**2. Electrospun Antioxidant/Antibacterial Materials for Medical Packaging**

Electrospinning is one of the most prominent techniques currently being used in the development of a number of products for biomedical applications, as discussed in the preceding section [86–88]. The electrospun creates ultrathin fibers collected in a random pattern. The mats produced in this way are used as filters, catalytic carriers, dressings and drug delivery systems [89]. Currently, scientific research focuses on the use of nanofiber properties and the focus on determining the parameters of electrospinning of biopolymers for medical and pharmaceutical applications [90–92]. In this technique, varying electrified fields are applied to produce polymer filaments, which can then be embedded in various device platforms (briefed in introduction section). The basic device for electrospinning consists of four parts: a syringe containing a polymer solution, a metallic needle, a power source and a metal collector (with variable construction) [93]. The polymer solution is extruded through the tip of the needle by forming a polymer stream that is leached out of the needle and expands as a result of deflection and dissipation of the electric charge voltage of the solution surface. The basic set for electrospun fibers is shown in Figure 3 [94]. Electrospinning of anisotropic fiber yarns (Biohybrid) was carried out via the extraction of microfibrils from bacterial cellulose networks [94]. In the equipment, a plastic syringe of 5 mL was used as the polymer reservoir in the continuous feed system. An aluminum reservoir that was filled with water was used and the fibers were subsequently collected on the surface of the water 120 mm from the needle tippet [94].

The polymeric solution stream flows towards the metal manifold with simultaneous evaporation of the solvent and then the nanofibers are deposited on the collector surface. When nanoparticles are deposited instead of nanofibers, the process takes place using electrospray [95,96]. Electrospinning is a fiber production process with a diameter of 0.01 to 10 μm by using electrostatic forces. In the electrospinning technique, a syringe filled with a polymer solution has a high potential source from 10 to 30 kV. The electrical voltage produces free electrons, ions or pairs of ions attracted to the electric field [97]. One of the elements is Taylor's cone, in which the polarity of the solution depends on the generator's voltage. The drive between similar charges in the electric space acts against the surface tension and fluid elasticity in the polymer solution, distorting the drop to the shape of the cone structure. In addition to the critical charge density, the Taylor taper becomes unstable and the liquid stream is released from the tip of the cone. Then, in the presence of the electric field, the polymer stream is formed, creating a light continuous form of the fiber. The fluid stream through continuous stretching becomes unstable because the number of spiral paths accumulated on the collector electrode increases [98]. This area is called whipping region. Polarized electrospun nanofibers move down to collision with less collector plate potential. The collector's morphology affects the straightening of the fiber. Different collectors are used, such as drum rotary collector, movable belt collector and straight mesh collector. To produce nanofibers with controlled morphology, parameters such as molecular weight of the polymer, surface tension, solution viscosity, solution conductivity, flow rate, temperature, collector morphology and distance of the collector apex are optimized [99]. It has been found that the diameter of the fibers increases with increasing concentration and viscosity. Increasing the molecular weight reduces the risk of interference on fibers such as balls and drops. It was determined that nanofibers can be formed with a variety of secondary structures. Thus, nanofibers with a core-shell structure, with an empty interior or with a porous structure may be formed [99,100]. As a drug delivery system, a mesh made of nanofibres produced by the electrospinning method offers a number of advantages. This is an attractive method due to its ability to produce nanoscale materials and structures of exceptional quality [101]. This allows substances to be encapsulated and drugs and biologically active substances placed on polymer nanofibers [102]. Biologically active substances can be attached to nanofibers like a mesh in the electrospinning process. In this way, antibacterial and antioxidant materials are created for medical applications [103,104]. Coating materials containing chitosan formulations with antioxidant and antifungal properties were also formed [88,105].

**Figure 3.** Electrospinning setup with a spinneret–water surface working distance of 120 mm and a spool running at 15 rpm/min. The spool (hollow) was designed to collect fibers with minimal spool–fiber yarn contact [94]. Reprinted with permission from Ref [94]. Copyright American Chemical Society, 2010.

By choosing a base mesh polymer, it can be easily designed to have improved mechanical properties, biocompatibility and cellular response, which makes mesh a good medical product in the nanocomposite materials sector. The electrospinning creates a macroporous scaffolding containing randomly oriented or aligned nanofibres on which the drug is placed. Electrospun nanofiber scaffolds provide the optimal environment for vaccinated cells [88]. Therapeutic compounds such as lipophilic and hydrophilic drugs, proteins, antimicrobials, etc. can be incorporated into the polymer nanofiber mesh by using monoaxial or coaxial electrospinning [106].

