Blended Gels of Sodium Carboxymethyl Cellulose Incorporating Antimicrobials for Absorbance and Wound Healing Applications

  • Renata Nunes OliveiraEmail author
  • Garrett Brian McGuinness
Living reference work entry
Part of the Polymers and Polymeric Composites: A Reference Series book series (POPOC)


Wound healing is frequently enhanced by the application of dressings which maintain a moist environment and provide for absorption of exudates. In many cases, dressings with antibacterial properties are considered beneficial, while barrier properties and mechanical integrity are also important. This chapter initially reviews the role of natural and herbal antimicrobial products including propolis, honey, and Punica granatum (pomegranate) as potential constituents for wound care biohydrogels. The applicability of a wide variety of polysaccharides, including carboxymethyl celluloses, in wound care biomaterials is then considered. Sodium carboxymethyl cellulose (NaCMC) is able to form hydrogels by chemical crosslinking. Where a combination of properties is desired, blending with other polymers may be advantageous. The chapter concludes by examining recent progress with systems that incorporate a natural antimicrobial (propolis) within blended cryogels of NaCMC and poly (vinyl alcohol). PVA and its blends can form strong and relatively stiff hydrogels by a physical crosslinking process which occurs during freeze-thawing cycles. Crystallites are formed which anchor the polymer chains, creating a polymer network that can swell in the presence of fluids or exudates. Such composite gels retain acceptable mechanical properties even when loaded with up to 30% propolis. Dressings containing 15% propolis or more were effective against S. aureus and also exhibited high fluid uptake. Hydrogels containing NaCMC therefore have significant potential to meet the requirements for an effective wound care dressing, particularly when blended with natural antimicrobials and embedded in robust hydrogel matrices such as those of PVA cryogels.


PVA Cryogels Polysaccharides Carboxymethyl cellulose Hydrogels Wound care 

1 Introduction

Infection is viewed as a major problem in open wounds and is the cause of death of many people who have suffered burns or trauma. Traditional wound care treatments include cleansing and the application of ointments or bandages, but increased understanding of both biomaterials science and wound healing has led to significant advances in wound care technology in recent years. Hydrogels containing synthetic or natural antimicrobials are now considered an important class of materials in terms of providing successful treatment options.

Several natural products present antimicrobial properties and promote healing and can themselves be considered as an alternative topical wound care treatments. Honey, propolis, pomegranate, and many other natural products can be used to treat wounds. Some of these products retain water in their structure, which can also assist healing by moisturizing the site. However, it is often considered advantageous to present these substances to the wound site by means of a suitable dressing which can consistently moisturize the area and provide for controlled release.

Hydrogels of many forms have also been used for wound healing for decades, mainly due to their high propensity for fluid uptake and their associated ability to provide moisture to the wound site. Such gels are based on tridimensional networks of hydrophilic polymers and include gels based on poly (vinyl alcohol) (PVA), starch, and sodium carboxymethyl cellulose (NaCMC) [1, 2, 3, 4]. The potential of NaCMC to be a component of gels that promote healing and release natural antimicrobials is a focus of this chapter.

CMC is a natural polymer which can be converted to NaCMC by a two-step reaction, where the CMC is first modified to be able to absorb water and then reacts with a sodium compound. NaCMC is a polysaccharide that is generally biocompatible and relatively cheap and can absorb high amounts of water or aqueous fluids. NaCMC is able to form hydrogels by chemical crosslinking or, where specific properties such as increased mechanical strength are desired, by blending with other polymers. PVA and its blends can form strong and relatively stiff hydrogels by a physical crosslinking process which occurs during freeze-thawing cycles, and its role as a robust matrix for composite wound care gels will be explored in this chapter. The origin of these robust properties is the PVA crystallites that are formed during freeze-thawing, which securely anchor the polymer chains in a three-dimensional network. It will be shown that NaCMC blended or composite gels can combine high fluid uptake capacity with the ability not only to provide moisture but also to deliver antimicrobials to the wound site. Gels based on NaCMC can be considered not only for wound care but also as carriers for therapeutic drugs.

The goal of this work is to review options and approaches for the development of suitable hydrogel platforms for wound care, based on the properties of NaCMC and PVA hydrogels and the incorporation of natural antimicrobials.

2 Wound Healing

Wounds involve a disruption of the continuity of the skin and can be caused by incision, trauma, burns, or an underlying medical reason. Acute wounds, such as those due to surgery or trauma, usually heal in approximately 4 weeks and follow the three stages of healing. However, full recovery of skin mechanical properties can take up to a year [5]. Chronic wounds are usually linked with a chronic disease, such as diabetes mellitus, ischemia, or venous stasis disease, which interferes with the healing process (e.g., venous leg ulcers, diabetic foot ulcers). These wounds take longer to heal, present an insufficient repair process, and can suffer reduced oxygen supply [5, 6, 7].

Wound healing is a complex mechanism, essentially consisting of four stages: coagulation, inflammation, proliferation, and maturation. Chronic wound healing can stall in the inflammation phase, during which neutrophils and then macrophages arrive at the wound site.

The proliferative phase itself is comprised of four stages: epithelization, angiogenesis, granulation (endothelial cell migration and capillary formation), and collagen deposition (in which endothelial cells and fibroblasts are the main participating cells). The final stage of chronic wound healing is maturation, where the collagen deposition is more organized, with the collagen fibers being thicker and aligned with the original collagen fibers of the skin. The tensile strength of the de novo skin reaches its maximum, 80% of the tensile strength of the original skin, after 3 months [3].

For wound healing, the wound site has to initially be cleaned (ensuring an absence of necrotic tissue, foreign material, and sources of infection). In addition to cleansing, the development of dressings led to the observation that a moisturized environment also helps wound healing. In 1960, Wichterle and Lim reported the possibility of the permanent use of plastics in contact with living tissue and that a moist environment accelerated reepithelialization [8]. Progression to the proliferative stage of healing may be affected by the bacterial burden, the moisture balance at the wound site, or the presence of necrotic tissue [2009 Gist]. In order to address the latter effects, hydrogels may be favored for the application since they provide a moisturized environment and they help autolytic debridement [9].

