For several centuries silver is known for its antibacterial effects. The middle ear is an interesting new scope for silver application since chronic inflammations combined with bacterial infection cause complete destruction of the fragile ossicle chain and tympanic membrane. The resulting conductive deafness requires tympanoplasty for reconstruction. Strategies to prevent bacterial growth on middle ear prostheses are highly recommended. In this study, rabbits were implanted with Bioverit® II middle ear prostheses functionalized with silver containing dense and nanoporous silica films which were compared with pure silica coatings as well as silver sulfadiazine cream applied on nanoporous silica coating. The health status of animals was continuously monitored; blood was examined before and after implantation. After 21 days, the middle ears were inspected; implants and mucosal samples were processed for electron microscopy. Autopsies were performed and systemic spreading of silver was chemically analyzed exemplarily in liver and kidneys. For verification of direct cytotoxicity, NIH 3T3 cells were cultured on similar silver containing silica coatings on glass up to 3 days. In vitro a reduced viability of fibroblasts adhering directly on the samples was detected compared to cells growing on the surrounding plastic of the same culture dish. In transmission electron microscopy, phagocytosed silver silica fragments, silver sulfadiazine cream as well as silver nanoparticles were noticed inside endosomes. In vivo, clinical and post mortem examinations were inconspicuous. Chemical analyses showed no increased silver content compared to controls. Mucosal coverages on almost all prostheses were found. But reduction of granulation tissue was only obvious around silver-coated implants. Single necroses and apoptosis in the mucosa were correlated by intracellular accumulation of metallic silver. For confirming supportive healing effects of middle ear implants, silver ion aggregates need to be tested in the future to optimize biocompatibility while assuring bactericidal effects in the middle ear.
GoldenbergREmmetJR. Current use of implants in middle ear surgery. Otol Neurotol2001; 22(2): 145–152.
5.
GeyerG. Materialien zur Rekonstruktion des Schallleitungsapparates. HNO1999; 47(2): 77–91.
6.
TurckCBrandesGKruegerI. Histological evaluation of novel ossicular chain replacement prostheses: An animal study in rabbits. Acta Otolaryngol2007; 127(8): 801–808.
7.
VogtJCBrandesGEhlertN. Free Bioverit® II implants coated with a nanoporous silica layer in a mouse ear model - a histological study. J Biomater Appl2009; 24(2): 175–191.
8.
EhlertNMuellerPPStieveM. Mesoporous silica films as a novel biomaterial: Applications in the middle ear. Chem Soc Rev2013; 42(9): 3847–3861.
HouseJWTeufertKB. Extrusion rates and hearing results in ossicular reconstruction. Otolaryngol Head Neck Surg2001; 125(3): 135–141.
12.
LensingRBleichASmoczekA. Efficacy of nanoporous silica coatings on middle ear prostheses as a delivery system for antibiotics: An animal study in rabbits. Acta Biomater2013; 9(1): 4815–4825.
13.
DarouicheRO. Antimicrobial approaches for preventing infections associated with surgical implants. Clin Infect Dis2003; 36(10): 1284–1289.
14.
HesseDEhlertNLüßenhopT. Nanoporous silica coatings as a drug delivery system for ciprofloxacin: Outcome of variable release rates in the infected middle ear of rabbits. Otol Neurotol2013; 34(6): 1138–1145.
15.
HesseDBadarMBleichA. Layered double hydroxides as efficient drug delivery system of ciprofloxacin in the middle ear: An animal study in rabbits. J Mater Sci Mater Med2013; 24(1): 129–136.
16.
AlexanderJW. History of the medical use of silver. Surg Infect (Larchmt)2009; 10(3): 289–292.
BadiouWLavigneJPBousquetPJ. In vitro and in vivo assessment of silver-coated polypropylene mesh to prevent infection in a rat model. Int Urogynecol J2011; 22(3): 265–272.
19.
RoeDKarandikarBBonn-SavageN. Antimicrobial surface functionalization of plastic catheters by silver nanoparticles. J Antimicrob Chemother2008; 61(4): 869–876.
20.
JansenBRinckMWolbringP. In vitro evaluation of the antimicrobial efficacy and biocompatibility of a silver-coated central venous catheter. J Biomater Appl1994; 9(1): 55–70.
21.
BenvenistyAITannenbaumGAhlbornTN. Control of prosthetic bacterial infection: Evaluation of an easily incorporated, tightly bound, silver antibiotic PTFE graft. J Surg Res1988; 44(1): 1–7.
22.
JacquartSSiadousRHenocq-PigasseC. Composition and properties of silver-containing calcium carbonate-calcium phosphate bone cement. J Mater Sci Mater Med2013; 24(12): 2665–2675.
23.
KarchmerTBGiannettaETMutoCA. A randomized crossover study of silver-coated urinary catheters in hospitalized patients. Arch Intern Med2000; 160(21): 3294–3298.
24.
