Sustainable dressings for wound healing

Abstract

The field of chronic wound care has been rapidly evolving. With a market size for care of chronic wounds in billions of USD, this is not an insignificant area to encourage more sustainable practices and processes. The sourcing of starting materials for wound dressings from renewable resources is the first crucial step in ensuring that the environmental impact is minimized. Next important choice is to select methodologies in accordance with the principles of green chemistry. This involves utilizing green solvents as reaction media in the chemical processes for preparing dressing materials.

In many cases, like production of hydrogels, chemical crosslinking reagents are often employed. These can be, in general, easily replaced by enzymes like peroxidases, tyrosinases and sortases. Process intensification strategies have emerged as a powerful approach to ensure economy and sustainability in production of materials at large scale. Use of microwave radiations and ultrasonication instead of heat to accelerate reaction rates in production of dressing materials helps in many cases to inject sustainability in care of chronic wounds.

This review attempts to highlight the ongoing efforts and future possibilities in the area of the development of cost-effective wound dressings by sustainable methods.

Graphical Abstract

Introduction

Wounds are caused by injuries, burns, surgeries, pressure ulcers, venous ulcers, arterial ulcers, neuropathic ulcers, or diseases like diabetes or abnormal blood pressure. Wounds with impaired healing i.e. those which do not heal in a reasonable time period are called chronic wounds and are a source of considerable socio-economic burden. It has been reported that about 1–2% of the world population will have a chronic wound at some time in their lives. This estimate is largely based upon the data from the developed countries and is an underestimate of the number at the global level [1]. In UK, a 2012–13 study estimated that about 2.2 million patients were treated by the National Health Service. In USA, in 2009, > 6.5 million patients were treated for chronic wounds and this costed about USD 25 billion [2]. It is reported that globally, an amputation is carried out every 30 s due to a chronic diabetic wound [3]. Hence importance of the innovations in wound care cannot be over-emphasized. The advances in material science have led to the development of dressings utilizing polymers, nanocomposites, foams, hydrocolloid, hydrogels, hydrofibers, alginates, transparent films, growth factor dressings, impregnated medicated dressings, collagen dressings, enzymatic debridement dressings and other innovative materials, embedded with drugs, sensors, and even theranostic devices [4]. However, the thrust towards seriously leveraging sustainable chemistry into the design of the wound dressings seems to be missing. There are some important reasons for introducing sustainable practices in this sector. Given the growing demand/market size for wound dressings, it is desirable that we worry about their effects “from cradle to grave’’ on environments. This includes obtaining raw materials from renewable sources; designing production processes which are benign and consume less energy and finally keeping in mind the biodegradability of the massive waste generated after the dressings have been discarded. Some recent articles have described efforts towards introducing sustainable approaches at various stages of design and production of dressings for chronic wounds. Such efforts include use of naturally occurring materials; replacing chemical catalysts with enzymes; employing deep eutectic solvents or ionic liquids [5] and utilizing incorporation of process intensification approaches like microwaves [6], ultrasonication assistance [7], or flow catalysis [8].

This review is an effort to bring together the challenges and opportunities in introducing sustainable practices at all the stages in the production of dressings for care of acute or chronic wounds at a single place.

The coverage includes bringing in strategic thinking from the disciplines of both green chemistry and biotechnology. Hence, the review also aims to encourage cross-fertilization of ideas as this may lead to achieving greater sustainability in the use of the wound dressings.

Wound healing process

Wound dressings promote rapid healing by preventing infection, reducing inflammation and pain, and minimizing scarring, while maintaining a moist environment and allowing gas exchange. They should also be non-adherent, easy to remove, provide debridement, and be sterile, non-toxic, and non-allergenic. The wound healing process consists of four phases (Fig. 1). The first phase is hemostasis which consists of vasoconstriction, platelet aggregation and function of coagulation cascade, leading to thrombus [clot] formation; typically lasting from seconds to hours. The next step of inflammation involves release of cytokines and growth factors, recruitment of macrophages and neutrophils via chemotaxis and lasts from hours to days. The proliferation phase consists of epidermal resurfacing, fibroplasia, angiogenesis and synthesis of extracellular matrix [ECM], extending from days to several weeks. Finally, the maturation or remodeling stage leads to formation of ECM, development of scar tissue, wound closure and skin contraction, which may take weeks to even months [9, 10].

Fig. 1

Wound healing process. Taken from ref. [10]. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Acute wounds generally heal naturally and efficiently, typically in 6–8 weeks [11]. Chronic wounds, on the other hand, take longer time to heal due to factors involved in the four above mentioned phases of hemostasis, inflammation, proliferation, and remodeling [9]. The local factors include tissue hypoxia [important for cell metabolism], excessive exudate, necrotic tissue, infection, and overproduction of inflammatory cytokines [interleukin, IL-1 and Tumor necrosis factor, TNF-α]. Moreover, prolonged inflammation increases levels of metalloprotease and finally degrades the extracellular matrix [ECM]. Chronic wounds may result from diabetic foot ulcers [DFU]; abnormal blood pressure and burns; venous ulcers; arterial ulcers; nephropathic ulcers, neuropathic ulcers and surgical interventions [4, 12, 13].