Microorganisms such as bacteria and fungi can colonize the wound site, resulting in infection, which can delay the healing [10]. Infection not only delays the healing; according to Madaghiele and colleagues, “Wound infection, which further increases the local tissue damage, is a common complication, while systemic inflammatory and immunological responses might lead to a higher predisposition to life threatening sepsis and multi-organ failure” [11]. It is therefore desirable to impart suitable antimicrobial properties to wound dressing hydrogels by incorporating bactericidal substances.

3 Natural Products for Wound Care

Synthetic antibiotics such as methicillin have been used in order to control and inhibit wound infection. However many bacteria, such as Staphylococcus aureus (the most common cause of infection in wounds), are resistant to these antibiotics. Herbal products are gaining increasing consideration as an alternative to synthetic drugs as a means to control infection [12, 13, 14].

Complementary and alternative medicine and Ayurveda medicine use herbal substances for therapies. Natural products have been used in wound care since they contain antioxidants, antimicrobials, and anti-inflammatory substances. These substances present in natural products have the potential to kill microbials and so stimulate healing, reepithelialization, and collagen production [15].

3.1 Wood and Plant Extracts

Aloe vera is a succulent plant that has a composition based on anthracene hydroxyl derivatives (aloins A and B2), chromone compounds, and aloe resins A, B2, and C. Aloe vera presents anti-inflammatory, antibacterial, antifungal, and anti-arthritis effects [15]. It stimulates wound healing by enhancing fibroblast growth, it increases the oxygen access and the blood supply to the wound, and it stimulates the collagen production and the wound tissue collagen strength [16].

Wood extracts can also be useful for wound care. According to Sachdeva and co-authors, who studied the extract of Jatropha curcas L. “The plant contains Organic acids, Cyclic triterpenes stigmasterol, Curcacycline A, Curcin, a lectin Phorbolesters Esterases, Sitosterol and its d-glucoside. The leaf and bark have been shown to contain glycosides, tannins, phytosterols, flavanoids and steroidal sapogenins.” In addition, ointment containing the extract increased wound healing rates in rats [17].

Arnica montana is a native herb of Central Europe and Siberia. It is known to have helenalin and dihydro-helenalin ethers, as well as sesquiterpene lactones as active anti-inflammatory/pharmacological compounds [18, 19]. The application of Arnica in dog wounds acted not only as an anti-inflammatory but also as an analgesic [20]. It is suggested that Arnica stimulates the tissue’s extracellular matrix synthesis [21].

The bark of Carallia brachiata is effective in wound treatment, where its bark presents proanthocyanidins (carallidin, mahuanin), which have free radical scavenging activity, and parahydroxybenzoic acid. The extracts of Carallia brachiata were found to be active in the healing of rat wounds [22].

Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is produced by certain plants and can be considered a wound healing compound. Curcumin acts as an anti-inflammatory, anti-bactericidal, and antioxidant agent. In addition, curcumin stimulates tissue granulation and collagen deposition, enhancing the wound healing [23].

According to Nicolaus and collaborators, the main constituents of Calendula officinalis, also a plant extract, are “Pentacyclic triterpenes from the ψ-taraxastene, taraxastene, lupene, Δ12-oleanene and Δ12-ursene types.” Calendula is an effective wound healing agent, although its specific mechanism of action is not well described [24].

The composition of Lavandula aspic L. is based on terpenes and terpenoids, where linalool, 1,8 cineole, and camphor are the main components. Lavender oils and extracts present bactericidal, anti-inflammatory, and antioxidant activities. Lavender ointment enhanced rats wound healing rates and protein synthesis [25]. In addition, phenolic acids, flavonoids, flavones, and flavonols were found in Lavandula angustifolia and Urtica dioica L. (a plant of the Urticaceae family, known to present flavonoids, carotenoids, sterols, and minerals) extracts, presenting high antibacterial activity against Staphylococcus aureus [26].

Punica granatum (pomegranate) is a small tree from the Mediterranean region. It presents phenolic compounds, flavonoids, tannins, and epicatechin. Since it presents several active compounds, pomegranate extracts are bactericidal, anti-inflammatory, and antifungal. Pomegranate extracts increase the collagen synthesis and the wound contraction in rat wounds, and it presents higher activity against P. aeruginosa than against S. aureus and E. coli. It also diminishes the inflammatory phase time and stimulates the formation of granulation tissue [27, 28, 29].

3.2 Bee Products

Honey and propolis are produced by Apis mellifera bees, with compositions that vary according to the geographical location of collection, the botanical origin, the climate (temperature, rainfall), the season, and local plant nutrition, among other factors [30, 31, 32]. There are approximately 320 types of honey [33]. Propolis can be bacteriostatic and honey fungistatic, and, in high concentration, propolis can be bactericidal and honey, fungicidal [34, 35].

Honey generally presents flavonoids and polyphenols, which can act as antioxidants. The main antimicrobial agent in honey is hydrogen peroxide. In contact with aqueous solutions, honey’s enzyme glucose oxidase is activated, which oxidizes glucose, generating H2O2. In addition, honey presents bioactive components, such as the vitamins E – tocopherol and A – retinol, and cinnamic acid. Honey presents a moisturized environment and is a barrier to bacterial infection as well as having antimicrobial activity [33, 35].

McLoone and coworkers compiled several studies regarding the antimicrobial properties of honey for wound care [36]. Honey from South Gondar/Ethiopia, from Amazonas/Brazil, and from Slovenia and Tualang and honey from Malaysia all inhibited E. coli and S. aureus. Some of the mentioned honeys presented activity against other bacteria. For example, Brazilian honey was effective against the Proteus vulgaris and Klebsiella species; Slovenian honey was active against P. aeruginosa and Malayan honey against Streptococcus pyogenes and P. aeruginosa. Furthermore, the growth of C. albicans was inhibited by honey from Al-Baha, Saudi Arabia [36].

