3.1.2. Dextran Composites with Natural Polymers

Dextran is a non-toxic homoexopolysaccharide, mostly produced by lactic acid bacteria. It is made up of glucose subunits interconnected with α-(1→6) bonds, and forms a linear backbone. However, liner chains also have D-glucose side chains as branches attached with

α-(1→4), α-(1→3), or α-(1→2) linkage. Dextran exhibited diversity in molecular weights that range from 40–70 kDa. Dextran is water soluble, increases viscosity, and has a tendency to expand in the presence of water, contributing to the volume expansion in the case of plasma volume compensation, gelling agent in foods and pharmaceuticals [6,11]. It is also used in the preparation of molecular sieves while purifying macromolecules [20]. The solubility and nontoxicity of dextran have a big role in its application for drug delivery and preparation of wound dressing materials for biological systems.

Dextran was oxidized with periodate-assisted oxidation, followed by a reaction with chitosan hydrochloride. The composite did not have any cytotoxicity and offered minimal swelling in phosphate-buffered saline, along with good adhesiveness. The optimum adhesive strength of the composite, i.e., 200–400 gf/cm2, was 4–5-fold higher than commercial fibrin glue. The burst strength of the composite was 400–410 mm of Hg, which makes it suitable to be used as a medical sealant to control bleeding during surgical procedures. It also works under high blood pressure conditions. Both, adhesiveness and hemostat were assessed and found to be suitable in a rabbit liver injury model [64]. Besides medical adhesiveness, dextran has shown commendable suitability for in vivo applications, such as drug delivery and wound healing. Dextran composites alone can contribute to both adhesiveness and drug-carrying capacity. Even though a number of drugs are available for wound dressing and tissue repair, in some cases, injury worsens due to failure of wound dressing, mainly attributed to poor bioavailability, hydrophobic nature of drugs, and high level of reactive oxygen species. Dextran-based composites have offered the solution for all these challenges of rapid tissue repair. The drug delivery and bioavailability can be improved further when used in the nano form due to increased surface area. Andrabi et al. [65] have fabricated a composite nano-hydrogel with gelatin, oxidized dextran, and curcumin and cerium oxide-based nano-formulation. Two types of dextran derivatives have been used, i.e., alkylated dextran with 1-bromohexadecane (O-hexadecyl-dextran) and oxidized dextran. Curcumin nanoparticles were synthesized with alkylated dextran, while, on the other hand, cerium oxide nanoparticles were loaded onto the gelatin hydrogel with oxidized dextran. Altogether, these formulations form a hybrid nano-hydrogel that is used for wound healing. Here, alkylated dextran was amphiphilic in nature, which maintains the bioavailability of the drug (curcumin). Cerium oxide acts as an antioxidant and controls the reactive oxygen species and other free radicals. Hydrogel has shown a prolonged and consistent release of the drug, with ~63% release in 108 h. It also promotes cell migration to induce wound healing, along with antioxidant and in vivo anti-inflammatory activity (~39%).

Poor wound healing raises concerns in cases of noncompressible injuries due to a higher rate of blood loss. These injuries mostly occur from gunshots or injuries with sharp objects, such as knives, etc. In the absence of timely repair of the injury, higher blood loss and trauma-assisted mortality have been observed. Cryogels were prepared from oxidized dextran, chitosan, collagen, and polydopamine nanoparticles. In the formulation, dextran was used as a crosslinker, while chitosan was a hemostatic agent. The cryogels have an intensively branched and interconnected macroporous structure, with a high capacity to absorb blood or water. In vitro assessment suggested a very high coagulation potential due to strong procoagulant ability, and high adhesion potential for fibrinogens and blood cells. Moreover, it can activate platelets and associate intrinsic pathways. It reduced bleeding time and blood loss [66]. The dextran–thyme magnesium-doped hydroxyapatite composite is prepared by mixing salt precipitate with dextran and essential oil solution (Figure 4). The composites have shown antimicrobial activity and have considerable results against *Staphylococcus aureus*, *Enterococcus faecalis*, *E. coli*, *Pseudomonas aeruginosa*, and *Candida albicans.* The composites have the potential for application as antimicrobial coating materials [67].

**Figure 4.** Preparation of antimicrobial coatings with dextran, thyme essential oil, magnesium salt, and hydroxyapatite, as suggested by Iconaru et al. [67].

