**3. Biopolymers for Biomedical and Pharmaceutical Packaging**

Active and modern packaging biomaterials contain natural substances that are abundantly found in nature [1,11,128]. Biomaterials are often based on natural polysaccharides [129–133]. Among polysaccharides, Alginates have found applications in the food sector, water purification, biomedicine and packaging [73,134–139]. Algae contain nutrients such as vitamins, salts, iodine and sterols. Organisms containing large amounts of alginate in the cell walls are the brown algae Phaeophyceae such as Fucus, Laminaria, and Aseophyllum. The amount of alginates obtained generally depends on the species of algae and the extraction methods used [140]. They are linear polymers composed of (1→4)-α-L-guluronic acid blocks (GG) β-D-mannuronic acid blocks (MM) additionally, of heteropolymeric sequences of M and G (MG blocks) [74,80]. In biomedicine, alginates are used for controlled drug release, encapsulation, scaffolds in ligaments, tissue engineering and in dentistry for the preparation of forms in the presence of slow-release calcium salt [141]. The pharmaceutical industry uses purified alginates for dispersion or stabilization of substances. In biomedicine, alginates are used for controlled drug release, encapsulation, scaffolds in ligaments, tissue engineering and in dentistry for the preparation of forms in the presence of slow-release calcium salt. Figure 7 shows the application areas of alginate hydrogels. The alginate produces edible coatings with good barrier and mechanical properties allowing the protection of active ingredients by encapsulation [3]. Garlic oil is often added as a natural antibacterial agent in such coatings. Alginate is partially dusted with calcium and mixed with starch to obtain high water retention in the paper coating. This is important in order to obtain a uniform mass and coating by pressing to improve its rheology [85]. Alginates have found a number of applications in biomedical sciences as wound dressing materials [142]. Especially sodium alginate used in the form of a hydrogel has stimulated more and more scientific interest due to its physicochemical properties. Materials made of alginate are considered to be friendly to humans due to tissue biocompatibility, which allows for their use in biomedical engineering [135,140]. Highly absorbent dressing materials are formed by the production of wet spinning fibers. With the addition of calcium and sodium, high-absorbency sodium and calcium fibers were produced. Antimicrobial fibers were also formed by adding alginic acid or silver. By adding zinc, the fibers that generate the immune system were created. Fibers for immobilizing or supporting bioactive molecules were readily prepared [143]. Antimicrobial properties were imparted to cotton fabrics employing alginate–quaternary ammonium complex nanoparticles [144]. Using the ionic gelation method, a new type of nanoparticle (average size of 99 nm) that was composed of sodium alginate (SA) and 3-(trimethoxysilyl) propyl-octadecyldimethylammonium chloride (TSA) was synthesized. Fibers exhibited an efficient antimicrobial activity that was even maintained after 30 laundry cycles (non-leaching antimicrobial agent) [144]. Ionic gelation was used to develop a new class of nanoparticles that consists of sodium alginate (SA) and 3-(trimethoxysilyl) propyl-octadecyldimethylammonium chloride (TSA). The ratio of SA/TSA was found to exhibit a significant effect on the average size of the SA–TSA nanoparticles. Nanoparticles having an average size of 99 nm were selected for the study and, after using a pad-dry-cure method, were loaded onto cotton fabrics. Different characterization techniques were used to analyse the treated fabrics. It was concluded from the study that the SA–TSA nanoparticles exhibit high potential to be used as a non-leaching agent imparting robust antimicrobial characteristics to the studied cotton fabrics [144]. The new generation of medical textiles marks the field of expansion for scientists and researchers [145]. The current dressings are non-toxic, bacteriostatic, antiviral, non-allergic, hemostatic, highly absorbent and, above all, biocompatible. It is possible to modify them so that they contain medicines with some mechanical properties. Current textile materials in modern packaging are also highly diverse. These include tapes, fabrics, non-woven fabrics, knitted fabrics, composite materials [16,146]. Lignin and cellulose [147,148] are the most abundant natural polymers available as by-products of various industries. Recent scientific reports show that lignin is increasingly used as an essential component of hydrogels [149]. This allows for the creation of various types of materials, especially in the medical or pharmaceutical sector [150]. It is also possible to add additives to dressings such as odor absorbing, soothing pain and irritation.

**Figure 7.** Various applied applications of alginate based hydrogels [135]. Reprinted with permission from Ref. [135]. Copyright Elsevier, 2018.

Nanofibres are being used in the treatment of wounds due to interesting properties such as fiber diameter at the nanoscale, porosity, low weight. Polymers from various natural resources are attracting the attention of more and more scientists for exploring their use in wide range of application [151–153].

