The use of silver hydrogel in wound treatment as an alternative to reduce antibiotic- resistant pathogens

Medical science is currently at an early stage for effectively controlling skin damage. One of the main barriers to good wound healing is bacterial infection, which poses a risk of long-term harmful effects. A clean wound, free of bacterial infections, is essential for the quick and effective regeneration of the skin. Hydrogel is one of the best biomaterials for antibiotic delivery in wound areas due to its high hydrophilicity, distinctive three-dimensional network, good biocompatibility, and cell adherence. Although many antibiotics are successful in treating infected wounds, improper or repetitive use of these medications may cause germs to become resistant. Notoriously, antimicrobial resistance in pathogenic bacteria is already considered a serious global public health issue. Recently, the use of silver associated with nanotechnology has been reconsidered as an important alternative to reduce the spread of antibiotic-resistant pathogens. Silver hydrogel dressings have become effective agents in wound management, substituting the use of antibiotics. The objective of this review is to show the importance of hydrogels in wound treatments, as well as the antibacterial properties of silver hydrogels and their implications in wound care.


Introduction
The skin is unquestionably the organ of the human body most vulnerable to injury, scrapes, and burns. Notoriously, the damaged epithelium and connective structures weaken the human body's capability to protect the outer environment.
Consequently, it is essential to remodel a healthy epidermis or even additional skin layers. When the healing process takes longer, the wound's typical microbiota alters and hosts more aggressive bacteria (Serra et al., 2015). Gram-positive bacteria, primarily Staphylococcus aureus, are more prevalent in the early stages of chronic wound development (García-Pérez et al., 2018;Serra et al., 2015). Gram-negative organisms (e.g., Escherichia coli and Pseudomonas spp.) are more prevalent and more prone to infiltrating the deeper layers of the skin in advanced stages, negatively impacting the tissues (Lyczak et al., 2000;Petkovšek et al., 2009). To combat the health problem caused by wound infections, different types of wound dressings have been created to protect the wound from bacterial contamination and to hasten the wound healing process (e.g., sponges, hydrogels, films, hydrocolloids, and hydrofiber mats) (Ahmed & Boateng, 2018;Capanema et al., 2017;Koehler et al., 2018;Yao et al., 2017;Ye et al., 2018). Recent studies have focused on incorporating bacteriostatic or bactericidal antibiotics into the wound dressings to assist wound healing (e.g., quinolones, tetracyclines, aminoglycosides, and cephalosporins) (Anjum et al., 2016;Michalska-Sionkowska et al., 2018;RǍdulescu et al., 2016). Although many antibiotics are effective in the treatment of infected wounds, repeated or incorrect use of these drugs might lead to bacterial resistance (Rai et al., 2016). Notoriously, at least one of the most widely used antibiotics cannot effectively treat 70% of the bacteria that cause wound infections (Friedman et al., 2016). For example, strains of Staphylococcus aureus and Pseudomonas aeruginosa were both considerably resistant to antibiotic treatment, according to a study done on 470 samples of wound secretions with bacterial identification (Pirvanescu et al., 2014). The abusive and inappropriate use of antibiotics has brought the crisis of resistant bacteria to light. Such a situation is considered a global threat and one of the main problems that science and medicine currently face (French, 2010;Hawkey, 2008). According to the World Health Organization (WHO), by 2050, antimicrobialresistant bacteria will cause the death of more than 10 million people per year (Kraker et al., 2016). In this scenario, it is necessary to seek alternatives to help fight against antibiotic-resistant bacteria.

