Chemical and biochemical functionalization of middle ear implants

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Mechanical Adaptive Silicone Composites for UV-triggered Facilitated Cochlear-Implant Removal

The removal of the cochlear implant (CI), which in some cases is without alternative, is still an act of simple pulling, not only causing harm for the patient by damaging tissue but also making reimplantation more difficult. For that reason, it is necessary to develop mechanisms to make an explantation easier. To overcome this problem adaption of the mechanical properties by light-degradable periodic mesoporous organosilica (PMO) can be one solution. By introducing PMO nanoparticles into the CI's silicone matrix, the particles act as a stiffening agent, which can be degraded by irradiation with UV light. Using this mechanism, the silicone becomes softer, thus making explantation easier and safer for patients. Here first results, concerning the creation of a silicone composite material with light-sensitive adaptive mechanical properties are reported

Core-Shell-Nanoparticles with Superparamagnetic Properties for Novel Applications as Biomaterials

Due to the increasing average age of the population, the number of implants is also increasing and with it the number of explantations. Therefore, facilitated implant removal is of great interest. A nanocomposite consisting of superparamagnetic core-shell nanoparticles (CSNPs) and a synthetic polymer is supposed to be used as implant coating, aiming for a stimulus-inducible modification of the composite's rheological properties by hyperthermia. Here, the first steps following this concept, the synthesis and modification of the CSNP are reported. In this work magnetite nanoparticles build the core and are surrounded by a periodic mesoporous organisilica (PMO) shell. For this reason, the CSNP are referred to as magnetic PMO (mPMO) particles in the following

Mesoporous silica films as a novel biomaterial: Applications in the middle ear

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. © The Royal Society of Chemistry 2013

Nanoporous Silica Films as Novel Biomaterial: Applications in the Middle Ear

We have introduced nanoporous silica as a novel biomaterial. Nanoporous silica is non-toxic and biocompatible. It provides a high surface area and pore volume, uniform and tunable pore sizes and the possibility for chemical modification. We have shown that nanoporous silica coatings on middle ear prostheses provide a suitable basis for installing various functionalizations which can improve the healing after the insertion of the implant.DF

Different cell populations are inducible by BMP-2 covalently covered Bioverit® II implants in rabbit subcutis and middle ear

To optimize the function of implants the formation of surrounding connective tissue should be adapted in dependence to the mechanical conditions. Therefore, with nanostructured silica coated Bioverit® II implants were only partly reacted with recombinant BMP-2. The histology was compared 28, 84 and 301 days after implantation in the rabbit middle ear and subcutis, respectively. The whole tissue blocks were embedded in Epon, sequentially grinded, stained with Toluidine Blue O and Eosin G. The granulation tissue covering the implants varies related to cell types, cell amounts, extracellular matrix and vessels. Whereas the high cell density and the angiogenesis predominated in the subcutis, the formation of new bone could only be recognized in the scar around the implants in the middle ear.SFB/599/project D1

Nanoporous silica coatings on implant surfaces: characterization, stability, biocompatibility and drug release properties

Nanoporous silica coatings for drug release purposes were prepared on medical implants. As substrate, we chose Bioverit® II, which is a commercial available glass-mica ceramic implant material. The coating was prepared by a dip-coating technique in which long-chain organic molecules act as placeholders for the pores. Characterization of the coatings by scanning transmission electron microscopy and X-ray diffraction showed a disordered nanoporous system with a layer thickness of 30–150 nm. The nanoporous structure was stable for about 12 h in a typical cell culture medium and rearranged to a packing of silica nanoparticles. The coating allowed cell attachment and showed excellent biocompatibility in cell culture tests independently of the particular cell type examined. In vivo, implant-tissue interactions were examined in the middle ear in a novel mouse model. Whole genome expression profiling showed no persisting inflammatory response in the presence of the implants. Release profiles of the antibiotic ciprofloxacin demonstrated that the coating is suitable for a local drug delivery. The drug loading capacity could be drastically increased after sulfonic acid modification of the Bioverit® II surface

Preparation and PET/CT imaging of implant directed 68Ga-labeled magnetic nanoporous silica nanoparticles

