Hydrogels for Wound Dressings: Applications in Burn Treatment and Chronic Wound Care

Abstract

Severe skin injuries such as burns and chronic wounds are a subject of interest in the medical field, as they require much attention. These types of wounds are susceptible to serious complications, which can worsen the health of patients and reduce their quality of life. Hydrogels have emerged as innovative wound dressings for treating acute and chronic wounds, including burns, diabetic foot ulcers, venous leg ulcers, and pressure ulcers. These polymeric networks provide a moist wound environment, promote cellular migration, and offer antimicrobial properties, being recognized as superior to conventional dressings. This review aims to explore recent advancements in hydrogel-based wound dressings, emphasizing the state-of-the-art technologies used for this purpose and the trend of achieving personalized therapeutic approaches. Despite the promising in vitro and in vivo findings described in this review, further clinical validation and large-scale manufacturing optimizations are required for widespread clinical adoption.

1. Introduction

The skin is the largest organ of the human body, with an extensive surface area of approximately 1.8 m², playing a vital role in the protection and function of biological systems, such as hydration, vitamin D synthesis initialization, and thermal regulation [1,2,3]. It protects internal tissues and organs from damaging external factors, acts as a physical–chemical barrier against pathogens, and maintains the body’s homeostasis. Through its site and roles, the skin is susceptible to damage, and it can be affected by a plethora of physical, chemical, and biological factors that can produce severe acute and chronic injuries, such as bruises, burns, ulcers (e.g., diabetic ulcers, venous ulcers), and deep cuts (e.g., surgical wounds) [2,3,4]. Also, systemic factors such as age, metabolic, vascular, autoimmune diseases, or various treatments may affect the healing process. Acute injuries tend to be repaired using a well-organized and effective healing process, which results in long-term skin recovery. Chronic wounds, on the other hand, are described as wounds that cause superficial, partial, or full-thickness skin loss, heal through secondary intention, and do not maintain maximum anatomical and functional integrity [4,5].

Chronic wounds have a prevalence of 1.47 cases per 1000 people according to UK statistics, and are more common in older people. The prevalence of chronic wounds can vary by region, community, and the patient’s lifestyle (e.g., reduced mobility, poor nutrition, immobility). Chronic wounds are associated with diseases such as diabetes, which can lead to diabetic foot ulcers or venous leg ulcers. Venous leg ulcer prevalence is about 1.5–3 cases per 1000 people, being more common in women and older people, with an annual incidence of 1.2%. Diabetic foot ulcers represent a complication of diabetes with serious consequences that can lead to lower-limb amputation and increased mortality. Its prevalence varies between 1.2 and 20% in hospitals [5].

On the other hand, burns are a type of injury that can affect the skin, being caused by several sources, such as heat, cold, friction, radiation, electrical sources, and chemicals, which represent a cause of death and morbidity worldwide. Thermal (heat) burns occur through the partial or total destruction of skin cells and are caused by hot liquids (scalds), hot solid spatters (contact burns), and flames (flame burns). According to the WHO [6], around 180,000 people die because of burns annually, and the majority of them (two-thirds of all deaths) occur in low- and middle-income countries, regions of Africa, and South-East Asia, and the death rate from burns in children is more than seven times higher than in high-income countries. For example, in Bangladesh, 173,000 children are affected by moderate or severe burns every year. In contrast, in other countries such as Egypt, Pakistan, and Colombia, 17% of children are affected and develop temporary disabilities, and 18% suffer permanent disabilities. However, in 2008, there were over 410,000 burn injuries in the United States, with roughly 40,000 requiring hospitalization, according to the WHO. Also, according to the WHO, burns involve high direct and significant indirect costs, with treatment estimated at USD 88,000/patient [6].