Methodology
The current study is an integrated literature review that synthesizes information on the use of silver hydrogel in wound treatment as an alternative to reduce antibiotic-resistant pathogens and incorporates the relevance of important research findings in practice. A literature review from bibliographic research in reliable scientific databases such as Science Direct, Scopus, Wiley Online Library, and Scielo was done between July and September 2022. To search for scientific articles, terms such as "silver hydrogel," "wound treatment," "antibiotic-resistant pathogens," "biomedicine," "infection," and "medical treatment" were used. Criteria such as articles mostly in English, open-access availability, and preferably published between 2012 to 2022 were adopted for the selection of the most relevant publications on the use of silver hydrogel in wound treatment as an alternative to reduce antibiotic-resistant pathogens. However, it is important to note that although a few articles used in this review were published before 2012, they were still included in the present study due to their scientific importance, and most have a more reasonable number of citations. This review did not include dissertations, thesis, or information found on web pages.

Hydrogel: Morphology and classification
The synthesis of poly (hydroxyethyl methacrylate) in 1960 is considered the beginning of modern hydrogel research (Wichterle & Lím, 1960). In this context, Wichterle and Lim sought to develop such polymeric matrices for biomedical purposes, with potential application to the human body. According to Kokabi, in 1989, Rosiak implemented the use of hydrogels as a basic material for the manufacture of wound dressings (Kokabi et al., 2007). And since then, there has been considerable progress in the synthesis and applications of hydrogels in the most diverse areas of knowledge. Hydrogels are cross-linked polymeric networks with a three-dimensional configuration capable of absorbing large amounts of water or biological fluids without suffering structural damage. This characteristic of hydrogels is attributed to the presence of hydrophilic groups, such as -OH, -COOH, -CONH, -CONH2, and -SO3H, in polymers that form the structures of hydrogels (Hamidi et al., 2008;Ullah et al., 2015).
Hydrogels are classified according to the method of formation, the ionic charge, and how the networks are reticulated (Nascimento & Lombello, 2016). Concerning the formation of chains, hydrogels are classified as homopolymers when only one type of monomer is used; copolymers when more than one type of monomer is used; and interpenetrating polymers when the polymeric chains of a given hydrogel penetrate and entangle with the chains of another hydrogel, forming blends (Nascimento & Lombello, 2016). Regarding the ionic charge, hydrogels are classified as neutral when they do not present ionizable groups (e.g., methyl methacrylate); cationic when they have groups capable of forming cations by changing the pH of Research, Society andDevelopment, v. 11, n. 12, e387111234849, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i12.34849 4 the reaction medium; and anionic when the hydrogel presents anion-forming groups, also due to the pH variation of the reaction medium (Nascimento & Lombello, 2016). Interestingly, the polymeric chains of a hydrogel can be chemically or physically linked, leading to permanent or reversible gels ( Figure 1). Chemical hydrogels are formed by different macromolecular chains that are permanently joined through covalent bonds and can also be obtained by cross-linked polymers in the dry state or solution. On the other hand, physical hydrogels originate through electrostatic attraction, ionic bonds, hydrogen bonds, or hydrophobic interactions between polymer chains. They are often reversible and can be dissolved by changing the environmental conditions of the solution, such as pH, ionic strength, or temperature (Hoffman, 2012). Physical crosslinking, more specifically, ionotropic gelation, also allows the encapsulation of the most diverse materials in hydrogels, such as cells, drugs and enzymes. This method produces microparticles, which are generated by extrusion of the polymeric dispersion containing the material to be encapsulated. The hydrogel spheres are produced when the solution containing the polymer is dripped onto the crosslinking solution, responsible for forming intra and intermolecular crosslinks, leading to a three-dimensional network (Bulmer et al., 2012;Prezotti et al., 2014). Ionotropic gelation is a simple, fast, and economical technique. On the other hand, hydrogels formed by this type of gelation present difficulties in controlling the release rate of the encapsulated material for a long period (Yeo et al., 2001).

