Three major properties namely biocompatibility, biodegradability, and appropriate hydrophobicity are indicated for cellulose polymer. As forms of nano scale, cellulose nanocrystal (CNC) and cellulose nanofibril (CNF) can be prepared commonly by acid hydrolysis and high pressure homogenization (Alavi 2019). These nanomaterials (NMs) are employed to improve the mechanical strength of hydrogel, cryogels, and scaffold (Abdelgawad et al. 2020). Functionalization of cellulose can be completed by targeting its hydroxyl groups to improve mechanical strength, biochemical reactivity, and absorbency in physiochemical conditions. AgNPs are often synthesized via the reduction of Ag+ ions and stabilizing of ensuing NPs by hydroxyl groups of this polymer without any additional stabilizers (Alavi and Nokhodchi 2020). Sustained release of Ag+ ions is critical to hinder the growth of MDR bacteria and formation of biofilm at wound site. Ag nanowires (AgNWs) with higher aspect ratio (length to diameter ratio) can improve the release of Ag+ ions and mechanical properties of wound dressings. Stretchable wound dressing has been made combining the bacterial cellulose (BC) with AgNWs in three volume ratios of 10 : 4.5, 10 : 3, and 10 : 1, wherein after 24 h, sustained release of Ag+ ions was observed at the period 9 days for all volume ratios; highest tensile stress and Young’s module were 1.56 MPa and 2.88 GPa, respectively for the volume ratio of 10 : 4.5. Additionally, the complete wound closure after 12 days as well as significant antibacterial effect (≈ 100% after 6 h) against E. coli and S. aureus bacteria were indicated for this volume ratio (Wan et al. 2020). Wound dressings based on polymeric hydrogels encompassing AgNPs are interesting alternative to enhance the antibacterial activity with wound healing properties in vitro and in vivo. AgNPs have been loaded on hydrogel composed of cellulose carbamate using Tween 80, cetyl trimethylammonium bromide (CTAB) and rarasaponin as values of 7.53, 9.94 and 10.15 mg/g, sequentially. Compared to other groups, higher antibacterial effect was indicated for AgNPs (99.4 µg) @hydrogel-CTAB as inhibition zone diameters (IZDs) of 18.98 and 19.84 mm toward E. coli and S. aureus, which may be caused by synergistic effect of AgNPs with cellulose carbamate and CTAB surfactant. It is worth noting that CTAB has positive charge with high affinity for the negative charge of cell membranes (Bundjaja et al. 2021). Stability and durability of AgNPs is critical factor for employing these NPs in a large-scale production. There are various derivatives for cellulose such as hydroxypropyl methylcellulose and ethylcellulose, which can contribute in synthesis and stabilization of AgNPs at 25 and 4.0 °C for long period (~ 3 months). Antibacterial activity of four types of AgNPs involving bare AgNPs, ethylcellulose (EC)-AgNPs, hydroxypropyl methylcellulose (HPMC)-AgNPs, methylcellulose (MC)-AgNPs and polyethylene glycol (PEG6000)-AgNPs toward E. coli and S. aureus were evaluated in a comparative way. Internalization of HPMC-AgNPs > EC-AgNPs > MC-AgNPs formulations into bacteria was higher compared to PEG-AgNPs and pure AgNPs for both bacteria significantly E. coli (Figure 1). Higher penetration ability of HPMC, EC, and MC into the bacterial cell membrane with phospholipid structure, more NPs production by these cellulose derivatives, and sustained release of silver ions may be reasons for this difference (Abdellatif et al. 2021).
The linear polymer polysaccharide containing D-glucosamine and N-acetyl-D-glucosamine by β-(1→4)-linkage, is obtained from the chitin shells of shrimp and other crustaceans such as crabs and lobsters by alkaline treatment (Alavi and Rai 2019). Suitably-designed scaffold with large pores size (≥250 µm) promote the adherence, proliferation and migration of skin cells which leads to rapid regeneration of dermal tissue. Further, chitosan (C56H103N9O39) with amine groups can interact with negative charge of cell envelope of bacteria and synergize the antibacterial activity of AgNPs. Wound dressing comprising chitosan-collagen-AgNPs (spherical by size in the range of 10-25 nm at concentration of 10 µg/mL) illustrated accelerated wound healing via promotion of the fibroblasts migration, more expression of α-smooth muscle actin (α-SMA), and macrophage performance (Figure 2). Dead cells at wound site can be eliminated by increasing the number of IL-10 levels and M2 macrophages in inflammatory phase (J. Wang and Xu 2020). In another study, a faster wound healing by abundant granulation tissue, higher collagen formation, lower levels of macrophage and vessel density were indicated for the electrospun chitosan-based NFs containing AgNPs at concentrations of 12 and 60 mg in comparison with control samples after 14 days of treatment. Moreover, this investigation demonstrated that the inorganic ions and proteins can slow down and block the release of Ag+ from AgNPs (Shao et al. 2019).