#### 3.1.3. Xanthan Composites with Natural Polymers

Xanthan is a hetero-exopolysaccharide, comprising glucose, mannose, and glucuronic acid. It is produced and secreted by *Xanthomonas campestris*. Biochemically, it is made of repeated units of pentasaccharides interconnected with β 1, 4-linked d-glucose backbone. The chain also has a substitution with trisaccharide side-chain linkage. The monosaccharide composition represents β-D-glucose, α-D-mannose, and α-D-glucuronic acid in a 2:2:1 ratio. Xanthan is known for its high viscosity, emulsion stabilization, and shear-thinning activity. Xanthan is non-toxic and biocompatible, but it is disadvantaged by poor electrical conductivity and stability of heat [20]. In comparison to macrostructures, the application of nanomaterials increases the interactions at a molecular level, has a higher surface area, and reduces the drug dosage required due to the higher efficiency of drug delivery in the nano form [68,69]. The application of EPS composites as nanomaterials might improve the performance, hence efforts have been made to incorporate the nanomaterials into the composite.

Nanocomposites comprising sodium alginate and xanthan gum, reinforced with cellulose nanocrystals and/or halloysites, are highly porous, with an extensive pore network. Nanotubes and nanocrystals have uniform dispersion and partial orientation within a composite. Composites with nanocrystals and nanotubes have porosity ranging from 91.7 ± 0.81% to 88.5 ± 0.64%, and water uptake capacity ranging from 14.73.7 ± 0.46 g/g to 11.34 ± 0.32 g/g. The composite is thermally stable and has high compressive strengths of 91.1 ± 1.2 kPa to 114.4 ± 0.6 kPa in dry form, and 9.0 ± 0.8 kPa to 10.6 ± 0.8 kPa in wet form. The composite has high cytocompatibility for MC3T3-E1 osteoblastic cells, and the viability of the cells increased with nanotube components in the composite. Both nitrocellulose and nanotubes increased the mechanical stability of the composite, along with conducive bioactivity, including higher cell adhesion and proliferation. The compressive strength of the composites was higher than alginate alone, as well as the alginate-xanthan gum blend, i.e., 91 kPa and 80.7 kPa. The blending of xanthan gum lowered the stiffness, which was further improved by the addition of nanocrystals and nanotubes, with the maximum strength reaching 114.4 kPa [70]. Mechanical strength and adhesion are important parameters for

wound dressing material. Hydrogels of xanthan gum and Konjac glucomannan blend have shown significant firmness and cohesiveness when both polymers are used in an equal ratio, i.e., 1:1. All the blends prepared with components of 1:1 and 2:3 ratios (glucomannan: xanthan gum) have a water content of more than 99% and water contact angle of less than 90◦. This feature is also important, as it prevents dehydration in wounds and supports healing by improving cell adhesion. In vitro analysis suggested that even after 72 h of contact, the hydrogel did not affect the morphology and viability, and supported the proliferation of fibroblasts. The hydrogel also provides cell migration during the healing phase that aided in rapid wound healing, which led to the full coverage of the wound site after 12 h, while in the control, it took 24 h [52].

Medical adhesives have been used in device and tape manufacturing. Biocompatible adhesive might offer a durable and user-friendly alternative for application. Feng et al. [71] have developed medical-grade adhesives with soybean protein sources at different concentrations of xanthan gum. The composite comprising 0.5% xanthan and 0.5% soybean proteins have shown a maximal adhesion strength of 321 kPa, which was 2.6-fold higher than the control, i.e., SP alone. The addition of xanthan increased the viscosity of the composite and improved the hydrogen bond. On a molecular basis, the addition of xanthan reduced the α-helix content and increased the β-sheet content in the protein secondary structure. The composite has shown a compact and viscous surface that supports adhesion. Sometimes, bone injuries need support and artificial implants for regeneration and recovery. Zia et al. [72] have prepared a polymer composite with xanthan gum, chitosan, and nanohydroxyapatite and polyelectrolyte complex. Osteo-conductive tri-composite scaffolds were prepared for osteo-regeneration. The composite scaffold, containing polymer electrolyte and hydroxyapatite in the ratio of 1:1, exhibited a commendable porous structure with a compressive strength swelling ability with slower degradation rates. Analysis in simulated body fluid, xanthan gum, chitosan, and nano-hydroxy apatite have apatite-like surface structures. In vitro interaction studies revealed that the nanocomposite scaffold with chitosan and nanohydroxyapatite supported cellular viability, attachment, and proliferation of MG-63 cells.