Many honeys present antimicrobial activity related to the presence of H2O2. However, Manuka honey is obtained from Leptospermum scoparium trees (New Zealand and Australia), and its activity is not related to hydrogen peroxide but rather to the presence of MGO (methylglyoxal) and leptosperin. Manuka honey can act synergistically with synthetic antibiotics, e.g., vancomycin. It can work against infections with increased antimicrobial resistance, and it has been shown to enhance wound healing rate [37, 38].

Propolis presents different compounds with up to 300 constituents potentially present, which vary depending on its origin and climate. Flavonoids and phenolic compounds are found in propolis, such as CAPE and cinnamic acid derivatives that would be responsible for the antioxidant, anti-inflammatory, anticancer, and antiviral activities [32, 40, 41]. Propolis from temperate climates presents high amounts of flavanones and flavones and low phenolic acids and esters, whereas propolis from tropical climates is rich in prenylated derivatives of p-coumaric acid and some isoflavonoids and phenolic compounds [42, 43].

Propolis compounds’ mechanism of action against bacteria is to alter the membrane permeability of the cell, inhibit cell division, and inhibit the synthesis of some proteins [35, 49]. Propolis has antimicrobial activity against gram-positive bacteria, e.g., Staphylococcus aureus and Staphylococcus epidermis, but limited action against gram-negative bacteria and also against some fungi, e.g., Candida albicans [32, 39, 44, 45]. Several other natural products can be used in wound care, but the ones presented provide a suitable overview for the purposes of the present work.

4 Polysaccharides

This section will review a range of polysaccharides in the context of their having potential for wound care biomaterials applications. Among the polysaccharides of interest is agar, which is obtained from seaweeds. It is a hydrophilic, gel-forming polysaccharide, which can allow substitution on the hydroxyl groups and where the type and amount of substitution depend on, for example, its origin and type of extraction [46]. Agar is composed by agarobiose (4-d-galactopyranosyl-3,6-anhydro-l-galactose), which was identified after the partial hydrolysis of agar, by 2-methyl 3,6-anhydro-l-galactose dimethylacetal, which was identified in methylated agar, and by 3,6-anhydro-l-galactose dimethylacetal, identified through the methanolysis of the agar [47, 48].

Alginate is an anionic linear polysaccharide obtained from marine algae. It is composed of (1–4)-α-l-guluronic acid blocks (GG blocks), (1–4)-β-d-mannuronic acid blocks (MM blocks), and mixed sequences MG. The amount of each type of block depends on the algae type, age, and method of extraction. The M/G ratio determines the solubility of alginate in water, as well as its mechanical properties. In addition, the GG blocks are the main blocks to interact with calcium ions, which allow the chains crosslinking [49, 50].

Glucan is a class of polysaccharides that present glucose as monomer, e.g., glycogen, cellulose, and dextran. Glucans can be found in the cell wall of plants and cereal seeds. Some can be produced by fungi, molds, and yeasts. Depending on the bonds among glucopyranose units, different compounds can be formed. There are homopolymers of d-glucose, but the conformation of α- and β-glucans occurs according to the condensation of the OH groups [51]. Dextran and cellulose will be detailed later on in the present work.

Carrageenan (sulfated galactans) is anionic polysaccharides extracted from red algae, where the d-galactose molecules are bonded in an alternated α-1,3 and β-1,4 pattern. According to Webber and collaborators, “They are classified as kappa (κ), iota (ι), and lambda (λ) according to their sulfate substitution pattern and 3,6-anhydrogalactose content.” Carrageenan dissolved in water forms a viscous solution, and it can be used as an emulsifier, for example, in the food industry [52, 53].

Chitin, a linear polysaccharide composed of (1–4)-linked 2-acetamido-2-deoxy-β-d-glucopyranose units, can be extracted from organisms like mollusks, crustaceans, insects, fungus, and algae. Chitin is a biocompatible and biodegradable material [54]. Chitosan is a cationic polymer obtained from the deacetylation of the chitin, which presents interesting properties, like accelerating wound healing [55].

According to Del Valle, “Cyclodextrins are cyclic oligosaccharides consisting of six -cyclodextrin, seven -cyclodextrin, eight -cyclodextrin or more glucopyranose units linked by -(1,4) bonds. They are also known as cycloamyloses, cyclomaltoses and Schardinger dextrins. They are produced as a result of intramolecular transglycosylation reaction from degradation of starch by cyclodextrin glucanotransferase (CGTase) enzyme” [56].

Dextran is a glucose-based polysaccharide produced by Leuconostoc mesenteroides bacteria, and it is composed of α-1,6-glucopyranosidic linkages. The bacteria convert sucrose to dextran through an enzyme, dextransucrase [57].

Among the several available gums, guar gum, xanthan gum, gellan gum, acacia gum, and sterculia gum are used in biomaterials and for drug delivery systems [58, 59, 60]. The guar gum, extracted from a leguminous plant Cyamopsis tetragonoloba, is mainly composed of galactomannan and low amounts of moisture, protein, and fiber [61]. Gellan gum, an anionic polysaccharide composed of tetrasaccharide repeat unit of (1–3)-β-d-glucose, (1–4)-β-d-glucuronic acid, (1–4)-β-d-glucose, and (1–4)-α-l-rhamnose as the backbone, is produced by Sphingomonas elodea bacteria [62]. Xanthan gum is an anionic polysaccharide (1, 4-linked β-d-glucose backbone with trisaccharide side chain), which is the product of Xanthomonas campestris (aerobic bacteria) fermentation of sugars. In addition, these authors add “Acacia gum (GA) is an exudate from of Acacia Senegal trees and is a complex acidic branched polysaccharide.” The acacia gum is a heteropolysaccharide containing a polypeptide, and it would be mainly composed by arabinogalactan and arabinogalactan protein [63].

