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...

Delivering therapeutics to mucosal tissues such as the nasal and gastrointestinal tracts, is highly desirable due to ease of access and dense vasculature. However, the mucus layer effectively captures and removes most therapeutic macromolecules and devices. In previous work, we have shown that nanoengineered microparticles (NEMPs) adhere through the mucus layer, exhibiting up to 1000 times the pull-off force of an unmodified microsphere, and showing greater adhesion than some chemical targeting means. In this paper, we demonstrate that nanotopography improves device adhesion in vivo, increasing retention time up to ten-fold over unmodified devices. Moreover, we observe considerable adhesion in several cell lines using an in vitro shear flow model, indicating that this approach is promising for numerous tissues. We then demonstrate that nanowire-mediated adhesion is highly robust to variation in nanowire surface charge and cellular structure and function, and we characterize particle loading and elution. We present a form of cytoadhesion that utilizes the physical interaction of nanoengineered surfaces with subcellular structures to produce a robust and versatile cytoadhesive for drug delivery. These nanoscale adhesive mechanisms are also relevant to fields such as tissue engineering and wound healing because they likely affect stem cell differentiation, cell remodeling, migration, etc.

To circumvent the barriers encountered by macromolecules at the gastrointestinal mucosa, sufficient therapeutic must be delivered in close proximity to cells 1 . Previously, we have shown that silicon nanowires penetrate the mucous layer and adhere directly to cells under high shear 2 . In this work, we characterize potential reservoirs and load macromolecules into space created between nanowires. We show significant increases in loading capacity due to nanowires while retaining adhesion of loaded particles under high shear. KeywordsNanowires; adhesion; drug delivery; hierarchical nanostructures Mucosal tissues, such as those lining the oral cavity and gastrointestinal tract, have great potential for delivery of therapeutic macromolecules, but drug absorption is often thwarted by chemical and physical barriers. The epithelia is covered in a 1-50 μm motile mucus gel layer with pores of roughly 100 nm [3][4][5] . Like chyme, which clears the entire small intestine within 150 to 240 minutes 6, 7 , the mucus layer turns over every 50-170 minutes 8 . As a result of the viscosity and motility of the mucus, therapeutic macromolecules take longer to diffuse to cells, increasing their susceptibility to degradation and removal 1 .Adhesion and encapsulation technologies have been developed to combat the harsh gastrointestinal environment. Increased residence time in the upper small intestine and adhesion in close proximity or directly to cells increases the local concentration gradient at the epithelial layer, promoting transport 9-11 . Encapsulation in polymers, microparticles, or nanoparticles can protect therapeutics from degradation, ensuring that they remain active until they are released near the tissue.Numerous adhesives have been developed with the intent of increasing microparticle gastrointestinal residence time. However, most chemical adhesives function through mucoadhesion, primarily attaching to the mucus layer on top of the tissue, and thus being * Additional contact information for Tejal A. Desai: Tejal.Desai@ucsf.edu, phone -415-514-4503, fax -415-476-2414. Supporting Information Available: Further descriptions of the methods used in this paper, as well as theoretical surface area and geometry calculations and discussion, elution curves, and a consideration of loading capacity and therapeutic efficacy are available in the Supporting Information section. This material is available free of charge via the Internet at http://pubs.acs.org. 14,15 , and may lead to potentially toxic accumulations in the liver, kidneys, and spleen 16,17 . Microparticles can be fabricated with hollow reservoirs or engineered pores using photolithography, etching, or anodization 9, 18 . Although these technologies significantly improve loading capacity compared to nanoparticles, the additional fabrication complexity considerably increases the overall cost of the devices, and the larger size reduces diffusion through the mucus layer. NIH Public AccessWe have shown that integrating the diffusive properties at the nanoscale,...

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