Polymeric porous scaffolds were made from chitosan and xanthan, along with 5% hydroxyapatite and brushite, for advanced mesenchymal stem cells. Composite scaffolds have an amorphous structure phase, having major bands of amide for chitosan and xanthan. Scaffolds have porous structures with calcium phosphate fillers. The elasticity modulus was higher for composite scaffolds with brushite than with hydroxyapatite and composite alone. Composites alone have a higher cell viability than scaffold–calcium phosphate, having acceptable cell viability. The composite with any calcium phosphate forms had a higher inflammatory response after 48 h, while scaffold + hydroxyapatite with mesenchymal stem cells had the lowest inflammatory cell number. It was clear from the work that calcium phosphate improved mechanical strength, but lowered cell viability. The toxic effect was countered by the addition of mesenchymal stem cells [73]. Now, the era of 3D printing has started, but the fabrication of biological structures needs supportive and efficient materials with a high mechanical strength and elasticity modulus. Piola et al. [51] developed crosslinked 3D-printable hydrogel with gelatin and xanthan gum, especially for wound dressing. The results have suggested that both gelatin and xanthan gum are important for composite formation, but xanthan concentration is crucial for the printability of the composite, as 1–1.2% of xanthan is required to attain printability, irrespective of the concentration of gelatin; however, 1.2% concentration was optimum.

#### 3.1.4. Pullulan Composites with Natural Polymers

Pullulan, an unbranched homopolysaccharide, is composed of triose units made from three glucose units interconnected by α-1,4 glycosidic bonds. These maltotriose units are linked with each other by α-1,6 glycosidic bonds. It is produced by *Aureobasidium pullulans* from starch, and secreted out [74,75]. The α-bond contributes to its aqueous solubility and flexibility. Overall, it is a biodegradable, nontoxic, and biocompatible polymer [76]. The characteristics are suitable for hydrogels and hybrid polymer fabrication, but the main drawbacks are its high-water solubility and hygroscopic nature. In addition, it has poor support for cell adhesion and proliferation, and is poorly osteogenic, mainly attributed to its hydrophilicity [77,78].

For making bone grafts, mechanical strength and degradation profile are important parameters. Usually, a hydrogel has a porous structure with intense networking. Pullulan is one of the non-immunogenic biopolymers that can be used for scaffold fabrication. Pullulan–dextran composite scaffolds, together with interfacial polyelectrolyte complexation fibers, have an improved adhesion for cells in comparison to pullulan. Further addition of extracellular proteins proved beneficial for cell adhesion and growth. The composite scaffold induced endothelial cell growth and followed the zero-order release kinetics for bovine serum albumin, as well as vascular endothelial growth factor [79]. Hydrogels are made from pullulan and covered with 5% hydroxyapatite nano-crystals and 3% poly(3-hydroxybutyrate). Making composites with fillers, such as butyrate, increased the compressive modulus of the composite scaffold by 10 times. The adhesion support for cells was improved by the presence of hydroxylapatite nanocrystals [78].

Posterior segment eye diseases need invasive intravitreal-injection-assisted treatment. However, prolonged injections become painful and can be countered with the use of an efficient drug delivery system. Kicková et al. [80] prepared pullulan–dexamethasone conjugates for sustainable drug delivery. Dexamethasone was loaded onto pullulan in a 1:20 ratio, and attached with pullulan via hydrogen bonds. The composite particles were stable at a wider range of temperatures, from 4 to 37 ◦C, at a physiological pH. At pH 5.0, these composites were acting like lysosomes and released the drug slowly, as 50% of the drug was released in the vitreous, while at pH 5.0, this occurred across a 2-day period. In vitro evaluation of biocompatibility showed no signs of toxicity on the retinal pigment epithelial cell line (ARPE-19).

Sustainable drug release from the composites has also opened the path for designing matrices and scaffolds for wound healing. The research work of Chen et al. [81] has proved that dressing materials have a critical role in wound healing time, pattern, and cellular response on wound healing, from in-depth histologic and histopathologic analysis in mice models. The dressing materials made from collagen hydrogel followed a human-like wound-healing model in mice. In comparison to the control, the hydrogel of pullulan– collagen induced rapid wound closure and healing, healing with less dense and shorter collagen fibers with random alignment.

