*4.3. Composite-Forming Ability of EPS*

Usually, EPSs are water-soluble (except a few, such as cellulose) and hydrophilic, which makes EPS prone to degradation in storage, as well as in the cellular environment. This also influences the selection of drug and secondary polymers, as components with similar charges usually make an unstable system due to repulsion. Due to the presence of hydroxyl and carboxylic functional groups, most of the EPS molecules are negatively charged, and thus loading of negatively charged groups and blending with negatively charged polymers is not possible due to electrostatic repulsion [137,148,149].

Derivatization of exopolysaccharides is one of the most common approaches to change the net charge, as well as improve interaction with other molecules, as observed in the case of cellulose, which is insoluble in water as well as organic solvents. The availability of the hydroxyl functional group makes it possible to modulate its chemical nature, including solubility, hydrophilicity/hydrophobicity, and mechanical strength either, by degradation or derivatization. Cellulose ether is the derivative prepared by replacing the hydroxyl group with the hydrocarbon group. It includes carboxymethyl, methyl, hydroxypropyl methyl, and hydroxyethyl derivatives of cellulose. Derivatization of cellulose has improved thermoplasticity, apart from hydrophilicity of derivative, in comparison to native cellulose [150]. Similar changes were also observed in gellan gum hydrogel used for muscular injury. The addition of laminin protein improved the muscular tissue auto-healing capacity, but 3D hydrogel needs extensive crosslinking and porous structure. To attain a stable porous interconnected structure, gellan gum was derivatized with divinyl sulfone. The composite of gellan gum–divinyl sulfone derivative and gellan gum was used to prepare 3D hydrogel and functionalized with laminin-derived peptide. The composite was encapsulated with skeletal muscle cells. The modification of gellan gum with divinyl sulfone improved cross-linking that stabilized the 3D framework of hydrogel [151].

#### *4.4. Stability and Degradation Products of EPS Composites*

Exopolysaccharide composites are comprised of EPS and natural or synthetic polymers. EPS mainly has polysaccharides as a major component, while natural polymers may also have proteins and lipids, etc. Each biopolymer, including sugar/carbohydrate, proteins, lipids, and nucleic acids, is prone to degradation and may endure only a few hours to a few weeks (depending upon the environment or type of polymer). The study conducted by McClatchy et al. [152] also proved that the stability of proteins depends upon the cellular environment. One of the advantages of the use of composite scaffolds made with natural polymers is the complete degradation of EPSs such as pullulan, dextran, etc., as well as secondary polymers, into CO2 and H2O. Some nitrogen-containing polymers, such as chitin and chitosan, release amino sugars which can be utilized by microorganisms and living cells [153,154]. To overcome the challenges associated with stability, synthetic polymers can be used instead of natural polymers. Some of the common synthetic polymers used in biomedical applications are polyarylsulfones, polysulfone,

polyvinylpyrrolidone, polyamide, polycarbonate, polyacrylonitrile, PMMA, polyester polymer alloy, ethylene vinyl alcohol copolymers; and molecular-thin nanoporous silicon membranes are the common synthetic polymers used in hemodialysis membranes; polymethyl pentene in extracorporeal membrane oxygenation; polyester, polyether, and polycarbonate-based polyurethanes in catheters; nylon, polyurethanes with acrylate in wound dressing; fibrin glue in sealants and adhesive; expanded polypropylene, polytetrafluoroethylene, polyethylene terephthalate, polyvinylidene difluoride membrane in surgical meshes; and poly-tetrafluoroethylene, polyethylene terephthalate, dacron, nylon in scaffold and ligament repair [155]. It has been proven that the addition of synthetic polymer has improved the mechanical and woven strength of natural exopolysaccharides. Kenawy et al. [91] have shown that the addition of poly(vinyl alcohol) (PVA)to dextran has improved the mechanical stability of the composite for electrospinning. Further addition of citric acid as a cross-link had a conducive effect on the mechanical, as well as tensile strength and stability of the composite due to extensive cross-linking.

### *4.5. Side Effects of Synthetic Polymers*

As discussed in the above section, synthetic polymers have positive results when blended with exopolysaccharides, but these synthetic polymers have shown side effects in a living system. Much literature has emphasized side effects and immunogenic responses with synthetic polymers. Acrylates are used in baby diapers, and prostheses [156], but acrylates may lead to serious allergic responses and dermatitis [157]. Similar kinds of side effects have also been observed with other synthetic polymers and adhesives, including anaphylaxis allergic reaction and arachnoid plasty in the case of fibrin glue [158,159], volitional swallowing, gastrointestinal obstruction, asthma, and allergy with polyethylene terephthalate [160] and oxidative stress from polypropylene used in mesh surgery [161]. On the other hand, some polymers have offered advantages over others, as their degradation product can be utilized in cells as in the case of poly-lactides. These kinds of polymers release lactic acids and respective oligomers upon degradation, which can be utilized by the cell during normal metabolism [162].

The major challenges associated with the commercialization of exopolysaccharidebased composites are its bulk-scale production, cost-effective recovery, and detailed analysis for optimum storage and transit conditions. However, there is no literature available that provides any information about the degradation of EPS composites, suitability of application, commercial cost of the products, and appropriate stability profile.

#### **5. Conclusions**

Exopolysaccharides have proven their candidature in the biomedical and healthcare sector mainly attributed to their biocompatibility, nontoxicity, and degradability. However, their limited mechanical and tensile strength, along with solubility in different solvents, obstructs their commercialization. Synthetic polymers have higher stability and strength, but are disadvantaged by side effects and compatibility issues. In order to achieve both compatibilities as well as tunability in strength, adaptability, and stability, composites are preferred over EPSs. The blending of natural and synthetic polymers might improve the physical and chemical characteristics. The composites have offered higher tensile and mechanical strength, along with water retention, slower degradation, drug-carrying capacity, and compatibility for biological applications, including 3D scaffold and wound dressing material fabrication, drug carrier properties, and biomedical sealant potential. Composites can support biological tissue and support healing due to improved adhesion and cell proliferation. The commercialization of composites needs in-depth study regarding stability in storage and transport, degradation behavior, and cost of the final product.

**Author Contributions:** V.A.: Conceptualization, methodology, writing—review and editing; A.K.B.: investigation, resources; J.R.B.: writing-review and editing; V.K.: writing—review and editing; G.K., G.K. and Y.-H.Y.: supervision, writing—original draft preparation; S.K.B.: Conceptualization, methodology, writing—review and editing, supervision. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by the Research Program to Solve Social Issues with the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT [Grant No. 2017M3A9E4077234], and by the National Research Foundation of Korea (NRF) (NRF-2022M3I3A1082545, NRF-2022R1A2C2003138 and NRF-2021R1F1A1050325). This study was also supported by the R&D Program of MOTIE/KEIT [grant number 20016324].

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** The authors acknowledge KU, the research professor the program at Konkuk University, Seoul, South Korea and Chandigarh University, Punjab India.

**Conflicts of Interest:** The authors declare no conflict of interest.
