absence of enzymes that attack the β (1→4) linkage [50]. However, an ideal scaffold should be constructed from materials degradable in the organism for replacement by natural extracellular matrix. Oxidation of cellulose (i.e., achieved by using various oxidizing agents, such as nitrogen oxides, free nitroxyl radicals, NaClO2, or CCl4) is one of the methods to increase the degradability since the oxidized polymer readily undergoes chain shortening to give oligomers which will be further hydrolyzed to smaller fragments, including glucuronic acid and glucose by hydrolytic enzymes [51, 52]. The oxidation of cellulose converts glucose residues to glucuronic acid residues containing –COOH groups which modulate the degradation kinetics of cellulose, its pH, its swelling capacity in a water solution, and mechanical stability. Additionally, the polar and negatively charged nature of the –COOH groups facilitate the oxidized cellulose to be used for functionalizing with various biomolecules [51].
Although cellulose is mainly obtained from vegetal products, it is also produced extracellularly by bacteria from the genera Gluconacetobacter, Sarcina, and Agrobacterium [53]. The most prominent and well-known bacterial cellulose producing species is Komagataeibacter xylinus (Gluconacetobacter xylinus). K. xylinus is not the sole species among acetic acid bacteria with tremendous potential for bacterial cellulose production, since also other species, like Komagataeibacter medellinensis, Komagataeibacter hansenii, Komagataeibacter oboediens, Komagataeibacter nataicola, Komagataeibacter rhaeticus, Komagataeibacter pomaceti, and Komagataeibacter saccharivorans have been shown as stupendous cellulose producers. Of note, acetic acid bacteria species used for cellulose production are considered as “generally recognized as safe-GRAS” [54, 55]. Previous studies have shown that through oxidative fermentation, cellulose producing bacteria can use various types of sugars in both synthetic and non-synthetic media as carbon sources [54, 56]. Cellulose is formed as a thick gel or pellicle on the surface of the growth medium in stationary culture conditions. This cellulose is different from plant cellulose in its degree of polymerization, crystallinity, higher purity, and tensile strength. Besides, unlike the vegetal cellulose that presents mainly the Iβ structure, bacterial cellulose has Iα and Iβ crystalline forms. Biocompatibility property of bacterial cellulose made it suitable for several biomedical applications [57]. Similar to plant cellulose, modifications of bacterial cellulose has been investigated to utilize it for biomedical applications. These efforts include processes for changing the surface chemistry of bacterial cellulose by incorporating different substrates such as small molecules, inorganic nanoparticles, and polymers to improve its functionality [57, 58]. In addition, to be used for tissue engineering, several composites were designed by taking the advantage of porous structure and mechanical strength of bacterial cellulose, such as composites of bacterial cellulose/collagen, bacterial cellulose/agarose, bacterial cellulose/poly(3-hydroxybutyrate) (PHB), bacterial cellulose/chitosan and bacterial cellulose/hydroxyapatite (Hap) [54]. However, it should be mentioned that like plant cellulose, the high crystalline nature and absence of enzyme which could break β (1→4) glycosidic linkage of bacterial cellulose in the human body prevent its degradation in vivo [54]. Although this feature of cellulose is advantageous for providing long term support as a scaffold material, a scaffold should degrade in time to allow the healing and regeneration process. Besides this, degradation products should be biocompatible [59]. Different approaches have been evaluated to enhance the degradability of bacterial cellulose such as chemical methods including modification of bacterial cellulose by periodate oxidation [60]. In another study, aldehyde groups were introduced to bacterial cellulose nanofibers [61]. Though, Yadav et al. used a metabolic engineering-based approach to induce the degradability of cellulose: N-acetylglucosamine (GlcNAc) residues were introduced into cellulosic biopolymers during de novo synthesis from Gluconacetobacter xylinus. The presence of GlcNAc enabled bacterial cellulose to be susceptible to lysozyme and also disrupted the highly ordered cellulose crystalline structure. Accordingly, in vivo studies showed that modified cellulose from the engineered strain was almost entirely degraded at day 10 and was completely undetectable at day 20 while little to no degradation of the cellulose obtained from the control bacteria at either time point [62].