Brief insight into wound healing dressings

Wound dressings have evolved considerably to address various needs throughout the different stages of the healing process. Gauze sponges, made from 100% cotton, are versatile and economical, suitable for cleaning, dressing, packing, or preparing wounds. Gauze bandage rolls can be used as a primary layer or for additional protection, particularly for wounds on limbs or the head [14]. Non-adherent pads are ideal for wounds with light to moderate drainage, protecting without sticking and providing an easy, all-in-one solution. For burns and wounds with similar drainage levels, non-adherent wet dressings maintain a moist wound bed, promoting cell migration without adhering to the wound [15].

Foam dressings, composed of ultra-soft and highly absorbent material, are perfect for wounds with moderate to heavy discharge, such as pressure injuries [16]. Calcium alginates, highly absorbent and capable of holding up to 20 times their weight in moisture, are especially useful for deep, tunneling wounds like arterial ulcers [17]. Currently, synthetic dressings like hydrogels and silicone meshes are commonly used for dry and necrotic wounds [18]. Hydrogel dressings add moisture to dry wounds, aiding in the breakdown of dead tissue and promoting cell growth [14]. Chen et al. developed an antibacterial and biodegradable composite hydrogel dressing by using oxidized alginate and carboxymethyl chitosan. They added gelatin microspheres loaded with tetracycline hydrochloride for enhanced effectiveness [19]. Transparent film dressings allow moisture transfer, secure the wound, and enable visualization, making them excellent for covering intravenous drip sites [20]. Table 1 briefly highlights the advantages and disadvantages of the various types of wound healing dressings.

Table 1 Advantages and disadvantages of wound dressings

Most of the above mentioned dressings utilize synthetic/ semisynthetic polymers and adhesives such as polyurethane, polyethylene glycol (PEG), polyvinyl alcohol, and polyacrylamide, which provide durability, flexibility, and an extended shelf life. However, these materials are non-biodegradable, leading to significant medical waste, approximately 70—80% of synthetic/ semisynthetic dressings contribute to the non-sustainable dressing segment. Once discarded, they typically end up in landfills, where they persist for decades, contributing to environmental burden. Additionally, the manufacturing process for synthetic wound dressings is energy-intensive and involves the use of various chemicals that can produce harmful by-products, thereby increasing environmental pollution [21]. Furthermore, many of these dressings are contaminated with biological fluids, they are categorized as hazardous waste, typically requiring incineration, a process that can release toxic gases [22]. With growing environmental awareness, comprehensive solutions for effective wound care are being developed. A systematic search for biodegradable dressing materials, particularly those sourced from renewable origins has provided effective wound care solutions with reduced environmental impact. Additionally, nanomaterial technology has introduced another innovation in wound dressings as it enables controlled drug release and targeted therapy using sustainable materials [23]. Recently, Wang et al. have described a nanocomposite prepared from chitosan, astralagalus polysaccharide [AP] and dihydromyricetin [24]. AP exhibits antibacterial, immunomodulatory activity, promotes release of cytokines and demonstrates a good water vapor barrier as a membrane whereas dihydromyricetin exhibits antiparasitic, antibacterial and anti-inflammatory activities. It is interesting to note that microwave-based extraction method for AP is available which adds to the green quotient and the self-assembled nanocomposite of AP utilizes no harsh chemicals for its synthesis. Another study by Reves [25] revealed that a nano silver/zinc oxide (Ag/ZnO)—loaded chitosan composite dressing, displayed high porosity, a substantial swelling ratio, and prolonged moisture retention, along with enhanced blood-clotting capability, suggesting its potential for wound care. Additionally, 3D printing technology also offers customizable solutions with biocompatible and sustainable materials, thus reducing the environmental footprint of wound care [26]. Such advancements represent a significant step forward in creating wound dressings that are both effective and environment—friendly, aligning with broader sustainability goals in healthcare.

Sustainable wound dressing materials

Ghomi et al. [27] have listed chitin, chitosan, bamboo viscose, gelatin, feather keratins, alginate, collagen [also crosslinked collagen], collagen peptides, silk fibroin and bacterial cellulose as dressing materials from natural sources. The polymers of natural origin also include dextran, hyaluronic acid, κ-carrageenan etc. which are formulated into dressings of different types and can be loaded with drugs. It is important to emphasize that these natural polymers are biocompatible, non-toxic, and safe, while also actively supporting the wound healing process [27, 28]. For instance, chitosan promotes macrophage function; gelatin is anti-inflammatory; alginate promotes hemostasis; κ-carrageenan absorbs exudates, facilitates thrombus formation and exhibits antioxidant and antiviral effects. Hyaluronic acid is reported to be antibacterial, anti-adhesive and viscoelastic; while fibroin is useful as hemostatic and is permeable to both oxygen and water vapor [29]. Cellulose helps to prevent bacterial infection. Thus, it is not surprising that many commercial dressings made from these polymers are already available in the market. Table 2 summarizes few important examples of sustainable polymers, their chemical structures, along with sources, advantages, and marketed products:

Table 2 Sustainable polymers used in wound dressings, their chemical structures, sources, advantages, and marketed preparations [28, 30,31,32,33,34,35,36,37,38].

