Intracochlear drug delivery systems

Abstract

Introduction: Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases.

Areas covered: Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases.

Expert opinion: Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed-sequence delivery devices for treatment of these diseases.

Fig 1

Cast of a guinea pig cochlea, showing the locations along the length of the scala tympani where various frequencies are detected, along with a notional placement of a cannula for intracochlear drug delivery near the 30 kHz point.

Fig 2

Image showing a drug delivery technique in which drug is infused into the scala tympani near the base, and a posterior canalostomy is opened to reduce concentration gradients by modulating the resistance along the delivery path. Reprinted from Ref [[, Hearing Research, Vol. 268, D.A. Borkholder et al., “Murine intracochlear drug delivery: Reducing concentration gradients within the cochlea”, pp. 2-11, (2010), with permission from Elsevier.

Fig 3

Photograph with dimensions of microfluidic intracochlear drug delivery chip developed by Draper Laboratory and the Massachusetts Eye and Ear Infirmary, containing a displacement chamber, valves and fluidic vias for delivery of compounds through a single cannula into the cochlea using a reciprocating delivery profile.

Fig 4

Three flow profiles are shown, all of which were used to deliver DNQX (300 μM), a glutamate receptor blocker that elevates thresholds for the compound action potential (CAP). Flow profiles from the early prototype [15], shown in black, produced threshold alterations (center) of around 25 dB at high CFs that built up slowly during the delivery period (shaded bar). Right Modification of the delivery profile (blue) produced larger and more rapid changes in CAP thresholds (around 40 dB for high characteristic frequencies (CFs). Further modification (red) induced threshold changes unrelated to drug delivery (data not shown).

Fig 5

Illustration of two methods of drug delivery from a cochlear implant device is given. (a) Prototype of a catheter designed for atraumatic insertion into the cochlea, shown inserted into a model of the cochlea and attached to a syringe. The catheter can be up to 20 mm in length and has thin walls and a small wall diameter, resulting in a highly flexible construction. (b) Insertion of an electrode array highlighted by green dye infused from the catheter. (c) Drug delivery enabled by laser-drilled holes of 50 micron diameter to enable enhanced drug distribution in the cochlea. (d) Elution of pharmaceutical-grade dexamethasone mixed with medical-grade silicone elastomer; the drug is contained in the lower region (opaque). Reprinted from Ref [], Drug Discovery Today, Vol. 15, H. Staecker et al., “Cochlear implantation: an opportunity for drug development”, pp. 314-321, (2010), with permission from Elsevier.