Abstract

Severe burns result in deep and extensive wounds that are associated with a high mortality rate. While wound closure is an essential part of the treatment for such injuries, merely providing superficial coverage of the defect is inadequate. Adequate reconstruction requires repairing the damaged area from the innermost layers outward. Hydrogel dressings have become a very popular choice due to their unique properties: contributing to wound moisture, cooling and soothing, and autolytic debridement. This type of dressing offers the potential to overcome disadvantages of traditional treatments and allows partial skin regeneration. This review aims to outline the benefits of hydrogel dressings, emphasizing their role in wound healing and tissue regeneration, particularly in the context of chronic burn wounds. The discussion also covers how these dressings may address current shortcomings in wound care and provides a focused overview of specific attributes and potential future improvements in the field. This review enhances the general understanding of their therapeutic implications by examining the benefits of hydrogel dressings.

Introduction

It is estimated that between 7 and 12 million people (8,955,228 new burns in 20191) with burns require medical attention each year2. It is one of the leading causes of morbidity and mortality, especially in underdeveloped countries. Even when skin damage has healed, it is still profoundly transformed. This has a negative impact on the patient's physical, mental, and emotional well-being.

Burns occur due to exposure to heat sources, which can come from many different agents: fire, boiling water, electricity, chemicals, etc. The extent of the burn correlates with the severity of illness, causing long-term disability and death. Based on the severity of the burn, burns can be classified as follows: Burns that affect only the epidermis (pink or red, dry, without blisters, and moderately painful) are classified as group 1. They do not leave scars and heal relatively quickly, within 5 to 10 days. An example of this type 1 burn is a sunburn. Next, burns that spread into the dermis are classified as group 2; blisters and wet spots appear on the burn surface, and treatment lasts from 3 to 8 weeks, often leaving scars. This is the most common type of burn injury in daily life. Third-degree burns involve the full thickness of the skin and subcutaneous structures. These burns are complex, with dry, rough (central) and wet (marginal) areas. When left to heal naturally, the tissue often shrinks and changes structure, causing long-term injury. It takes more than eight weeks for this group to recover. Burns in the third degree and above typically require the implant method. Burns with charred (blackened) skin, where the entire skin structure is severely damaged and may expose bone, are classified as category 4. This is the most severe type of burn, with a high likelihood of death. The burn wound is shown in Figure 1.

Treating burns is a major challenge because systemic inflammatory response syndrome, sepsis, and multi-organ dysfunction syndrome—often caused by infection3—are still the leading causes of illness and death in burn patients. Burn injuries are complex and can easily progress from acute to chronic4. Complications of burns include scarring, contractures, and eschars, which have long-term negative impacts on a patient’s physical and mental health [4, 5]. These complications are the leading cause of death in most cases5.

Burn wounds disrupt the normal skin barrier and weaken many host defense mechanisms, the most important of which is preventing infection3. The main methods for managing burn infections often include wound care, isolation of the affected area from the environment, systemic antibiotic treatment, and autologous, allogeneic, or xenogeneic skin grafts to improve wound healing6. However, each of these methods has significant drawbacks: excessive and long-term antibiotic use can lead to bacterial resistance and changes in the human microbiome, while there is a limited supply of skin grafts and potential immune reactions to non-autologous grafts. New approaches to designing wound dressings have shown considerable promise by providing active processes for wound treatment. The unique three-dimensional network of hydrogels has a high water affinity compared to traditional wound dressings—which can cause skin irritation, dryness, and inadequate protection—thereby creating a moist healing environment with biological compatibility and biodegradability. Hydrogels protect the wound by offering ideal conditions for skin regeneration, thereby supporting effective treatment of infectious diseases. This is most important for contributing to smaller wound size, restricting the proliferation of infectious agents, and assisting tissue repair and healing by enhancing the body’s inherent healing capabilities7.

× Figure 1 . Burn classification (drawn with Biorender). Burns are classified by the depth and severity of the injury . First-degree burns show damage only to the epidermis, are pink or red, dry, and do not produce blisters (though they may peel). They are moderately painful, heal in 5–10 days without scarring, and are exemplified by a sunburn. Second-degree burns extend into either the papillary or reticular dermis, are blistered and moist due to destruction of dermal blood vessels, and can be quite painful. Healing time varies depending on burn depth, from 3–8 weeks; scarring may result. Second-degree burns are the most common type of burn injury. Third-degree burns involve the complete thickness of the skin, including rough, dry, and wet areas. If left untreated, such burns result in permanent tissue changes. Category 4 burns are very serious and involve charred skin, possibly exposing bone. Figure 1 . Burn classification (drawn with Biorender). Burns are classified by the depth and severity of the injury . First-degree burns show damage only to the epidermis, are pink or red, dry, and do not produce blisters (though they may peel). They are moderately painful, heal in 5–10 days without scarring, and are exemplified by a sunburn. Second-degree burns extend into either the papillary or reticular dermis, are blistered and moist due to destruction of dermal blood vessels, and can be quite painful. Healing time varies depending on burn depth, from 3–8 weeks; scarring may result. Second-degree burns are the most common type of burn injury. Third-degree burns involve the complete thickness of the skin, including rough, dry, and wet areas. If left untreated, such burns result in permanent tissue changes. Category 4 burns are very serious and involve charred skin, possibly exposing bone. Hydrogels in Burn Wound Management