Polyvinyl alcohol [PVA] as a biodegradable and biocompatible hydrogel has been investigated for designing wound dressings [35]. Additionally, other sustainable materials such as chitosan, polylactic acid, siricin and keratin are also being explored for electrospinning applications. Many workers have described the fabrication of nonwoven cellulose hydrogel layers [39,40,41,42,43]. Their studies highlighted the enhanced absorption of wound exudate and the capability of incorporating antibacterial loading an antimicrobial agent such as titanium particles, while maintaining excellent air permeability in the dressings [42,43,44,45]. Recently, Mani et al. have reviewed sustainable electrospun materials for fabrication of wound dressings [43, 44].

The importance of exploiting waste for useful purposes as a part of the circular economy has been pointed out recently by Roy and Gupta [45]. Sandoval et al. have written a comprehensive review on reuse of plant and animal waste for developing sustainable materials [44]. The biodegradability, adequate material strength and elastic modulus of several [composite] materials described by them suggest that many may be worth considering as materials for preparation of modern and advanced wound dressings. The review mentions utilization of seeds [of mango and citrus plants]; leaves [of cactus, orange, pineapple and green tea]; peels [banana, orange, lemon, garlic]; rice and pineapple husk; flax, straw and corn cobs from plant sources. Among waste from animal sources, crab and lobster shells; fish skin and bones; wool waste; hair and feathers have been extensively investigated. Of course, one has to ensure that these starting materials are free of pathogens before their processing. The main challenge is to develop sustainable processes for their pretreatment and conversion into the finished products.

Another important sustainable option is the use of biodegradable polymers. Hence, some brief discussion on biodegradability of the polymers may be pertinent. The aim should be to be able to efficiently degrade them within a reasonable time period and reintegrate them into the circular economy [45]. The recent article by Susana et al. constitutes a good case history in this regard [46]. They highlight the challenges associated with plastic recyclability, noting that only 9% plastic could be recycled in early years. Poly[lactic acid] as an example of so called biodegradable polymer is a case in point. Despite being considered biodegradable, its production in 2021 was 457,000 tons and its industrial composting requires 84 days at 60 °C. Susana et al. propose a strategic solution that combines many sub-strategies, which have gradually evolved into a successful approach. Let us backtrack and look at what all led to this brilliant work.

In recent years, ILs have emerged as a valuable green solvent for depolymerization reactions. At the same time the versatility of enzymes has been expanded through their use in green solvents including ILs and DES [47]. Brogan et al. [48] demonstrated the modification of glucosidase to enhance its solubility in an IL and have successfully used it to convert cellulose into glucose. In such cases, both biocatalyst engineering and medium engineering are required so that [a] the enzyme dissolves and is still active under the reaction conditions which also generally involves elevated reaction temperature, [b] the polymer also dissolves, and [c] hydrolysis is favored over reverse synthesis.

Among the enzymes used often in non-aqueous solvents are hydrolases in general and lipases in particular [49]. Lipases have been long known to work well in ILs. Altering surface charges on hydrolases has been shown to improve their catalytic activity in non-aqueous solvents [50]. The approach of Susana et al. consisted of modifying lipase B from Candida antarcticawith N,N’-Dimethyl 1,3-propanediamine by using carbodiimide coupling which puts higher positive charges on the enzyme [46]. The modified lipase was complexed with a surfactant glycolic acid ethoxylate lauryl ether. In this form the melting temperature [Tm] of the enzyme increased to 71 °C making it much more thermostable for catalyzing the hydrolysis at the elevated temperature. The surfactant-enzyme complex was soluble in the ILs. The search for the best IL led these workers to identify [1-ethyl-3-methylimidazolium trifluoro sulfonate/ emim]. The biocatalyst depolymerized poly[lactic acid] completely to the monomer within 40 h at 90 °C. The reaction was carried out at the controlled humidity of 90% to ensure that the hydrolysis is favored over reverse reaction which polymerizes lactic acid as it accumulates at higher % conversion. This illustrates how putting together information from different areas can lead to innovative solutions in our search for a more sustainable technology [46].

Crosslinking technology in sustainable hydrogel dressings

A snapshot of sustainable starting materials in the context of wound dressings has been provided in the above section. Next desirable goal is to employ as far as possible principles of green chemistry and green engineering to synthesize or tailor the material to the desired product which in this case is an ideal wound care dressing component [51].

Crosslinking plays a vital role in various stages of designing wound dressings. Hydrogels are fabricated using crosslinking agents either by self-assembly processes mediated by non-covalent interactions such as ionic, inter molecular hydrogen bonding interactions or chemical coupling strategies such as Schiff base reaction or free radical polymerization using UV radiation or via enzymatic reactions, as shown in Fig. 2 [52].

