# Alginate Modification and Lectin-Conjugation Approach to Synthesize the Mucoadhesive Matrix
## 3 Alginate Application in Drug Delivery
### Alginate Hydrogel  
Alginate hydrogels are biocompatible and structurally identical to the macromolecular-based component of the biological body. Hydrogels are defined as three-dimensional networks in which hydrophobic polymers chains are crosslinked together [25]. The crosslinking of alginates, specifically, can be conducted via ionic, covalent, and cell pathways as well as by free radical polymerization [26; 27]. However, ionic crosslinking is the typical way to synthesize alginate gels, and calcium has been traditionally used to establish crosslinking. The tendency to use ionic crosslinking is supported by the fact that it offers an adequate method for active substance entrapment without affecting their bioactivity [28]. A critical factor in controlling the gelation process using divalent cations is the gelation rate. Gel uniformity and greater mechanical integrity are expected from a slower gelation system [29]. When crosslinking alginates, calcium carbonate and calcium sulfate have shown different gelation rates [30]. With a rapid gelation rate, the calcium chloride is suitable for ionic crosslinker for a bioencapsulation scheme, whereas others are more favored in tissue engineering scaffolds. The gelation rate also depends on the temperature; low temperature reduces the Ca\({}^{2+}\) reactivity, leading to low gelation rates, well-ordered network structures, and improved mechanical properties [26]. On the other hand, the alginates' M/G ratio and molecular weight contribute to the variation of the physicochemical properties of their ionic-crosslinked gel. The geometries of the G-block, M-block, and alternating regions are different due to particular shapes and modes of linkage in the alginate sequence. Thus, their intermolecular crosslinking with divalent ions is dissimilar and gives other gel characteristics. A higher content of G-block results in higher tensile strength and modulus and more extensibility than for alginates richer in M-blocks [31]. In addition, a rheological study of high molecular weight alginate fluid gels showed rapid gelation kinetics and higher viscosities than lower molecular weight [32]. The alginate source and the gelling ion conditions (type and concentration) affect the gel stability and permeability. A study on calcium, barium, and strontium ions has been conducted, forming alginate microbeads [33]. These three different cations reacted differently with the G- and M-blocks of alginate, resulting in diverse stability, permeability, gel strength, and distribution of alginates in the gel beads. Besides ionic crosslinking, many alternative approaches to produce alginate gels have been investigated. Alginate can be covalently crosslinked using carbodiimide chemistry, and one study found that the crosslinker type and the crosslinking density adequately affect hydrogel properties [34]. The crosslinking density affected the mechanical propertiesof hydrogels, and the type of crosslinking molecules influenced the swelling properties. Another representative strategy prompting the covalent crosslinking in alginate is free radical polymerization. Alginate-methacrylate hydrogels can be prepared through photopolymerization, obtaining mechanical properties that are dominated by the molecular conformation and electron density of the methacrylate reactive groups [35]. Nevertheless, if the alginate polymer chain's surface is decorated with cell adhesion ligands, cell cross linking most likely also produces alginate gels [36]. The properties of alginate hydrogels, such as high-water content, nontoxicity, soft consistency, biocompatibility, and biodegradability, make them sufficient candidates as drug carriers. As reported previously, alginate hydrogel could synthesize into nanogel, and it has good stability in biological fluid because of the low deriving for aggregation [37]. An alginate nanogel loaded with gold nanoparticles creates a thermos-responsive platform suitable for chemo-photothermal therapy for breast cancer [38].