Inner ear delivery: Challenges and opportunities

Abstract

Objectives: The treatment of inner ear disorders remains challenging due to anatomic barriers intrinsic to the bony labyrinth. The purpose of this review is to highlight recent advances and strategies for overcoming these barriers and to discuss promising future avenues for investigation.

Data sources: The databases used were PubMed, EMBASE, and Web of Science.

Results: Although some studies aimed to improve systemic delivery using nanoparticle systems, the majority enhanced local delivery using hydrogels, nanoparticles, and microneedles. Developments in direct intracochlear delivery include intracochlear injection and intracochlear implants.

Conclusions: In the absence of a systemic drug that targets only the inner ear, the best alternative is local delivery that harnesses a combination of new strategies to overcome anatomic barriers. The combination of microneedle technology with hydrogel and nanoparticle delivery is a promising area for future investigation.

Level of evidence: NA.

Keywords: inner ear disorders; intracochlear delivery; microneedles; nanoparticles.

Figure 1

Schematic of ear anatomy. Anatomic barriers include the cochlea encased in bone, blood‐labyrinth barrier (not shown), round window membrane, oval window, and eustachian tube. Printed with permission from Jeffrey W. Kysar, PhD and Anil K. Lalwani, MD

Figure 2

Cross section of the guinea pig RWM, pentachrome stain. The RWM is suspended between bone, which is stained in green, shown on the left at ×8 magnification. The three layers of the RWM can be appreciated at ×40 magnification, shown on the right. The outer epithelial layer, in contact with the middle ear space, is composed of low cuboidal epithelial cells connected by tight junctions. The central connective tissue layer is stained beige due to its composition of collagen (yellow) and elastic fibers (black). The inner epithelial layer is composed of squamous epithelial cells with large extracellular spaces allowing contact between the connective tissue matrix and the perilymph. RWM, round window membrane. Printed with permission from Jeffrey W. Kysar, PhD and Anil K. Lalwani, MD

Figure 3

Microneedles for cochlear delivery. Microneedles are designed to create precise perforations in the round window membrane to enhance diffusion after intratympanic injection. The figure shows a microneedle design used for the human round window membrane, fabricated using two‐photon polymerization. Printed with permission from Jeffrey W. Kysar, PhD and Anil K. Lalwani, MD

Figure 4

Several routes of cochlear delivery. The delivery of a therapeutic agent to the cochlea can be performed by: diffusion of the agent across an intact round window membrane with a gelatin sponge (A), intracochlear injection through the round window membrane (B), and infusion with osmotic minipump through cochleostomy (C). Printed with permission from Anil K. Lalwani, MD

Figure 5

Hybrid ear cube. The hybrid ear cube is a silicone‐based implant that consists of a cuboid portion placed in the middle ear adjacent to the oval window (shown) or round window and a cylindrical structure that passes through the oval window or round window that remains in contact with the perilymph.93 The cuboid structure has two halves that can be loaded with two different drug formulations and acts as a drug reservoir such that drugs can diffuse through the cylindrical portion into the perilymph. Reprinted from European Journal of Pharmaceutical Sciences, Volume 126, Gehrke et al., Hybrid Ear Cubes for local controlled dexamethasone delivery to the inner ear, pages 23‐32, 2019, with permission from Elsevier