Baron et al. [82] also used a pullulan composite for wound healing and drug delivery. Hydrogels made from oxidized pullulan and dopamine have possible applications in hemostatic wound dressing. Cryogels were prepared by (hemi)acetal and Schiff base bonds between dialdehyde pullulan and dopamine. Two types of formulation were prepared, i.e., PD1 by pullulan derivatives attached with dopamine derivatives and PD2 by adsorbed dopamine on the scaffold. PD1 is loaded with 20% dopamine, while PD2 has only 1.14% carried within the polysaccharide network. The porosity was maximum in the scaffold alone (80.41%) and reduced after loading; however, the network density was maximal in PD1 (47.1%). The water adsorption capacity was minimum for the crude scaffold (31.41%) due to the smooth texture and the maximum PD1 (59.01%). The PD1 hydrogel exhibited fast swelling initially, followed by stabilization. In comparison to the crude scaffold and PD2, PD1 has the highest mechanical stability of 558 N. The in vitro hemolytic analysis suggested a high rate of hemolysis in PD2, i.e., 99.04%, followed by 7.12% in PD1 and a minimum for the crude scaffold (0.15%).

#### 3.1.5. Levan Composites with Natural Polymers

Levan and gellan are exopolysaccharides extensively used in the food industry. Levan is a bioactive, user-friendly, non-toxic homo-exopolysaccharide produced by microorganisms, as well as plants. Among microorganisms, *Aerobacter levanicum*, *Bacillus subtilis*, *B. polymyxa*, *Corynebacterium laevaniformans*, *Pseudomonas* sp., and *Streptococcus* sp. are

among some common producers of levan. It is one of the natural fructans, made of fructose subunits interlinked by β-(2→6) glycosidic linkages, along with side chains attachment via β-(2→1) linkage to the main backbone. It is commonly used as a thickening/gelling agent, encapsulating material, and alternative to petrochemicals in medical applications [83]. Levan is soluble in water, as well as in oil. In industries, it is used as gum, sweetener, flavor carrier, surface finishing additive, gelling agent, emulsifier, cryoprotector, and osmoregulator. Its bioactivity includes antitumor and antihyperlipidemic and radioprotector activities [84].

Levan has an immunomodulatory effect on the host, hence it is commonly used as a drug carrier, as well as drug coating material. Bovine serum albumin was used as a model compound, and was encapsulated in levan nanoparticles to assess carrying and release behavior. The nanoparticle has surface charges ranging from +4.3 mV to +7.6 mV, varying in particle size, from 200 nm to 537 nm. With the increase in size, the encapsulation capacity of nanoparticles also increased from 49.3% to 71.3%. Both types of particles have shown controlled release of BSA during in vitro analysis [85]. Besides drug delivery, levan has also been used as tissue filler. Due to its flexibility, an injectable biofiller was designed with levan, together with carboxymethyl cellulose and Pluronic F127, for the regeneration of soft tissue. The hydrogel offered an elastic modulus higher than hyaluronic acid hydrogel. The presence of interconnected pores also makes it suitable to be used as a filler. In vitro analysis has confirmed that levan improved cell proliferation and collagen synthesis in human dermal fibroblast cells without any cytotoxicity. The levan hydrogel was stable over 2 weeks in vivo, which was higher than the Pluronic F127 hydrogel or hyaluronic acid hydrogel alone. Apart from this, the levan hydrogel has also shown anti-wrinkle activity in wrinkle model mice, which was also higher in comparison to the hyaluronic acid hydrogel [86]. The hydrolysed derivative of the levan polysaccharide is prepared for nanoparticle synthesis by the electro-hydrodynamic atomization (EHDA) technique, and loaded with resveratrol (encapsulation efficiency 13.8 ± 1.3%). The drug-loaded nanoparticles have followed first-order kinetics in resveratrol release at different pHs, as higher loading is accompanied by a more gradual release. It showed a burst release mechanism, as 65–70% of the drug was released initially, followed by slow release. There was no sign of toxicity during in vitro assessment with human dermal fibroblast cell lines (PCS-201-012) [87]. Activation of metalloproteinase supports the healing of injured tissue. The application of levan in biomedical dressing sealants is limited, as it gets removed in a wet environment. The addition of catechol improved the adhesion strength of the levan composite to 42.17 ± 0.24 kPa (>3 times of fibrin glue), that persists even in a wet environment, and allowed for its application in hemostatic surgeries and wound healing. Besides adhesion, it also induced rapid blood clotting and healing of rat skin incisions. In comparison to levan, the composite has a lower endotoxin level [88]. The major challenge with levan is its cost and lower yield, thus the cost of composites and prepared products will also be high. For better market reach, bulk and cost-effective production is necessary.