Even if most injuries tend to recover naturally in approximately two weeks, depending on the injury type the healing process may sometimes be longer, allowing for infection to occur. Various factors can interfere with wound healing, leading to chronic or non-healing wounds [2,3]. Wounds can affect patients’ quality of life, from a physical point of view, due to pain, limitations in physical functions, complications, and difficulties in performing daily activities, from an emotional point of view (e.g., anxiety, depression), and also from a social point of view [7].

Skin wound treatments are characterized as “conventional” or “regenerative”. Regardless of esthetic or functional changes, conventional treatment causes scar formation [4]. Wound management has evolved significantly, from using conventional bandages to creating contemporary materials that promote healing, prevent infection, and aid in tissue regeneration. Wound dressings have been designed to be placed on the wound and promote healing through the characteristics presented in Figure 1. Traditional dressings, or inert dressings (cotton pads, gauze, and bandages), are the most commonly used clinical dressings due to their low cost and simple manufacturing procedure. However, various drawbacks limit their applicability, such as difficulty maintaining wound moisture and the proclivity to adhere to granulation tissue [8,9]. Modern dressings can provide a better alternative because they provide a wet environment for wound healing. Modern dressings are more effective than conventional dressings in terms of biocompatibility, degradability, and moisture retention. These novel developments in dressings include pain relief and improved hypoxic or anaerobic environments. As a result, a wide variety of polymers, in the form of films, foams, hydrocolloids, alginates, and hydrogels, have been researched to provide new conditions for wound healing and are used in clinical practice. One of the more recent advantages in wound dressing formulations and an indirect technique to reduce inflammation by resolving the bioburden is realized using antimicrobial agents such as antiseptics, antibiotics, and natural compounds [8,9,10]. Also, regenerative wound therapy is a novel and fast-emerging area of biomedical research that aims to restore skin to its pristine function by reestablishing damaged cells and skin tissue without scarring [4].

Selecting the right wound dressing can lead to much faster and easier wound healing, which is important in maintaining the skin’s physiologic properties [12]. However, there is no perfect wound dressing that fits all wound types, so a wound dressing must be designed that meets the needs of the type of injury based on various criteria, such as the ability to absorb exudate without allowing for dehydration of the wound, the ability to cover the wound and not allow gaps between the wound and the dressing while maintaining its position for a desired period, the ability to prevent contamination of the wound and surrounding areas, an analgesic effect, the need to maintain the appropriate temperature required in wound healing, ease of use, and cost-effectiveness [12,13,14]. At the same time, a wound dressing that provides excessive moisture leads to excessive hydration, dysregulation of the skin’s function as a barrier, and lesions that subsequently cause ulcerations [12]. Obtaining an adequate moisture balance in a wound can significantly improve wound healing. Thus, dressings should allow for wound exudate to be absorbed, preventing excess moisture, which can lead to maceration, a process that results from excess moisture on the epithelial surface, resulting in swollen, ‘bleached out’ tissue, while drying wounds can lead to poor tissue healing and regeneration [9,15]. Thus, wet dressings can lead to healing without inflammation and scaling because of the moist environment [9]. On the other hand, an ideal wound dressing should be biocompatible, biodegradable, non-toxic, and hypoallergenic, allowing for gas exchange, granulation, and re-epithelialization [12,14,16].

Among the modern wound dressing possibilities, hydrogels represent a class of materials with excellent properties for enhancing the natural healing processes. Through their remarkable water absorption capacity, hydrogels have a significant moisturizing ability, making them ideal candidates for treating chronic wounds and burns [17,18]. Moreover, their appealing degradation properties render these materials suitable for the incorporation and controlled release of bioactive substances that accelerate wound healing [19]. Thus, hydrogels’ versatility and favorable biological and physicochemical properties are the main pillars for their exploitation in various studies focused on developing improved wound dressings.

