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Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored.

Without bioadhesive delivery devices, complex compounds are typically degraded or cleared from mucosal tissues by the mucus layer. 1-3 While some chemically-modified, micro-structured surfaces have been studied in aqueous environments, 4,5 adhesion due to geometry alone has not been investigated. Silicon nanowire-coated beads show significantly better adhesion than those with targeting agents under shear, and can increase the lift-off force 100-fold. We have shown that nanowire coatings, paired with epithelial physiology, significantly increase adhesion in mucosal conditions. KeywordsNanowire; nano-structure; bioadhesion; mucoadhesion; gecko-inspired; drug delivery; mucosa Because of their easy accessibility, large surface area, and rich blood supply, mucous membranes (mucosae), such as intestinal, nasal, ocular, vaginal, and buccal tissues, are frequently targeted for therapeutic drug delivery. 1,6 However, the mucosae present significant barriers to permeation, including a 1-450 μm motile mucous gel layer, tight junctions, and in some tissues, harsh enzymes and low pH. 7 Delivery devices have been able to protect compounds from chemical degradation, but without adhesion to the underlying epithelium, the *Additional contact information for Tejal A. Desai: -Tejal. Desai@ucsf.edu, phone -415-514-9695, fax -415-476-2414 Under nanoadhesive conditions, as the number of adhesive elements per surface area increases (ie: diameter of individual elements decreases), the surface area to volume ratio increases and van der Waals adhesion is predicted to increase 24,25 . Furthermore, because mucosal epithelia exhibit nano-structured microvilli, available surface area contact is considerably increased on the cell surface [26][27][28][29] . Thus, by decreasing the diameter of the elements on the device surface to the nano-scale and targeting a microvilliated surface, it may be possible to generate strong bioadhesive forces due to geometric features alone.To test the interaction of microvilli and nano-structures, a prototype device was created to couple the adhesive characteristics of nanowires with the drug delivery capacity of beads. A standard vapor liquid solid method for synthesizing silicon nanowires on flat wafer surfaces was modified to achieve growth of size-specific nanowires on the surface of 30-50 micron diameter glass beads (Figure 1). 30A Caco-2 cell monolayer was used as an in vitro model of the intestinal mucosa because the cells display a microvilliated structure which closely corresponds to that found in vivo 31 . From scanning electron microscopy ( Figure 1b), significant interdigitation of the nanowires and microvilli was visible at the cell-nano-structure interface, showing significant areas of contact between the cells and nanowires.In order to characterize the effects of geometric and chemical modifications of the nanowires, three nanowire test geometries and a control group with no nanowires (See Table 1 in Supporting Information) were fabricated. A subset of the long nanowire group and the contr...