Applications of hydrogel
In the last 20 years, scientific research on hydrogels has intensified. Countries such as the U.S., China, Japan, South Korea, Germany, and the United Kingdom stand out in conducting studies to develop and improve techniques for synthesizing and characterization of these polymer matrices, thus expanding the scope of their applications (Mahinroosta et al., 2018). The advantages of using these matrices include ease of preparation, use of natural products, biodegradability, biocompatibility, prolonged stability, and ease of biochemical modification of the formed structures (Ischakov et al., 2013). Such properties determine the application of the hydrogel in the fields of tissue engineering (Pensaifini et al., 2017), wound dressings (Rakhshaei & Namazi, 2017

Hydrogel as wound dressings
Most modern wound care solutions ensure a warm and moist environment, widely acknowledged as crucial in promoting quick healing Tan et al., 2019). The formation of the granulation tissue and the facilitation of skin cell division are best supported by a moist healing environment, which further promotes complete wound healing (Rowan et al., 2015). Thus, an ideal dressing is able to maintain high humidity levels at the wound site while simultaneously removing surplus exudates; it also needs to be non-toxic, non-allergenic, comfortable, and affordable, allow for oxygen and water vapor exchange, and provide protection against microbial invasion (Negut et al., 2018;Nischwitz et al., 2019). Importantly, the cooling action and low tissue adhesion of hydrogel-based dressings help treated patients experience less pain compared to the other wound dressings (Madaghiele et al., 2014;Sood et al., 2014).
The hydrogel model used as a wound dressing was first developed by Rosiak and consists of water, poly(N-vinyl-2pyrrolidone) (PVP), poly(ethylene glycol) (PEG), and agar, the last used as a pre-molding (Rosiak et al., 1989). Hydrogels can be used as dressings to keep the wound bed moist, facilitating the body's intrinsic enzymes to break down necrotic or nonviable tissue and promote cell regeneration (Wang et al., 2007). The properties that turn hydrogels into biomaterials are (1) their high water content (around 90% water and 10% natural or synthetic polymers) , which contributes to their biocompatibility; (2) low interfacial tension, which improves its ability to adhere to organic tissues and absorb proteins and tissue fluids; (3) physical properties similar to organic tissues, represented by its softness and elasticity, which minimizes mechanical irritation to friction; and (4) porous structure that allows the diffusion of metabolites and good oxygen permeability (Patel & Mequanint, 2011). Hydrogels can also be applied as a matrix for controlled release of active ingredients and antimicrobial agent (Hoque et al., 2018). The incorporation of therapeutic substances in the hydrogel membranes and the release of these agents in the wound result from a series of factors defined by the degree of crosslinking produced by irradiation (Maitra & Shukla, 2014). Hydrogels generated through radioactivity exhibit a strong reducing power, so gamma radiation has been used to reduce metal ions to synthesize nanoparticles in solution, especially silver nanoparticles (Shin et al., 2004). Radiation is used in manufacturing hydrogels to facilitate crosslinking and simultaneous sterilization, resulting in a product free of toxic residues, simplifying the manufacturing process, and lowering production costs (Benamer et al., 2006).

Sterilization of hydrogels for biomedical applications
Given the increasing complexity and diversity of biomaterials, in particular hydrogels, it is necessary to develop and validate new, safe and reproducible sterilization methods that allow them to be sterilized effectively after their manufacture, without compromising their properties and without high associated costs. Interestingly, the sterilizing process in hydrogels has been the subject of very few scholarly works in the previous ten years-less than 0.3% of all papers on the Web of Science portal-despite its significance from a scientific, clinical, and economic perspective. The sterilization of polymeric materials, such as hydrogels, must be carried out with special care. Under certain conditions, sterilization may cause degradation, discoloration, embrittlement, odor generation, promoting additional cross-linking, or even inducing toxic effects in materials subjected to the process (Ahmed et al., 2013;Murray et al., 2013;Phillip et al., 2013;Vanichvattanadecha et al., 2010). For instance, the simultaneous occurrence of the cross-linking and polymeric chain scission processes during gamma irradiation makes it challenging to interpret the benefits of the process (Zajko & Klimant, 2013). Importantly, sterilization at high temperatures generally leads to two main events: main chain reaction, which can result in breakage or further cross-linking; and side chain reaction, which can result in group elimination or cyclization (David, 1975). Regarding the oxidative processes, the polymers can be oxidized, partially degraded, or subjected to additional cross-linking. This exposure is characterized by an induction period during which the polymer may not show obvious changes. Nevertheless, the production of hydroperoxides may have long-term consequences (Rabek, 1975).