Brown alga such as Turbinaria turbinata, Sargassum filipendula, Macrocystis pyrifera,Saccharina longicruris, Sargassum carpophyllum, and Sargassum siliquosum as well as bacteria namely P. aeruginosa have the ability to produce hydrophilic polymer of alginate containing three types of block structure: G block (poly α-L-guluronic acid), M block (ß-D-mannuronic acid), and MG block (both polyuronic acids) with β-(1-4) glycosidic linkage (1-4) (García‐Ríos et al. 2012; Valentine et al. 2020). AgNPs have been incorporated in the matrix of sodium alginate and collagen via interactions between the amine group of collagens and the carboxylate group of alginates with AgNPs. In this way, NaBH4 and polyvinyl pyrrolidone (PVP) were employed, respectively as reducing and stabilizing agents to obtain spherical AgNPs with the mean particle size of 7 nm. AgNPs in concentration of 50 µM exhibited negligible cytotoxicity against NIH3T3 cell line with bacterial inhibition toward E. coli and S. aureus as inhibition zone diameters (IZDs) of 2.7 and 1.9 mm, respectively (Zhang et al. 2018). As an efficient strategy, polydopamine (PDA) spheres (a mean diameter of 0.430 μm) were decorated by AgNPs (size in the range of 50–70 nm) followed by immobilization on oxidized sodium alginate (OSA) wound dressing. Significant porosity value of 77.30 % (relative to hyaluronic acid/cationized dextran (73 %) and quercetin/duck’s feet collagen/hydroxyapatite (76.36 %)) and blood compatibility at concentration of 200 ppm made this NC ideal as a safe wound dressing (Liang et al. 2020).
In addition to enzymatic extraction (Ahmad et al. 2017), partial acid and alkaline hydrolysis of type I collagen from the skin, bones, cartilage, and meat can produce gelatin types A and B, respectively (Yang et al. 2019). Gelatin as an extracellular matrix (ECM) protein may be used to prepare drug and gene delivery systems, wound dressings, tissue engineering, and 3D cell culture (Han and Lv 2019; Afewerki et al. 2019). PVP-stabilized AgNPs have been aminated via 3-aminopropyltriethoxysilane (APTES) treatment at 70 ○C for 12 h and incorporated in the carboxylated CNF to achieve injectable nanoformulation for wound therapy in nursing infants. This formulation was employed to accelerate inflammation and proliferation phases of wound healing by increasing the number of white blood cells (WBCs) specifically neutrophils at wound site after 14 days of treatment compared to control group of CNF/gelatin (Gou et al. 2020). It is noteworthy that in the inflammation phase, increased capillary permeability and migration of cells particularly neutrophils to the wound tissue would help sterilize the wounds and release proteases to remove the denatured ECM followed by transformation of monocytes into macrophages in the wound site, regulated by cytokines such as monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β (TGF-β) (J. Wang and Xu 2020). Wound healing activities for combination of metal NPs (MNPs)/metal oxide NPs (MONPs) with important growth factors (GFs) involving fibroblast growth factor (FGF), epidermal growth factor (EGF), bone morphogenic proteins (BMPs), TGF-β, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) in wounds’ healing phases of hemostasis, inflammation, proliferation, and remodeling/maturation have been reviewed previously (Alavi and Rai 2020). Incorporation of AgNPs (0.004 M) in hydrogel formulated as sodium alginate/gelatin in the ratio of 80:20 displayed prowess for the topical application with MIC values toward P. aeruginosa (0.5 ppm) and S. aureus (53 ppm), higher consistency and a significant epithelialization after 14 days treatment compared to control and hydrogels without AgNPs (Figure 3) (Diniz et al. 2020).
Three types of CAR including kappa, iota, and lambda are commercial polymers, which are commonly deployed in food and pharmacy industries. The stabilization of MNPs/MONPs, gelling and thickening applications, specifically in food industry, have been reported for CAR as a sulfated polymer of galactose units linked alternatively by β-1,4 and α-1,3 (Pandey et al. 2020). CAR and carboxymethyl CNC were used to formulate cryogel loaded AgNPs with 100% reduction ability towards E. coli and S. aureus. This polymeric composition instigated desirable controlled and sustained release by 40 µg/mL of AgNPs within 250 min. rapid wound healing; suitable mechanical strength of this wound dressing originated from CAR and carboxymethyl CNC polymers, respectively (Abdelgawad et al. 2020). In addition to anti-planktonic and anti-biofilm activities towards P. aeruginosa and S. aureus, the stability of CAR-Ag NPs was indicated for 6 months in a colloidal medium which is due to the suitable interaction of CARs by their hydroxyl (-OH) groups with AgNPs (Goel et al. 2019).
