# Mucoadhesive Hydrogel Nanoparticles as Smart Biomedical Drug Delivery System
## 1 Introduction  
Hydrogels can be defined as network structures configured at two or three dimensions which have the ability to imbibe high amounts of aqueous solutions or biological fluids [1]. This affinity for water adsorption is mostly related to the presence of hydrophilic (e.g., amide, amino, carboxyl, and hydroxyl) groups on their molecular chains [2]. Due to the presence of these groups, several physicochemical properties have contributed to the classification of hydrogel systems such as porosity, structure softness, swelling capacity, and elasticity [3]. These properties are more similar to biological system than those of any other synthetic biomaterial [4]. To reinforce their structure and strengthen their mechanical force, hydrogels are cross-linked either by using physical mechanisms or chemical cross-linkers [5]. The cross-linkers in the polymer network are formulated by covalent bonds, hydrogen binding, van der Waals interactions, or by physical entanglements [6]. Furthermore, the hydrogel system becomes more solid and insoluble in any solvent, once its polymer chains are cross-linked [7]. Such hydrogels can be assembled with cryo-gelation [8], gas foaming [9], micro-emulsion formation [10], freeze-drying [11], and porogen leaching [12]. It is reported that the porous capacity and swelling behavior of abydrogel mostly depend uponcross-linkers [13], chemical structure of the repeating unit or chemical composition [14], network structure [15], solvent concentration, surrounding medium, polymer molecular weight, quality of solvent, and the specific stimulation. Hydrophilic hydrogels show distinctive properties due to adsorption of high amounts of water in their structures compared to hydrophobic polymericnetworks. Hence, hydrophobic groupsmay collapse in the presence of water. The collapsed chains minimize their exposure to water molecules, ultimately resulting in lower swelling ratios [16].  
Efficient delivery systems have been developed based upon on the understanding of their interactions with the biological environment, target cell population, target cell surface receptors, changes in cell receptors that occur with progression of disease, mechanism and site of drug action, drug retention, multiple drug administration, molecular mechanisms, and pathology [17]. For these reasons, many reports have referred to bio-adhesive polymers as promising materials that should be integrated into the moieties of nanoparticles [18]. This is in part due to their reactive potential and good penetration into stomach and mucosal layers. Bio-adhesive polymers are classified according to their interactions with biological systems into subgroups: mucoadhesive polymers which can penetrate mucus layers (e.g., ocular, nasal, vaginal, and small intestinal); gastro-adhesive polymers which can adhere onto stomach lining; and stimuli responsive polymers which can react to biological stimulants (e.g. glucose, enzymes, pH, and inflammation) (Figure 1) [19]. In addition to tablets, patches, gels, ointments, and film formulations; mucoadhesive nanoparticles have emerged recently to improve the controlled delivery of drugs. For nasal, vaginal, ocular, and oral administration, many nanoparticles have been optimized to possess mucoadhesive properties [20; 21; 22].