Marker retention in the cochlea following injections through the round window membrane

Abstract

Local delivery of drugs to the inner ear is increasingly being used in both clinical and experimental studies. Although direct injection of drugs into perilymph appears to be the most promising way of administering drugs quantitatively, no studies have yet demonstrated the pharmacokinetics in perilymph following direct injections. In this study, we have investigated the retention of substance in perilymph following a single injection into the basal turn of scala tympani (ST). The substance injected was a marker, trimethylphenylammonium (TMPA) that can be detected in low concentrations with ion-selective microelectrodes. Perilymph pharmacokinetics of TMPA was assessed using sequential apical sampling to obtain perilymph for analysis. The amount of TMPA retained in perilymph was compared for different injection and sampling protocols. TMPA concentrations measured in fluid samples were close to those predicted by simulations when the injection pipette was sealed into the bony wall of ST but were systematically lower when the injection pipette was inserted through the round window membrane (RWM). In the latter condition it was estimated that over 60% of the injected TMPA was lost due to leakage of perilymph around the injection pipette at a rate estimated to be 0.09 μL/min. The effects of leakage during and after injections through the RWM were dramatically reduced when the round window niche was filled with 1% sodium hyaluronate gel before penetrating the RWM with the injection pipette. The findings demonstrate that in order to perform quantitative drug injections into perilymph, even small rates of fluid leakage at the injection site must be controlled.

Intracochlear Drug Injections through the Round Window Membrane: Measures to Improve Drug Retention

“…More consistent and efficient delivery would be expected when the solution was directly injected into perilymph. With applications by intracochlear injection into the cochlear apex [Salt et al 2006] or by injections through the RW membrane [Salt et al 2007, Hahn et al 2012], concentrations in perilymph were found to be higher, with lower variation and the substances were distributed more uniformly along scala tympani. Effective deliveries of viral vectors have been accomplished with single intracochlear injection procedures [Stover et al 1999; Kawamoto et al, 2001; Staecker et al, 2014].…”

An animal model of cochlear implantation with an intracochlear fluid delivery system

“…From this perspective, it is necessary to obtain longer delivery time with constant drug concentrations. In the guinea pig, perilymph fluid leakage and diffusion toward the cochlear aqueduct can noticeably affect the drug concentration in the middle and upper turns when locally administered as a bolus [19]. In the human, the cochlear aqueduct is not as wide as in the animal but pericochlear leakage during intraoperative injection might affect the drug diffusion, therefore delivery away from cochleostomy and deep inside the cochlea might be more efficient in reaching the apical hair cells.…”

Principles of Local Drug Delivery to the Inner Ear

“…For low injection rates, the induced rate of perilymph flow may be low, and spread from the injection site will be dominated by diffusion. This has been demonstrated both by real-time measurements of markers [67] and by functional measures during pulsed injections into the basal turn of the ST [68]. For higher injection rates, the spread of drug can only be predicted if the fluid outlet site is known.…”

“…However, when perilymph concentration was measured following injections through the RWM with fine (20-µ M OD) bevelled pipettes held in a micromanipulator, small leaks around the pipettes caused significant washout of the drug [67]. It was calculated that the leakage rate under these conditions averaged just 90 nl/min, which was sufficient to wash out the drug but was not visible with an operating microscope.…”

“…This is in large part because of the requirement for a safe and feasible way of drug delivery to the inner ear, especially to minimize damage to hearing, which became a major component of local gentamicin applications in the treatment of Ménière’s disease. Animal studies, however, showed that perilymph drug levels achieved with RWM applications are highly variable [29,37,54,61] and that more consistent perilymph concentrations can be achieved by intracochlear injections of substances [67]. However, based on experience with surgical procedures that involve perforation of the inner ear such as stapedectomy or the cochlear implantation of patients with residual hearing, it is well known that perforation and/or surgical manipulation of the ear carries a significant risk of deafness.…”