This review recognizes areas of ongoing discussion on the use of hydrogels to produce wound dressings for chronic wounds or burns. It indicates the need for further research to consolidate their role and importance in the wound healing area, in clinical practice, to improve the patient’s quality of life, and to discover new strategies. In this regard, papers published in English between 2020 and 2024 (e.g., reviews and in vitro and in vivo studies) were selected and analyzed in this review. The information was provided from scientific databases such as Google Scholar, PubMed, Scopus, Web of Science (Clarivate Analytics), Elsevier (ScienceDirect), SpringerLink, MDPI, Wiley Online Library, Frontiers, and Taylor & Francis using a variety of combinations of the following keywords: “hydrogel wound dressings”; “chronic wound healing”; “burn healing”; “biocompatible hydrogels”; “in vitro and in vivo studies for burn and chronic wounds care”.

2. Hydrogels in Wound Care Management

2.1. Hydrogels Properties

As previously mentioned, hydrogels continue to be studied for treating skin lesions, whether caused by various conditions or wounds, such as burns. Hydrogels represent a three-dimensional (3D) network that is usually made of cross-linked polymer chains, with a high water-absorption and swelling capacity due to the presence of hydrophilic groups (e.g., -COOH, -OH, -CONH₂,-NH₂, -SO₃H, and -CONH) [20,21]. The constituent polymers of a hydrogel can form crosslinked networks both chemically and physically. Physical cross-linking involves hydrophobic interactions, hydrogen bonding, and ionic interactions, compared with chemical cross-linking, which connects polymers via covalent connections, such as disulfide, Schiff base, and borate ester, depending on the nature of the polymers [22]. Additionally, hydrogels can be synthesized using several techniques, including radiation, freeze–thawing, or chemical processes, thus obtaining cross-linked networks that allow undergoing water expansion, reaching a state of equilibrium and maintaining their initial structure. They can be flexible and soft due to their water-absorption capabilities and are widely used in everyday products such as baby diapers, soft contact lenses, solid air fresheners, and jiggle sweets [20,21]. These properties can enable hydrogels to adapt to wounds on any body part surface [23]. Additionally, the biodegradable properties of hydrogels can prevent the appearance of secondary damage during the dressing replacement, and their 3D network structure, similar to natural extracellular matrix (ECM), promotes cell adhesion, proliferation, and migration [22]. This quality can be used in wound healing to absorb exudate, promote oxygen flow, and offer enhanced moisture for the wound, which can facilitate the healing process [24]. Also, transparent hydrogels allow for monitoring the wound healing progress without removing the dressing [23].

The hydrophilic nature of hydrogels and their properties (physical, chemical, and biological) demonstrate high potential for use in the manufacture of wound dressings, with the ability to be used to fill spaces, function as wound dressings, or serve as drug delivery systems [25,26,27,28]. In this sense, hydrogel-based wound dressings were initially used only to cover wounds, maintaining an easy wettability of the wound healing environment and passively participating in the healing process [29]. By providing the necessary wettability, the hydrogels can generate an optimal microclimate between the wound bed and the dressing while also conferring a cooling effect that reduces the discomfort caused by pain [30]. Thus, the development of hydrogels has become a subject of intense study, leading to new properties that can lead to wound repair. The latest research has led to the development of hydrogel-based wound dressings with improved physical, chemical, and biological properties (Figure 2), which are also more adhesive, self-adapting hydrogels and promote faster wound healing [23,25,26]. One of the main advantages of using hydrogels is the incorporation of bioactive agents, antiseptics, antibiotics, anti-inflammatories, and antioxidants, which represent a great route to topical administration through adjusting their composition and sensitivity to wound stimuli to resolve inflammation, prevent infection, and promote wound healing [29].

To obtain a suitable hydrogel for the manufacture of dressings, characteristics such as the mechanical properties of hydrogels (e.g., compressive and stretching properties), adhesion, and bioactivity must be considered. Since the wounds may be in movable parts, these hydrogels must be adapted to have strong adhesion and high flexibility so that the wound is not aggravated by dislocation of the dressing, the dressing does not fall off, and thus infections do not occur, which could lead to delayed healing. In this regard, bioglue and nanoparticles can be used, which lead to much better adhesion and can stick firmly to the wound area, contribute to stopping bleeding, and prevent potential wound contamination and the development of infections [31,32].