The importance of AgNPs in the treatment of wound infections
Treating wound infections caused by antimicrobial-resistant bacteria is a challenging task owing to the inability of conventional antibiotics to treat such infections (Rai et al., 2009). Metal nanoparticles (NPs) are viewed as potential alternatives to commonly used antibiotics since they have independently shown bactericidal effectiveness against numerous diseases, have the ability to reduce adverse drug reactions, and do not cause microbial resistance (Yang et al., 2017). NPs achieve their bactericidal effect by releasing toxic metal ions or by producing reactive oxygen species (ROS) when it comes into contact with a bacterial cell wall (Kumar et al., 2018). Moreover, NPs can also damage mitochondria, disrupt metabolic pathways, enter the cell wall, and impact proton efflux pumps by altering pH and disrupting the surface charge of membranes (Kumar et al., 2018;Wang et al., 2017).
Silver is a metal obtained largely as a by-product of lead mining, it is often associated with copper, and its medicinal properties have been used for over 2000 years (Alexander, 2009). Nanocrystalline silver was introduced as a wound dressing in . The exact mechanism of action of AgNPs is not clearly understood, which has generated discussion within the scientific community (Baptista et al., 2018;Franci et al., 2015). Importantly, a number of variables, including size, shape, size distribution, coating, agglomeration, surface electrical charge, concentration of nanoparticles, and release of Ag+ ions, are crucial for the antibacterial activity of AgNPs (Dakal et al., 2016;Durán et al., 2016;Ouay & Stellacci, 2015;Pareek et al., 2018a;Ramalingam et al., 2016). It has been observed that using silver nanoparticles to raise the surface-to-volume ratio effectively improves the bactericidal effectiveness of the silver ions (Nam et al., 2015). Increased contact area with the bacteria occurs concurrently with an improvement in surface-to-volume ratio (Nam et al., 2015). The silver must be in its ionic form to function as an antibacterial agent. Thus, the nanoparticles' increased surface area allows for the production of more silver ions, which can interact with bacteria in a variety of ways (Bondarenko et al., 2013). For example, AgNPs smaller than 10 nm have demonstrated a more effective antibacterial effect than larger particles . AgNPs' size is a key determinant of their antibacterial effectiveness; the smaller the particle, the greater the surface area and interaction with bacterial surfaces and intracellular structures (Pareek et al., 2018a(Pareek et al., , 2018b. The main consequences of these interactions are DNA base mismatches and consequent inhibition of replication (Manna et al., 2015), denaturation of enzymes and structural proteins (Yuan et al., 2013), and inhibition of translation signals (Vyshnava et al., 2016). Moreover, AgNPs adhere to the bacterial cell membrane and cause structural changes that affect its permeability and transport, leading the cell to an imbalance in cellular respiration and consequently death (Dakal et al., 2016;Khalandi et al., 2017;Sondi & Salopek-Sondi, 2004). Silver is a soft acid, so its ions have a natural predisposition to interact with soft bases. Several bacterial cell structures are composed of sulfur and phosphorus, which are soft bases. Since bacterial DNA contains sulfur and phosphorus as its main components, the interaction with ions impairs DNA structure and function, causing bacterial death (Khalandi et al., 2017).