#### 3.1.6. Gellan Composites with Natural Polymers

On the other hand, gellan gum is a hetero exopolysaccharide composed of two β-Dglucose, β-D glucuronic acid, and α L-rhamnose subunits. It is an anionic, water-soluble polysaccharide, secreted by *Sphingomonas elodea*. Gellan gum is a strong gelling agent, able to form a gel at very even low concentrations. Based on the gel-forming ability, two types of gellan gums are available, i.e., low-acyl form that makes hard and brittle gel, and the second high-acyl form, that produces soft and elastic gels. It can be used to make low-viscosity suspensions, and as a gelling agent in industries [74]. It can offer diverse forms in gelling ability, but it lacks stability against stress and shear tolerance for tissue engineering. Zheng et al. [89] have blended gelatin with gellan gum to prepare injectable scaffolds applicable for skin regeneration. The aim was to cover irregularly shaped wounds followed by recovery. Gelatin and gellan gum had a synergetic effect on the composite

hydrogel and exhibited both shear-thinning, as well as self-recovering abilities. Further addition of tannic acid induced rapid wound healing in mice model.

Some of the studies have also shown the application of biopolymer composites as a cell carrier in addition to drug compounds, as suggested in the case of retinal pigment epithelium cells. The deterioration and damage in retinal pigment epithelium cells lead to blindness that can be cured with the replacement of damaged cells with healthy ones. Kim et al. [90] have shown that hydrogels prepared from gellan gum and silk sericin can be used as a cell carrier also. Sericin improved the compressive strength of composite over gellan gum to support the growth and proliferation of cells. A composite of gellan gum with 0.5% sericin has shown compressive strength to 10 kPa and improved the gene expression associated with ARPE-19 cell proliferation.

#### *3.2. Exopolysaccharide Composites with Synthetic Polymers*

Similar to natural polymers and biomolecules, synthetic polymers have also been used to make a composite with exopolysaccharides, which improves the binding ability and woven strength of any fiber. The section summarized some of the composites of exopolysaccharides and synthetic polymers.

#### 3.2.1. Dextran Composites with Synthetic Polymers

Dextran composites are prepared with synthetic polymers mainly to improve the water/solvent interaction behaviors, biodegradability, and mechanical strength. In the context of medical/healthcare-associated operations, polymers have higher strength or compounds with additional health benefits have a critical contribution. The fabrication of advanced fabric with biodegradability and inbuilt healing power might improve the treatment and revolutionize healthcare practices. A biocompatible dressing material fiber was prepared with electrospun poly(vinyl alcohol)–dextran, prepared from dextran and poly(vinyl alcohol) by using citric acid as a cross-linker, followed by loading with sodium ampicillin. The mechanical strength was mainly governed by the concentration of citric acid, as it determines the degree of cross-linking. However, swelling, adsorption of protein, and drug release were decreased, as the CA concentration increased, while high concentrations of dextran induced the proliferation of HFB-4 cells and offered higher antimicrobial activity. After 24–48 h of treatment, all the fabrics had the potential to accelerate the wound gap closure [91]. Kenawy et al. [91] used a composite of poly(vinyl alcohol)–dextran nanofibers for injury dressing materials. The composite was prepared by poly(vinyl alcohol) and dextran cross-linked with sodium ampicillin-loaded citric acid. The composite was electrospun for the fabrication of dressing material. The composite made with 10% PVA–10% dextran and 5% citric acid offered the best nanofiber suitable for dressing materials. The concentration of the cross-linker, i.e., citric acid, greatly influenced the characteristics, including mechanical stability, thermal stability, and water uptake. The composite nanofibers with a high concentration of dextran have encouraged the proliferation of HFB-4 cells.