Gelatin, a denatured polypeptide product of collagen, is a promising biomaterial as a scaffold. It has some unique regenerative characteristics, including its chemical similarities to the native extracellular matrix, low antigenicity, biocompatibility, and biodegradability. Besides, gelatin is cheap and abundant, and also has accessible functional groups that allow chemical modifications with other biomolecules [63]. However, low solubility in concentrated aqueous media, high viscosity, poor mechanical properties, and sensitivity to enzymatic degradation properties limit its applications as a scaffold material [63, 64]. The approach of combining gelatin with a wide range of polysaccharides has been used to overcome these drawbacks of gelatin. Hydrogels are three-dimensional cross-linked porous networks that consist of biopolymers or polyelectrolytes and would swell with a large amount of water or biological fluid [65]. Hybrid hydrogels composed of gelatin and polysaccharides, mainly cellulose, alginate, and hyaluronic acid, provides green and natural platforms for cell and tissue engineering. The combination of gelatin with polysaccharides is advantageous to better mimic the proteoglycan containing extracellular matrix. In addition, gelatin-polysaccharide biomaterials have been described to show biocompatibility, mechanical resilience, high stability, low thermal expansion, antimicrobial and anti-inflammatory properties [63].
Hyaluronic acid, also called hyaluronan, is an acidic, non-sulfated glycosaminoglycan present throughout the human body. Hyaluronic acid maintains the viscoelasticity of the extracellular matrix, therefore supports cellular structure and functions. It also keeps tissues hydrated and maintains the integrity of the extracellular matrix. Mechanistically, hyaluronic acid is known to interact with the receptors CD44, Intercellular Adhesion Molecule 1 (ICAM-1), and Hyaluronan-mediated motility receptor (HMMR), and these receptor-ligand interactions have been shown to regulate cell behaviors such as motility and adhesion [40, 66]. Hyaluronic acid is receiving special attention in a broad range of applications including cosmetics industry, biomedical and tissue engineering applications. As a main component of the extracellular matrix, hyaluronic acid is involved in tissue repair and displays advantageous physical–chemical properties, like biodegradability, biocompatibility, and viscoelasticity. Commercially, hyaluronic acid has been isolated from rooster combs; besides, it has also been produced using genetically modified bacteria [40, 67]. Biological activity of hyaluronic acid depends on its molecular weight: high molecular weight hyaluronic acid has been evaluated to show a pro-resolving response, while low molecular weight hyaluronic acid is known with its pro-inflammatory and pro-angiogenic activities [68]. It has been hypothesized that molecular weight dependent physiological effects of hyaluronic acid can be caused by an interaction between hyaluronic acid and certain receptors via different states of aggregation [69]. Nevertheless, hyaluronic acid has some disadvantages including short turnover and poor mechanical properties. Therefore, chemical modification or crosslinking approaches targeting carboxyl groups, hydroxyl group, and –NHCOCH3 of hyaluronic acid have been studied to overcome these limitations [70]. Investigation and manufacturing composite scaffolds to improve cell viability, proliferation, attachment, differentiation, vascularization, and host integration properties have been gaining attention [66, 67]. For example, a biomimetic scaffold consisting of a bioglass–collagen–hyaluronic acid–phosphatidylserine composite has been evaluated to enhance the adhesion, proliferation, and migration properties of human mesenchymal stem cells. In another study, hyaluronic acid, silk fibroin, and collagen combinations showed to be osteogenetic [66]. Hyaluronic acid-based materials are also used in hydrogel form to obtain high water content, oxygen, nutrients, and metabolites permeable scaffolds. For instance, Zanchetta et al. designed a hydrogel scaffold based on hyaluronic acid, chondroitin 6 sulfate, and dermatan sulfate with a promising osteogenesis-promoting property in rat models [71]. Hyaluronic acid is also considered as a promising candidate for central neural tissue engineering, because of its interconnected porous structure which facilitates the delivery of nutrition and penetration of cells, nerve fibers and blood vessels. In in vivo models, hyaluronic acid was demonstrated to be effective in reducing glial and peripheral scar formation and enhancing neural regeneration [72, 73]. The modulus of hyaluronic acid hydrogels was also reported to affect differentiation of neural progenitor cells: most of the neural progenitor cells cultured in hydrogels with