Fig. 2

Processes leading to the formation of hydrogels. Taken from ref. [52]. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The approach of chemical crosslinking deserves a more detailed discussion.

Chemical cross linking

A promising avenue in the pursuit of environmentally friendly crosslinking methods involves exploring nature itself. Disulfide bridges in proteins serve as a prime example of naturally occurring crosslinks. Indeed, nature harnesses crosslinking in various systems, and its significance extends to both agriculture and medicine [53].

Some naturally occurring chemical cross-linkers such as genipin [54] have been explored as green options while crosslinking polymers or proteins. In an example of yet another such cross-linker, Liu Chennan and colleagues [55] reported a wound healing artificial skin made up of chitosan nanocomposite hydrogel cross-linked with vanillin and supported with graphitic carbon nitride and starch-capped silver nanoparticles [Ag NPs]. In a separate investigation, Kim et al. [56] have developed a self-assembled hydrogel consisting of polymers derivatized by biotin and streptavedin aimed at enhancing durability and shear elasticity. This exploits the well-known affinity pair of biotin and avidin or its derivatives like streptavidin. This approach represents yet another general method for carrying out a self-assembly process.

Crosslinking using enzymes

A major route for bringing in green chemistry is to use enzymes [instead of chemical bifunctional reagents] for crosslinking purposes. Transglutaminases [EC 2.3.2.13] [57]; the oxidoreductases [1.14.11] [58], Tyrosinases [EC 1.14.18.1] [59], Peroxidases [EC1.11.1.7] [60] and Laccases [EC 1.10.3.2] [61] are the most important crosslinking enzymes in biological systems.

Transglutaminases [TG]

It forms the crosslink between the γ-carboxyl of glutamic acids with ε- lysine in proteins. The isopeptide bond can form both intra—and intermolecular crosslinks in proteins. Blood clotting [Factor XIII], keratinization of epidermis and wound healing involve TG catalysed reactions. The TG family [TGF] comprises 9 members, including tissue TG [tTG], which exists in two conformations: a GTPase-like ‘closed conformation’ and a crosslinking-active “open conformation”. High calcium ion / GTP ratio [as in extracellular environments] leads to crosslinking activity. tTG is a component of macrovesicles [MVs] secreted from some cancer cell surfaces into their immediate space. MVs increase metastasis. tTG oligomerizes fibronectin [a glycoprotein over expressed in cancer cells] which facilitates attachment of MVs to surrounding cells initiating their transformation to cancer cells [62]. tTG also oligomerizes vascular endothelial growth factor in MVs; the oligomers bind to the endothelial cells and promote angiogenesis.

Tyrosinases

Enzymatic browning due to tyrosinase enzymes is responsible for production of melanin, the skin pigment. In fact, the reactive o-quinones during melanin formation react with amino [and thiol] groups of skin proteins to form melanoproteins. Such crosslinks are not only responsible for color of hair and bird plumages but also constitute browning reactions taking place in humus formation and maturation of tea leaves. The dark brown color of adult cockroaches also arises from crosslink formations by tyrosinases. However, o-browning reaction can have detrimental effects on various agricultural products during storage/processing due to the presence of polyphenols like caffeic acid and chlorogenic acid, which produce their o-quinones which react with endogenous proteins [63].

Laccases

These enzymes have much broader substrate specificity as compared to tyrosinases and also generate free radicals of phenols / polyphenols, amines / diamines, benzenethiols. Laccases can crosslink pentosans and different residues in peptides and proteins. Various precursors such as dextran, galactoglucomannan, carboxymethyl cellulose, gelatin, hyaluronic acid etc. when cross linked with tyramine, aminophenol, 4-hydroxyphenyl acetic acid or hydroxyphenyl propionic acid forms graft polymers. When these graft polymers are oxidized by reacting with laccase and peroxidase, it forms a reactive species that crosslinks and forms hydrogel [64].

Oxidase enzymes

During the hemostasis/inflammation phase, large amounts of reactive oxygen species [ROS] are produced by NADPH oxidase secreted by neutrophils and macrophages. NADPH oxidase uses molecular O₂ to produce O₂⁻, which is converted into H₂O₂ by superoxide dismutase. In parallel, NO synthase produces NO, which reacts with O₂⁻ to produce peroxynitrite [ONOO⁻]. These ROS oxidatively kill bacteria, while on the other side collagenases and elastases are produced by macrophages and neutrophils degrade the dead tissue and bacteria. Besides killing bacteria, the ROS stimulate the reduction of blood flow to the site of injury, thereby stopping bleeding. Beyond hemostasis/inflammation, ROS [especially H₂O₂and NO] participate in many cell signaling activities including stimulating the release of growth factors such as platelet-derived growth factor PDGF, the transforming growth factor beta [TGF- β] family, interleukins [IL], fibroblast growth factor [FGF], and vascular endothelial growth factor [VEGF], which are important for cell recruitment, proliferation, migration, differentiation of fibroblasts, endothelial cells, and keratinocytes [65].