#### 3.2.2. Cellulose Composite with Synthetic Polymers

Bacterial cellulose is suitable for the fabrication of biopolymers, especially for healthcarerelated applications, manufacturing scaffolds, implants, artificial blood vessels, and wound dressing materials, for wound and burn cases. The composite of bacterial cellulose with poly(vinyl alcohol) and hexagonal boron nitride was used for the preparation of a 3D scaffold for bone tissue engineering, using 3D printing technology. In composite bacterial cellulose, the major characteristics of the scaffold were determined. The addition of cellulose reduced the pore size in the composite and increased the viscosity to 81.3 mPa.s. Composites with bacterial cellulose have a lower tensile strength and the highest break in elongation, i.e., 93% was observed in the case of the composite prepared with 0.5% cellulose, 12% poly(vinyl alcohol), and 0.25% boron nitride. The biocompatibility assessment with human osteoblast cells suggested that at a lower concentration of cellulose, the viability of cells reduced by it further increased when the concentration of cellulose increased from

0.1/0.2% to 0.25 and 0.5%. The composite also offered a surface for cell adhesion and proliferation [92].

In a similar line, Zhang et al. [93] have fabricated macroporous hydrogels with dextran and polydopamine to be used as a carrier for antibiotics. Polydopamine affected the structure, as well as the functionality of the hydrogel, as with the increase in the concentration of dopamine, the pore size decreased and the surface area increased. The hydrogel has shown an increase in negative charge with the increase in the concentration of polydopamine in the composite, but the storage modulus and mechanical strength was increased. With the increase in dopamine content, the swelling ratio of hydrogel reduced and induced deswelling, which was due to the reduced pore size and higher interaction of dopamine with the internal structure of the hydrogel. The hydrogel lowered the viability of NIH3T3 cells slightly on the first day, but then no further cytotoxicity effect was reported. Hydrogels with a higher concentration of polydopamine were found to be suitable for drug loading and release. Hydrogels have shown up to 71% chlorhexidine acetate loading in 4.5 h, followed by its release of 12.58%, 16.06%, and 22.03% after 12, 24, and 48 h, respectively. The trend suggested that drug release was reduced with an increase in dopamine concentration. The work of Wang et al. [94] also emphasized the application of a cellulose composite for the preparation of artificial blood vessels with small diameters for thrombosis patients. A composite of poly(-caprolactone) and cellulose acetate was used to prepare nanofiber membranes for its further application in tubular scaffold fabrication, using different types of stainless-steel collectors. The composite scaffolds have water contact angles of 126.5◦ and 105.5◦, which was increased by constructing a square-groove. In comparison to other collector mesh, scaffolds with a large mesh have 30% and 148% higher tensile strength over random-flat and tubular scaffolds, respectively. Similarly, the long mesh also offered 103% higher suture retention strength. Biocompatibility assessment revealed that the long mesh scaffold has 88% cell viability, and the blood coagulation index (BCI) was 5 min, which was around 89% of the standard value.

#### 3.2.3. Xanthan Composites with Synthetic Polymers

Extracellular polysaccharides are one of the most suitable materials for the preparation of scaffolds, grafts, and dressing materials, as they have water retention capacity, significant mechanical and tensile strength, and adaptability similar to the natural organs and tissues. In addition, it also supports cell adhesion, growth, and proliferation.

Cell growth has a direct influence on the conductivity and impedance of the medium, which may be used as an indirect method to assess and monitor cell growth within polymeric scaffolds. A conducting polymer composite was designed for the preparation of porous scaffolds with poly(3,4-ethylenedioxythiophene) and xanthan gum and compared with PEDOT: polystyrene sulfonate scaffolds (Figure 5). The semisynthetic composite scaffold carries important characteristics, such as the conductivity of poly(3,4-ethylenedioxythiophene), along with the biocompatibility and mechanical strength of xanthan gum. Composite scaffolds have interconnected pores, with a size range of 10–150 μm, that can be tuned as required, and Young's module range was 10–45 kPa. The composite scaffold supports the cell growth of MDCK II eGFP and MDCK II LifeAct epithelial cells [95].

