Abstract
Mucus secretions typically protect exposed surfaces of the eyes and respiratory, gastrointestinal and female reproductive tracts from foreign entities, including pathogens and environmental ultrafine particles. We hypothesized that excess exposure to some foreign particles, however, may cause disruption of the mucus barrier. Many synthetic nanoparticles are likely to be mucoadhesive due to hydrophobic, electrostatic or hydrogen bonding interactions. We therefore sought to determine whether mucoadhesive particles (MAP) could alter the mucus microstructure, thereby allowing other foreign particles to more easily penetrate mucus. We engineered muco-inert probe particles 1 µm in diameter, whose diffusion in mucus is limited only by steric obstruction from the mucus mesh, and used them to measure possible MAP-induced changes to the microstructure of fresh human cervicovaginal mucus. We found that a 0.24% w/v concentration of 200 nm MAP in mucus induced a ∼10-fold increase in the average effective diffusivity of the probe particles, and a 2- to 3-fold increase in the fraction capable of penetrating physiologically thick mucus layers. The same concentration of muco-inert particles, and a low concentration (0.0006% w/v) of MAP, had no detectable effect on probe particle penetration rates. Using an obstruction-scaling model, we determined that the higher MAP dose increased the average mesh spacing (“pore” size) of mucus from 380 nm to 470 nm. The bulk viscoelasticity of mucus was unaffected by MAP exposure, suggesting MAP may not directly impair mucus clearance or its function as a lubricant, both of which depend critically on the bulk rheological properties of mucus. Our findings suggest mucoadhesive nanoparticles can substantially alter the microstructure of mucus, highlighting the potential of mucoadhesive environmental or engineered nanoparticles to disrupt mucus barriers and cause greater exposure to foreign particles, including pathogens and other potentially toxic nanomaterials.
Highlights
Engineered or synthetic nanoparticles are increasingly used in diverse applications, ranging from ultra-light high strength materials to electronics, cosmetics and medicine
Effect of mucoadhesive particles (MAP) on mucus microstructure In agreement with our previous work [14,18], the diffusion of 1 mm muco-inert (PEG-coated) probe particles was strongly hindered in control mucus samples treated with 3% v/v saline, as evident by their constrained and non-Brownian trajectories (Figure 2A and Video S1)
The probes exhibited more diffusive trajectories in aliquots of the same native mucus samples treated with 3% v/v MAP at a toxicologically relevant dose of 0.24% w/v final concentration
Summary
Engineered or synthetic nanoparticles are increasingly used in diverse applications, ranging from ultra-light high strength materials to electronics, cosmetics and medicine. These and other mucoadhesive particles are unlikely to perturb the microstructure of mucus at low exposure levels, at high concentrations, they may crosslink mucin fibers and cause them to bundle together, enlarging pores in the mucus gel (Figure 1). To detect changes in the mucus microstructure, we use 1 mm muco-inert particles as probes whose diffusional speeds can be related to effective pore sizes in the mucus gel.
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