Engineering the Mucus Barrier

Abstract

Mucus selectively controls the transport of molecules, particulate matter, and microorganisms to the underlying epithelial layer. It may be desirable to weaken the mucus barrier to enable effective delivery of drug carriers. Alternatively, the mucus barrier can be strengthened to prevent epithelial interaction with pathogenic microbes or other exogenous materials. The dynamic mucus layer can undergo changes in structure (e.g., pore size) and/or composition (e.g., protein concentrations, mucin glycosylation) in response to stimuli that occur naturally or are purposely administered, thus altering its barrier function. This review outlines mechanisms by which mucus provides a selective barrier and methods to engineer the mucus layer from the perspective of strengthening or weakening its barrier properties. In addition, we discuss strategic design of drug carriers and dosing formulation properties for efficient delivery across the mucus barrier.

Keywords: mucoadhesive particles; mucolytic; mucosal drug delivery; mucus barrier; mucus composition; mucus penetration.

Figure 1

Hierarchical structure of gel-forming mucins. Adapted from (2).

Figure 2

Increased mucus amount in Cystic Fibrosis (CF, CftrΔF508 mouse) compared to wildtype (WT). (A) Mucus distribution in ileum of WT and CF mice immunostained for Muc2 (green) and nuclei (blue). Arrows point to mucus attached to goblet cells. Scale bars=100 μm. (B) Representative confocal images of WT and CF villi (red) overlaid with 2 μm particles (green). Scale bars=50 μm. Adapted from (37).

Figure 3

Methods to break down mucin structure.

Figure 4

Exposure of mice to emulsifiers (1% CMC (B) or 1% P80 (C)) in drinking water for 12 weeks decreased mucus (Muc2 (green)) thickness and decreased distance between bacteria (red) and colonic epithelium (actin (purple), DNA (blue)). Scale bar= 20 μm. Adapted from (120).

Figure 5

Drug carrier size, surface properties, and dosing solutions affect the ability to penetrate mucus and reach underlying epithelium. Large drug carriers are size excluded, mucoadhesive drug carriers can adhere to mucus to increase residence time, but may be eliminated due to mucus clearance, and mucus-penetrating drug carriers have minimal interactions to allow penetration of the mucus layer. Dosing formulation properties (i.e. large volume, or hypotonic formulations) improve drug carrier distribution and retention in the mucus layer. Adapted from (150).