cell compatibility, flexibility, and degradation. Although 3D bioprinting is a promising technique for tissue engineering and regenerative medicine, developments in the biomaterial ink field still need further improvements to be used in clinical trials.
6.2.2.2 Wound Healing
Wound injuries range from minors, such as the ones that resulted from daily activities, to life-threating chronic or severe wounds resulted from serious incidents or diseases. In addition to the type of wound being treated, a better understanding of the healing stages of the wound and the physical–chemical features of the available dressings are necessary for an efficient treatment. Therefore, a proper design of wound dressings is important to promote as well as accelerate the wound healing process and reduce the healing time concurrently [97]. Because of their biocompatibility and nonimmunogenic and antimicrobial properties, natural polysaccharides have been commonly used in wound-dressing development.
Glycosaminoglycans are the components of the extracellular matrix and they play important roles during the wound healing phases and promote wound recovery by leading to rapid granulation, enhanced cell proliferation, migration, and vascularization, and by modulating inflammation process [98]. Since natural polysaccharides are rich in glycosaminoglycans, they have been proposed to facilitate the healing process [99]. Glycosaminoglycans are negatively charged linear polysaccharides with the ability to interact with several proteins. The electrostatic characteristic of glycosaminoglycan provides interaction with cationic neutrophils and this interaction reduces neutrophil overactivation as well as prevents excessive protease production; therefore, especially for severe wound injury, chronic inflammation can be prevented and the wound can efficiently proceed from the inflammatory stage to the proliferative (tissue growth) phase of healing [99].
Plant-derived polysaccharides modulate the immune system in several ways: they can activate immune cells, including lymphocytes, natural killer cells, and macrophages, and also stimulate complement activation and promote the production of cytokines [100]. Macrophages are cells of innate immune system and activation of macrophages is crucial to respond to the pathogens rapidly. Natural polysaccharides support the wound healing process by stimulating macrophage activation which results in the secretion of cytokines, enhanced proliferation and phagocytic activity of macrophages, and the generation of reactive oxygen species (ROS) [101, 102]. Most research has reported that plant polysaccharides initiates the immune response and exerts an immunomodulatory action through binding to specific receptors on the surfaces of macrophages: macrophages can interact with plant-derived polysaccharides and/or glycoproteins by CD14, Toll-like receptor 4 (TLR4), scavenger receptor (SR), complement receptor 3 (CR3), dectin-1, and mannose receptor (MR). This receptor–ligand interaction initiates a series of intracellular signaling cascades resulting in the transcriptional activation of cytokine expression and inducible nitric oxide synthase (iNOS) expression and production of inflammation-related cytokines [100, 103]. For instance, the mechanism of action of β-glucan (i.e., a group of β-D-glucose polysaccharides) is mediated by several receptors, most importantly by dectin-1. Once binding to the dectin-1, β-glucan stimulates an effective immune response, including phagocytosis and proinflammatory factor production [104]. For instance, Martins et al. claimed that a polysaccharide-rich fraction of the medical mushroom Agaricus brasiliensis was able to regulate the host response by triggering cytokine secretion from monocytes through enhancing TLR4 and TLR2 expression [105].
Natural polysaccharides, such as chitosan, fucoidan, alginate, and hyaluronic acid, are considered as proper candidates for the stimulation of wound healing. For example, as a highly absorbent, biodegradable, non-adherent, and hydrophilic natural polysaccharide, alginate (a linear polysaccharide composed of β-D-mannuronic acid and α-l-guluronic acid residues linked via 1→4 glycosidic linkages), is used for fabricating wound dressing materials in different forms, including films, hydrogels, nanofibers, foams, and in the form of topical formulations [106, 107]. Salts of alginic acid, obtained from seaweed, are known to facilitate and enhance the wound healing process by promoting a moist wound healing environment, supporting debridement, absorbing excess wound exudate, and forming a non-adherent gel [108]. In in vivo models, compared to commonly used wound dressing containing carboxymethyl cellulose, calcium alginate wound dressing was shown to reduce wound size, support reepithelialization, minimize hypertrophic scar formation, and regulate cytokines, in addition to its function in maximizing antimicrobial effects [109]. When the dressing is contacted with the wound, an ion-exchange reaction takes place between the sodium in the exudate and the calcium in the alginate, giving rise to a hydrophilic gel as a byproduct. This soluble gel structure creates a moist wound environment and therefore prevents scabs from forming and promote the growth and migration of cells to support the formation of new tissues [110]. The gel-forming property of alginate was also reported to reduce the pain experienced by the patient during dressing changes [111].
