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the treatment of severe wounds.

      Although there is considerable merit in using natural polysaccharides in wound treatment because of their anti-inflammatory and hydrating effects, there is a risk that a natural polysaccharide may prompt the overactivation of the immune system and result in irritation due to its heterogeneous and complex structure. Therefore, investigation of the structural characteristics and structure–function aspects, assessment of proper purity, and development of new and sensitive methods to accurately determine the purity of isolated polysaccharides are essential for the use of these natural polymers in biomedical applications with safety. Also, especially for the treatment of chronic wounds, development and characterization of composite materials seem to be necessary to achieve improved physicochemical, mechanical and biological features, such as better swelling characteristic, lower protein adsorption property, enhanced moisturizing and antimicrobial activities, and reduced wound contraction and scar formation properties. Besides, wound healing materials have to be developed for sustaining microbial contamination during storage.

       6.2.2.3 Drug Loading and Delivery

      Several properties of natural polysaccharides make them promising agents in the pharmaceutical sector for drug loading and delivery applications: (i) they can be obtained from reproducible plant materials, (ii) they can be manipulated by enzymatic and chemical methods, (iii) they are biocompatible, biodegradable, and have low immunogenic properties, (iv) they can be designed as stimuli-responsive (e.g., pH and ion-sensitiveness) drug delivery systems, (v) ionic polysaccharides are mucoadhesive, (vi) they can be conjugated or they can make complexes with bio-macromolecules, such as peptides and proteins, (vii) they can easily form gels, and (viii) they can form interpenetrated polymeric networks and semi-polymeric networks [4].

      For the drug delivery, the gel structure forming property of polysaccharides are very attractive. Gels are 3D polymeric networks trapping a continuous liquid phase and thus they can be used to manage the release kinetics of embedded drugs [122]: the physicochemical properties of the polysaccharide gels (i.e., polymeric network chains trapping the huge amount of liquid) make them useful for the transportation and release of vaccines, proteins, peptides, and nucleic acid-based drugs [123]. By exhibiting high water‐retaining capacity, renewability, biodegradability, biocompatibility, and nontoxicity, polysaccharides offer ideal structures for hydrogel networks. Besides, these polysaccharides can be gelatinized and functionalized easily [4, 124]. A hydrogel is also a good drug delivery system because of its particular advantages in preventing drug degradation and thus avoiding obstacles such as short half‐life and poor water solubility [124].

      Natural polysaccharides such as starch, cellulose, hyaluronic acid, and glycogen, have been engineered by using several methods such as chemical modification, co-polymer grafting, and atom transfer radical polymerization to obtain superior molecules for pharmaceutics [125]. For example, cellulose nanocrystals were grafted with polyethyl ethylene phosphate through the ring-opening polymerization and Cu(I)-catalyzed azide-alkyne cycloaddition by “click” chemistry approach, and this azide-tailored negatively-charged nanocrystals were encapsulated with the anticancer drug doxorubicin for targeting cancer cells [126]. In another study, the bioconjugation approach was used for targeted drug delivery: polyethylene glycol-conjugated hyaluronic acid nanoparticles have been developed to enhance selective entry of cytotoxic drugs into CD44, hyaluronic acid receptor over-expressing cancerous cells [127].

Natural polysaccharides can be also used in hydrogel form for drug delivery. For instance, as a complex branched glucan, dextran contains several numbers of hydroxyl groups that can be chemically modified with divergent functional groups to form hydrogels. Dextran hydrogels have been considered valuable vehicles for controlled drug release because of their biocompatibility along with flexibility and biodegradability. Besides, dextran hydrogels can form an extracellular matrix resembling 3D hydrophilic network structures that can be produced by either chemical or physical crosslinking approaches. In this 3D matrix structure, water molecules occupy the empty spaces between networks of polymer chains. To achieve a controlled drug release, drugs can be integrated into these dextran matrices [81]. Between the matrices suitable for the controlled drug release, a notable role is played by those systems that are capable of responding to the changes in the external environment. Dextran hydrogels can be modified to respond to changes in the pH and the ionic strength of the environment to alter network structure, swelling behavior, permeability or mechanical strength. Therefore, since pH values change along the gastrointestinal tract, pH-responsive dextran hydrogels can be particularly advantageous to be used in the gastrointestinal system to obtain a specific release [128].