Most hydrogels are highly hydrophilic and have good biocompatibility. In addition, hydrogels with suitable pore structures can meet the needs of gas exchange during the healing process in general and particularly for burns8. They act as a temporary protective barrier, replacing damaged skin tissue in the wound. This is important because hydrogels can be designed to release bioactive agents in ways that enhance their therapeutic potential. The controlled-release mechanism adds another layer of functionality to hydrogel dressings and makes them versatile tools in the handling of wounds—particularly burns—where the healing process is highly elaborate and warrants specialized care8. Hydrogels have been widely used and have played an indispensable role in both research and clinical practice (Figure 2 ). Several studies have demonstrated the effectiveness of hydrogels applied in the treatment of burns based on the following effects they provide:

Cools burn wounds and closes the wound

The initial burn wound is not the only problem. The accumulated energy at the burn wound surface should also be a concern. This accumulated energy can be transmitted deeper or spread around the wound, causing tissue near the damage to be affected7. The easiest and most common method of eliminating this energy is running water. Although there is still concern about infection in the water—especially in areas where living standards are uncertain—it remains the recommended method because of its prevalence. Hydrogel dressings may be a more optimal alternative. They quickly dissipate heat accumulated in the skin. The more water-based they are, the more effectively they can absorb heat, quickly cool the wound, and reduce pain, making the patient feel more comfortable. In addition, they serve as a temporary protective barrier against external infectious agents. The water content of the hydrogel is essential in cooling, as water helps stabilize the wound’s temperature, especially in pediatric patients. The ability to hold large amounts of water makes them an effective heat-regulating shield for wounds in particular and the body in general. Along with that ability, the diffusion of biologically active substances in the hydrogel sheet and the delivery of drugs to the wound site are also highly appreciated7.

Fiona M. Wood’s research at the Burn Registry of Australia and New Zealand (BRANZ) analyzed data from 2009 to 2012 regarding water first aid after burns. In total, 68% of the patients performed first aid before hospital admission. Forty-six percent cooled for more than 20 minutes, associated with a 13% reduction in the probability of skin graft surgery (p = 0.014) and a 48% reduced probability of ICU admission (p 9. One study reported that 25 women who were to undergo breast reconstruction surgery consented to test the burn and cooling model without developing any side effects. Increased contact times produced deeper burns: contact for 7.5 seconds at a temperature of 70°C resulted in partial-thickness burn injuries. However, cooling at 16°C for 20 minutes conserved 25.2% of skin thickness. These findings, therefore, indicate that cooling as an immediate first-aid treatment for burns exerts a beneficial effect10. A pig model was used to study partial-thickness burns. The groups were treated with flowing water at 15°C for varying durations (10, 20, 30 minutes, and 1 hour) and delay times (immediate, 10 minutes, 1 hour, and 3 hours) compared with an untreated control group. Subdermal temperature was monitored, and the wounds were observed weekly for 6 weeks to assess re-epithelialization, surface area, and aesthetics. The results showed that immediate cooling with cold water for 20 minutes improved re-epithelialization and reduced scar tissue, while other time intervals also provided benefits11.

The faster the wound closes, the lower the risk of infection and the formation of hypertrophic scars. An example is an ultra-short peptide assembled to form a super-coiled hydrogel scaffold. These scaffolds are non-cytotoxic and do not induce an immune response. For partial-thickness burns, these nanofibrous hydrogels accelerated wound closure and dermal and epithelial regeneration with wound closure rates of 86.2% and 92.9% after 14 days, respectively, compared with 62.8% of burned areas healed using Mepitel®—a commercial dressing12. Another study in rats showed that gelatin hydrogels also promote effective wound healing of second-degree burns in a rat model13. A hydrogel with quercetin reduced burn size by 45–50% by day four in a mouse model of second-degree burns, which was similar to what was observed in the group treated with silver sulfadiazine. In the wounds that healed with the treatment, tensile strength estimates, biochemical markers, connective tissue signs, and NF-κB levels were restored by day 21 to levels similar to those of normal skin. Silicone gels were shown to promote rapid epithelialization in 16 burn wounds at skin surface depth (mean 8.4 days), compared with ointment-impregnated dressings (median 14 days, p 14. Results showed less pain and exudate by mere observation of the absorbent materials from both types of dressings. In nine mixed deep and superficial dermal burns, the silicone gel also provided fast epithelization—an average of 12 days—compared with control wounds with an average of 22 days (p