Peroxidases

Endogenous peroxidases in flours crosslink gluten proteins with arabinoxylans or crosslink arabinoxylans [via their ferulic acids] to form larger and insoluble arabinoxylans. Animal peroxidase in basal membranes generates hypobromous acid which leads to formation of sulfilimine crosslinks in the collagen of these membranes. Basal membranes, below all tissue cell layers, play a critical role in organs [66].

Glucose oxidase [EC 1.1.3.4]

Glucose oxidases and other hexose oxidases generate hydrogen peroxide [H₂O₂] which in turn oxidizes sulfhydryl groups into disulfide crosslinks [for example in gluten and arabinoxylans] [67]. Wound dressing composed of alginate and glucose oxidase enzymes also produce H₂O₂ and lactoperoxidase enzyme. This H₂O₂ oxidizes thiocyanate, bromide and iodide to hypothiocyanite [OSCN⁻], hypobromite / hypoiodite [OBr⁻ / OI⁻] serving as potential antimicrobial agents. These agents facilitate the wound debridement process, absorb wound exudates and thereby inhibit growth of microorganisms [68].

Lysyl Oxidase[LOX]

This enzyme, also known as protein lysine-6-oxidase [EC 1.4.3.13] initiates crosslinking in collagen and elastin by oxidative deamination of specific lysine and hydroxylysines. It is over expressed under hypoxia and involved in cancer progression [particularly breast cancer]. It is also upregulated in adipose tissues with obesity and fibrosis [69]. Its role in insulin dependent diabetes mellitus is also known for quite some time [70]. The collagen in these patients has increased crosslinking due to formation of Maillard type advanced glycosylation products by nonenzymatic route as well as LOX catalyzed formation of dihydroxylysinonorleucine and subsequent tri- and tetra- functional crosslinked products. The changes in capillary basement membranes due to this are associated with retinopathy and nephropathy.

Lipoxygenase [EC 1.13.11.12]

Lipoxygenases also generate free radicals which can oxidize thiols to disulphide crosslink or generate reactive crosslinking molecules like malondialdehyde [71].

Sulfhydryl oxidases

These include both glutathione oxidase [EC 1.8.3.3] and thiol oxidases [EC 1.8.3.2]. These enzymes generate disulfide bridges [72].

Sortase [EC 3.4.22.70]

These enzymes function as transpeptidases, facilitating the sequence-specific ligation of proteins. Strijbis et al. [73] have reported the use of sortase to convert linear proteins into circular ones which were more stable towards denaturation. Also, Li et al. 2017 [74] used sortase to obtain dimers and trimers of subunits of a dehydrogenase/reductase with improved thermostability. While the above discussion shows how enzymes can form crosslinks in other proteins, it may be interesting to add that some structural proteins in the eukaryotic cytoskeletons also act as crosslinking proteins. The cytoskeleton in eukaryotic cells consists of 3 types of filaments: Actin filaments, microtubules and intermediate filaments [75]. However, a large number of accessory proteins control the assembly of filaments and are also essential for filamentous motion as well as movements of cellular organelles on the filaments. Actin filaments are organized in networks by actin binding proteins [such as fascin, filamine, cortexillin and anillin]. These networks are dynamic assemblies. The in vitro cell motility assay showed that these actin binding proteins crosslink the actin filaments and play a crucial role in the way the filaments are organized as well as in cell motility under different conditions [76]. The actin and myosin networks are particularly instrumental in wound repair, while microtubules facilitate the delivery of membrane and other components to the wound site.

Fabrication of wound dressings using enzyme-mediated crosslinking methods

While not all enzymes discussed above have yet been utilized for crosslinking in design of wound dressings, enzyme-mediated crosslinking has been employed in several instances. Sobczac [77] has listed the use of various enzymes employed in crosslinking for preparation of polymer hydrogels.

The crosslinking by transglutaminase for forming hydrogels of fibrin, collagen, gelatin and hyaluronic acid has been described in the context of tissue engineering but the approach is equally useful for fabrication of wound dressings [78]. However, enhancing the mechanical stability of these hydrogels remains a challenge. In another study, Kim et al. [79] used tyrosinase to crosslink green tea polyphenol epigallocatechin gallate to the free amino groups on chitosan. This group had earlier used chemical crosslinking to link polyphenols to alginate and hyaluronic acid and decided to try enzyme mediated crosslinking to develop a greener method. The stable hydrogel facilitated skin regeneration in a wound. The polyphenol helped as it acted as a scavenger of the free radicals generated by immune cells like macrophages and down regulated tissue necrosis factor and interleukin-1. Polyphenols also are known to be antimicrobial. Kim et al. successfully developed a tissue adhesive hydrogel by combining hyaluronic acid and gelatin crosslinked with mushroom type tyrosinase [80]. The hydrogel, featuring strong tissue adhesive characteristics, holds promise for applications in cartilage engineering and regeneration [81]. Moreover, increased levels of the enzyme and substrate led to reduced gelation times. Research by Lu et al. showcased the potential of human adipose-derived stem cells encapsulated in a gelatin/microbial transglutaminase hydrogel for enhancing wound healing through improved angiogenesis [82]. Recently Rusu et al. [83] explored the self-assembly of nanogels to enhance self-healing capacity and drug distribution within the hydrogel network. Transglutaminase-mediated crosslinking played a crucial role in the rapid formation of these hydrogels and encapsulating nanogels under mild conditions. Zang et al. [84] addressed the mechanical challenges of enzymatically cross linked biohydrogel by employing chitosan with phloretic acid cross linked with horseradish peroxidase and gelatin cross linked with transglutaminase enzyme. The biohydrogel displayed enhanced strength and durability. Ding et al. [85] developed an enzymatically crosslinked hydrogel capable of mimicking the cellular microenvironment for biomedical applications. The study involved blending gelatin and tyramine solutions with chitosan-sialic acid to create the hydrogel, followed by crosslinking facilitated by horseradish peroxidase. The outcome demonstrated potential for various biomedical applications, notably in wound dressing.