LiuJSonshineDAShervaniS. Controlled release of biologically active silver from nanosilver surfaces. ACS Nano2010; 4(11): 6903–6913.
25.
MoronesJRElechiguerraJLCamachoA. The bactericidal effect of silver nanoparticles. Nanotechnology2005; 16(10): 2346–2353.
26.
FengQLWuJChenGQ. A mechanistic study of the antibacterial effect of silver ions on Escherichia and Staphylococcus aureus. J Biomed Mater Res2000; 52(4): 662–668.
27.
ParkH-JKimJYKimJ. Silver-ion-mediated reactive oxygen species generation affecting bactericidal activity. Water Res2009; 43(4): 1027–1032.
28.
MatsumuraYYoshikataKKunisakiS. Mode of bactericidal action of silver zeolite and its comparison with that of silver nitrate. Appl Environ Microbiol2003; 69(7): 4278–4281.
29.
ChernousovaSEppleM. Silver as antibacterial agent: Ion, nanoparticle, and metal. Angew Chem Int Ed2013; 52(6): 1636–1653.
30.
SchierholzJLucasLRumpA. Efficacy of silver-coated medical devices. J Hosp Infect1998; 40: 257–262.
31.
LansdownABG. A pharmacological and toxicological profile of silver as an antimicrobial agent in medical devices. Adv Pharmacol Sci2010.
32.
AhamedMAlsalhiMSSiddiquiMKJ. Silver nanoparticle applications and human health. Clin Chim Acta2010; 411(23-24): 1841–1848.
33.
CholeRABrummettRETinlingSP. Safety of silver oxide-impregnated silastic tympanostomy tubes. Am J Otol1995; 16(6): 722–724.
34.
CholeRAHubbellRN. Antimicrobial activity of silastic tympanostomy tubes impregnated with silver oxide: A double-blind randomized multicenter trial. Arch Otolaryngol Head Neck Surg1995; 121(5): 562–565.
35.
UllrichDKreutzerS. Vergleichende Untersuchung von Paukendrainage-Röhrchen: Eine randomisiert-prospektive Studie zur Verträglichkeit von Silberoxid-beschichteten Silikon- und Gold-beschichteten Silberröhrchen. Laryngorhinootologie2006; 85(7): 501–505.
36.
SuhMLeeHParkJ. A mesoporous silica thin film as uptake host for guest molecules with retarded release kinetics. ChemPhysChem2008; 9(10): 1402–1408.
37.
WeipingCLideZ. Synthesis and structural and optical properties of mesoporous silica containing silver nanoparticles. J Phys: Condens Matter1997; 9(34): 7257–7267.
38.
UsachevaTLedenkovSSharninV. Complex formation of Ag+ with polyether 18-crown-6. J Therm Anal Cal2002; 70: 379–385.
39.
StieveMHedrichHJBattmerRD. Experimental middle ear surgery in rabbits: A new approach for reconstructing the ossicular chain. Lab Anim2009; 43(2): 198–204.
40.
DIN 32645: 2008-11. Chemical analysis - Decision limit, detection limit and determination limit under repeatability conditions - Terms, methods, evaluation, Berlin: Beuth Verlag GmbH, 2008.
41.
DIN 38402-51: 1986-05. Examination of water, waste water and sludge; calibration of analytical methods, evaluation of analytical results and linear calibration functions used to determine the performance characteristics of analytical methods, Berlin: Beuth Verlag GmbH, 1986.
42.
BeutnerDHüttenbrinkKB. Passive and active middle ear implants. Laryngorhinootologie2009; 88(1): 32–47.
43.
DostPh. Biomaterialien in der rekonstruktiven Mittelohrchirurgie. Laryngorhinootologie2000; 79(2): 53–72.
44.
DanscherGLochtLJ. In vivo liberation of silver ions from metallic silver surfaces. Histochem Cell Biol2010; 133(3): 359–366.
45.
EhlertNBadarMChristelA. Mesoporous silica coatings for controlled release of the antibiotic ciprofloxacin from implants. J Mater Chem2011; 21(3): 752–760.
46.
AroraSJainJRajwadeJM. Interactions of silver nanoparticles with primary mouse fibroblasts and liver cells. Toxicol Appl Pharmacol2009; 236(3): 310–318.
47.
PaukschLHartmannSRohnkeM. Biocompatibility of silver nanoparticles and silver ions in primary human mesenchymal stem cells and osteoblasts. Acta Biomater2014; 10(1): 439–449.
48.
PaascheGCeschiPLöblerM. Effects of metal ions on fibroblasts and spiral ganglion cells. J Neurosci Res2011; 89(4): 611–617.
49.
LansdownABGSampsonBLaupattarakasemP. Silver aids healing in the sterile skin wound: Experimental studies in the laboratory rat. Br J Dermatol1997; 137(5): 728–735.
50.
WrightJBLamKBuretAG. Early healing events in a porcine model of contaminated wounds: Effects of nanocrystalline silver on matrix metalloproteinases, cell apoptosis, and healing. Wound Repair Regen2002; 10(3): 141–151.
