Overcoming barriers: a review on innovations in drug delivery to the middle and inner ear

Abstract

Despite significant advances in the development of therapeutics for hearing loss, drug delivery to the middle and inner ear remains a challenge. As conventional oral or intravascular administration are ineffective due to poor bioavailability and impermeability of the blood-labyrinth-barrier, localized delivery is becoming a preferable approach for certain drugs. Even then, localized delivery to the ear precludes continual drug delivery due to the invasive and potentially traumatic procedures required to access the middle and inner ear. To address this, the preclinical development of controlled release therapeutics and drug delivery devices have greatly advanced, with some now showing promise clinically. This review will discuss the existing challenges in drug development for treating the most prevalent and damaging hearing disorders, in particular otitis media, perforation of the tympanic membrane, cholesteatoma and sensorineural hearing loss. We will then address novel developments in drug delivery that address these including novel controlled release therapeutics such as hydrogel and nanotechnology and finally, novel device delivery approaches such as microfluidic systems and cochlear prosthesis-mediated delivery. The aim of this review is to investigate how drugs can reach the middle and inner ear more efficiently and how recent innovations could be applied in aiding drug delivery in certain pathologic contexts.

Keywords: biomaterials; drug delivery; hydrogel; inner ear; microdevices; middle ear; nanoparticle.

FIGURE 1

Anatomical barriers to drug penetration in the middle and inner ear, and routes of local delivery. (A) Tympanic membrane. The TM consists of a stratified outer epithelium, a lamina propria (radial and circular fibrous) containing fibroblasts and a thin layer of mucosal epithelium. Intratympanic and topical drugs are administered here. (B) Round window membrane. The RWM consists of an outer epithelium, a connective tissue layer containing fibroblasts, collagen and elastic fibers and an inner epithelium. Intratympanic drugs are administered here. (C) Biofilm. Biofilm forms an encapsulated layer of extracellular proteins to protect pathogenic microorganisms against antibiotics. (D) Blood labyrinth barrier. The stria vascularis contains 3 cell layers: the marginal, intermediate and basal cell layers. The BLB consists of pericytes, endothelial cells and macrophages and surrounds the capillaries that are embedded within the intermediate cell layers of the stria vascularis. As shown in the inset in (D), an enlarged view is shown to illustrate the cellular component of the BLB system. Systemically administered drugs would need to cross the BLB to access the inner ear.

FIGURE 2

Schematic of nanoparticle types for drug delivery. (A) Micelles. Micelles consist of a single layer of amphipathic lipids surrounding a lipophilic payload. (B) Liposomes. Liposomes consist of an amphipathic lipid bilayer encapsulating either or both a hydrophilic payload in the core and/or a lipophilic payload inside the lipid bilayer (latter not depicted in cartoon). (C,D) Lipid core nanoparticle. Characterized by an outer shell of polymers (C) or other lipids (D) surrounding a lipid droplet core containing the therapeutic payload. (E). Polymeric nanoparticle. Made entirely of polymers and can carry both hydrophilic and lipophilic payloads depending on the polymer used. This particular depiction represents dendrimers, which consist of long, branched chains of polymers encapsulating the therapeutic payload.