Sterculia gum is “the dried exudates obtained from the stem and branches of Sterculia tree” [64]. Its composition is mainly galacturonic acid, β-d-galactose, glucuronic acid, and l-rhamnose [59].

According to Alonso-Sande and colleagues, glucomannan “GM is a hydrocolloidal polysaccharide consisting in β-1,4 linked mannose and glucose residues” [65]. Pectin is a polysaccharide composed by d-galactopyranosyluronic acid units [66]. Pullulan is a neutral linear polysaccharide consisting of α–1, 6-linked maltotriose residues. It is produced by Aureobasidium pullulans fungal [67].

Starch consists of mainly of two polysaccharides, amylose (a linear chain with few branches) and amylopectin (a very branched chain), and intermediate materials. Starch properties vary according to the amounts of each component [68]. Amylose usually is composed of smaller chains than amylopectin [69].

Xylan is a heteropolysaccharide, very abundant in plant biomass. Its chemical composition depends on the botanic source, although it basically consists of a linear backbone of 1,4-linked d-xylopyranose residues [70, 71].

4.1 Cellulose

Plants’ cell walls are composed of bundles of cellulose fibers, ensuring the structural integrity of the walls [72]. Cellulose, C6H10O5, a chain of sugar molecules, is the most abundant natural polymer and polysaccharide. It is found in plants, usually in combination with lignin and other polysaccharides. Cellulose is a linear homopolymer composed of d-anhydroglucopyranose units, linked by β-(1 → 4) glycosidic bonds. Cellulose, which is insoluble in water, is used in several applications, such as in wood for construction, as textile fibers in cotton or paper, and as a raw material for charcoal production [73, 74, 75, 76].

Bacterial or microbial cellulose is a version of cellulose produced by bacteria, for example, the gram-negative bacteria A. xylinum which consumes the nutrient broth (the source of carbon) through biochemical reactions to synthesize linear β-1,4-glucan polymers, which are later secreted by the organisms. Outside the cells, the polymers form microfibrils and ultimately bundles of microfibrils. The morphology and chemical composition of these fibers mimic the collagen fibers, and they are categorized as bioartificial, since these scaffolds are not synthetic or from animal origin. Microbial cellulose is a promising nontoxic material for wound healing [77, 78].

Cellulose can be chemically modified by reacting it with an alkali and then by letting the carboxymethylation occur, resulting in an anionic linear polymer with a carboxyl substitution, known as carboxymethyl cellulose (CMC) [75, 79, 80]. Among the cellulose derivatives, cellulose acetates are soluble in acetone and other solvents, while methylcellulose, ethyl hydroxyethyl cellulose, and sodium carboxymethyl cellulose are soluble in water. Sodium carboxymethyl cellulose is obtained through the reaction of cellulose with alkali and monochloroacetic acid. It is a linear anionic water-soluble polymer and a vastly used polyelectrolyte in pharmaceutical industry [76, 81].

Hydroxypropyl cellulose (HPC), according to Ogawa and collaborators, is a “cellulose-derivative to which a hydroxypropyl group is introduced as the substitute of 2, 3, 6-OH group, is soluble in both water and organic solvents. The average substitution ratio of the hydroxypropyl group in typical HPC is 2.0–4.5 per glucose unit” [82]. Carboxymethyl celluloses and hydroxypropyl celluloses are biocompatible polymers [83]. Dialdehyde cellulose is the product of a regioselective oxidation of cellulose using periodate. It is biocompatible and biodegradable [84].

4.2 Hydrogels of Cellulose with Synthetic or Natural Products

Sodium carboxymethyl cellulose (NaCMC) hydrogels can be crosslinked by gamma radiation, although considerable degradation can occur. It has been observed that NaCMC samples present optimum swelling degree at pH ~7, with reduced levels of swelling at low and high pH. The swelling degree of samples increases with temperature. The NaCMC is nontoxic and biocompatible, and the gels can be considered suitable for biomedical applications [85]. Hydrogels based on carboxymethyl cellulose-methacrylate crosslinked by photopolymerization presented superior swelling capacity, diffusion of proteins, and enzymatic degradation, although with a low shear modulus. The gels supported cell adhesion and viability, thereby showing initial potential to be used as scaffolds [83].

4.2.1 Hydrogels of Cellulose and Synthetic Molecules

Carboxymethyl cellulose-poly (ethylene oxide) hydrogels presented ~660% media uptake; they also exhibited enzyme degradation and acceptable biocompatibility. Smooth muscle cells could adhere and migrate through the gels surface and pores, where extracellular matrix was synthesized [86].

Lower substituted hydroxypropyl cellulose (hydroxypropyl substitution ratio of 0.1–0.5) hydrogel presents increased adhesive strength and tensile strength with the increase of polymer in the hydrogel but lower adhesive strength than the silicone dressings, reducing the risk of trauma to the neo-formed skin. The gels also presented superior water uptake and transpiration [82].

Dialdehyde cellulose hydrogel loaded with chloramphenicol were bactericidal (against S. pneumoniae, S. aureus, and E. coli) and presented higher fibroblast adhesion and proliferation than the bacterial cellulose-chloramphenicol samples. Both samples released 99% of the drug within 1 day [84].

CMC-poly(N-vinyl pyrrolidone)/PVP hydrogels showed increased swelling capacity with increases in the proportion of CMC in the gels, while the gel fraction decreased. The blends presented mechanical strength superior to that of pure CMC gels, as well as superior flexibility and water uptake. The blends are viewed as being potential alternative low-cost materials for dressings [87].

4.2.2 Hydrogels of Cellulose and Natural Macromolecules

Bacterial cellulose and acrylic acid (AA) hydrogel crosslinked by electron beam radiation were investigated with respect to wound care applications. The increase in AA and in radiation dose increased the gel’s mechanical properties, but nonetheless the gel’s swelling capacity in simulated wound fluid decreased. The gels were nontoxic to human skin fibroblasts [88].