Hyaluronic acid (HA)
HA, hyaluronate or hyaluronan, is anionic polymer of nonsulafted glycosaminoglycan (disaccharides of N-acetyl-D-glucosamine and D-glucuronic acid) with high molecular weight, and is present in prokaryotic and eukaryotic cells particularly in ECM section with the critical role in proliferation and migration of human cells in epithelial, neural, and connective tissues; inflammation response, angiogenesis and granulation of wounds are influenced positively by HA (Alemzadeh et al. 2020). According to molecular weight (MW) property, 1–25 × 104, 25–10 × 104, > 1 ×106, > 6 × 106 Da were indicated for low MW, medium MW, high MW and very high MW of HA, respectively. All four stages of wound healing are influenced distinctly by low and high molecular weight of HA through interaction with the CD44 receptors related to granulocytes and monocytes as well as various interleukins such as IL-6, IL-1β, and IL-8. (Graça et al. 2020). Wrapping bacteria, reactive oxygen species (ROS) production, lipid peroxidation, membrane disruption, interaction with glutathione (GSH), adenine, and proteins leakage were indicated as main antibacterial mechanisms for graphene oxide (GO) (Nanda et al. 2016; Mohammed et al. 2020). HA-AgNPs NC was loaded on the GO sheet in solution of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide. Bactericidal activity against S. aureus could be synergized by heat conversion ability of HA-AgNPs-GO, resulting from the higher specific surface area of GO, under near infrared (NIR) irradiation (808nm for 2 min) from 25.5 ºC to 58.4 ºC. Wound healing was effected by controlled release of Ag+ ions from HA-AgNPs under hyaluronidase enzyme (Ran et al. 2017). Inflammatory step of wound healing can be affected negatively by ROS species, which can be controlled by suitable formulations of Ag and HA. Polygalacturonic acid (PGA), an herbal polymer, was employed as a reducing and stabilizer agent to prepare AgNPs followed by incorporation in nanofibers (NFs) comprising HA and poly vinyl alcohol (PVA) by electrospinning technique. Antibacterial activities were not observed for (PGA/HA)-PVA, while incorporation of AgNPs imparted significant antibacterial effects on B. subtilis, S. aureus, and E. coli. In addition, the percentages of wound contraction for (PGA/HA)-PVA and (AgNPs-PGA/HA)-PVA after 14 days were 97.42 and 99.51% relative to 92.43% for Garamycin® cream as a control group (El-Aassar et al. 2020).
Pectin, acidic hetropolysaccharides (linear chain of alpha (1-4) linked D-galacturonic acid; C6H10O7) with high molecular weight (194.14 g/mol) are found in the cell walls of plant species. They are used as antioxidant, emulsifiers, food coloring agent, anti-infective agent, and stabilizers of NPs in the food and pharmaceutical industries (Mercado-Mercado et al. 2020; Jiang et al. 2020). Combination of pectin with other synthetic and natural polymers has been deployed as novel wound bandages to reduce the disadvantages of each individual polymer by itself. NFs comprising AgNPs/polyvinylalcohol (PVA)/polyvinylpyrrolydone (PVP)/pectin/mafenide acetate (MF) were electrospun in the weight ratio of 0.7 and 91.8 wt% for AgNPs and PVA as well as 2.5 wt% for PVP, pectin and MF, respectively. NPs were synthesized in PVA solution and mixed in solution of pectin, MF, and PVP followed by electrospinning on a grounded collecting drum. Higher antibacterial effect, although not adequate enough, was indicated against Gram-negative bacteria relative to Gram-positive bacteria owing to difference in thickness of bacterial cell wall. Moreover, the releases rate of AgNPs was influenced mainly by their interaction with the functional groups such as –SO2 and –NH2 of MF (Alipour et al. 2019). The size of AgNPs was affected by two parameters including weight percentage of pectin (extracted from citrus peel) (0.5, 1, and 2%) and temperature (20 and 60 ○C), wherein smaller diameter of NPs (8 nm) was obtained for 1% of pectin in 60 ○C. MIC values for pectin-AgNPs showed 31.25 and 500 µM towards E. coli and S. epidermidis after 24 incubation compared to glutathione-AgNPs with MIC amounts of 140 and 1680 µM, respectively. In this regard, the ability of pectin to adhere to the bacterial membrane increases the antibacterial activity of AgNPs (Pallavicini et al. 2017).