Nanofibers can help treat skin damage and can be considered a substitute for skin tissue [107]. The drug enclosed in the nanofiber mesh is released by various mechanisms when the nanofibrils mesh is swollen, biodegradable or absorbed by the human body. As an effective dressing, it inhibits bacterial growth during wound healing. The lower drug release rate allows for non-wound healing of wounds from a few days to several weeks [100,105]. Polymer after electrospinning acts as a barrier controlling the release of loaded molecules. The advantage of this method is the ability to close almost all drugs (especially hydrophobic) in the core, regardless of the drug-polymer interaction. Drugs, proteins, uptake factors and genes can be included in nanofibers [105].

Silver nanoparticles exhibit the capability to interact with bacteria. This allows the size of silver nanoparticles 1–10 nm in diameter. The smaller size provides better antibacterial activity. Scientific research has proven the antibacterial activity of electrospun nanofibers containing polylactic acid and silver nanoparticles (AgNPs) against Staphylococcus aureus and *Escherichia coli*. Fibers of silver nanoparticles and polyethylene oxide were mixed with polyurethane fibers exhibiting antibacterial activity on *Escherichia coli* [103,105]. Antimicrobial efficacy increases with an increase in the concentration of silver. The activity can also be increased by reducing silver nanoparticles. Smaller silver nanoparticles have the ability to disperse the bacterial membrane and inhibit bacterial growth. Antimicrobial activity of electrospun nanofibers results from the distribution of silver nanoparticles to electrospun nanofibers. Increased access of silver nanoparticles to electrospun nanofibers increases microbial capacity [108–110]. Polyacrylonitrile fibers combined with silver nanoparticles showed antibacterial activity on gram positive Bacillus cereus and gram negative *Escherichia coli*. The fibers formed from the combination of silver nanoparticles and Nylon 6 have an antibacterial effect on the gram of negative *Escherichia coli* and gram positive on Staphylococcus aureus [111].

Antioxidative effects of electrospun nanofibers have also been proven by obtaining multifunctional biomaterials, especially through the use of vitamin E and natural biopolymers [105]. Fibers resulting from the combination of polylactic acid, silver nanoparticles and vit. E inhibited the growth of *Escherichia coli* up to 100%. The release time of silver ions from nanofibres immersed in water lasted up to 10 days. It was proved that the combination of polylactic acid nanofibres, silver nanoparticles and vitamin E showed antioxidant activity in studies on fresh apple juice [112].

It has been proven that nanofibers act as a membrane that actively reduces polyphenol oxidase activity. Such materials can be used for preservation in the food industry in fruit and juice packaging [105,112]. Nanofibers can be coated with biocompatible polymers (hydrolysed collagen, elastin, hyaluronic acid, chondroitin sulfate). In this way, the electrospun fibers are coated with pure polyurethane to use the substance to improve the antibacterial effect of urinary catheters. The membranes thus obtained, have good antimicrobial activity on *Escherichia coli*, Salmonella typhimurium, Listeria monocytogenes [105].

Much research has been focused on the learning and operation of plant extracts using electrospun fibers [113,114]. Researchers have managed to encapsulate with the use of electrospun fibers several raw plant extracts such as Centella asiatica, baicalein, green tea, Garcinia mangostena, Tecomella undulata, aloe vera, Grewia mollis, chamomille, grape seed, Calendula officinalis, Indigofera aspalathoides, Azadirachta indica, Memecylon edule and Myristica andamanica [112]. Also, essential oils such as linalool, pinene, eugenol and cymene are used [115–117]. Antibacterial action with essential oils is determined by their hydrophobic nature. Bioactivity of essential oils combined using electrospun fibers to create scaffolding of fibers with antibacterial properties and thermo-mechanically controlled mobility. Electrospinning of chitosan nanoparticles and cinnamon essential oils in the ratio 1:1 has been demonstrated [112]. Fibers with a diameter of 38-55 nm were formed. The fibers were prepared from an aqueous solution containing 5% w/v acetic acid and various concentrations of essential oil (0.5 and 5.0% by volume). After fabrication, the fibers were cross-linked with glutaraldehyde to increase the stability of their chemical properties. The activity of chitosan nanofibres and ether oil particles has

