Peri-implantitis caused by multispecies biofilms is a major complication in dental implant treatment. The bacterial infection surrounding dental implants can lead to bone loss and, in turn, to implant failure. A promising strategy to prevent these common complications is the development of implant surfaces that inhibit biofilm development. A reproducible and easy-to-use biofilm model as a test system for large scale screening of new implant surfaces with putative antibacterial potency is therefore of major importance. In the present study, we developed a highly reproducible in vitro four-species biofilm model consisting of the highly relevant oral bacterial species Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar and Porphyromonas gingivalis. The application of live/dead staining, quantitative real time PCR (qRT-PCR), scanning electron microscopy (SEM) and urea-NaCl fluorescence in situ hybridization (urea-NaCl-FISH) revealed that the four-species biofilm community is robust in terms of biovolume, live/dead distribution and individual species distribution over time. The biofilm community is dominated by S. oralis, followed by V. dispar, A. naeslundii and P. gingivalis. The percentage distribution in this model closely reflects the situation in early native plaques and is therefore well suited as an in vitro model test system. Furthermore, despite its nearly native composition, the multispecies model does not depend on nutrient additives, such as native human saliva or serum, and is an inexpensive, easy to handle and highly reproducible alternative to the available model systems. The 96-well plate format enables high content screening for optimized implant surfaces impeding biofilm formation or the testing of multiple antimicrobial treatment strategies to fight multispecies biofilm infections, both exemplary proven in the manuscript.

To generate bioactive coatings for medical implants, a novel procedure has been developed using a coating of mesoporous silica for controlled drug delivery. Plain glass slides were used as substrates. The mesoporous coatings were then loaded with the antibacterial drug ciprofloxacin. The drug release kinetics were investigated in a physiological buffered solution. The drug loading capacity of the unmodified mesoporous coatings was low but could be increased nearly ten-fold (to about 2 mg cm À2 of the macroscopic surface) by functionalizing the mesoporous surface with sulfonic acid groups. To achieve a controlled drug release over an extended time period, further coatings were added. Covering the surface of the drug loaded mesoporous silica layer by dip-coating with bis(trimethoxysilyl)hexane resulted in an organosiloxane layer which retarded the release for up to 30 days. By an additional evaporation coating with dioctyltetramethyldisilazane, the release of ciprofloxacin was prolonged for up to 60 days. The biocompatibility of the different coatings was tested in cell culture assays. The presence of the additional silane-derived hydrophobic coatings somewhat reduced the biocompatibility. The antibacterial efficacy of the materials was demonstrated by using clinically relevant biofilm-forming pathogenic bacteria. A test where the sequential release of ciprofloxacin (in 2 days intervals) and the bacterial viability were tested in parallel showed good concordance in the results. The material where a sulfonate-functionalized mesoporous silica layer is loaded with ciprofloxacin and then coated by an organosiloxane layer derived from bis(trimethoxysilyl)hexane showed the best results with regard to antibacterial efficacy and will further be tested in animal experiments.

In this tutorial review we present the process of the development of functional implants using mesoporous silica. The different steps from chemical synthesis and physicochemical characterization followed by in vitro testing in cell culture assays to clinically relevant in vivo animal studies are examined. Since the end of the 1990s, mesoporous silicas have been considered as biomaterials. Numerous investigations have demonstrated their non-toxic and biocompatible properties. These qualities in combination with the unique properties of high surface area and pore volume, uniform and tunable pore sizes and chemical modifiability are the reasons for the great scientific interest in this field. Here we show that besides bulk materials or mesoporous silica nanoparticles, mesoporous silica films are highly promising as coatings on medical prostheses or implants. We report on the development of functionalized mesoporous silica materials specifically for middle ear applications. Middle ear prostheses are used to restore the sound transmission through this air-filled cavity when the small bones of the middle air (the ossicular chain) have been destroyed by disease or by accidents. In addition to optimal restoration of sound transmission, this technique bears several challenges, e.g. an ongoing bacterial infection or the displacement of the prosthesis due to insufficient fixation. To improve the healing process, a mesoporous silica coating was established on ceramic middle ear prostheses, which then served as a base for further functionalizations. For example, the bone growth factor BMP2 was locally attached to the coating in order to improve the fixation of the prosthesis by forming a bony connection to the remainder of the ear bones. Further, an implant-based local drug delivery system for the antibiotic ciprofloxacin was developed with the aim of fighting bacterial infections. Further possibilities using mesoporous silica nanoparticles as part of a composite on an implant are briefly discussed. Key learning pointsThe way from clinical problems to improved implant materials: materials development, in vitro and in vivo testing. Establishment of mesoporous thin silica films on ceramic surfaces. Degradation of mesoporous silica films in physiological medium. Implant-carried mesoporous silica films as drug delivery systems. Implant-based delivery of biomolecules using mesoporous silica coatings.

Sensorineural hearing loss (SNHL) can be overcome by electrical stimulation of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Restricted CI performance results from the spatial gap between the SGNs and the electrode, but the efficacy of CI is also limited by the degeneration of SGNs as one consequence of SHNL. In the healthy cochlea, the survival of SGNs is assured by endogenous neurotrophic support. Several applications of exogenous neurotrophic supply have been shown to reduce SGN degeneration in vitro and in vivo. In the present study, nanoporous silica nanoparticles (NPSNPs), with an approximate diameter of <100 nm, were loaded with the brain-derived neurotrophic factor (BDNF) to test their efficacy as long-term delivery system for neurotrophins. The neurotrophic factor was released constantly from the NPSNPs over a release period of 80 days when the surface of the nanoparticles had been modified with amino groups. Cell culture investigations with NIH3T3 fibroblasts attest a good general cytocompatibility of the NPSNPs. In vitro experiments with SGNs indicate a significantly higher survival rate of SGNs in cell cultures that contained BDNF-loaded nanoparticles compared to the control culture with unloaded NPSNPs (p<0.001). Importantly, also the amounts of BDNF released up to a time period of 39 days increased the survival rate of SGNs. Thus, NPSNPs carrying BDNF are suitable for the treatment of inner ear disease and for the protection and the support of SGNs. Their nanoscale nature and the fact that a direct contact of the nanoparticles and the SGNs is not necessary for neuroprotective effects, should allow for the facile preparation of nanocomposites, e.g., with biocompatible polymers, to install coatings on implants for the realization of implant-based growth factor delivery systems.

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