Cellulose-pullulan hydrogels (pullulan is a starch produced by fungus to improve adhesiveness and degradation) were formed through an enzyme reaction of tyramine-immobilized CMC with horseradish peroxidase (HRP) and H2O2 for crosslinking, adding pullulan. Tyramine was introduced to the CMC carboxyl group, where increased HRP and H2O2 raised the elastic modulus of the gels (G′). The gels supported low cell proliferation, exhibited low cytotoxicity, and prevented tissue adhesion [89].

BC (bacterial cellulose)-chitosan hydrogels adsorbed higher amounts of Candida rugosa lipase than microcrystalline cellulose-chitosan beds, and the same pattern was observed for the catalytic activity of lipase. The lipase also presented higher thermal stability when crosslinked to BC-chitosan material [90].

Bacterial cellulose (BC) and collagen have been combined in a hydrogel for wound care. Collagen is a class of protein present in a fiber morphology which guarantees the integrity of the extracellular matrix. In the combined hydrogel, collagen decreases the BC crystallinity and thermal stability. BC/collagen hydrogels promoted faster reepithelialization than dextran hydrogels and in addition showed adhesion to the wound site and promoted autolytic debridement [91, 92].

4.2.3 Hydrogels of Cellulose Incorporating Natural Antimicrobials

Some cellulosic membranes incorporating propolis have been developed recently. Biocellulose membranes were prepared by Barud and collaborators [45], and the membranes were then immersed in propolis to obtain bactericide dressings. These membranes were effective against Staphylococcus species and also were seen to promote a better tissue repair in the early periods of the healing in the in vivo tests.

Cellulose hydrogels, loaded with honey and then gamma irradiated, were tested as wound dressings in rats. Increasing the dose of radiation led to higher gel content and to lower swelling degree (the presence of high degree of crosslinking led to low network expansion). It was observed that increased amounts of honey in the samples led to lower gelation (honey acts as a plasticizer, which impedes the crosslinking) and high swelling. The gels were effective against S. aureus and E. coli. In addition, wound contraction in rats was accelerated in the presence of CMC-honey gels [93].

CMC dressings containing chestnut honey, crosslinked by gamma radiation, showed potential as dressings, since they supported granulation tissue growth, they were non-adherent, they increased the rate of wound contraction, and they were effective against S. aureus and E. coli. In addition, increased levels of honey in the gels led to higher swelling capacity and lower compressive strength [94].

5 PVA Hydrogels

5.1 Properties of PVA and PVA Gels

The synthesis of poly (vinyl alcohol) (PVA) consists of two steps: chain polymerization of vinyl acetate monomers, forming polyvinyl acetate, followed by hydrolysis of the polyvinyl acetate, to generate the poly (vinyl alcohol), usually exhibiting a large molecular weight distribution [95].

Since the polymerization does not achieve 100% conversion, the PVA is a copolymer of PVA and polyvinyl acetate, where the degree of hydrolysis represents the degree of conversion. PVA with a high degree of hydrolysis has low solubility in aqueous fluids, since high amounts of acetate groups impede the formation of hydrogen bonds of hydroxyl groups. The dissolution occurs in temperatures higher than 70 °C [96].

PVA is a classic synthetic polymer used to synthesize hydrogels for wound care, due in part to its well-established biocompatibility [97]. PVA exists as a semicrystalline polymer, presenting inter- or intramolecular bonds [95, 98]. Hydrogels of PVA are transparent and biodegradable, they swell in aqueous fluids, and their mechanical properties can be adjusted according to the crosslinking process [95, 99, 100]. These gels can be used as contact lenses, in artificial hearts, as drug delivery systems, as articular cartilage, in catheters, as burn dressings, and as temporary skin substitutes [99, 101].

PVA hydrogels can easily be prepared by first dissolving the polymer in water or aqueous fluids. When PVA is placed in water, water molecules occupy the space between amorphous chains, possibly disentangling or dissolving them. PVA’s crystals can unfold layer by layer, leading on to full dissolution of the polymer [102]. PVA’s glass transition temperature (Tg) is affected by the molecular weight distribution, since the presence of short chains acts as a plasticizer, diminishing the Tg value [103].

PVA can be chemically or physically crosslinked. Chemical crosslinking can be done by radiation or by the addition of a chemical crosslinker. The chemical crosslinker must be a bifunctional reagent in order to react with the chains, connecting them. Chemical crosslinkers for PVA include boric acid, phenyl boronic acid, dialdehydes, dicarboxylic acids, dianhydrides, acid chlorides, epichlorohydrin, citric acid, succinic acid, and tartaric acid [104, 105].

When the PVA is submitted to gamma radiation, polymeric radicals are formed –(CH2-C˙HO)– and/or –(CH2-CHO˙)– and these radicals interact with each other through combination and disproportionation to form inter- and intramolecular bonds [106, 107]. Radiation technique crosslinks the PVA by forming covalent bonds between the groups originally in the chains, and it also sterilizes the gels. In addition, there is a high gelatinization and a low formation of sub-products [106].

PVA hydrogels can be manufactured by casting, where the polymer solution is poured in a mold and the PVA is physically crosslinked. Physical crosslinking by cryogelation involves freezing an aqueous PVA solution, causing ice crystals to form, thereby pressing together polymer chains in the remaining ice-free regions. When the chains are close together, they can pack into crystallites which involve hydrogen bonds between chains. When thawed, the ice crystals melt, leaving macropores, and the phase that is rich in PVA prevents the structural collapse of the gel [98, 107, 108, 109, 110, 111]. The PVA crystallites act as physical crosslinking points between chains, resulting in a nondegradable 3D structure – a cryogel [112].

The mechanical properties of the cryogel depend on the rate and on the temperatures of freeze-thawing, in addition to the dependence on solution concentration and on the molecular weight of the polymer. For PVA hydrogels, freezing cycles as short as 1 h are sufficient to make insoluble gels with a high swelling capacity (required to keep a moisturized environment that improves healing), and, although long cycles resulted in higher mechanical strength, they also contributed to lower swelling capacity [111, 113, 114].