This may be the appropriate place to point out that crosslinking also plays a pivotal role in different stages of wound healing. During the hemostasis phase, the conversion of soluble fibrinogen into fibrin necessitates crosslinking. In the final remodeling phase of the wound healing process, the reduction in scar thickness and the enhancement of mechanical strength in new skin are achieved through collagen cross linking.

Applications of green solvents for production of dressings

Recently, Mahmood et al. have discussed the use of IL in extraction of chitin/chitosan, agar/agarose, guar gum, starch, silk, collagen and keratin [5]. However, even more interesting is the use of both DES and ILs as green solvents for wound healing purpose. In recent years, there has been a growing usage of ILs as permeation enhancers and as a new class of formulations. In recent years, new generations of ILs have been described which are definitely superior in this respect [86,87,88]. The hydrophilic ILs facilitate the movement of molecules along the paracellular pathway and disturb the tight connection of the stratum corneum, causing fluidization of the cell membrane, while the hydrophobic substances prefer the transcellular pathway and disrupt the epithelial barrier, creating a pathway within the subcutaneous layer (refer to Fig. 3] [87]). Due to electrostatic interactions, ILs are attracted towards negatively charged outermost layer of bacterial cell membranes. The hydrophobic extended alkyl chains of the ILs permeate the lipid-rich region within cell membrane and damage the bacterial cell surface. The incorporation of borate ions creates a 3D network structure that limits the escape of antibacterial ILs and promotes moisture retention, hence enhancing the efficacy of wound healing.

Fig. 3

Utilizing antimicrobial properties of ionic liquids in (A) prevention of biofilm formation (B) Wound healing (C) Wound dressing. Taken from ref. [87] which is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Xu et al. synthesized and evaluated polymeric ionic liquid [PIL] membranes containing imidazolium cations coordinated with zinc ions [89]. The PIL membranes containing zinc exhibited enhanced antibacterial efficacy against E. coli, S. aureus, and C. albicans in comparison to the PIL membranes without zinc. The improved effectiveness of this treatment was attributed to the synergistic effect of the positive charges generated by the imidazolium cation and zinc ions, which specifically targeted the negatively charged surface of the bacteria. Similarly, the gauze dressing when coated with benzimidazolium based dipodal IL exhibited enhanced antibacterial efficacy against pathogens in laboratory experiments, in contrast to the gauze that was not coated. This was particularly evident in its ability to inhibit bacterial proliferation. Crucially, the ILs exhibited no harmful effects on mammalian cells. They exhibited a significant propensity to form complexes / chelates with metal ions such as Fe³⁺ on the bacterial cell wall surface, hence causing the cell death due to iron deficiency [90].

DESs have been also used instead of IL in the healing dressings due to their safety, biocompatibility, water solubility, non-inflammability, very low volatility, and non toxicity [86]. Silva et al. explored wound healing DESs composed of menthol and saturated fatty acids such as stearic acid, myristic acid, and lauric acid for their potential application in wound dressing [91]. Another study found that the combination of menthol and stearic acid exhibited the most promising formulation for wound healing [92].

Applications of microwaves and ultrasonics in preparation of wound healing dressings

Microwave (MW) irradiation enables rapid and uniform heating, which lowers energy consumption and is environmentally friendly while preserving sensitive compounds and enabling precise synthesis. This method enhances safety by reducing the use of solvents and limiting exposure to toxic chemicals [93]. Wang et al.prepared hydrogel formulation of interpenetrating polymer network of poly(chitosan–gelatin) / polyvinylpyrrolidone crosslinked by 1,2-epoxy-4-vinyl cyclohexane via microwave and ultrasound [94]. The mechanical properties of hydrogels obtained via microwaves and ultrasonic waves exhibited the highest tensile strength compared to the hydrogels prepared by conventional methods and with use of microwave only.

Mahmood et al. have developed a method using microwave-treated polymer blend film for wound healing in diabetic animals [95]. The film was tested for physicochemical attributes and wound healing potential. The formulation optimized using microwave technology showed enhanced properties like high moisture adsorption, decreased water vapor transmission rate, delayed erosion, high water uptake, smooth surface morphology, higher tensile strength, increased glass transition temperature and enthalpy. In vivo data showed faster wound healing and enhanced collagen deposition. Microwave-treated films are effective for improving diabetic wound healing.

