Nanostructure-Mediated Transport of Therapeutics through Epithelial Barriers.

The ability to precisely treat human disease is facilitated by the sophisticated design of pharmacologic agents. Nanotechnology has emerged as a valuable approach to creating vehicles that can specifically target organ systems, effectively traverse epithelial barriers, and protect agents from premature degradation. In this review, we discuss the molecular basis for epithelial barrier function, focusing on tight junctions, and describe different pathways that drugs can use to cross barrier-forming tissue, including the paracellular route and transcytosis. Unique features of drug delivery applied to different organ systems are addressed: transdermal, ocular, pulmonary, and oral delivery. We also discuss how design elements of different nanoscale systems, such as composition and nanostructured architecture, can be used to specifically enhance transepithelial delivery. The ability to tailor nanoscale drug delivery vehicles to leverage epithelial barrier biology is an emerging theme in the pursuit of facilitating the efficacious delivery of pharmacologic agents.

Impact of Microdevice Geometry on Transit and Retention in the Murine Gastrointestinal Tract.

Oral protein delivery technologies often depend on encapsulating or enclosing the protein cargo to protect it against pH-driven degradation in the stomach or enzymatic digestion in the small intestine. An emergent methodology is to encapsulate therapeutics in microscale, asymmetric, planar microparticles, referred to as microdevices. Previous work has shown that, compared to spherical particles, planar microdevices have longer residence times in the GI tract, but it remains unclear how specific design choices (e.g., material selection, particle diameter) impact microdevice behavior in vivo. Recent advances in microdevice fabrication through picoliter printing have expanded the range of device sizes that can be fabricated in a rapid manner. However, relatively little work has explored how device size governs their behavior in the intestinal environment. In this study, we probe the impact of geometry of planar microdevices on their transit and accumulation in the murine GI tract. Additionally, we present a strategy to label, image, and quantify these distributions in intact tissue in a continuous manner, enabling a more detailed understanding of device distribution and transit kinetics than previously possible. We show that smaller particles (194.6 ± 7 µm.diameter) tend to empty from the stomach faster than midsize (293.2 ± 7 µm.diameter) and larger devices (440.9 ± 9 µm.diameter) and that larger devices distribute more broadly in the GI tract and exit slower than other geometries. In general, we observed an inverse correlation between device diameter and GI transit rate. These results inform the future design of drug delivery systems, using particle geometry as an engineering design parameter to control device accumulation and distribution in the GI tract. Additionally, our image analysis process provides greater insight into the tissue level distribution and transit of particle populations. Using this technique, we demonstrate that microdevices act and translocate independently, as opposed to transiting in one homogeneous mass, meaning that target sites will likely be exposed to devices multiple times over the course of hours post administration. This imaging technique and associated findings enable data-informed design of future particle delivery systems, allowing orthogonal control of transit and distribution kinetics in vivo independent of material and cargo selection.

Salivary gland cell aggregates are derived from self-organization of acinar lineage cells.

OBJECTIVE: The objective of this study was to characterize the mechanism by which salivary gland cells (SGC) aggregate in vitro. DESIGN: Timelapse microscopy was utilized to analyze the process of salivary gland aggregate formation using both primary murine and human salivary gland cells. The role of cell density, proliferation, extracellular calcium, and secretory acinar cells in aggregate formation was investigated. Finally, the ability of cells isolated from irradiated glands to form aggregates was also evaluated. RESULTS: Salivary gland cell self-organization rather than proliferation was the predominant mechanism of aggregate formation in both primary mouse and human salivary gland cultures. Aggregation was found to require extracellular calcium while acinar lineage cells account for ∼80% of the total aggregate cell population. Finally, aggregation was not impaired by irradiation. CONCLUSIONS: The data reveal that aggregation occurs as a result of heterogeneous salivary gland cell self-organization rather than from stem cell proliferation and differentiation, contradicting previous dogma. These results suggest a re-evaluation of aggregate formation as a criterion defining salivary gland stem cells.