Amy Hampson

Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF

ABSTRACT Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug‐delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain‐derived neurotrophic factor (BDNF) via this catheter with a mini‐osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter ‐ whether dry or when delivering AP or BDNF for 4 weeks ‐ was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

The Effect of Round Window Sealants on Delayed Hearing Loss in a Guinea Pig Model of Cochlear Implantation.

Aim: To determine whether the type of material used to seal the cochlea after round window cochlear implantation influences delayed hearing loss. Background: Cochlear implants are now prescribed to patients with residual, low-frequency hearing. This hearing—which provides perceptual benefits for the implanted ear—is frequently lost for unknown reasons weeks to months after surgery in a proportion of patients. A post-surgical change in cochlear mechanics, related to the material used to seal the cochlea after round window implantation, may contribute to this loss. Methods: An electrode array was implanted in guinea pigs via the round window, which was then sealed with muscle, periosteum, or fibrin glue. Auditory brainstem responses (ABRs) to pure tones (2, 8, 16, 24, and 32 kHz) were recorded before surgery and 1, 4, and 12 weeks after surgery, with subjects then euthanized and their cochleae harvested for histological analysis. Results: Muscle and periosteum, but not fibrin glue, exhibited delayed threshold rises at 2 kHz. Twelve weeks after implantation, 2 kHz threshold shifts differed significantly between muscle (mean, 27.1 dB) and fibrin glue (9.3 dB), but not between these groups and periosteum (19.3 dB). Muscle was sometimes associated with much greater tissue reactions than the other sealants. Most cochleae had injuries to the basilar membrane and/or osseous spiral lamina, regardless of sealant. Hair cell counts did not differ significantly among sealants. Conclusion: Delayed, low-frequency hearing loss was observed when cochleae were sealed with muscle or periosteum, but not when cochleae were sealed with fibrin glue.

A comparison of cochlear distribution and glucocorticoid receptor activation in local and systemic dexamethasone drug delivery regimes

Abstract Local and systemically delivered glucocorticoids are commonly administered to protect the cochlea against damage associated with a variety of insults. There is reason to believe that dexamethasone administered by these routes may arrive at cochlear target sites via different pathways. Clinically, there is a lack of clarity as to which route is more effective in any specific circumstance. This study explores dexamethasone distribution within the guinea pig cochlea following local and systemic delivery methods. A combination of mass spectroscopy and immunohistochemistry were employed to compare both perilymph distribution, tissue uptake and receptor activation. Local administration of dexamethasone to the round window membrane resulted in greater perilymph concentrations, with a basal to apical gradient that favours the cochlear base. Tissue immunofluorescence was intimately related to perilymph concentration following local administration. Systemic administration resulted in much lower perilymph concentrations, with an inverse basal to apical gradient favouring the cochlear apex. Lower perilymph concentrations following systemic administration were associated with minimal tissue immunofluorescence. Despite this, GR activation of the SGNs was equivalent in both administration regimes. These results bring into question the efficacy of measuring perilymph concentrations alone as a surrogacy for dexamethasone distribution and activity in the cochlea, suggesting that the steroid ligand may arrive at its target receptor via alternative pathways. Our results suggest an equivalence in efficacy between local and systemic administration routes early after drug delivery, when the ultimate outcome of GR activation is the goal. HighlightsLocal delivery of dexamethasone resulted in greater perilymph concentrations.Basal to apical perilymph gradients are achieved with local administration.Dexamethasone tissue distribution is closely related to perilymph concentrations.Glucocorticoid receptor activation in the spiral ganglion was equal in both delivery methods.

Effect of cochlear implantation on middle ear function: A three-month prospective study: Effect of CI on Middle Ear Function

To determine if cochlear implantation has a delayed effect on the middle ear conductive hearing mechanism by measuring laser Doppler vibrometry (LDV) of the tympanic membrane (TM) in both implanted and contralateral control ears preoperatively and 3 months postoperatively, and then comparing the relative change in LDV outcome measures between implanted and control ears.

Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients

&NA; Glucocorticoids have direct anti‐inflammatory, anti‐oxidant and anti‐apoptotic effects on cochlear hair cells. Cochlear glucocorticoid therapy has gained particular attention for its ability to enhance the protection of residual hearing following hearing preservation cochlear implantation. Local drug delivery methods achieve high drug concentrations within the inner ear fluids but are reliant upon diffusion across the round window membrane. Diffusion has been shown to demonstrate large individual variability. This study explores the role of “adjuvant agents”, which when administered with glucocorticoids, enhance inner ear absorption and distribution. Guinea pig cochleae were administered either dexamethasone alone or in combination with hyaluronic acid, histamine, or combination histamine and hyaluronic acid, targeted at the round window membrane. Control subjects received saline. Perilymph was sampled from the cochlear apex, and basal to apical dexamethasone concentrations recorded with mass spectroscopy. Cochleae were harvested, and immunohistochemistry employed to explore dexamethasone tissue penetration and distribution. Basal to apical gradients were observed along the scala tympani, with higher dexamethasone concentrations observed at the cochlear base. Gradients were more pronounced and uniform when administered on a hyaluronic acid sponge, while histamine increased absolute concentrations reaching the inner ear. Tissue penetration correlated with perilymph concentration. Our results demonstrate that adjuvant agents can be employed to enhance dexamethasone absorption and distribution in the inner ear, thus proposing therapeutic strategies that may enhance steroid facilitated hearing protection.