5.2 Blended and Composite PVA Gels

PVA has been blended to different polymers in order to obtain appropriate material for wound dressings. PVA, poly(N-vinylpyrrolidone) and glycerol were mixed, cast, and crosslinked by freeze-thawing and gamma radiation. The gels presented improved water uptake. Silver was also incorporated in the gels, and these were able to accelerate healing and presented antibacterial properties [115].

PVA and polyethylene glycol (PEG) were combined with CaCl2 and crosslinked with gamma radiation. The gel’s swelling capacity was adequate to stimulate wounds’ granulation and reepithelialization, and they were nontoxic and a barrier to microbial penetration [116].

Hydrogel fibers composed of PVA and polyacrylic acid (PAA) presented pH-sensitive properties, with the presence of PAA leading to higher swelling rate [117]. PVA-PEG hydrogels blended and submitted to electron beam irradiation presented high healing rates compared to gauze [118].

Biphasic systems such as PVA-gelatin have also been produced, and triphasic systems like PVA-chitosan-gelatin, abbreviated as PCG, were successfully manufactured by gamma radiation. They presented higher tensile strength than the comparator PVA-gelatin hydrogel. PCG gels presented appropriate hemostatic effects, swelling capacity, and water evaporation rate [119]. PVA can be combined to polysaccharides, natural polymers that could improve the PVA gel properties for wound care applications.

5.3 PVA–Polysaccharide Gels

Several studies have investigated the properties of gels formed from blends of PVA with polysaccharides, frequently for biomedical applications such as tissue engineering or wound healing. PVA-agar gels were prepared by casting without any additional crosslinking process, for purposes that require biocompatibility. In the swelling evaluation, the presence of agar was found to help the gels to keep the water uptake in the network. Hydrogen bonds are formed between PVA and agar. The agar altered the transition temperature of the PVA gels, whereupon the PVA-agar gels presented slightly higher melting temperature than pure agar. The gels did not present high mechanical properties, and the gels containing agar were more elastic [47].

Blends of PVA and alginate, chemically crosslinked with sodium sulfate, presented stability at temperatures in the range of 50–80 °C, and they were effective in the application of immobilized naringinase [120]. A freeze-thawing physical crosslinking process was applied in a different study, and PVA-sodium alginate hydrogels loaded with ampicillin showed antibacterial properties as expected. The presence of alginate increased the gel’s swelling capacity and protein adsorption, but it reduced the gels elasticity and gel fraction [121].

PVA-β-glucan hydrogels prepared by casting without crosslinking presented promising results for wound healing. The presence of glucan increased the gel’s swelling rate and the gels’ ductility, the glucan was released from the gels, and rat wounds healed in half of the time compared to rats treated with gauze [122].

Carrageenan blended with PVA and freeze-thawed showed improved cell adhesion and proliferation [123]. PVA-κ-Carrageenan gels γ-irradiated presented higher swelling capacity with the increase of Carrageenan in the gels [124]. PVA-κ-Carrageenan freeze-thawed gels loaded with Lactobacillus bulgaricus extract showed antimicrobial properties and high healing rate [125].

PVA was blended with chitin and then chemically (epichlorohydrin) and physically (freezing-thawing process) crosslinked. The gel containing 25% PVA/75% chitin showed compressive strength 20× higher than the chitin gels. In addition, PVA-chitin gels were considered to exhibit suitable biocompatibility for the intended use [126].

PVA and chitosan have also been blended in several studies. Following chemical crosslinking, it was observed that the water content in the gels, the vapor transmission, and the permeability to vitamin B12 and creatinine increase with the rise of chitosan in the gels [127]. In a separate study, it was observed that the addition of chitosan to PVA (freeze-thawed samples) increased the cells attachment to the gels without sacrificing the physical properties [128].

PVA-β-cyclodextrin hydrogels chemically crosslinked with glutaraldehyde were investigated as drug delivery systems [129]. Poly (vinyl alcohol)/β-cyclodextrin freeze-thawed hydrogels presented porous morphology, and the pore diameters depend on the amount of β-cyclodextrin. DSC analysis revealed that there were interactions between PVA and β-cyclodextrin. Tests also indicated compatibility between blood and the blended hydrogel [130].

PVA-dextran freeze-thawed blends presented altered crystallinity due to the presence of dextran. Dextran broadened the crystal size distribution and led to lower thermal stability of the gels [131]. In addition, the presence of dextran in the PVA freeze-thawed gels was associated with lower gel fraction, lower maximum strength, reduced thermal stability and higher swelling ability, water vapor transmission rate, elasticity, porosity, and protein adsorption [132].

PVA-gum hydrogels have also been considered for wound dressing applications. Sterculia gum crosslinked to PVA increased the gel’s swelling capacity [59]. PVA gels and gellan gum can be crosslinked with gamma radiation, and the presence of the gum not only increases water uptake of the gels but also their biocompatibility [58]. PVA-acacia gum hydrogels presented superior swelling properties and drug release capacity [133].

PVA and konjac glucomannan (KG) freeze-thawed hydrogels presented characteristics superior to PVA gels and to KG gels. Hydrogen bonds formed between PVA and KG and PVA-KG gels presented higher elastic properties, Young’s modulus, and compressive strength than konjac glucomannan gels [134].

PVA blended with pectin hydrogels has also been investigated with respect to the wound healing field. Cast blends prepared without any additional crosslinking process presented reduced elastic and viscous modulus above the gels’ Tg as the proportion of PVA in the gels increased [135]. Freeze-thawed PVA-pectin hydrogels displayed interaction between the two polymers, where the pectin decreased the gel’s crystallinity, and it was possible to incorporate drugs in the gels [136].

