The attachment of mucin to the epithelial surface may be considered as an interaction of a number of charged and neutral polymer groups with the mucin through noncovalent bonds. Understanding the mechanisms of mucoadhesion is fundamental to the development of mucoadhesive. One may view the entire process to be simply a physical entanglement—a currently accepted mechanism for the attachment of cross-linked polyacrylates to mucin (10). The polymer undergoes swelling in water, which permits entanglement of the polymer chains with mucin on the epithelial surface of the tissue (11). The un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin molecule.
The mucoadhesion phenomenon has also been explained using the mechanisms of nonbiological adhesion, such as electron transfer (12), wetting (13-16), diffusion (11,17-20), adsorption (21-23), fracture (24-25), and mechanical interlocking theories (26). Although these theories provide some insights into the mechanisms of mucoadhesion, no one theory by itself has successfully explained the phenomenon of mucoadhesion. Considering the number of factors involved in this process, this is not surprising.
Understanding molecular interactions between mucin and mucoadhesive may provide a better hypothesis for mucoadhesion. When two molecules coalesce, the interaction is composed of attractive and repulsive forces. The magnitudes of these two forces determine whether the molecules will interact or not. For mucoadhesion to occur, the attractive interaction should be larger than nonspecific repulsion. Attractive interactions result from van der Waals forces, hydrogen bonding, electrostatic attractions, and hydrophobic bonding. Repulsive interactions occur as the result of electrostatic and steric repulsions. The theories relating to these phenomena are detailed elsewhere (27).
The bioadhesive process can be conceptualized as the establishment of intimate contact, by diffusion or network expansion, of the polymer chains, with subsequent interpenetration (11). This physical model is depicted in Figure 2. In swellable hydrogels, an expanded polymer is a necessary prerequisite for adhesion, and this process may be further enhanced by visco-elastic deformation of the bioadhesive and substrate tissue by applied force or pressure.
When anionic polymers interact with anionic mucin, the maximum adhesion occurs at an acidic pH, indicating that it is the protonated form
of the mucoadhesive that is responsible for the bioadhesion. Therefore, hydrogen bonding plays an important role in bioadhesion (28).
In addition, the expanded nature of both mucin and polymer networks permit mutual interpenetration. Interpenetration/interdiffusion of mucin and the adhesives results in increased contact and henceforth physical entanglement of the two different macromolecules. The physical entanglement is time dependent and may be enhanced by promoting intermolecular interactions between specific functional groups on the two polymers. Strong mucoadhesion depends on the moderate interactive forces between mucus and mucoadhesives, which will allow diffusion and subsequent entanglements among polymer chains. A number of factors may affect interpenetration; i.e., chain segment mobility, chain entanglement, cross-linking density of the networks, swelling, porosity, and compatibility of adhesives and mucin.
While a number of polymers will attach to mucin through noncovalent and covalent bonds, the former is preferred, since the strength of attachment is sufficiently strong. The removal occurs primarily through mucin turnover. The strength of adhesion between polycarbophil (partial structure shown in Fig. 3) and mucin is sufficiently stronger to resist rinsing. Forcible removal leads to rupture of mucin-mucin bonds and polymer-mucin bonds. The water-swellable yet water-insoluble systems are preferred as mucoadhesives, since predictable drug release from such systems would be easier to obtain. Moreover, toxicity concerns will also be less for an insoluble polymer. Table 1 lists some of the representative mucoadhesives.
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