To enhance the swelling capacity, combinations of alginate with other polysaccharides in the form of hydrogels have been also explored. For instance, Xing et al. characterized alginate–chitosan hydrogels for wound dressing and found that this combination enhances the water holding capacity by 80% without showing cellular toxicity [112]. In another study, Devi et al. described the preparation and characterization of fibrin–chitosan–sodium alginate composite to be used as a functional wound dressing. Chitosan is a linear aminopolysaccharide obtained from the alkaline N-deacetylation of chitin while fibrin is a blood plasma protein essential for clot formation. Fibrin scaffold is used to control surgical bleeding, accelerate wound healing, seal off or cover the holes in body organs, and also it provides a slow-rate release delivery of drugs. A 4.0% w/v fibrin, 0.1% w/v chitosan, and 0.2% w/v sodium alginate containing hydrogel was reported to exhibit good mechanical properties, including thickness, elongation, and tensile strength, and the authors suggested that this new hydrogel formulation has a potential to be used as a wound dressing material [113].
The Plantago belongs to the Plantaginaceae family which comprises several herbs or sub-herbs grow up in warm climate regions or the tropics. Since ancient times, Psyllium (Plantago ovata) has been used as a therapeutic agent. It has been suggested to be used for the treatment of diarrhea, constipation, irritable bowel syndrome, colon cancer, inflammatory bowel disease, diabetes, and hypercholesterolemia. The husk of the seeds of various species of Psyllium has been reported with their therapeutic effects. A mucilaginous polysaccharide is the primary ingredient of these seeds and husk [114]. Since mucopolysaccharides derived from Psyllium have been reported with their wound cleansing, wound healing, and scar formation limiting properties [115], investigation of Psyllium-derived polysaccharide-based wound healing materials, such as films, hydrogels, and composite materials, have been gained attention [116, 117]. Chronic wounds, such as diabetic wounds, continues to be a persistent health problem globally. Therefore, attempts for investigation of novel wound healing strategies are increasing. Recently, Ponrasu et al. developed a composite hydrogel scaffold model which morin, a plant-derived flavonol with antioxidant activity, was loaded onto hydrogel scaffolds prepared from Psyllium seed husk polysaccharide and human hair keratins crosslinked with sodium trimetaphosphate. They showed that the use of this composite scaffold significantly reduced the re-epithelialization time and enhanced the rate of wound contraction by accelerating collagen synthesis in diabetic rats compared to controls [118]. In another study, a lauroyl grafted hydrophobic glycolipid derivative of alginate has been incorporated into Psyllium husk gel. The composite film has been analyzed for its protein adsorption property and antimicrobial activity to verify its utility in biomedical applications. The results showed that the composite films have better physicochemical and mechanical properties compared to films without glycolipid. Additionally, incorporation of the glycolipid derivative was shown to improve the antimicrobial activity of the composite film [117].
Besides the plant-derived polysaccharides, bacterial polysaccharides, such as bacterial cellulose, have been also investigated to be used in wound healing applications. Bacterial cellulose has several advantages over plant-derived cellulose, such as high porosity, elevated water uptake capacity, purity, permeability to liquid and gases, enhanced surface area, and mechanical robustness. Compared to vegetal cellulose, bacterial cellulose