Nanofibers of alginates were created by electrospinning in the presence of various synthetic polymers and surfactants [154]. The electrospinning process has been used inexpensively by an efficient technique for the production of nanofibers with the use of biopolymers and other organic substances used in medicine and pharmaceuticals [93,155]. This technique is used to create dressings, drug delivery systems and scaffolds in tissue engineering. The electrospinning creates ultrathin fibers, collected in a random set [156]. The mats that are created during this process are used as wound dressings, catalytic carriers and nanocomposites with many applications [99]. The versatility of the electrospinning technique is so developed that it allows for its use in drug delivery systems and the creation of poly (lactide-co-glycolide) scaffolds, which allows the permanent release of the drug from nanofibres while maintaining their structure and biological activity [86,157]. Nanofibres have also been used in the chemical field as catalysts, sensors and chemical and physical adsorbents. Still, most popular is the use of unique properties of nanofibers prepared using different biopolymers via electrospinning [158]. Several materials have been commercialized under different trademarks such as Coalgan from Brothier Laboratories (France), which is sold as an haemostatic fibers pad for nosebleeds; Algosteril® or Sorban® are also non-woven dressing absorbing rapidly and retains wound fluid resulting in haemostasis and accelerates wound healing. Alginate based hydrogels were also synthesized and used as novel platform for in situ preparation of metal–organic framework [MOF] [159]. In order to establish the feasibility of the synthesis technique, the Hong Kong University of Science and Technology-1 [HKUST-1] –alginate composite was selected as a model system. Figure 8 shows the schematic for the preparation of the MOF–alginate composite and Figure 9 displays the cross-section backscattered electron images. It was concluded from the study that MOF particles can be incorporated into the alginate substrates and for in situ MOF growth, the metal ion cross-linked alginate hydrogels provided outstanding templates.

**Figure 8.** (**A**) Schematic of the preparation of the MOF–alginate composite. Photographs of (**B**) alginate hydrogels cross-linked by Cu2+ right after the addition of a sodium alginate aqueous solution to a Cu2+ aqueous solution, (**C**) alginate hydrogels cross-linked by Cu2+ after being washed with water and ethanol, and (**D**) HKUST-1–alginate hydrogels [159]. Reprinted with permission from Ref. [159]. Copyright American Chemical Society, 2016.

**Figure 9.** Cross-section backscattered electron images of (**A**) HKUST-1– and (**B**) ZIF-67–alginate composites and their corresponding EDX elemental maps (scale bar of 60 μm). (**C**) Chemical composition of sodium alginate, HKUST-1, and ZIF-67. Schematic of the formation of (**D**) the HKUST-1–alginate composite, (**E**) the ZIF-67–alginate composite, and (**F**) the "egg-box" model of metal ion cross-linked alginate [159]. Reprinted with permission from Ref. [159]. Copyright American Chemical Society, 2016.

#### *Smart Biopolymers*

Intelligent biopolymers are becoming more and more attractive in biotechnology and medicine, as well as in packaging [160,161]. They are used in biomedicine and tissue engineering. Intelligent biopolymers have been reported to play an important role in drug delivery [22,162,163]. They are easy to produce, are a good carrier of nutrients and maintain the stability of the drug [150,164]. It is possible to inject them in vitro as a liquid and they can form a gel at body temperature. Thermosensitive polymers are used to solubilize hydrophobic drugs and are used in the production of preparations with low solubility drugs as a drug carrier. The use of intelligent polymers for drug delivery is promising in view of the mechanism of drug release observed [165]. External and internal stimuli that affect the mechanism include temperature, light irradiation, electric current and intelligent hydrogels that can immobilize enzymes have the ability to gel by phase transition [165]. The chemical signal translates into a mechanical signal causing shrinking or swelling of the gel. This phenomenon is used for the controlled release of the drug. The diffusion of the drug from the beads depends on the condition of the gel [166]. The intelligent polymer is generally integrated with a wall microcapsule or a liposome lipid bilayer. The conformational transition of the polymer affects the integrity of the

microcapsule or liposome and allows controlled release of the drug incorporated into the microcapsule or liposome [167].

Thanks to the use of drugs released in hydrogels, pharmaceutical aspects can increase productivity, profitability and wide range of applications [70]. One example of an insulin delivery system is a hydrogel comprising an insulin-containing reservoir within a poly (methacrylic acid-g-ethylene glycol) copolymer in which glucose oxidase was immobilized [168,169]. Currently, there is a limited research on fluorinated polymers as a drug carrier in drug delivery applications. Polymer membranes have been used as passive materials for drug release due to their ability to be hydrophilic to hydrophobic in surface wettability. The characteristics of the process are reversible and can go to the initial state [170,171]. The use of lipid based biopolymers for cancer therapy has been recently reviewed [172]. In this article, authors have focused on the advantageous biologic and physicochemical characteristics including controlled drug release, long circulatory half-lives and facile targeted therapy of the natural and synthetic lipid.