PVA and pullulan cannot be successfully cast in combination, since they undergo phase separation and present phase interfaces that weaken the gel’s mechanical properties. Chemical crosslinking is required to obtain gels with appropriate characteristics [137]. PVA and starch can be blended and films can be cast. The addition of starch diminishes the tensile strength of the PVA-starch films [138]. In a separate study on gels, PVA and starch were blended and submitted to radiation. The presence of starch increased the gel strength and decreased the swelling properties. In addition, amylose and amylopectin were mixed to PVA separately in order to evaluate their influence on the PVA gel properties, and amylose was found to be the main reactive component of starch [139].

A xylan-PVA hydrogel has also been developed for potential biomaterials applications. Maleic anhydride-xylan (MX) was blended with PVA. The presence of MX decreased the swelling capacity of the gels and increased their strength. The hydrogels were considered generally nontoxic [140].

5.4 PVA Hydrogels Containing with Natural Products

A common strategy for the development of wound care biomaterials is to use gels based on PVA, often invoking their cryogelation abilities, to act as a matrix for natural antimicrobials.

In one example, PVA-polyacrylamide films prepared by casting were able to incorporate pomegranate peel [141]. PVA gels prepared by freeze-thawing and loaded with pomegranate or Arnica presented physical interactions between PVA-Arnica and PVA-pomegranate; the natural products lowered the PVA sample’s crystallinity and swelling degree; pomegranate samples released more phenols and flavonoids to phosphate buffer saline (PBS) solution than Arnica. On the other hand, PVA-Arnica samples presented superior mechanical properties to those of the PVA-pomegranate samples [142].

In another study, PVA-poly(N-vinylpyrrolidone)-Aloe vera hydrogels were prepared by combinations of freeze-thawing and/or gamma radiation. Increased Aloe vera in the gels led to lower gel strength and gel fraction and to higher swelling degrees. The hydrogels containing Aloe vera accelerated wound healing rates in rats [143].

PVA-Aloe vera films prepared by casting showed that the components do not interact, where Aloe vera’s active compounds (e.g., anthraquinones, saponins) remain unaltered by PVA. The gels containing the lower (5%) amount of Aloe presented the higher bactericidal (E. coli, P. aeruginosa) and fungicidal (Aspergillus flavus, Aspergillus tubingensis) effects, probably because interactions between active compounds, which happen in samples with more Aloe, are avoided and there is less physical impediment to the delivery of these compounds. Aloe release happens in steps, where there is a burst release in the beginning due to the aggregates of Aloe on the sample surface, followed by a slower release, since the remaining Aloe is trapped in PVA networks [144].

Chitosan/PVA films loaded with pomegranate/mint extracts were prepared by casting for a potential food packaging application. The addition of extracts increased tensile strength. Samples containing the extracts presented antioxidant characteristics and were bactericidal to S. aureus and to B. cereus [145].

PVA-curcumin films were also prepared by casting. The samples sustained progressive curcumin release up to 17 days, and more curcumin was delivered to the media as the samples contained more curcumin in their composition. The release was more effective in acidic or basic pH than in neutral pH, since curcumin presents low solubility in water [146].

Targeting wound care applications, PVA gels incorporating a Brazilian propolis were produced by cryogelation. Samples delivered propolis to the media over 24 h and delivered more propolis to neutral media than to acidic media (Fig. 1). The presence of propolis diminished the crystallinity of the gels. More propolis in the gels meant more propolis delivery and a higher weight loss from the samples. Increases of propolis content up to 35% led to higher mechanical properties, while a 15% propolis content in the samples was enough for the gels to be active against S. aureus, Fig. 2. The material was also shown to act as a barrier to microbial penetration [147].
Fig. 1

Propolis cumulative release profile of PVA-propolis samples. The PVA-propolis samples were immersed in (a) PBS and (b) solution pH 4.0, and the propolis delivered was quantified after regular intervals of time for 4 days [147]

Fig. 2

Tensile tests of all swollen samples, PVA and PVA-propolis samples, after 1 day of immersion in (a) PBS and (b) solution pH 4.0; (c) antimicrobial activity of the PVA-propolis samples against S. aureus [147]

In an associated study, freeze-thawed PVA hydrogels incorporating a propolis of UK origin presented a swelling degree of at least ~200%, where the lower threshold of swelling occurred for the samples with the highest amount of propolis. It can be hypothesized that the additional propolis may initially occupy and even swell the gels’ pores, to then be replaced by media as it is released, leading to a lower apparent swelling effect. High amounts of propolis in the samples led to higher propolis delivery as expected [148].

PVA-honey films were prepared by casting and crosslinked with borax. The gels presented a swelling profile divided in two steps: first the filling of the network with media and, second, the release of honey and achievement of a swelling equilibrium. The gels permeability was appropriate for moderate or high exudative wounds. The gels were also active against S. aureus and were able to release erythromycin [149].

In another study, PVA-cassava starch blends were prepared by casting and mixed with nanoparticles of starch containing curcumin and then dried. The curcumin was released from the films by diffusion and erosion mechanisms. The films were non-cytotoxic to normal cells, but they presented an anti-cancer effect [150]. PVA-carboxymethylate chitosan-honey hydrogels crosslinked by gamma radiation and freeze-drying have also been studied. These gels were bacteriostatic and increased the rate of wound healing in rats [151].

5.5 PVA-Cellulose Hydrogels with Natural Products

This section considers work done to understand the properties of films and gels that combine PVA with various forms of cellulose, particularly as a matrix for natural antimicrobial products.

It has been observed that PVA covered the fibers of bacterial cellulose (BC) in cast dried composites of the two materials, filling the space between them, thereby increasing the density of the composite material. Incorporation of BC fibers increased the tensile strength and elastic modulus, but the toughness and the swelling capacity decreased [152].

PVA-CMC-gelatin were crosslinked with N,N′-methylene bis acrylamide, and the gels were loaded with povidone-iodine. The wound size of mice decreased considerably when treated with the gels containing iodine. Increasing the proportion of any polymer of the blend increased the gel’s swelling capacity. The release of iodine increased with higher proportions of CMC or PVA [10].

