Research PaperCannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF
Introduction
The optimal method for local drug administration to the inner ear has not yet been established. Sustained drug delivery via the semi permeable round window membrane (RWM) (Goycoolea and Lundman, 1997) is a promising approach, but not without its challenges. Persistence of the drug to be delivered at the middle ear surface of the RWM is required for sustained delivery (Salt et al., 2011). Varied attempts have been made at increasing this persistence through the use of sustained release biodegradable-solid (Plontke et al., 2014, Silverstein et al., 1999) or viscous carriers (Endo et al., 2005, Salt et al., 2011), such as hydrogels (Piu et al., 2011). Other methods have involved repeated or continuous administration of liquid compounds (Cayé Thomasen et al., 2004, Wagner et al., 2005). One method of achieving continuous administration over a prolonged time course involves the use of a microcatheter placed adjacent to the RWM in its bony niche, connected to a drug delivery pump. This method has seen success in the delivery of glucocorticoids (Lefebvre and Staecker, 2002), aminoglycosides (DeCicco et al., 1998) and neurotrophins (Goycoolea and Lundman, 1997, Sly et al., 2012). This method offers the advantage of a predictable duration of delivery, with a consistent concentration of drug present at the delivery site during that time.
There is a paucity of literature regarding potential adverse local effects of continuous or repeated drug administration to the round window niche. Middle ear granulations have been noted after microcatheter delivery of concentrated glucocorticoids in humans (Plontke et al., 2006, Salt et al., 2011), though the authors suggested that mobility of the catheter due to inadequate fixation was the likely stimulus. Thickening and inflammation of the RWM was noted after repeated intratympanic instillation of hydrocortisone solution (Nordang et al., 2003, Plontke et al., 2014, Silverstein et al., 1999) in rats, though this effect was thought to be due to the specific compound, as instillation of dexamethasone in the same manner resulted in no such changes. Thickening of the RWM has also been seen in response to application of polymyxin E, as well as combination medications (Cortisporin; Monarch Pharmaceuticals, Bristol, USA) containing bacitracin, neomycin, polymyxin B and hydrocortisone, with no thickening in response to triamcinolone or cefmenoxime (Endo et al., 2005, Ikeda et al., 1991, Salt et al., 2011). Experimental stiffening or obliteration of the round window may cause a cochlear conductive hearing loss in guinea pigs (Nageris et al., 2012, Piu et al., 2011), with similar losses seen in human patients with congenital or acquired immobility or obliteration of the RWM (Cayé Thomasen et al., 2004, Linder et al., 2003, Wagner et al., 2005). The primary aim of this paper is to determine whether chronic drug delivery via a microcatheter approach can be performed without risk to hearing. This is important in order to ascertain whether drugs can be applied long-term to the RWM, in order to prevent or treat hearing loss.
One class of proteins with therapeutic potential are the neurotrophins (Lefebvre and Staecker, 2002, Phimister et al., 2015, Sly et al., 2012, Wan et al., 2014). Brain-derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) are of particular interest in inner ear therapeutics, as they have been demonstrated to be critical to the development and neuronal organisation of the cochlea (DeCicco et al., 1998, Staecker et al., 1996a, Staecker et al., 1996c). Both have been shown to aid survival of spiral ganglion neurons in experimental deafness models (Endo et al., 2005, Gillespie et al., 2004, Miller et al., 1997, Noushi et al., 2005, Staecker et al., 1996b), with BDNF also having been shown to improve ABR thresholds beyond baseline at high frequencies in normal-hearing guinea pigs (Sly et al., 2012). More recently there have been suggestions that neurotrophins may have a therapeutic role in the treatment of hidden hearing loss (Phimister et al., 2015, Sly et al., 2016). For these reasons, BDNF was the active drug delivered via the RWM microcatheter in these experiments. Here we examined whether the better-than-normal hearing elicited by neurotrophins (Sly et al., 2012) persisted after cessation of the treatment. This is of interest because although neurotrophins reduce electrically evoked ABR thresholds for the duration of drug delivery some studies have shown that its effect is transient, lasting only as long as the drug is administered (Gillespie et al., 2003, Landry et al., 2011, Shepherd et al., 2005), while others have shown persistent effects long after the neurotrophins delivery has ceased (Ramekers et al., 2015). The reason(s) for these disparate study outcomes are not known, and may be informed by knowing the persistence of neurotrophins' effects on the hearing cochlea.
Section snippets
Materials and methods
Ethics approval for the described experiment was obtained from the Animal Research Ethics Committee of the Royal Victorian Eye and Ear Hospital (project 12/240AR).
Results
Twenty Dunkin Hartley tri-coloured guinea pigs (11 females and 9 males, ranging from 429 to 1037 g) were allocated to AP (n = 6), BDNF (n = 9) or ‘Dry Cannula’ (n = 5) groups.
All drug-delivery manipulations to the round window caused some hearing loss
The presence of the AP had a detrimental effect upon hearing in its own right, being associated with poorer ABR thresholds whilst it was being delivered than afterwards. Whatever the cause for the hearing loss, its transient nature implies a temporary cochlear change. At least two possibilities for this could be considered. The first is that the constant wetting of the RWM changed its physical and mechanical properties. The second is that the ionic content of the AP had a detrimental effect
Conclusions
The presence of a microcatheter adjacent to the RWM was detrimental to hearing, particularly when delivering AP. In this respect, the current paper did not replicate the findings of Sly and colleagues (Sly et al., 2012), where normal saline applied to the round window caused minimal hearing loss. The most likely explanation for the degradation in hearing was either a change in the mechanical properties of the round window, or alternatively a reduction in function of the hair cells. The
Acknowledgements
The authors would like to thank Michelle Stirling (animal husbandry), Scott Chambers and Leon Winata (technical assistance), Prue Nielsen (histological processing) and James Fallon (Igor software routine development) for their assistance. This work was funded by the Garnett Passe and Rodney Williams Memorial Foundation, Melbourne, Australia.
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