Small-sized magnesium cylinders influence subchondral bone quality in osteoarthritic rabbits - an in vivo pilot study.

No optimal therapy exists to stop or cure chondral degeneration in osteoarthritis (OA). While the pathogenesis is unclear, there is consensus on the etiological involvement of both articular cartilage and subchondral bone. Compared to original bone, the substance of sclerotic bone is mechanically less solid. The osteoproliferative effect of Mg has been shown repeatedly during development of Mg-based osteosynthesis implants. The aim of the present study was to examine the influence of implanted high-purity Mg cylinders on subchondral bone quality in a rabbit OA model. 10 New Zealand White rabbits received into the knee either 20 empty drill holes or 20 drill holes, which were additionally filled with one Mg cylinder each. Follow-up was at 8 weeks. Micro-computed tomography (µCT) was performed. After euthanasia, cartilage condition was determined, bone samples were collected and processed for histological evaluation and elemental imaging by micro-X-ray fluorescence spectrometry (µXRF). Articular cartilage collected post-mortem showed different stages of lesions, from mild alterations up to exposed subchondral bone, which tended to be slightly lower in animals with implanted Mg cylinders. µCT showed significantly increased bone volume in the Mg group. Also, histological evaluation revealed distinct differences. While right, operated limbs did not show any significant difference, left, non-operated controls showed significantly less changes in articular cartilage in the Mg group. A distinct influence of implanted cylinders of pure Mg on subchondral bone of osteoarthritic rabbits was shown. Subsequent evaluations, including other time points and alternative alloys, will show if this could alter OA progression.

Encapsulated cell device approach for combined electrical stimulation and neurotrophic treatment of the deaf cochlea.

Profound hearing impairment can be overcome by electrical stimulation (ES) of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Thus, SGN survival is critical for CI efficacy. Application of glial cell line-derived neurotrophic factor (GDNF) has been shown to reduce SGN degeneration following deafness. We tested a novel method for local, continuous GDNF-delivery in combination with ES via a CI. The encapsulated cell (EC) device contained a human ARPE-19 cell-line, genetically engineered for secretion of GDNF. In vitro, GDNF delivery was stable during ES delivered via a CI. In the chronic in vivo part, cats were systemically deafened and unilaterally implanted into the scala tympani with a CI and an EC device, which they wore for six months. The implantation of control devices (same cell-line not producing GDNF) had no negative effect on SGN survival. GDNF application without ES led to an unexpected reduction in SGN survival, however, the combination of GDNF with initial, short-term ES resulted in a significant protection of SGNs. A tight fibrous tissue formation in the scala tympani of the GDNF-only group is thought to be responsible for the increased SGN degeneration, due to mechanisms related to an aggravated foreign body response. Furthermore, the fibrotic encapsulation of the EC device led to cell death or cessation of GDNF release within the EC device during the six months in vivo. In both in vitro and in vivo, fibrosis was reduced by CI stimulation, enabling the neuroprotective effect of the combined treatment. Thus, fibrous tissue growth limits treatment possibilities with an EC device. For a stable and successful long-term neurotrophic treatment of the SGN via EC devices in human CI users, it would be necessary to make changes in the treatment approach (provision of anti-inflammatories), the EC device surface (reduced cell adhesion) and the ES (initiation prior to fibrosis formation).

Biodegradable polymeric coatings on cochlear implant surfaces and their influence on spiral ganglion cell survival.