A series of composites were prepared with xanthan gum, citric acid, gelatin, glutaraldehyde, and HPLC-grade water, and evaluated for wound healing potential in rat skin wound models. All the composites have >90% of water-holding capacity. The presence of free and bound water was confirmed with FTIR studies, with inter- as well as intramolecular hydrogen bonds. Similar to water holding capacity, all the hydrogels have also shown significant wound healing capacity in deep second-degree skin burns in rats. After 20 days of application, a composite of xanthan gum–gelatin–glutaraldehyde and xanthan–citric acid and glutaraldehyde had a higher wound healing rate over others, as well as the control [96].

**Figure 5.** 3D scaffold prepared with xanthan gum and poly(3,4-ethylenedioxythiophene), as described by del Agua et al. [95].

Malik and et al. [97] prepared an oral, drug carrier composite with chitosan, xanthan gum, monomer 2-acrylamido-2-methylpropane sulfonic acid, and potassium persulfate by free radicle polymerization technique. The components were crosslinked with N N methylene bis-acrylamide. The composite was loaded with acyclovir as a model antiviral drug commonly prescribed in herpes simplex virus infections. The composite had a higher thermal stability and a porous structure that encapsulated the drug compound. The composite hydrogel has shown pH-dependent drug releasing behavior. Ilomuanya et al. [98] prepared a hybrid composite with antibacterial, antioxidative, and anti-inflammatory behavior for wound dressing. The composite was prepared with poly(vinyl alcohol) and xanthan gum/hypromellose/sodium carboxymethyl cellulose. Composites with silver nanoparticles have higher antimicrobial potential and have inhibition of >99% against wound pathogens such as *Acinetobacter baumannii*, *E. coli*, *K. pneumoniae*, *P. aeruginosa*, *S. aureus*, *S. epidermidis*, and *Candida albicans*. Maximum bactericidal effect was observed from hypromellose nanocomposite, with 99.9% growth reduction, within 1 h of application. Dressing material prepared with composites also has free radical scavenging behavior, along with a reduction in the inflammatory response in RAW 264.7 macrophages. Animal model studies have confirmed that the hypromellose-based nanocomposite has a higher wound-healing process.

#### 3.2.4. Gellan Gum/Levan Composite with Synthetic Polymers

Composites with synthetic and natural components may have a higher applicability rate as natural polymers are biocompatible and biodegradable, but the addition of synthetic material may prolong the lifespan and modify the surface texture for the attachment of polymer. A levan-based composite was prepared with two different forms of levan, i.e., hydrolyzed and sulphated. Both hydrolyzed and sulfated levans were synthesized by microwave-assisted acid hydrolysis, with 5% acetic acid at 60% operating power for 60 s and mixing with chlorosulfonic acid for 24 h, respectively. The composite blend of 10% polycaprolactone (THF:DMF) and the aqueous solution of sulfated levan and hydrolysed levan in polyethylene oxide was used for coaxial electrospinning. The composite fiber has higher ultimate tensile strength and it increased with ShHL concentration. The composite increased the viability of L929 fibroblasts and HUVECs [99]. Adrover et al. [100] have prepared the composite beads for drug delivery with gellan gum, calcium ions (CaCl2), and with/without synthetic clay laponite ionotropic gelation technique. The addition of laponite

reduced the swelling degree of polymeric beads. Gellan gum and gellan-silicate composite beads were loaded with theophylline and cyanocobalamin for in vitro release behavior. Laponite controlled the drug entrapment efficiency, as well as the slower drug release into the gastric environment. Theophylline followed Fickian behavior for drug release, while cyanocobalamin release behavior was greatly influenced by the physical/chemical interaction of the composite and drug.

For bone regeneration, an ideal membrane is of utmost importance that not only induces cell proliferation followed by mineralization, but is also able to withstand stress. A composite of calcium–poly-γ-glutamic acid and glycerol with gellan gum was studied for bone regeneration. In composite membranes, calcium aggregates are distributed uniformly and act as commendable performers in protein adsorption, and bone cell proliferation with MG63 cells. The hydrogel has promising results for bone repair, and γ-PGA acts critically. The exopolysaccharide member acts as biocompatible material, and γ-PGA improved cell adhesion and proliferation. It also increased the secretion of alkaline phosphatase and induced mineralization. The third member, 'glycerol', enhanced mechanical strength, elongation at break, as well as diffusion rate. Both glycerol and γ-PGA delayed the degradation of the composite [101]. The main contribution of synthetic polymers in the composite is to improve the tensile and mechanical strength and delay the degradation, an important feature that is required to provide sufficient time for tissue repair and recovery.