Concerns with the use of AgNPs
Several aspects influence the toxicity of AgNPs in hydrogels, including concentration and particle characteristics such as synthesis method, size, shape, surface electrical charge, and coating (Zhang et al., 2014). Researchers found that silver is cytotoxic to human dermal fibroblast cells in a concentration-dependent manner (Anisha et al., 2013). Studies have suggested that the use of hydrogel dressings with AgNPs may harm human health (e.g., potential cytotoxic effect on organic tissues) (Boonkaew et al., 2014) and the environment (Rezvani et al., 2019;Saleem Khan et al., 2015;; however, this fact is not fully understood and is relatively unexplored. Importantly, as nanotechnology developed, experts were able to create a therapeutic window that increases the antibacterial capabilities of silver, lowers its minimum inhibitory concentration, and lessens its toxicity to healthy human cells (Nam et al., 2015). As a result, many wound dressings containing silver (e.g., Acticoat, Bactigrass, Tegaderm, Fucidin, and PolyMem Silver) have been approved for market introduction by the U.S. Food and Drug Administration (FDA) (Verma et al., 2016). When applying wound dressings to the wound site, cytotoxicity and antibacterial activity must be balanced. Even though the efficiency of silver ions has been clinically tested, caution should be exercised in using this treatment since unanticipated adverse effects may emerge in some circumstances. It is important to note that the limited efficacy of silver ion release, the limited number of silver species, the inability of silver ions to reach the wound bed, and the fast consumption of silver ions may require higher concentrations of silver compounds within the wound treatment, which could be fatal to healthy host cells (Atiyeh et al., 2007).
AgNPs can potentially harm the environment, particularly the soil microbiota, by killing the bacteria responsible for denitrification, impairing the nitrogen cycle, and, consequently, affecting soil nitrification, essential for plant growth . Toxic effects can also extend to aquatic environments where silver ions can interact with fish gills affecting fish osmoregulation (Rajkumar et al., 2016). Oxidative stress and lipid peroxidation have also been observed in fish brain tissue due to exposure to silver nanoparticles (Afifi et al., 2016;Saleem Khan et al., 2015). Oxidative stress develops through the formation of reactive oxygen species (ROS) and damage to cellular components, such as DNA, depletion of antioxidant molecules, binding and deactivation of proteins, and damage to the cell membrane (McShan et al., 2014;Zhang et al., 2016).

Synthesis of AgNPs
Two approaches are used to obtain metallic nanoparticles, including AgNPs top-down and bottom-up methods. The top-down method consists of successively breaking the metal into its conventional size until it reaches nanometric size, while the bottom-up method consists of building nanomaterials by grouping atoms and subatomic particles (Lee & Jun, 2019; Mukherji et al., 2019;Tri Handok et al., 2018). AgNP synthesis commonly employs physical and chemical techniques; however, biological synthesis or biosynthesis research has gained notoriety (Beyene et al., 2017).
Among the physical techniques used in the synthesis of AgNPs, those that use evaporation (e.g., condensation) and laser ablation processes stand out. The evaporation/condensation processes are based on the formation of silver vapors and consequent cooling; however, this technique requires large energy expenditures to keep the heating system stable and above 1,000 °C (Harra et al., 2015). The laser ablation method involves "cutting" the silver to its conventional size with nanometrically calculated laser beams . Both techniques require high cost and maintenance equipment, making the synthesis by chemical and biological routes more economically viable.
Compared to physical techniques, the synthesis of AgNPs by chemical methods offer a wider range of technologies and lower prices. The main methods include chemical reduction, microemulsion, photoreduction, electrochemical synthesis, and microwave irradiation (Iravani et al., 2014). The most widely used is chemical reduction, which consists of using chemical agents (e.g., sodium borohydride, sodium citrate, and ascorbic acid) to reduce silver ions (Ag + ) to reduced silver (Ag 0 ), with consequent aggregation and formation of AgNPs (Praveena et al., 2016;Zain et al., 2014). However, AgNPs synthesized by this method have high instability and a high aggregation probability, requiring surfactants (amines, acids, alcohols, and thiols) to ensure stability and prevent AgNPs from settling (Toh et al., 2015).
The synthesis of AgNPs using physical and chemical methods require equipment with high operating costs, chemical reagents with high toxicity, and the generation of by-products with polluting potential (Bilal et al., 2017). Given these negative points, the use of organisms and their bio compounds emerge as an alternative for synthesizing silver nanoparticles, a process known as biosynthesis, nanobiotechnology, or green synthesis (Ebrahiminezhad et al., 2017). The biological synthesis of silver nanoparticles employs biomolecules of diverse origin, especially those from bacteria, yeasts, filamentous fungi, mushrooms, and plants (Table 2) (Keat et al., 2015). In this type of synthesis, the approach used is of the bottom-up type, where the reduction of silver ions (from an aqueous solution of silver nitrate) to AgNPs occurs by the action of enzymes and phytochemicals (Abdelghany et al., 2018;Siddiqi & Husen, 2016). In addition to reducing silver, these bio compounds also act in stabilizing AgNPs, reducing the possibility of aggregation and maintaining the biological activity of these nanomaterials (Raghavan et al., 2016). Table 2. Organisms responsible for the biological synthesis of silver nanoparticles.