Utilization of low-frequency [high-power] ultrasonic treatment in hydrogel preparation is advantageous due to its physical effects, including increased shear rates, generation of free radicals in solution, and heat production. Ultrasonic treatment improves even dispersion and distribution of components, promotes quick linking of polymer chains within hydrogels, modifies the viscoelastic properties of the gel and also facilitates the effective release of encapsulated drug. However the extensive implementation of ultrasound in polymer manufacturing has been hampered by its high-power demands and restricted monomer conversion [96].

Cai et al. [96] as shown in Fig. 4 demonstrated the use of ultrasound technique for efficiently regulating protein structure during the solution assembly stage. Silk fibroin proteins dissolved in a formic acid and CaCl₂ solution system underwent treatment with ultrasound at different durations and intensities. Ultrasound improves the interaction between calcium ions and silk molecules, leading to more intermolecular β-sheet and α-helix configurations. This structure alteration makes silk film water-resistant and swellable. Ultrasound-treated silk textiles have improved thermal stability, biocompatibility, breathability, mechanical strength, and flexibility. Adjusting ultrasonication conditions controls enzymatic degradation of the product and biological responses, such as cell growth and proliferation to it.

Fig. 4

The mechanism of ultrasonic treatments on silk fibroin materials regenerated from the formic acid-CaCl₂ solution system. Taken from ref [96]. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

You et al. have recently developed a sponge dressing derived from the fermentation liquid of Lactobacillus plantarumZDY2013 [LFL] through ultrasonic-microwave-assisted synthesis [97]. The LFL was treated with zinc acetate dihydrate using sonication to form LFL-ZnO. A sponge dressing was then fabricated using LFL-ZnO, polyvinyl alcohol and sodium alginate via a cyclic freeze–thaw process followed by freeze-drying. The resulting composite sponges exhibited a porous structure conducive to wound penetrant absorption, moisture retention, and favorable biodegradation and thermal degradation properties. Incorporating LFL-ZnO, renowned for its potent antibacterial properties, not only bolstered the sponge's structural integrity but also heightened its antibacterial efficacy.

Microwave assisted method has been often utilized for extraction of biopolymers from the cells of microalgae. This technique has been particularly effective in the microwave-assisted water extraction of hybrid carrageenan from Mastocarpusstellatusred algae, leading to notable improvements in extraction yields [98]. Hence, one can explore the use of electromagnetic waves to assist in biopolymer production, potentially leading to the development of novel methods to achieve high yields and economic efficiency.

Some advanced sustainable dressings

It is noteworthy that design of even some advanced dressings with sustainable approaches has been possible. Shinde et al. developed a green synthesis method for producing silver thin films with large areas containing nanoparticles using guava leaf extract as a reducing agent. This approach enabled rapid and uniform production of silver films with varying thicknesses [99]. Gupta et al. investigated a multifunctional biocomposite consisting of chitosan, gelatin, and silver nanoparticles synthesized via an eco-friendly method [100]. The biocomposites exhibited high water uptake and demonstrated substantial antibacterial activity against E. coli, as well as promising biocompatibility and wound healing potential in vitro. These findings suggest the potential of the silver nanoparticle-biocomposite as an effective topical dressing for various biomedical applications. Wang et al. developed a natural, degradable, anti-inflammatory and antimicrobial hydrogel wound dressing utilizing aloe vera as an active component along with sodium hyaluronate and dopamine [101]. This hydrogel dressing stands out for its degradability, biocompatibility, and environmental friendliness. Tested with NIH-3T3 fibroblast cells, it displayed cytocompatibility and exhibited antibacterial properties against both gram-positive [S. aureus] and gram-negative [E. coli] bacteria. Additionally, it promoted skin tissue regeneration and accelerated wound healing in mouse skin post-surgery, achieving full recovery within a mere 12 days. Griffin et al. [102] prepared hydrogel of hyaluronic acid based microporous annealed particles which showed increased tissue regeneration in healed wounds when peptides of D-amino acids were used for crosslinking hyaluronic acid chains. These scaffolds degrade in the protease-rich wound environments. When peptides of D-amino acids were tried as linkers, the scaffolds surprisingly did not show lower proteolysis. However, they resulted in increased tissue regeneration in case of healed cutaneous wounds. It turns out that these scaffolds resulted in better recruitment of IL-33 type 2 myeloid cells and provoked adaptive immune response specific to D-peptides. This interesting observation should lead to some further innovative work in the design of sustainable wound care dressings.