Background: Implant infections caused by biofilm forming bacteria are a major threat in orthopedic surgery. Delivering antibiotics directly to an implant affected by a bacterial biofilm via superparamagnetic nanoporous silica nanoparticles could present a promising approach. Nevertheless, short blood circulation half-life because of rapid interactions of nanoparticles with the host’s immune system hinder them from being clinically used. The aim of this study was to determine the temporal in vivo resolution of magnetic nanoporous silica nanoparticle (MNPSNP) distribution and the effect of PEGylation and clodronate application using PET/CT imaging and gamma counting in an implant mouse model. Methods: PEGylated and non-PEGylated MNPSNPs were radiolabeled with gallium-68 (68Ga), implementing the chelator tris(hydroxypyridinone). 36 mice were included in the study, 24 mice received a magnetic implant subcutaneously on the left and a titanium implant on the right hind leg. MNPSNP pharmacokinetics and implant accumulation was analyzed in dependence on PEGylation and additional clodronate application. Subsequently gamma counting was performed for further final analysis. Results: The pharmacokinetics and biodistribution of all radiolabeled nanoparticles could clearly be visualized and followed by dynamic PET/CT imaging. Both variants of 68Ga-labeled MNPSNP accumulated mainly in liver and spleen. PEGylation of the nanoparticles already resulted in lower liver uptakes. Combination with macrophage depletion led to a highly significant effect whereas macrophage depletion alone could not reveal significant differences. Although MNPSNP accumulation around implants was low in comparison to the inner organs in PET/CT imaging, gamma counting displayed a significantly higher %I.D./g for the tissue surrounding the magnetic implants compared to the titanium control. Additional PEGylation and/or macrophage depletion revealed no significant differences regarding nanoparticle accumulation at the implantation site. Conclusion: Tracking of 68Ga-labeled nanoparticles in a mouse model in the first critical hours post-injection by PET/CT imaging provided a better understanding of MNPSNP distribution, elimination and accumulation. Although PEGylation increases circulation time, nanoparticle accumulation at the implantation site was still insufficient for infection treatment and additional efforts are needed to increase local accumulation

PH-responsive release of chlorhexidine from modified nanoporous silica nanoparticles for dental applications

A pH-sensitive stimulus-response system for controlled drug release was prepared by modifying nanoporous silica nanoparticles (NPSNPs) with poly(4-vinylpyridine) using a bismaleimide as linker. At physiological pH values, the polymer serves as gate keeper blocking the pore openings to prevent the release of cargo molecules. At acidic pH values as they can occur during a bacterial infection, the polymer strains become protonated and straighten up due to electrostatic repulsion. The pores are opened and the cargo is released. The drug chlorhexidine was loaded into the pores because of its excellent antibacterial properties and low tendency to form resistances. The release was performed in PBS and diluted hydrochloric acid, respectively. The results showed a considerably higher release in acidic media compared to neutral solvents. Reversibility of this pH-dependent release was established. In vitro tests proved good cytocompatibility of the prepared nanoparticles. Antibacterial activity tests with Streptococcus mutans and Staphylococcus aureus revealed promising perspectives of the release system for biofilm prevention. The developed polymer-modified silica nanoparticles can serve as an efficient controlled drug release system for long-term delivery in biomedical applications, such as in treatment of biofilm-associated infections, and could, for example, be used as medical implant coating or as components in dental composite materials

Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor

State-of-the-art treatment for sensorineural hearing loss is based on electrical stimulation of residual spiral ganglion neurons (SGNs) with cochlear implants (CIs). Due to the anatomical gap between the electrode contacts of the CI and the residual afferent fibers of the SGNs, spatial spreading of the stimulation signal hampers focused neuronal stimulation. Also, the efficiency of a CI is limited because SGNs degenerate over time due to loss of trophic support. A promising option to close the anatomical gap is to install fibers as artificial nerve guidance structures on the surface of the implant and install on these fibers drug delivery systems releasing neuroprotective agents. Here, we describe the first steps in this direction. In the present study, suture yarns made of biodegradable polymers (polyglycolide/poly-ε-caprolactone) serve as the basic fiber material. In addition to the unmodified fiber, also fibers modified with amine groups were employed. Cell culture investigations with NIH 3T3 fibroblasts attested good cytocompatibility to both types of fibers. The fibers were then coated with the extracellular matrix component heparan sulfate (HS) as a biomimetic of the extracellular matrix. HS is known to bind, stabilize, modulate, and sustainably release growth factors. Here, we loaded the HS-carrying fibers with the brain-derived neurotrophic factor (BDNF) which is known to act neuroprotectively. Release of this neurotrophic factor from the fibers was followed over a period of 110 days. Cell culture investigations with spiral ganglion cells, using the supernatants from the release studies, showed that the BDNF delivered from the fibers drastically increased the survival rate of SGNs in vitro. Thus, biodegradable polymer fibers with attached HS and loaded with BDNF are suitable for the protection and support of SGNs. Moreover, they present a promising base material for the further development towards a future neuronal guiding scaffold. Copyright © 2022 Wille, Harre, Oehmichen, Lindemann, Menzel, Ehlert, Lenarz, Warnecke and Behrens