeM, et al.Biocompatibility of silver nanoparticles and silver ions in primary human mesenchymal stem cells and osteoblasts. Acta Biomater2014;10:439–449. Google Scholar
73 Greulich C , DiendorfJ, SimonT, et al.Uptake and intracellular distribution of silver nanoparticles in human mesenchymal stem cells. Acta Biomater2011;7:347–354. Google Scholar
74 Necula BS , van LeeuwenJP, Fratila-ApachiteiLE, et al.In vitro cytotoxicity evaluation of porous TiO₂-Ag antibacterial coatings for human fetal osteoblasts. Acta Biomater2012;8:4191–4197. Google Scholar
75 Albers CE , HofstetterW, SiebenrockKA, LandmannR, KlenkeFM. In vitro cytotoxicity of silver nanoparticles on osteoblasts and osteoclasts at antibacterial concentrations. Nanotoxicology2013;7:30–36. Google Scholar
76 Powers CM , BadireddyAR, RydeIT, SeidlerFJ, SlotkinTA. Silver nanoparticles compromise neurodevelopment in PC12 cells: critical contributions of silver ion, particle size, coating, and composition. Environ Health Perspect2011;119:37–44. Google Scholar
77 Powers CM , LevinED, SeidlerFJ, SlotkinTA. Silver exposure in developing zebrafish produces persistent synaptic and behavioral changes. Neurotoxicol Teratol2011;33:329–332. Google Scholar
78 Powers CM , SlotkinTA, SeidlerFJ, BadireddyAR, PadillaS. Silver nanoparticles alter zebrafish development and larval behavior: distinct roles for particle size, coating and composition. Neurotoxicol Teratol2011;33:708–714. Google Scholar
79 Kovvuru P , MancillaPE, ShirodeAB, et al.Oral ingestion of silver nanoparticles induces genomic instability and DNA damage in multiple tissues. Nanotoxicology2014;(Epub ahead of print). Google Scholar
80 Ucciferri N , CollnotEM, GaiserBK, et al.In vitro toxicological screening of nanoparticles on primary human endothelial cells and the role of flow in modulating cell response. Nanotoxicology2014;8:697–708. Google Scholar
81 Martínez-Gutierrez F , ThiEP, SilvermanJM, et al.Antibacterial activity, inflammatory response, coagulation and cytotoxicity effects of silver nanoparticles. Nanomedicine2012;8:328–336. Google Scholar
82 Vik H , AndersenKJ, JulshamnK, TodnemK. Neuropathy caused by silver absorption from arthroplasty cement. Lancet1985;1:872. Google Scholar
83 Sudmann E , VikH, RaitM, et al.Systemic and local silver accumulation after total hip replacement using silver-impregnated bone cement. Med Prog Technol1994;20:179–184. Google Scholar
S. A. Brennan: Data collection, Writing the paper.
C. Ní Fhoghlú: Data collection, Writing the paper.
B. M. Devitt: Data collection, Writing the paper.
F. J. O’ Mahony: Data collection, Writing the paper.
D. Brabazon: Data collection, Writing the paper.
A. Walsh: Data collection, Writing the paper.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
This article was primary edited by S. P. F. Hughes and first proof edited by G. Scott.