Applications of hydrogels based on silver for wound dressings
Despite the fact that a moist environment is necessary at the wound site, it may also raise the danger of microbial infections, which will lengthen the wound and/or slow down the healing process (Joshi Navare et al., 2020). Microbial colonization is undesirable because it may lead to major infections that may cause illness, septicemia, or even death (Zhang et al., 2021). Importantly, when wounds are colonized by opportunistic bacteria, the normal reparative and regenerative stages included in the healing process fail to occur (Simões et al., 2018). Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are the most frequent microbial strains present in infected wounds (Cardona & Wilson, 2015) . To prevent and treat infections, modern medicine relies on antimicrobial drugs like antibiotics, which work by either eliminating germs or preventing their growth (Abhishek Gupta et al., 2020). Therefore, hydrogels with antibacterial properties have enormous potential for use in clinical settings . Antimicrobial agents are typically divided into two categories: organic substances, such as antibiotics and organic mineral salts, and inorganic substances, such as silver (Banerjee et al., 2019), zinc (H. , and copper (Mohandas et al., 2018). Wound dressings with incorporated antimicrobial compounds have emerged as a practical alternative in recent years for reducing wound microbial colonization and infection and enhancing the healing process (Negut et al., 2018).
The hydrogel membrane with silver nanoparticles represents one of the alternatives used in the treatment of chronic wounds . This type of coverage adds the benefits of the hydrogel with the antimicrobial action of silver.
Clinical guidelines recommend that silver nanoparticle dressings be used on wounds where the infection is already established or on wounds with an excessive microbial load (Paladini et al., 2013). The most typical and inevitable impediment to wound healing is the development of an infection, which is relatively common in chronic wounds (Negut et al., 2018). Patients are heavily burdened and have a lower quality of life due to frequent dressing changes, repeated hospital admissions, and physical restrictions frequently associated with chronic wounds (Koehler et al., 2018). Hydrogel dressings with silver nanoparticles have a broad spectrum of antimicrobial activities (Dai et al., 2018). Importantly, the application of antimicrobial hydrogels as dressings combines hydrogel properties with the bactericidal action of silver and constitutes a good option for treating chronic wounds.
In vitro studies have demonstrated the hydrogel dressings with AgNPs' bactericidal activity in multidrug-resistant bacteria, including Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp., and Candida albicans (Bowler et al., 2004). Wu and collaborators studied novel silver-containing thermoplastic hydrogel membranes' synthesis, processing, and antimicrobial behavior (Wu et al., 2009). Antimicrobial activity was examined using exposure to Escherichia coli. Nanofiber hydrogels containing silver exhibited exceptional prominence against biofilm resistance in bacterial cultures (Wu et al., 2009). In another study, the hydrogels based on 2-hydroxyethyl acrylate and itaconic acid were synthesized by Vuković and collaborators and used for silver ions incorporation (Vuković et al., 2020). The hydrogels showed promising antibacterial activity against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA, indicating that they could be used to treat the potentially fatal illnesses (Vuković et al., 2020). Studies on chitosan hydrogel-based wound dressing formulations that contain and release nano-Ag and AgNPs have recently received attention (Hanif et al., 2016;Higa et al., 2016;Jaiswal et al., 2016;M.Y. et al., 2016;Nešović et al., 2017). Chitosan is a natural polysaccharide with hemostatic, bacteriostatic, and fungistatic properties suitable for medical applications (Koehler et al., 2018). To illustrate it, spherical AgNPs ranging from 10 to 30 nm were inserted into nanofiber surfaces to treat wounds (Wu et al., 2014). With 99% or more reduction in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, this nanostructure showed significant antibacterial activity and supported the growth of epidermal cells without cytotoxicity effects (Wu et al., 2014). Other researchers used coated polyester-nylon wound dressings with AgNPs to lower the incidence of exogenous wound-related infections (Radulescu et al., 2016). In vitro and in vivo studies showed improved inhibitory activity against bacterial colonization and biofilm formation, particularly against Pseudomonas aeruginosa, and fibroblast cells could grow normally (Radulescu et al., 2016).

