Particle Transport Through Mucus

Investigations of diffusion through mucus gels demonstrated that small molecules (e.g., testosterone with molecular weight 401 Da) diffuse rapidly through mucosal barriers, while large molecules become trapped, owing, in part, to steric hindrance [120,144]. Particle diffusion through mucus is related to interfiber spacing, decreasing approximately as the square root of mucin concentration [120]. The cutoff size for particles able to diffuse efficiently through mucus gels with high mucin concentration (e.g., thick colonic mucus) has been reported as 100 nm [120] (Fig. 3). Gene vectors are often larger than 100 nm, which may significantly limit their ability to permeate the mucosal layer and transfect cells. Mucus from cystic fibrosis patients was found to provide a size-dependent barrier to particle transport, with the smallest latex particles (124 nm) studied diffusing most efficiently and the largest latex particles (560 nm) becoming completely trapped in CF sputum [144].

If the translocation of particles through mucus were only a function of particle size, virus-sized latex particles (< 100 nm) would diffuse through mucus readily (Dmucus/Dpbs ~ 1, where D is diffusivity) (Fig. 4). However, latex particles adhere strongly to mucin fibers via hydrophobic interactions, resulting

Figure 4 Normalized diffusion coefficients for proteins and viruses in mucus. Dmuc/Dpbs ± SD is plotted for particles with molecular weights 15 kDa-20mou. For a particle that diffuses in mucus as fast as it diffuses in saline, Dmuc/Dpbs = 1. The lines drawn on the graph are the ratio predicted by Amsden's obstruction-scaling model, developed for modeling covalently cross-linked hydrogels. The solid line uses a mucin fiber radius of 3.5 nm and a mesh fiber spacing of 100 nm. The dotted line takes into account the 20% dilution of the mucus samples by increasing the mesh fiber spacing by 10%. (Reprinted from Ref. 151. Courtesy of the Biophysical Society.)

Figure 4 Normalized diffusion coefficients for proteins and viruses in mucus. Dmuc/Dpbs ± SD is plotted for particles with molecular weights 15 kDa-20mou. For a particle that diffuses in mucus as fast as it diffuses in saline, Dmuc/Dpbs = 1. The lines drawn on the graph are the ratio predicted by Amsden's obstruction-scaling model, developed for modeling covalently cross-linked hydrogels. The solid line uses a mucin fiber radius of 3.5 nm and a mesh fiber spacing of 100 nm. The dotted line takes into account the 20% dilution of the mucus samples by increasing the mesh fiber spacing by 10%. (Reprinted from Ref. 151. Courtesy of the Biophysical Society.)

in a sharp reduction of their diffusion rates through mucus [120,154] (Fig. 5). Surface charge may also be a factor in the translocation of particles through mucus [154]. The high density of negatively charged carboxyl and sulphate groups on the surface of mucus fibers bind positively charged particles [120]. Viruses may avoid the viscid nature of mucus by maintaining a surface that is densely coated equally with negative and positive charges [120]. The high density of negative charges reduces viral interaction with mucus fibers, while the positive charges aid entry into the mucus gel and glycocalyx [120].

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