Intraoperative force and electrocochleography measurements in an animal model of cochlear implantation

Abstract To preserve residual hearing, techniques for monitoring and reducing the effects of trauma during cochlear implant surgery are being developed. This study examines the relationships between intraoperative recordings (electrode insertion force and electrocochleography), trauma, and hearing loss after cochlear implantation. The study also evaluated the efficacy of intravenous steroids for reducing hearing loss after implantation. Thirty‐two normal‐hearing guinea pigs were randomly implanted with electrode arrays of differing stiffness (‘hard’ or ‘soft’). These arrays used an intracochlear electrode to record electrode insertion force and electrocochleography responses to a multi‐frequency acoustic stimulus during implantation. Additionally, sub‐cohorts of animals were administered intravenous saline (‘control’) or dexamethasone (‘steroid’) prior to surgery. Subsequent hearing loss was assessed using electrocochleography recordings from the round window membrane prior to surgery and 4 weeks after implantation. After 4 weeks, cochleae were harvested and imaged with thin sheet laser imaging microscopy. After 4 weeks, compound action potential (CAP) thresholds did not differ between steroid and control groups. The CAP amplitude at low‐mid frequencies decreased after implantation with a hard electrode, an effect which was partly negated by administering steroids. A decrease in the ‘intraoperative’ CAP amplitude preceded the reporting of insertion resistance by the surgeon by 5.94 s (±4.03 s SEM). Intraoperative CAP declines were also correlated with higher grades of trauma (r = 0.56, p < 0.01) and greater hearing loss (r = 0.56, p < 0.01). This relationship was not repeated with intraoperative cochlear microphonics. A rise in intraoperative force, which preceded the reporting of resistance by 0.71 s (±0.15 s SEM), was correlated with trauma (r = 0.400, p = 0.04) but not hearing loss (r = 0.297, p = 0.27). Preserving intraoperative CAP amplitudes during implantation was predictive of an atraumatic insertion and reduced post‐implantation hearing loss. A rise in force usually preceded the reporting of resistance, although by less than 1 s. These results suggest that intraoperative CAPs may offer a more robust feedback mechanism for improving hearing preservation rates than cochlear microphonic and electrode insertion force recordings, especially considering the rapid changes in insertion force and relatively slow human reaction times. Pre‐operative steroids were effective in reversing loss of CAP amplitude with hard electrodes and evoked by lower frequency tones, which suggests a possible role in reducing synaptopathy. HighlightsForce and electrocochleography performed during guinea pig cochlear implantation.Better hearing and less trauma relies on preserving compound action potentials.Rising force precedes surgical resistance by only 1 s.Preoperative steroids reverse low‐frequency responses with some electrode types.

Contents Vol. 18, 2013

Maurizio Barbara, Rome Olivier Bertrand, Bron F. Owen Black, Portland Th omas Brandt, München Barbara Canlon, Stockholm John P. Carey, Baltimore Douglas A. Cotanche, Boston Cor W.R.J. Cremers, Nijmegen Norbert Dillier, Zürich Robert Dobie, Sacramento Manuel Don, Los Angeles Jill B. Firszt, St. Louis Andrew Forge, London Bernard Fraysse, Toulouse Rick Friedman, Los Angeles Bruce J. Gantz, Iowa City Pablo Gil-Loyzaga, Madrid Anthony W. Gummer, Tübingen James W. Hall III, Gainesville Joseph W. Hall III, Chapel Hill Michael Halmagyi, Camperdown Rudolf Häusler, Bern Vicente Honrubia, Los Angeles Gary D. Housley, Auckland Karl-Bernd Hüttenbrink, Köln Pawel J. Jastreboff , Atlanta Margaret A. Kenna, Boston Philippe P. Lefebvre, Liège Bernd Lütkenhöner, Münster Linda L. Luxon, London Geoff rey A. Manley, Oldenburg Alessandro Martini, Padova Jennifer R. Melcher, Boston Brian C.J. Moore, Cambridge David R. Moore, Nottingham Cynthia C. Morton, Boston Donata Oertel, Madison Kaoru Ogawa, Tokyo Stephen J. O’Leary, Parkville Alan R. Palmer, Nottingham Lorne S. Parnes, London, Ont. Jean-Luc Puel, Montpellier Ramesh Rajan, Monash Yehoash Raphael, Ann Arbor J. Th omas Roland, Jr., New York John J. Rosowski, Boston Rudolf Rübsamen, Leipzig Mario A. Ruggero, Evanston Leonard P. Rybak, Springfi eld Richard J. Salvi, Buff alo Robert V. Shannon, Los Angeles Guido F. Smoorenburg, Besse sur Issole Haim Sohmer, Jerusalem Olivier Sterkers, Clichy Istvan Sziklai, Debrecen Peter R. Th orne, Auckland Shin-ichi Usami, Matsumoto P. Ashley Wackym, Portland Tatsuya Yamasoba, Tokyo Fan-Gang Zeng, Irvine The Science of Hearing and Balance