Antibacterial

Much importance must be given to the antimicrobial performance of hydrogels when they are used as wound dressings. In wound treatment, hydrogel dressings have gained wide acceptance due to their ability to provide an antimicrobial or bacteriostatic effect. Their key role is to inhibit the spread of unwanted microorganisms and fight against infection in the wound. Hydrogel dressings offer improved coverage of the wound surface to prevent infection, including acting as an effective barrier against external pathogens. Functional modifications of hydrogels are performed to provide enhanced antimicrobial activity by adding antimicrobial agents, including silver nanoparticles or antibiotics15. This increases the hydrogel’s potential to inhibit bacterial growth at the lesion site. Antibacterial interactions can occur by mechanisms such as disruption of the bacterial cell wall/membranes, interference with bacterial replication, or inhibition of bacterial metabolic pathways. Hydrogels have a complex structure that plays a twofold role in protecting against bacterial invasion. The connections in the hydrogel’s structure act like a physical barrier, blocking bacteria from reaching the wound surface.

Conversely, this structure permits the evaporation of water and the penetration of oxygen into the wound, thus providing favorable conditions for wound healing. Importantly, most hydrogel sheets are not intrinsically antimicrobial, although their structure provides a suitable framework for incorporating antimicrobial agents that can be added to achieve the overall antibacterial activity of the hydrogel dressing16. Such flexibility in action makes hydrogel dressings adaptable and powerful tools in medicine, specifically in wound management, where preventing infection is one of the most essential aspects.

There are many ways to impart antibacterial ability to hydrogel bandages, such as using nanoparticles, using antibiotics, using hydrogels with inherent antibacterial properties, or synergistic approaches, etc. All are shown in Table 1 . Nanotechnology is particularly interesting due to its broad-spectrum antibacterial ability and its lack of drug resistance.

Table 1.

List of antimicrobial hydrogels

Hydrogel dressing Antibiotic Antibacterial Activity Result Nanoparticle Polyvinyl alcohol and maleic acid 17 , Peptide 18 Nanocompozit 19 Polyethylene glycol (PEG) and polycaprolactone (PCL) 20 Ag Nano-silver interacts with bacterial membranes; thus, it causes membrane damage and results in cytoplasmic leakage. It ultimately inhibits growth and leads to the death of bacteria. Moreover, silver nanoparticles have a great binding ability and affinity with most of the macromolecules, having a great effect on the survival of bacterial species. ++ Gelatin 21 , HCZ 22 ZnO Similar to silver nanoparticles, ZnO nanoparticles can sustainably bind to bacterial cell membranes and destroy cell membranes, including lipids and proteins. Membrane integrity occurs and this causes the bacteria to die. Besides, Zn 2+ can destroy bacterial cells as a strong oxidant, induce oxidative stress on cytoplasm and induce cytotoxicity. + Poly(AAm-co-AMPS)-g-CMC 23 Titanium Dioxide Acts as a ROS-generating agent. It can lead to oxidative stress, causing damage to various cellular components and ultimately leading to cell death. + Polysaccharide 24 Other Ditto + Cellulose Nanocrystals 25 , Hydrogel 26 , N-(2-hydroxypropyl)-3-trimetylammonium chitosan clorua 27 Antibiotic Glycopeptides bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor, preventing its incorporation into the growing cell wall. These antibiotics are effective against Gram-positive bacteria; Aminoglycosides, including gentamicin and streptomycin, act by blocking protein synthesis. They bind to the bacterial 30S ribosomal subunit, causing a misreading of the genetic code during translation. This results in the incorporation of incorrect amino acids into the growing polypeptide chain. Quinolones, such as ciprofloxacin and levofloxacin, inhibit bacterial DNA synthesis. They target bacterial DNA gyrase and topoisomerase IV, essential DNA replication and repair enzymes. By inhibiting these enzymes, quinolones prevent the relaxation of supercoiled DNA, leading to DNA strand breakage and inhibition of nucleic acid synthesis. +++ CL/nHA 28 , O-Mannosylation 29 Glycopeptide 26 ++ Chitosan 30 , Hydroxypropyl methylcellulose and biodegradable microfibres 31 Quinolone