ABSTRACT
HYPOTHESIS/BACKGROUND: Local delivery of neurotrophic factors on the intact round window membrane (RWM) of hair cell-deprived cochleas reduces degeneration of the cochlear nerve. In an animal model of profound hearing loss, we investigated whether this otoprotective effect could be enhanced by perforation of the RWM. Such method could be highly relevant for future clinical applications. METHODS: Guinea pigs were deafened by coadministration of kanamycin and furosemide. Two weeks after deafening, Gelfoam cubes infiltrated with brain-derived neurotrophic factor (BDNF) were deposited onto the RWM of the right cochlea. In the experimental condition, the RWM was perforated. Electrically evoked auditory brainstem responses (eABRs) were recorded weekly. Two or four weeks after Gelfoam placement, both left (untreated) and right (BDNF-treated) cochleas were processed for histology. RESULTS: In BDNF-treated cochleas, both with and without perforation, neural survival in the basal turn of the cochlea was significantly larger than in untreated cochleas. Amplitudes of electrically evoked auditory brainstem responses were larger in BDNF-treated cochleas with an RWM perforation than in those without a perforation and comparable to those of normal-hearing controls. Perforation did not lead to collateral cochlear damage. CONCLUSION: When considering clinical applications of neuroprotective agents such as BDNF, delivery on a perforated RWM seems to be a safe and effective option.
Subject(s)
Brain-Derived Neurotrophic Factor/administration & dosage , Drug Administration Routes , Evoked Potentials, Auditory, Brain Stem/drug effects , Round Window, Ear , Animals , Deafness/chemically induced , Disease Models, Animal , Female , Furosemide/toxicity , Guinea Pigs , Kanamycin/toxicity , Round Window, Ear/chemistryABSTRACT
HYPOTHESIS: Introduction of microperforations in round window membrane (RWM) will allow reliable and predictable intracochlear delivery of pharmaceutical, molecular, or cellular therapeutic agents. BACKGROUND: Reliable delivery of medications into the inner ear remains a formidable challenge. The RWM is an attractive target for intracochlear delivery. However, simple diffusion across intact RWM is limited by what material can be delivered, size of material to be delivered, difficulty with precise dosing, timing, and precision of delivery over time. Further, absence of reliable methods for measuring diffusion across RWM in vitro is a significant experimental impediment. METHODS: A novel model for measuring diffusion across guinea pig RWM, with and without microperforation, was developed and tested: cochleae, sparing the RWM, were embedded in 3D-printed acrylic holders using hybrid dental composite and light cured to adapt the round window niche to 3 ml Franz diffusion cells. Perforations were created with 12.5-µm-diameter needles and examined with light microscopy. Diffusion of 1 mM Rhodamine B across RWM in static diffusion cells was measured via fluorescence microscopy. RESULTS: The diffusion cell apparatus provided reliable and replicable measurements of diffusion across RWM. The permeability of Rhodamine B across intact RWM was 5.1 × 10(9-) m/s. Manual application of microperforation with a 12.5-µm-diameter tip produced an elliptical tear removing 0.22 ± 0.07% of the membrane and was associated with a 35× enhancement in diffusion (P < 0.05). CONCLUSION: Diffusion cells can be applied to the study of RWM permeability in vitro. Microperforation in RWM is an effective means of increasing diffusion across the RWM.
Subject(s)
Drug Administration Routes , Permeability , Round Window, Ear/chemistry , Animals , Diffusion , Guinea Pigs , In Vitro Techniques , Models, TheoreticalABSTRACT
Controlled-release carriers for local drug delivery have attracted increasing attention for inner-ear treatment recently. In this paper, flower-shaped bovine serum albumin (FBSA) particles were prepared by a modified desolvation method followed by glutaraldehyde or heat denaturation. The size of the FBSA particles varied from 10 µm to 100 µm, and most were 50-80 µm. Heat-denatured FBSA particles have good cytocompatibility with a prolonged survival time for L929 cells. The FBSA particles were utilized as carriers to investigate the release behaviors of the model drug - rhodamine B. Rhodamine B showed a sustained-release effect and penetrated the round-window membrane of guinea pigs. We also confirmed the attachment of FBSA particles onto the round-window membrane by microscopy. The FBSA particles, with good biocompatibility, drug-loading capacity, adhesive capability, and biodegradability, may have potential applications in the field of local drug delivery for inner-ear disease treatment.
Subject(s)
Delayed-Action Preparations/chemistry , Drug Carriers/chemistry , Round Window, Ear/metabolism , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/ultrastructure , Animals , Cell Line , Cell Survival/drug effects , Delayed-Action Preparations/pharmacokinetics , Delayed-Action Preparations/toxicity , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Guinea Pigs , Materials Testing , Mice , Particle Size , Rhodamines/chemistry , Rhodamines/pharmacokinetics , Round Window, Ear/chemistry , Serum Albumin, Bovine/pharmacokinetics , Serum Albumin, Bovine/toxicity , Tissue DistributionABSTRACT
Pathology of a round window membrane rupture was demonstrated in a human temporal bone from a case in which labyrinthotomy had been performed through the round window membrane. Proliferation of mesothelial cells was seen in the inner layer of the membrane, and it appeared to be reinforced from the inside by these reactive cells. The middle layer of the membrane was thickened by increased collagen and elastin. The pathologic changes which take place during healing of the ruptured round window membrane are discussed.