Hydrogels based on silver for the treatment of burn
Burns are described as skin damage brought on by high temperatures or acidic substances, the two most typical causes (Butko et al., 2019;Jeschke & Gauglitz, 2020). Burn injuries interfere with the normal skin barrier and a number of other infection-preventing defensive processes (Mofazzal Jahromi et al., 2018). As a result, burn patients continue to be susceptible to a variety of invasive microbial infections until complete epithelialization occurs (Parikh et al., 2005). Silver nanoparticles are frequently used in wound therapy to provide therapeutically desirable qualities and an optimal environment for quick and efficient burn healing. Acticoat TM and PolyMem Silver®, two available silver-containing dressings to treat burns, were compared to a novel silver hydrogel dressing by Boonkaew and collaborators (Boonkaew et al., 2014). After 24 hours, most of the examined microbial strains were below the detection threshold, and bacterial viability was decreased by 94 to 99% (Boonkaew et al., 2014). Acticoat TM Flex 3 was tested on a fibroblast cell culture in vitro and on a real partial thickness burn patient (Rigo et al., 2013). According to the findings collected by cellular staining techniques, the AgNPs lowered mitochondrial activity without lysing skin cells or jeopardizing the integrity of the skin cells' nuclei (Rigo et al., 2013). The reduction in mitochondrial activity suggests a decrease in the number of bacteria, thus supporting the antibacterial properties of the silver-based hydrogel dressing (Rigo et al., 2013). In another investigation, a thermo-sensitive methylcellulose (MC) hydrogel containing silver oxide nanoparticles (NPs) was created via one-pot synthesis in which a silver acetate precursor salt (CH3COOAg) causes a salt-out effect in the MC solution (Kim et al., 2018). Interestingly, the MC hydrogel containing silver oxide NPs demonstrated remarkable antimicrobial activity and burn wound healing (Kim et al., 2018). Another study suggested a novel method for promoting vascularization in burn wounds (Banerjee et al., 2019). Contact burn wounds on the dorsum of the rats and were infected with Pseudomonas aeruginosa and treated with PEGylated fibrin hydrogel containing 50 mgs of silver sulfadiazine loaded chitosan microsphere (SSD-CSM-FPEG) (Banerjee et al., 2019). The proposed sequential treatment for infected burn wounds reduced bacterial infection while encouraging neovascularization and enhanced matrix remodeling (Banerjee et al., 2019).

Conclusion
There are still numerous obstacles to be addressed in the field of wound care. In order to treat non-healing wounds brought on by infection, cutting-edge materials that could be employed as wound dressings must be designed. Recent research has made it possible to create hydrogel wound dressings for delivering therapeutic molecules and medications to the wound site. The use of silver hydrogel dressing in wound treatment to prevent bacterial infection contribute to the improvement of wound management by creating an ideal environment for maximum wound recovery. Despite the large number of hydrogelbased solutions already on the market, the creation or improvement of advanced hydrogel dressings continues to be a significant topic of study to further enhance skin healing in reports to particular therapeutic applications. Antimicrobial hydrogels are a crucial subset of macromolecular antimicrobial substances that have shown notable effectiveness in both the prevention and treatment of drug-resistant illnesses.