51.
JahnkeKDostPSchraderMBiocompatibiliy studies of implants for reconstructive middle ear surgery. In: PortmannM (ed.). Transplants and implants in otology III, Amsterdam: Kugler Publications, 1996, pp. 41–46.
52.
ZahnertT. The differential diagnosis of hearing loss. Dtsch Arztebl Int2011; 108(25): 433–444.
53.
De SouzaCGoycooleaMVPathology of otosclerosis. In: De SouzaCGoycooleaMVSperlingNM (eds). Otosclerosis: Diagnosis, evaluation, pathology, surgical techniques, and outcomes, San Diego, CA: Plural Publishing, Inc, 2013, pp. 3–7.
54.
SchwagerK. Epithalisierung von Titanprothesen im Mittelohr des Kaninchens. Modellvorstellungen zur Mukosaentwicklung. Laryngorhinootologie1998; 77(1): 38–42.
55.
Van BlitterswijkCAKuijpersWDaemsWT. Epithelial reactions to hydroxyapatite. Acta Otolaryngol1986; 101(13): 231–241.
56.
ArnoldW. Reaktionsformen der Mittelohrschleimhaut. Arch Otorhinolaryngol1977; 216(1): 369–473.
57.
LochtLJPedersenMØMarkholtS. Metallic silver fragments cause massive tissue loss in the mouse brain. Basic Clin Pharmacol Toxicol2011; 109(1): 1–10.
58.
HernándezPPMorenoVOlivariFA. Sub-lethal concentrations of waterborne copper are toxic to lateral line neuromasts in zebrafish (Danio rerio). Hear Res2006; 213(1-2): 1–10.
59.
GreulichCBraunDPeetschA. The toxic effect of silver ions and silver nanoparticles towards bacteria and human cells occurs in the same concentration range. RSC Adv2012; 2(17): 6981–6987.
60.
BeerCFoldbjergRHayashiY. Toxicity of silver nanoparticles - nanoparticle or silver ion?Toxicol Lett2012; 208(3): 286–292.
61.
BoenigkJBeisserDZimmermannS. Effects of silver nitrate and silver nanoparticles on a planktonic community: General trends after short-term exposure. PLoS One2014; 9(4): 1–10.
62.
NavarroEPiccapietraFWagnerB. Toxicity of silver nanoparticles to Chlamydomonas reinhardtii. Environ Sci Technol2008; 42(23): 8959–8964.
63.
BuryNRWoodCM. Mechanism of branchial apical silver uptake by rainbow trout is via the proton-coupled Na+ channel. Am J Physiol1999; 277(5.2): 1385–1391.
64.
SilverS. Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. FEMS Microbiol Rev2003; 27(2-3): 341–353.
65.
LiuJHurtRH. Ion release kinetics and particle persistence in aqueous nano-silver colloids. Environ Sci Technol2010; 44(6): 2169–2175.
66.
MukherjeePAhmadAMandalD. Fungus-mediated synthesis of silver nanoparticles and their immobilization in the mycelial matrix: A novel biological approach to nanoparticle synthesis. Nano Lett2001; 1(10): 515–519.
67.
ThakkarKNMhatreSSParikhRY. Biological synthesis of metallic nanoparticles. Nanomedicine: NBM2010; 6(2): 257–262.
68.
MarchiolLMattielloAPošćićF. In vivo synthesis of nanomaterials in plants: location of silver nanoparticles and plant metabolism. Nanoscale Res Lett2014; 9(1): 101.
69.
Van der ZandeMVandebrielRJVan DorenE. Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. ACS Nano2012; 6(8): 7427–7442.
70.
WadheraAFungM. Systemic argyria associated with ingestion of colloidal silver. Dermatol Online J2005; 11(1): 12.
71.
FungMCBowenDL. Silver products for medical indications: Risk-benefit assessment. J Toxicol Clin Toxicol1996; 34(1): 119–126.
72.
Agency for toxic substances and diseases registry. Toxicological profile for silver, USA: Report, U.S. Public Health Service, 1990. December.
73.
ShinogiMMaeizumiS. Effect of preinduction of metallothionein on tissue distribution of silver and hepatic lipid peroxidation. Biol Pharm Bull1993; 16(4): 372–374.
74.
BaudinJPGarnier-LaplaceJLambrechtsA. Uptake from water, depuration and tissue distribution of 110m Ag in a freshwater fish, Cyprinus carpio L. Water Air Soil Pollut1994; 72(1): 129–141.
75.
LuomaSN. Silver nanotechnologies and the environment: Old problems or new challenges?, Washington DC, USA: Report, The project on emerging nanotechnologies, 2008. September.
76.
GoshegerGHardesJAhrensH. Silver-coated megaendoprostheses in a rabbit model - an analysis of the infection rate and toxicological side effects. Biomaterials2004; 25(24): 5547–5556.