To improve the electrode-nerve interface of cochlear implants (CI), the role of poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P(4HB)) as potential coating matrices for CI was assessed both in vitro and in vivo in terms of degradation behavior and effects on spiral ganglion neurons, the main target of the electrical stimulation with a CI. Growth rates of fibroblasts on the polymers were investigated and a direct-contact test with freshly isolated spiral ganglion cells (SGC) was performed. In addition, the effects of the polymer degradation inside the inner ear were evaluated in vivo. The polymer degradation was assessed by use of scanning electron microscopy in combination with an energy-dispersive X-ray analysis. In vitro, no influence of the polymers was detected on fibroblasts' viability and on SGC survival rate. In vivo, SGC density was decreased only 6 months after implantation in the basal and middle turns of the cochlea in comparison to normal-hearing animals but not between implanted groups (coated or uncoated). The analysis of the electrode models showed that in vivo P(4HB) is characterized by a gradual degradation completed after 6 months; whereas, the PLLA coatings burst along their longitudinal axis but showed only little degradation within the same time frame. In conclusion, both polymers seem to justify further evaluation as possible coating for CI electrodes. Of the two options, due to its excellent coating adhesion/stability and optimal degradation behavior, P(4HB) may prove to be the more promising biodegradable polymer for designing a drug delivery system from the surface of CI electrodes.

[In vitro neurite outgrowth induced by BDNF and GDNF in combination with dexamethasone on cultured spiral ganglion cells]. / Neuritenwachstum in vitro durch BDNF und GDNF in Kombination mit Dexamethason auf kultivierte Spiralganglienzellen.

BACKGROUND: The efficacy of cochlear implant performance depends, among many other factors, on the number of excitable spiral ganglion cells (SGCs) and the nerve-electrode interface. In earlier animal studies it has been demonstrated that neurotrophic factors are effective to improve SGC survival after experimentally induced deafness. With regard to their anti-inflammatoric and anti-proliferative effects, glucocorticoids (e. g. dexamethasone) are potentially interesting therapeutic agents to reduce connective tissue formation around the inserted electrode. The biological effects of a combined intervention of neurotrophic factors with steroids on SGCs are unknown. Therefore the objective of the study was to investigate possible trophic or even toxic effects of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and dexamethasone on neurite outgrowth of cultivated SGCs. METHODS: By using dissociated postnatal spiral ganglion cells (p3-5) for cultivation in the present study, the influence of the mentioned factors in various concentrations and combinations on neurite outgrowth of SGCs was analysed. RESULTS: Our results indicate significant trophic effects for BDNF (50 ng/ml) and a combination of BDNF with dexamethasone (100 ng/ml) on SGC neurite outgrowth. In contrast, single application of GDNF or dexamethasone in different concentrations caused no significant changes on neurite outgrowth when compared to the control condition. CONCLUSIONS: Neurite outgrowth induced by neurotrophic factors could not be observed to be reduced when dexamethasone is given at the same time. Therefore the demonstrated results provide a basis for further animal studies in this field of research.

[Neurotrophic factors of the GDNF family and their receptors are detectable in spiral ganglion cells of normal hearing as well as of deafened rats]. / Neurotrophe Faktoren der GDNF-Familie und ihre Rezeptoren lassen sich in Spiralganglienzellen hörender, aber auch ertaubter Ratten nachweisen.

BACKGROUND: Recent studies have shown that neurotrophic factors like BDNF, NT-3 and GDNF induce protective effects on spiral ganglion cells after noise- or drug-induced hearing loss. According to these studies it is suggested that deafness leads to a lack of neurotrophic factor or relating receptor expression in spiral ganglion cells, that has to be compensated by local cochlear application of these factors. METHODS: In the present study we examined the expression pattern of members of the GDNF family (GDNF, Neurturin, Artemin, Persephin) and their relating receptors (Ret, GFRalpha1 - 3) as well as BDNF and trkB on spiral ganglion cells of normal hearing and experimentally deafened rats (10 % neomycine). Indirect immunofluorescence was carried out to determine protein expression of these factors and their receptors 26 days following deafening. RESULTS: Our results demonstrate neurotrophic factor and receptor expression on spiral ganglion cells of normal hearing as well as experimentally deafened animals. CONCLUSIONS: Our data indicate that within a period of 26 days after deafening no detectable reduction of the GDNF-family member expression and their receptors was ascertainable on spiral ganglion cells by immunohistochemistry. Thus, a lack of neurotrophic factor expression is unlikely to be the only cause of spiral ganglion cell loss following deafening.