In another path-breaking approach, Wang et al. [103] demonstrated an innovative method involving combination of M2 macrophage cytomembranes and fibroblasts. This approach effectively regulated inflammation; promoted matrix reconstruction, neovascularization and angiogenesis respectively in a pre-clinical murine skin wound. Subsequently, the injection of TGF-β inhibitor effectively controlled cutaneous scar formation. Kim and Nair [104] have provided an insightful review on the role of macrophages in wound healing. A key step in the approach of Wang et al. was transformation of inflammatory phenotype M1 macrophage to anti-inflammatory M2 by contact with fibroblasts. It is M2 macrophages which secrete IL-10 and TGF- beta and thus promote angiogenesis and wound healing in general. Li et al. [105] have later described a simple combination of konjac glucomannan and gallic acid which transforms the M1 macrophages to M2 type. The dressing made of these two materials promoted wound closure, collogen deposition and angiogenesis. It may be pointed out that gallic acid is a common polyphenol which can be isolated from agricultural waste [45]. Kong et al. [106] described fabrication of a 3D hydrogel consisting of chitosan and composite nanoparticles made from melanin linked to C60 via glycine oligopeptide as the linker. The length of the oligoglycin and C60 content regulated the photodynamic and photothermal efficiency. The gel had high ROS / heat production in the upper region of the wound [to kill bacteria] and mild effect in the lower region which facilitated conversion of M1 phenotype macrophage to M 2 phenotype and ultimately their autophagy.

The approach of Daristole et al. [107] is worth mentioning as a simple sprayable dressing for large total body surface wounds. Their dressing applied by solution blow spinning consisted of a biodegradable blend of poly lactic-co-glycolic acid / polyethylene glycol [PLGA/PEG] /PEG loaded with antimicrobial silver. The dressing showed high exudate absorption, resulted in increased vascularization and required less frequent changes. One change which can easily further improve green quotient is employing green solvents instead of acetone or ethyl acetate for dissolving PLGA/PEG blend.

A mutifunctional composite hydrogel consisting of PVA-Iodine, carboxymethylcellulose [CMC] and carbamino quantum dots which self-assembles via H-bonds has been described recently [108]. PVA-Iodine when irradiated with near-IR or visible light elevates the temperature, accelerates migration of epidermal cells, releases iodine [and thus is antibacterial] in a pH responsive manner. The quantum dots could sense pH changes during wound healing [and hence obviate the need for frequent change in dressings]; CMC also aided wound healing.

An example of another sophisticated design is a dressing material which uses starch-chitosan granules embedded in gelatin network. As the chitosan occurs on the surface, it could be linked to a drug such as aspirin. The dressing patch can release the drug carrying granules in a stimuli-sensitive manner. The drugs, aspirin or niacin enhanced the bioadhesive nature, thus increasing the interaction of the granules with the wound surface. In a mouse dorsal skin wound, the released granules facilitated wound closure.

A class of materials as candidates for fabrication of futuristic wound dressings are intrinsically disordered polymers wherein elastin like polypeptides [ELPs] can guide cell localization in a spatiotemporal fashion. In addition to ELPs, these can use other intrinsically disordered protein regions from resilins, spider silk protein, fibrillin, titin and gluten [109].

Future perspective

The synthetic polymers and their composites have many attractive qualities and are bound to be part of fabrication of future dressings. It would be prudent to derive their basic building blocks from platform chemicals [45]. Also, an older article on green polymer chemistry which talked about bio-based building blocks, synthesis keeping in view the principles of green chemistry, degradability and recycling has valuable information which is still relevant [110, 111]. The important concept now subsumed in the biorefinery approach is that of platform chemical. It has been determined that about 12 low molecular weight compounds can replace building blocks of petrochemical origin in organic synthesis. Generally classified as C3, C4, C5, C6 chemicals, these can be obtained from biorefineries based upon lignocellulose, starch and other sugars [used for fermentation] and triglycerides [112, 113].

Often, a chemo-enzymatic route becomes necessary, and there are several green options available, where water is used instead of organic solvents as the reaction medium, for chemo-enzymatic routes [114, 115]. In this regard, it will be nice to see biosurfactants replacing chemical surfactants for even greater sustainability [116].

Self-healing hydrogel with sustainable designs are likely to become even more important in future [117]. Finally, mention may be made of two promising approaches which are yet to be exploited widely. Three phase partitioning is a simple process which uses benign substances like tert-butanol or ILs or dimethyl carbonate to extract polymers from natural sources. This process can be coupled with process intensification strategies as well to make it even more efficient [118]. Another interesting observation is that microwave pretreatment of xylans, pectin and cellulose was found to make these polymers more biodegradable [119]. The large waste material consisting of the dressings discarded after use constitutes a biohazard and it is high time that we start developing benign and efficient strategies for their degradation to safe small molecular weight products.

Conclusion

It is never too early to pay attention to the sustainability aspect of wound dressings. This review points out the progress and opportunities related to that. Specifically, that touches upon the following aspects:

• * Selecting renewable materials for producing dressings.

• * Extracting and separating these by green approaches.

• * Using enzymes, both as catalysts and crosslinking reagents instead of harsh chemicals, preferably in green solvents for designing and production of wound dressings.

• * Use process intensification strategies such as microwave assistance and ultrasonication to save energy during the production of these indispensable wound care materials.

These efforts align with Sustainable Development Goals [SDGs] of good health and well-being [SDG 3]; Industry, Innovation, and Infrastructure [SDG 9], and Responsible Consumption and Production [SDG 12].