been proven in action against *P. aeruginosa*, *E. coli*. Efficacy of the essential oil was demonstrated in a study in which cellulose acetate was used as a polymer matrix [118]. Fibers containing essential oils of peppermint and lemongrass were also analyzed. The generated scaffolds inhibited *E. coli* proliferation and were non-toxic to fibroblasts and keratinocytes [116]. The Shikonin component of Lithospermum erytrorhizon root dried was also used in the electrospinning technique [116]. It has anticancer, antioxidant, anti-inflammatory and antibacterial effects. Shikonina was encapsulated and placed on PCL/poly (trimethylene carbonate) fibers. Note that the drug was released in the first hour at an increased rate and then for 48 h at a fixed dose. The shikonin-laden fibers showed a profound effect against *E. coli and S. aureus*. The healing properties were also tested in combination with alkannins, which are naturally occurring hydroxynaphthoquinone. The connection was used for the preparation of topical and transdermal patches. Cellulose acetate, poly (lactic acid) (PLA) and two different poly (lactic-glycol) mixtures were used as a matrix. Inclusion complexes of cyclodextrins (CD-IC) with plant extracts and complexes with eugenol (EG) were also formed [119]. Eugenol has a bactericidal effect and, in combination with inclusion cyclodextrins, has been used in electrospun fibers. The use of cyclodextrins complexes, increases the solubility of natural extracts in water affects antioxidant and antibacterial activity. Chitosan-based dressings were also developed for biomedical applications. A mixture of chitosan, TiO2, poly (*N*-vinyl pyrrolidone) a synthetic polymer with good biocompatibility was prepared [120]. The membrane thus formed showed high activity against the microorganisms *S. aureus, B. subtilis, E. coli, P. aeruginosa*. The use of a membrane of chitosan, poly (*N*-vinylpyrrolidone) and silver oxide showed a similar effect, but with the added advantage of film transparency, allowing for observation of the wound [120].

Sodium alginate based nanofibers were also synthesized using polyethylene oxide (PEO) as "carrier polymer" [121]. It was concluded from the study that the sodium alginate on its own could not be electrospun. However, with the addition of a suitable polymer, it can be easily electrospun [121] and the PEO–PEO interactions with high molecular-weight entangled PEO were the key to "carrying" the alginate from the prepared solution to synthesise the fibers using electrospinning (Figure 4).

**Figure 4.** Schematic for the synthesis of alginate–polyethylene oxide blend nanofibers and the role of the carrier polymer in electrospinning. Reprinted with permission from Ref [121]. Copyright American Chemical Society, 2013.

In other studies, it was proved that nanofiber mats containing silver ions were more active compared to nanofibre mats without silver nanoparticles [122,123]. To monitor the human breath, smart fabrics were synthesized via electrospinning of the in situ assembly of well-dispersed Ag nanoparticles [124]. In this work, lightweight and flexible Ag/alginate nanofiber sensor were successfully developed that have the capability to sensitively monitor human breath (Figures 5 and 6). Figure 5 shows the schematic for the fabrication of Ag/alginate nanofibers and Figure 6 shows the SEM images of different alginate nanofibers.

**Figure 5.** Schematic diagram illustrating the fabrication process of Ag/alginate nanofibers. (**a**) Na-alginate nanofibers prepared by electrospinning. (**b**) Ion-exchange and in situ reduction processes. Reprinted with permission from Ref. [124]. Copyright American Chemical Society, 2018.

**Figure 6.** SEM images of (**a**) as-electrospun Na-alginate nanofibers and (**b**–**d**) Ag/alginate nanofibers obtained at different reduction times: (**b**) 10, (**c**) 20, and (**d**) 30 min. Reprinted with permission from Ref. [124]. Copyright American Chemical Society, 2018.

Other synthetic polymers such as polyurethane, polyacrylonitrile, poly (acrylamide), poly (nitrilesulfonic acid sodium salt, poly (sulphobetaine methacrylate) were also used to develop wound dressings. Fluoroquinolones and norfloxacin were attached to polyphosphates by chemical modification using amino acid esters (alanine, glycine, and phenylalanine) as chain extenders, and these components were then used to create nanofibers by electrospinning [125].

Antimicrobial biodegradable multilayer systems were developed using electrospinning, especially the active multilayer structures based on natural polymers [126]. The system was developed in such a way that it consisted of different layers; for example, alginate-based film as outer layer; using a PHBV8 film as outer layer or no outer layer. Different characterizations such as oxygen and water vapour permeabilities, intermolecular arrangement, transparency and thermal properties were evaluated. In addition the antimicrobial activity was also evaluated. Alginate based coatings for Food Packaging Applications have been recently reviewed by Tugce et al. [127]. In this article, authors have summarized the recent advances on the usage of alginate for recent edible coatings.