      Among many different polysaccharide polymers, gellan gum, a microbially derived polysaccharide, is drawing increased attention nowadays because of its favorable properties including abundance, nontoxicity, mucoadhesiveness, easy gelation, thermal and acid stability, and high transparency. Gellan gum has been suggested to be used for different purposes such as mucoadhesive or granulating agent, tablet binder, production of beads, films, microspheres and microcapsules, nanohydrogels, and nanoparticles [129]. For example, D’Arrigo et al. have designed a self-assembling nanohydrogel form based on gellan to deliver inactive prodrug prednisolone. This prodrug is processed into anti-inflammatory active drug prednisone in the liver. Since prednisolone is poorly soluble in water, it was chemically conjugated to the carboxylic groups of gellan and the hydrophobic moiety of prednisolone led to the self-assembly of nanohydrogels with an average size of about 300 nm with negative zeta potential values. This fabricated self-assembled gellan-based nanohydrogel was shown to enhance the solubility and cellular uptake of prednisolone [130]. Xanthan gum also meets the required properties for targeted delivery and controlled release of drugs in its nanoparticle, liposome, niosome, microsphere, hydrogel, dendrimer, or nanofiber forms. Because of its excellent flow properties, xanthan can stabilize many water-based systems. Besides, it remains effective over a broad range of pH, temperature, and ionic strength [81, 131]. When used alone or in combination with other macromolecules, such as cellulose derivatives, polyvinylpyrrolidone, karaya and guar gum, xanthan gum-based formulations have been shown to have a great ability to generate a drug release profile close to zero. On the other hand, the deacetylation of xanthan gum increases the negative charge of the polysaccharide to combine it with other biopolymers. Deacetylation also decreases the molecular weight and improves the solubility of xanthan gum; therefore makes the polysaccharide more preferable for pharmaceutical applications [132].

One of the novel drug delivery systems is microspheres. Microspheres contain dispersed drugs in a polymeric matrix structure and if it is modified properly for targeting the site of interest without untoward effects, they are reliable drug delivery systems for controlled release. Polysaccharides are abundant and cheap biopolymers and widely used as microsphere matrices to carry water-soluble model drugs. Polysaccharide-based microspheres of starch, chitosan, and alginate have been commonly used as biodegradable matrices to achieve controlled drug release [133]. For example, by using the emulsion solvent method, drugs can be loaded in alginate microspheres to obtain drug-loaded alginate microspheres. In this technique, the evenly mixed drug and alginate solution is emulsified under sonication followed by adding this mixture in a dropwise manner to an organic emulsion with constant stirring. The alginate-based microspheres can protect drugs from degradation as well as improve plasma half time for providing transport and release of drugs [45]. Some bioactive compounds, such as growth factors, can be denatured and lose their properties during the microsphere preparation steps: the organic solvent itself and also the presence of high shear stress can result in denaturation and therefore loss of biological activity of encapsulated proteins, including growth factors. To prevent this, microencapsulation technique, an attractive approach relies on the encapsulation of bioactive materials within a semipermeable polymeric membrane, can provide an alternative method to protect cells, drugs, small proteins, cytokines, growth factors or other bioactive compounds [45, 134]. Chitosan exhibits a good bio-adhesivity: it can bind to negatively charged mucosa cell surfaces very efficiently. This property makes it suitable for efficient drug adsorption. Furthermore, alginate/chitosan microcapsules have been shown to exhibit improved biocompatibility and mechanical strength for biomedical applications [134].

      In recent years, polysaccharide-based nanoparticles have also attracted interest as therapeutic agent carriers.

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