Mucoadhesion
Mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract, the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. Bioadhesion is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of polymers can be evaluated via rheological synergism studies with freshly isolated mucus, tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans.
Mucoadhesive bondings
Mucoadhesion involves several types of bonding mechanisms, and it is the interaction between each process that allows for the adhesive process. The major categories are wetting theory, adsorption theory, diffusion theory, electrostatic theory, and fracture theory. Specific processes include mechanical interlocking, electrostatic, diffusion interpenetration, adsorption and fracture processes.Bonding mechanisms
Wetting theory: Wetting is the oldest and most prevalent theory of adhesion. The adhesive components in a liquid solution anchor themselves in irregularities on the substrate and eventually harden, providing sites on which to adhere. Surface tension effects restrict the movement of the adhesive along the surface of the substrate, and is related to the thermodynamic work of adhesion by Dupre's Equation. Measuring the affinity of the adhesive for the substrate is performed by determining the contact angle. Contact angles closer to zero indicate a more wettable interaction, and those interactions have a greater spreadability.Adsorption theory: Adsorption is another widely accepted theory, where adhesion between the substrate and adhesive is due to primary and secondary bonding. The primary bonds are due to chemisorption, and result in comparatively long lasting covalent and non-covalent bonds. Among covalent bonds disulfide bonds are likely most important. Thiolated polymers – designated thiomers – are mucoadhesive polymers that can form disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. Recently several new classes of polymers have been developed that are capable of forming covalent bonds with mucosal surfaces similarly to thiomers. These polymers have acryloyl, methacryloyl, maleimide, boronate and N‐hydroxy succinimide ester groups in their structure. Among non-covalent bonds likely ionic interactions such as interactions of mucoadhesive chitosans with the anionically charged mucus and Hydrogen bonding are most important. The secondary bonds include weak Van Der Waals forces, and interactions between hydrophobic substructure.
Diffusion theory: The mechanism for diffusion involves polymer and mucin chains from the adhesive penetrating the matrix of the substrate and forming a semipermanent bond. As the similarities between the adhesive and the substrate increase, so does the degree of mucoadhesion. The bond strength increases with the degree of penetration, increasing the adhesion strength. The penetration rate is determined by the diffusion coefficient, the degree of flexibility of the adsorbate chains, mobility and contact time. The diffusion mechanism itself is affected by the length of the molecular chains being implanted and cross-linking density, and is driven by a concentration gradient.
Electrostatic theory: is an electrostatic process involving the transfer of electrons across the interface between the substrate and adhesive. The net result is the formation of a double layer of charges that are attracted to each other due to balancing of the Fermi layers, and therefore cause adhesion. This theory only works given the assumption that the substrate and adhesive have different electrostatic surface characteristics.
Fracture theory: Fracture theory is the major mechanism by which to determine the mechanical strength of a particular mucoadhesive, and describes the force necessary to separate the two materials after mucoadhesion has occurred. Ultimate tensile strength is determined by the separating force and the total surface area of the adhesion, and failure generally occurs in one of the surfaces rather than at the interface. Since the fracture theory only deals with the separation force, the diffusion and penetration of polymers is not accounted for in this mechanism.
Stages of mucoadhesive process
The mucoadhesive process will differ greatly depending on the surface and properties of the adhesive. However, two general steps of the process have been identified: the contact stage and the consolidation stage.Contact stage
The contact stage is the initial wetting that occurs between the adhesive and membrane. This can occur mechanically by bringing together the two surfaces, or through the bodily systems, like when particles are deposited in the nasal cavity by inhalation. The principles of initial adsorption of small molecule adsorbates can be described by DLVO theory.Adsorption theory
According to DLVO theory, particles are held in suspension by a balance of attractive and repulsive forces. This theory can be applied to the adsorption of small molecules like mucoadhesive polymers, on surfaces, like mucus layers. Particles in general experience attractive van der Waals forces that promote coagulation; in the context of adsorption, the particle and mucus layers are naturally attracted. The attractive forces between particles increases with decreasing particle size due to increasing surface-area-to-volume ratio. This increases the strength of van der Waals interactions, so smaller particles should be easier to adsorb onto mucous membranes.DLVO theory also explains some of the challenges in establishing contact between particles and mucus layers in mucoadhesion due to their repulsive forces. Surfaces will develop an electrical double layer if they are in a solution containing ions, as is the case with many bodily systems, creating electrostatic repulsive forces between the adhesive and surface. Steric effects can also hinder particle adsorption to surfaces. Entropy or disorder of a system will decrease as polymeric mucoadhesives adsorb to surfaces, which makes establishing contact between the adhesive and membrane more difficult. Adhesives with large surface groups will also experience a decrease in entropy as they approach the surface, creating repulsion.
Wettability theory
The initial adsorption of the molecule adhesive will also depend on the wetting between the adhesive and membrane. This can be described using Young's equation:where is the interfacial tension between the membrane and gas or bodily environment, is the interfacial tension between the bioadhesive and membrane, is the interfacial tension between the bioadhesive and bodily environment, and is the contact angle of the bioadhesive on the membrane. The ideal contact angle is 0° meaning the bioadhesive perfectly wets the membrane and good contact is achieved. The interfacial tensions can be measured using common experimental techniques such as a Wilhelmy plate or the Du Noüy ring method to predict if the adhesive will make good contact with the membrane.
Consolidation stage
Strong and prolonged adhesion
The consolidation stage of mucoadhesion involves the establishment of adhesive interactions to reinforce strong or prolonged adhesion. When moisture is present, mucoadhesive materials become activated and the system becomes plasticized. This stimulus allows the mucoadhesive molecules to separate and break free while proceeding to link up by weak van der Waals and hydrogen bonds. Consolidation factors are essential for the surface when exposed to significant dislodging stresses. Multiple mucoadhesion theories exist that explain the consolidation stage, the main two which focus on macromolecular interpenetration and dehydration.Macromolecular interpenetration theory
The Macromolecular Interpenetration theory, also known as the diffusion theory, states that the mucoadhesive molecules and mucus glycoproteins mutually interact by means of interpenetration of their chains and the forming of secondary semi-permanent adhesive bonds. It is necessary that the mucoadhesive device has features or properties that favor both chemical and mechanical interactions for the macromolecular interpenetration theory to take place. Molecules that can present mucoadhesive properties are molecules with hydrogen bond building groups, high molecular weight, flexible chains, and surface active properties.It is perceived that increase in adhesion force is associated with the degree of penetration of polymer chains. Literature states that the degree of penetration required for efficient bioadhesive bonds lies in the range of 0.2-0.5μm. The following equation can be used to estimate the degree of penetration of polymer and mucus chains:
with as contact time and as the diffusion coefficient of the mucoadhesive material in the mucus. Maximum adhesion strength is reached when penetration depth is approximately equal to polymer chain size. Properties of mutual solubility and structural similarity will improve the mucoadhesive bond.
Dehydration theory
The dehydration theory explains why mucoadhesion can arise rapidly. When two gels capable of rapid gelation in an aqueous environment are brought into contact, movement occurs between the two gels until a state of equilibrium is reached. Gels associated with a strong affinity for water will have high osmotic pressures and large swelling forces. The difference in osmotic pressure when these gels contact mucus gels will draw water into the formulation and quickly dehydrate the mucus gel, forcing intermixing and consolidation until equilibrium results.This mixture of formulation and mucus can increase contact time with the mucous membrane, leading to the consolidation of the adhesive bond. However, the dehydration theory does not apply to solid formulations or highly hydrated forms.