Biomedical Engineering Reference
In-Depth Information
of the oral cavity, is built by the binding of the high-molecular-weight mucin, MG1, to the surface
of the epithelium (Bykov 1996, 1997). The thickness of this mucus layer is different before and after
swallowing, and measures between 70 and 100 μm (Collins and Dawes 1987; Harris and Robinson
1992; Lagerlof and Dawes 1984). This mucus layer displays a thick gelatinous-like layer, struc-
tured as a three-dimensional network with a high water-holding capacity. Being highly viscoelastic,
it displays a shear-thinning gel that acts as a lubricant. It defends the epithelial cell layers from
pathogens, particles, and toxins, and enables the exchange of nutrients, gases, and water (Knowles
and Boucher 2002). Once substances are swallowed, they pass through the esophagus. Esophageal
glands located throughout the esophagus are involved in secreting mucus directly onto the surface
(Squier and Kremer 2001). In addition, exocrine glands in the submucosa produce a secretion that
is high in the concentration of bicarbonates. This is essential to neutralize refluxing stomach acid
(Long and Orlando 1999). The mucus of the following organs, that is, stomach, small intestine,
and large intestine, is chiefly produced by intraepithelial cells. Exocrine glands are also located in
the submucosa of the first part of the small intestine (duodenum). The thickness of the mucus layer
varies highly, depending on the location in the GI tract. The thickness of this layer increases from
proximal to distal parts of the small and large intestine with the greatest thickness in the stomach
(Atuma et al. 2001; Matsuo et al. 1997). The thickness of the mucus layer shows noticeable varia-
tions based on the method used for its determination. The fixation of the tissues is usually followed
by shrinking, thus yielding lower values. Endoscopic ultrasound measurements indicate the thick-
ness of the mucus layer in the stomach to be 897-1354 and 730-1136 μm in the rectum (Huh et al.
2003), but variations may be quite high because the thickness is dictated by the interplay between
mucus secretions by goblet cells and mucus erosions by mechanical shear and bacterial digestion,
particularly in the lower gut (Corfield et al. 1992; Hoskins and Boulding 1981). Additionally, the
pH can vary. The pH of the mucus in the oral cavity is estimated to be around 6.6. Gastric mucus
shows a broad pH range from 1 to 2 (luminal) to ~7 (epithelial surface) (Schreiber and Scheid 1997).
13.3.2 I
NteractIoN
of
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aNoMaterIals
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the
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ucus
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ayer
The characteristics facilitating the passage through the mucus are relatively well known: Electrostatic
repulsions from negatively charged sugar moieties favor the penetration of positively charged, hydro-
philic molecules; the passage of lipophilic compounds is slow (Avdeef and Testa 2002). It was thought
that NPs are incapable of penetrating the mucus layer since recent studies demonstrated that particu-
lar viruses, for example, the Norwalk virus (38 nm) and human papilloma virus (55 nm), diffused
into the mucus as rapidly as they do in water (Olmsted et al. 2001; Saltzman et al. 1994). The surfaces
of the viruses able to permeate the mucus are thickly coated with positive and negative charges.
Hence, this net neutral surface charge precludes mucoadhesion (Olmsted et al. 2001). Since the pore
size is around 100 nm, it is proposed that small particles might also be capable of diffusing through
the mucus. Olmsted et al. (2001) showed that small viruses diffused unhindered via the mucus,
whereas polystyrene microspheres, ranging 59 nm in size and covalently modified with carboxyl
groups, bound more tightly to mucins and clustered them into thick cables. The work by Dawson
et al. reported that carboxyl- and amine-modified polystyrene particles (100, 200, and 500 nm) were
embedded in cystic fibrosis sputum. Compared to negatively charged particles, positively charged
particles penetrated more rapidly in the sputum. Moreover, smaller particles underwent a signifi-
cantly faster transport (Dawson et al. 2003). Lai et al. investigated polystyrene particles ranging from
100 to 500 nm. The particle surface was covalently modified with a high density of low-molecular-
weight polyethylene glycol (PEG) and the diffusion into the mucus was examined. The results dem-
onstrated that the neutral surface charge increased the diffusion rate of all particles. Where larger
particles (200 and 500 nm) demonstrated a sixfold and fourfold lower effective diffusion coefficient
than that in water, the 100 nm particles were observed to be immobile in the mucus (Lai et al. 2007).
It was demonstrated by a study that slightly negatively charged, 14 nm latex particles crossed the dis-
tal colon mucus gel layer within 2 min and 415 nm large particles crossed in 30 min, whereas 1 μm
