## 3 A Cost-Efficient Method to Produce Microparticles--Ionic Gelation  
Plenty of different techniques may be used for encapsulation in biopolymeric matrices. [PERSON] and [PERSON] [50] comprehensively reviewed biopolymeric particles production, and divided the methods as: (i) Ionotropic gelation or external gelation, (ii) emulsification and internal gelation, (iii) the reverse microemulsion technique, (iv) emulsion crosslinking method, (v) emulsion-solvent extraction, (vi) the emulsification solvent diffusion method, (vii) emulsion-droplet coalescence method, (viii) complex coacervation, (ix) reverse micellar method, (x) self-assembly methods, (xi) water-in-oil emulsification, (xii) desolvation process, (xiii) pH coacervation method, (xiv) emulsification, (xv) nanoparticle albumin-bound (nab) technology, (xvi) self-assembly, (xvii) desolvation method, (xviii) methods involving hydrophobized pullulan derivatives, (xix) reverse micelle synthesis method, and (xx) emulsification-diafiltration. Each of the mentioned methods has its advantages and disadvantages, depending on the targeted application, but one of the most popular and widely used encapsulation methods is ionic gelation. The ionic gelation method is often utilized in the production of biopolymeric microparticles mainly because it uses mild conditions throughout the encapsulation process and economical production costs [51; 52]. Sodium alginate is a common biopolymer used to prepare biodegradable microparticles and the encapsulation procedure, and developed carrier mainly depend on its properties. Alginate-based microparticles are obtained by the dropwise addition of alginate in the bath containing divalent cations. The affinity of sodium alginate for divalent cations mainly depends on its composition. Guluronic acid-based alginate will be more prone to ion binding compared to manuronic acid-based alginate. The affinity for the metals follows order: Mg\({}^{2+}\) < Mn\({}^{2+}\) < Ca\({}^{2+}\) < Sr\({}^{2+}\) < Ba\({}^{2+}\) < Cu\({}^{2+}\) < Pb\({}^{2+}\)[53; 54; 55]. These cations diffuse in sodium alginate solution forming a gel matrix, due to the cation-binding crosslinks with alginate. Crosslinking density is mainly determined as per the concentration of the cation solution [56]. The binding of the cations is related to the precise chelation process, depending on the distribution of gluuronic acid blocks. This has been previously explained with the so-called \"egg-box\" model. The model is based on the steric configuration of the gluuronic acid blocks residues [57; 58]. This model describes the gel formation via sodium cation swap with calcium cation from two adjacent gluuronic acid blocks and forming a single ion bridge between the chains. Ca\({}^{2+}\) ions hold the alginate chains together, and with more bonds, the nature of biopolymer binds more Ca\({}^{2+}\) in a stable form. Guluronic groups of alginate correctly distance coordination of Ca\({}^{2+}\) between carboxyl and hydroxyl groups. This behavior is ascribed to the self-cooperative process between neighboring elements (Ising model) and is based on a physical bond with unfavorable entropy for the first divalent ion. The bond is favored for all ions to form a one-dimensional \"egg-box\" (a zipping mechanism) [56]. Kinetics of gelling kinetics are fast and adaptable, but also depend on polymer and cation type and their respective concentrations. With the use of a microdroplet generator (Figure 2) dripping in cation solution, microparticles can be easily prepared. A Microdroplet generator is used for the dropwise addition of sodium alginate into the bath containing divalent cations, where gelling occurs, and spheres are formed (more detail on the process can be found in Section 7.2). Conveniently, Ca\({}^{2+}\) has been widely used as a gelling cation, since it is chemical versatile and safe [56; 59]. Generally, sodium alginate produces rigid, but relatively porous hydrogels with weak physical and mechanical properties, which are important in delivering active agents [51; 60].