Microsystems technologies for drug delivery to the inner ear

Abstract

The inner ear represents one of the most technologically challenging targets for local drug delivery, but its clinical significance is rapidly increasing. The prevalence of sensorineural hearing loss and other auditory diseases, along with balance disorders and tinnitus, has spurred broad efforts to develop therapeutic compounds and regenerative approaches to treat these conditions, necessitating advances in systems capable of targeted and sustained drug delivery. The delicate nature of hearing structures combined with the relative inaccessibility of the cochlea by means of conventional delivery routes together necessitate significant advancements in both the precision and miniaturization of delivery systems, and the nature of the molecular and cellular targets for these therapies suggests that multiple compounds may need to be delivered in a time-sequenced fashion over an extended duration. Here we address the various approaches being developed for inner ear drug delivery, including micropump-based devices, reciprocating systems, and cochlear prosthesis-mediated delivery, concluding with an analysis of emerging challenges and opportunities for the first generation of technologies suitable for human clinical use. These developments represent exciting advances that have the potential to repair and regenerate hearing structures in millions of patients for whom no currently available medical treatments exist, a situation that requires them to function with electronic hearing augmentation devices or to live with severely impaired auditory function. These advances also have the potential for broader clinical applications that share similar requirements and challenges with the inner ear, such as drug delivery to the central nervous system.

Figure 1

a. A mid-modiolar section from a human temporal bone indicates the coiled structure of the cochlea as it winds around a central modiolius. Each segment (b.) contains 3 fluid filled structures, the scala tympani (ST) scala media (SM) and scala vestibuli (SV). The organ of Corti (OC) is shown at the base of the SM. Used with permission from Elsevier [47].

Figure 2

a. A schematic drawing of the reciprocating delivery system showing the flexible membrane and actuator. b. Photograph of wearable device for guinea pig studies. The device measures 5.5 × 4.0 × 3.8 cm. Used with permission from Karger AG Basel and Springer [52, 57].

Figure 3

CAP threshold shifts due to DNQX delivery at various frequencies. Three flow rate profiles are shown with higher flow rates causing increased threshold rises. Multiple experiments for each flow rate are shown. Used with permission from Elsevier [56].

Figure 4

Theoretical flow path within the cochlea and vestibular system for a cochleostomy-only infusion (green), and a cochleostomy-plus-canalostomy perfusion (red). Pressure driven flow is depicted with solid lines while dotted lines represent diffusion mechanisms. Cochlear aqueduct (ca); scala tympani (st), scala vestibuli (sv). Used with permission from Elsevier [9].

Figure 5

Frequency dependent DPOAE threshold shifts. Surgery and infusion of artificial perilymph had insignificant impact on thresholds, while frequency dependent threshold shifts were observed with 10mM salicylate. Statistical comparison of peak threshold shifts to baseline for each frequency and each surgical approach are shown on the figure (*p < 0.05, **p < 0.01, ***p < 0.001). Data are plotted as mean ± SEM (n = 8 animals for each approach). Used with permission from Elsevier [9].

Figure 6

Illustration of drug delivery enabled by laser-drilled holes of 50 micron diameter to enable enhanced drug distribution in the cochlea. Used with permission from Elsevier [64].

Figure 7

Micromolded cannula insertion stops. (Left) Polyimide micro-tubing is inserted through a micromachined silicon mold, with a precise volume of Silastic delivered and the tubing cut to length following Silastic cure. (Right) Scanning electron micrograph of the cannula with integrated insertion stop. Inset is tubing tip (magnification 320x). Insertion depth is A, the contact area for bonding is defined by dimensions B and C, and post-cut roundness is defined by D and E. Used with permission from IEEE [65].

Figure 8

SEM of the side of the microfluidic chip with small diameter (140-μm OD) tubing exiting in-plane. Used with permission from IEEE [67].