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The ciliated epithelium of the human respiratory tract is covered by the airway surface liquid, a protective fluid consisting of two layers: the periciliary layer (PCL), where motile cilia reside and generate fluid flow, and an overlying mucus layer. The complex structure and stratified nature of the PCL complicate both the prediction and quantification of fluid flow at the scale of individual or small groups of cilia, making it difficult to connect microscopic flows to macroscopic clearance. To tackle this challenge, we developed a methodology that involves "uncaging" a fluorescent compound to trace the flow field within the PCL. Fluorescence is activated at micrometric spots within the cilia layer, and displacement vectors and diffusion are recorded using high-speed video. Our experiments reveal a complex fluid transport pattern, with displacement velocity along the epithelial surface varying due to a nonuniform vertical flow field. Additionally, we observed that cilia expel fluid at their tips, a mechanism likely aimed at preventing pathogen access to the epithelium. Simulations, where cilia are modeled as arrays of rigid rods with length asymmetry, support these findings and offer insights into the dynamics of fluid transport in the respiratory tract and the critical role of cilia coordination.
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http://dx.doi.org/10.1073/pnas.2419032122 | DOI Listing |
Proc Natl Acad Sci U S A
July 2025
Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom.
The ciliated epithelium of the human respiratory tract is covered by the airway surface liquid, a protective fluid consisting of two layers: the periciliary layer (PCL), where motile cilia reside and generate fluid flow, and an overlying mucus layer. The complex structure and stratified nature of the PCL complicate both the prediction and quantification of fluid flow at the scale of individual or small groups of cilia, making it difficult to connect microscopic flows to macroscopic clearance. To tackle this challenge, we developed a methodology that involves "uncaging" a fluorescent compound to trace the flow field within the PCL.
View Article and Find Full Text PDFInt J Pharm
April 2025
TIPs (Transfers, Interfaces and Processes), Avenue Franklin Roosevelt, 50, Brussels, 1050, Belgium.
Nose-to-brain drug delivery offers a promising route for administering pharmaceutical substances directly to the brain. However, this pathway faces significant challenges, such as mucociliary clearance and enzymatic activity in the nasal cavity, which limit drug absorption. Although several formulation strategies exist to enhance drug solubility, diffusion across the airway surface liquid, and protection from enzymatic degradation, there is a lack of tools to systematically evaluate which strategy is best suited for specific molecules.
View Article and Find Full Text PDFPharmaceuticals (Basel)
December 2024
Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Natural and synthetic biopolymers are gaining popularity in the development of inhaled drug formulations. Their highly tunable properties and ability to sustain drug release allow for the incorporation of attributes not achieved in dry powder inhaler formulations composed only of micronized drugs, standard excipients, and/or carriers. There are multiple physiological barriers to the penetration of inhaled drugs to the epithelial surface, such as the periciliary layer mucus mesh, pulmonary macrophages, and inflammation and mucus compositional changes resulting from respiratory diseases.
View Article and Find Full Text PDFiScience
November 2024
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
In ciliates, membrane cisternae called alveoli interpose between the plasma membrane and the cytoplasm, posing a barrier to endocytic and exocytic membrane trafficking. One exception to this barrier is plasma membrane invaginations called parasomal sacs, which are adjacent to ciliary basal bodies. By following a fluorescent secretory marker called ESCargo, we imaged secretory compartments and secretion in these cells.
View Article and Find Full Text PDFACS Nano
July 2024
Soft Biomatter Laboratory, Department of Materials Science and Engineering, University of Virginia, Charlottesville, Virginia 22904, United States.
Pulmonary drug delivery is critical for the treatment of respiratory diseases. However, the human airway surface presents multiple barriers to efficient drug delivery. Here, we report a bottlebrush poly(ethylene glycol) (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface.
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