PVA-bacterial cellulose multilayered blends were loaded with vanillin (4-hydroxy-3-methoxybenzaldehyde), an antimicrobial agent. The material’s swelling behavior was altered by the presence of bacterial cellulose and vanillin, where increases led to a diminished swelling degree of the gels. Bacterial cellulose could reduce the amount of available OH groups in PVA chains, lowering the PVA’s polarity, crystallinity, and hydrophilicity. The vanillin release profile lasted 1 h [153].

In another study, freeze-thawed PVA-CMC hydrogels were combined with two synthetic antibiotics (ciprofloxacin and streptomycin) and two active anti-inflammatory natural products (tridax and the antibacterial turmeric). The gels loaded with ciprofloxacin and tridax presented high tensile strength and a water vapor transmission rate close to that of the skin. The gel containing tridax presented appropriate swelling capacity and gel fraction as well as displaying antibacterial properties against S. aureus and E. coli [154].

A separate study involved casting, mixing, and freeze-drying of PVA, CMC, and polyethylene oxide (PEO). In order to obtain membranes laden with either Aloe vera or curcumin, the respective component was mixed with the above polymers prior to freeze-drying. The gels presented high media uptake (~900%) and were able to release curcumin and Aloe vera to the media. The gels were bactericidal to the S. aureus and E. coli species. Increasing the Aloe vera or curcumin concentration in the dressings would be expected to increase their antimicrobial activity [155].

Cellulose/PVA/curcumin films were prepared by the ionic liquid method. There was compatibility between the phases, and the ionic liquid acted as a compatibilizer between PVA and cellulose. In addition, cellulose diminished the samples hydrophilicity [156]. Although electrospun materials are not in the scope of the present text, it is worth mentioning that ε-polycaprolactone-PVA-curcumin material for wound care was also studied. It was observed that 16% of curcumin was sufficient for the materials be active against S. aureus and E. coli, while maintaining fibroblast viability at 60% is considered to be an acceptable level [157].

In a recent study directed toward wound care applications, PVA-NaCMC hydrogels loaded with propolis were prepared by casting, followed by freeze-thawing. No chemical bonds between the three components were identified. The progressive incorporation of higher propolis amounts diminished the PVA gels’ crystallinity and reduced the gel tensile modulus and strength (Fig. 3a). In addition, higher propolis content led to higher delivery of phenols and flavonoids (Fig. 3b), as well as high weight loss and swelling degree (Fig. 3c). 15% of propolis in the samples was enough to inhibit S. aureus bacteria (80% reduction) [158].
Fig. 3

(a) Tensile responses of the PVA/NaCMC gel samples containing 0%, 3%, 15%, and 30% propolis immersed in PBS at 37C for 4 days [158]. (b) Phenolic compounds and flavonoids delivery as well as DPPH scavenging activity of PVA/NaCMC gel samples containing 0%, 3%, 15%, and 30% propolis, where GA = gallic acid and Q = quercetin [158]. (c) Swelling rate of the PVA/NaCMC gel samples containing 0%, 3%, 15%, and 30% propolis immersed in PBS at 37C for 4 days [158]

6 Conclusion

PVA is a biocompatible polymer and is a well-established hydrogel material. PVA blends have been produced by chemical (crosslinking agents, radiation) or physical (freeze-thawing) crosslinking. It is frequently combined with natural polymers or macromolecules, including polysaccharides and specifically CMC, when addressing wound care or tissue engineering requirements. Since the resultant blended or composite materials do not present antimicrobial properties, the addition of drugs or natural antimicrobials to these hydrogels is often contemplated. Synthetic drugs can cause resistance to some microorganisms, so herbal or natural products are attractive alternatives. In general, PVA-polysaccharide blends present high swelling capability combined with suitable biocompatibility. In combination with selected natural antimicrobial products, they can also have a bactericidal effect without compromising the wound healing process. Of the various polysaccharide options available, CMCs are widely available and can be successfully blended with PVA. In particular, blended gels of PVA and NaCMC, and releasing propolis, have been shown to have the ability to combine key attributes necessary for successful wound healing.

7 Future Scope

Hydrogels are a highly important class of biomaterial for the development of tissue engineering and wound healing therapies. Such applications require a strong understanding of the means by which the attractive characteristics of different kinds of gel components can be combined in a single product to meet the requirements of the patient. The overall objective of most hydrogel-based wound dressings is to maintain a moist and protected wound site, absorb any exudate, and deliver antimicrobial or therapeutic products to the wound site. Protecting the wound site requires a robust material, which is challenging for many hydrogel types.

In the work summarized here, the strengthening effect of the physical crosslinking in PVA-based cryogels has been exploited. There is much further scope to develop strong and highly elastic hydrogels based on other principles such as the double network gel approach or through fiber reinforcement. Strategies for improving the mechanical properties of biomedical gels could open up new avenues of material development and lead to interesting and more effective new solutions for patients by allowing greater flexibility to incorporate therapeutic potency.

Natural antimicrobials for wound dressings represent an attractive route for wound dressing development. The studies relayed in this chapter typically use extracts of natural substances which are incorporated prior to gelation of the biomaterial. It is possible that greater efficacy could be achieved through further study of the essential mechanisms of action at play and whether more sophisticated delivery systems could be developed in combination with future hydrogel structures. In particular, the possibility of developing nanoparticle carriers for natural antimicrobials would be worth exploring.



The authors would like to thank CAPES, CNPq, FAPERJ, and DCU.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Renata Nunes Oliveira
    • 1
    Email author
  • Garrett Brian McGuinness
    • 2
  1. 1.Chemical Engineering Post-Graduation Program – PPGEQFederal Rural University of Rio de Janeiro (UFRRJ)Rio de JaneiroBrazil
  2. 2.Centre for Medical Engineering Research, School of Mechanical and Manufacturing EngineeringDublin City UniversityDublinIreland

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