Starch (C6H10O5)n , the linear polymer of glucose as amylose and amylopectin in the branched form, is a renewable and biodegradable polysaccharide and has been applied for various applications such as drug delivery, micro and nano formulations of therapeutic agents, production of pharmaceutical tablets (Athira et al. 2018; Chen et al. 2020). This polymer has reducing and stabilizing functions in MNPs/MONPs synthesis in one-pot operation. Synthesized Ag/Au bimetallic NPs have been shown to affect the morphology change of E. coli as lacking flagella in treatment samples relative to control. IC50 values for these bimetallic NPs compared to AuNPs were 4.92±0.81 and 6.95±1.70 μg/mL against multidrug resistant (MDR) E. coli and methicillin-resistant S. aureus (MRSA) (Lomelí-Marroquín et al. 2019). Isolated starch from babassu mesocarp, a by-product of babassu oil, was utilized to synthesize AgNPs with different diameter size of 124.2, 119.1, and 181.7 nm by microwave, autoclave, and water bath methods, respectively. In a comparative way, MBC value of >27 μg/mL was determined for all NPs as well as AgNO3 salt against S. aureus. The prominent cell membrane damage, pore formation and the release of bacteria contents of E. coli was observed after treatment by AgNP prepared by water bath method (at sub value of MIC=6.75) (Bastos Araruna et al. 2020). Combination of AgNPs, starch, PVA, and GO as a scaffold showed synergic antibacterial effects with the Modulus and tensile strength of 145% and 26.81%, respectively (Usman et al. 2016). In this regard, GO can increase the antibacterial activities of AgNPs by lipid peroxidation resulting from carbon radicals (*C) and cellular membrane damage caused by sharp edge of GO (Alavi et al. 2020).
Cyclodextrin (CD) is belongs to a cyclic oligosaccharides family with a macrocyclic ring of glucose subunits bonded by α-1,4 glycosidic links in three main types namely 6: α-CD, 7: β-CD, and 8: γ-CD, which can be used to encapsulate hydrophobic drugs in interior section due to improve its bioavailability, solubility, and stability. α-CD and γ-CDs types are more water soluble relative to β-CD (Tian et al. 2020). Carboxymethyl-β-cyclodextrin (CM-βCD) as a derivative of CD has solubility of 50 mg/mL, which can be used to load and stabilize AgNPs in various micro and nano formulations. Two concentrations of CM-βCD involving 50 and 25 mg were reacted with chitosan (50 mg), and glutaraldehyde (0.013 mM) to produce hydrogels 1 and 2 (H1 and H2). Incorporated constant amount of AgNPs in this formulation illustrated different antibacterial properties dependent on CM-βCD concentration, wherein 19, 15, and 41.8 mm were observed for H1 and H2, and gentamycin (30 μg) toward E. coli (Mohamadi Zahedi and Mansourpanah 2018). Gallic acid (GA) (3,4,5-trihydroxybenzoic acid), is a phenolic acid found in plants such as tea leaves, gallnuts, and oak bark and has antibacterial activities against Listeria monocytogenes, Pseudomonas aeruginosa, E. coli, and S. aureus by irreversible changes in membrane and cell wall morphology (Li et al. 2019). Synergic effect of GA and its antibacterial activity in hydrogel formulation was obtained by incorporation and loading of these materials in β-CD and GO, separately. Hydrogel film comprising PVA/[email protected]βCD/Ag-GO demonstrated improved tensile strength (>126.2 MPa), sustained and slower GA release over 2 h and higher antibacterial activity towards E. coli and S. aureus compared to PVA/[email protected]βCD and PVA/βCD (Pooresmaeil and Namazi 2019). Hydroxypropyl-βCD (HP- βCD) with solubility of 45% (w/v), as another derivative of β-CD, has been used as a delivery system to increase the solubility of therapeutic agents in aqueous media of biological conditions (Wei et al. 2017); 1 wt% AgNPs in NFs of AgNPs-HP-βCD showed 11.6 and 10.7 mm for S. aureus and E. coli, respectively. Higher antibacterial capacity and The larger fiber diameter were observed for 2 wt% AgNPs in these NFs (Celebioglu et al. 2019). Thiomers, thiolated polymers, are polymers employed in micro and nanoformulations to augment the absorption of therapeutic agents in vaginal, eyes, mouth, and nose routes. Thiomers with low molecular mass can impart higher permeability and mucoadhesive properties to polymeric formulations (Palazzo et al. 2017). For instance, β-CD-SH1200 and β-CD-SH600 illustrated 46.37-and 39.73- fold higher mucoadhesion relative to β-CDs, respectively (Moghadam et al. 2018).