The hydrogel should have excellent bioadhesive properties and good mechanical elasticity, such as tensile and compression properties, to ensure that the dressing does not become displaced or damaged because of the high-frequency stretching and squeezing environment of wounds [31]. Thus, conventional hydrogels do not show excellent mechanical properties. They are susceptible to rupture or breaking, which may lead to an unfavorable response to external factors, limiting their use as wound dressings [33]. This fragility can impair their performance, even resulting in loss of functionality and secondary damage. Furthermore, excellent mechanical elasticity frequently coexists with self-healing characteristics, forming a physical barrier that aids in healing moveable wounds. As a result, hydrogels intended for use as wound dressings must have acceptable mechanical qualities [31]. Hydrogels with optimal mechanical properties can promote wound closure by stimulating keratinocyte proliferation/migration, angiogenesis and neovascularization, and bFGF and TGF-β1 secretion, as well as enhancing blood vessel formation, re-epithelialization, extracellular matrix synthesis, and remodeling [33].

Because hydrogels directly touch the wound, they should be immunologically neutral and can be classified as natural or synthetic polymers [23]. Table 1 provides an overview of the use of polymers in medical applications, especially for producing wound dressings. In this regard, natural polymers are preferred for use in hydrogel-based wound dressings due to their high biocompatibility and bioactivity, ability to be recognized as macromolecules, such as polysaccharides and proteins, by the human body, and their great potential as next-generation advanced wound dressings [23,34]. However, their low mechanical properties, poor strength, instability, and rapid degradation compared to synthetic polymers represent their major disadvantages [21]. On the other hand, synthetic polymers such as polyethylene glycol (PEG) or polyvinyl acid (PVA) have a variety of advantages, such as high biocompatibility and biodegradability, cost-effectiveness compared with natural polymers, and a wide range of sources that can contribute to an enhanced hydrogel stability and promote tunable properties. However, they have drawbacks; for example, they are difficult to modify according to the needs of the treatment and they lack biological activity [23,35]. At present, a principal challenge is the optimization of these hydrogels. Composite-based hydrogels can provide a balance between their mechanical properties and biofunctionality. In this respect, future research is needed, and clinical trials must be established to evaluate the long-term safety of materials and their efficacy in wound management.

2.2. Hydrogels’ Mechanism of Action in Wound Healing

In addition to their capacity to swell and absorb wound exudate, hydrogels can maintain wound moisture by delivering water molecules, promoting fast healing from injury, and preventing the wound from drying out. In this regard, moist conditions promote angiogenesis and collagen formation, providing a non-adherent surface and reducing pain and scab formation [24,29,101]. These properties and their porous structure also make hydrogels great candidates for drug delivery systems (DDS). Thus, the drugs are easily loaded, stored, and released with appropriate release kinetics [102,103]. In this way, hydrogels are designed to gradually release drugs, maintain optimal concentration in the desired area and adjacent tissues, and facilitate the administration of various therapeutic agents. As DDS, hydrogels can help in the topical and local administration of drugs such as antibiotics for the wound healing process [102]. The drugs can be delivered into gel carriers via precipitation, covalent bonding, physical encapsulation, hydrogen bonding, dipole interaction, ionic interaction, and surface absorption. The release mechanism of drugs from hydrogels can occur through diffusion, swelling, and chemical mechanisms [104]. The diffusion mechanism is the best-known mechanism of drug release and can be related to hydrogel porosity. Drug molecules diffuse through the gel matrix from a high-drug-concentration location (hydrogel). In the swelling mechanism of drug release, the hydrogels swell upon making contact with biological fluids, and then the drug is diffused when gel chain relaxation occurs. This phenomenon occurs when the diffusion rate of the drug is higher than the swelling rate of the hydrogel [104,105]. Drug release in chemically controlled delivery systems could occur via the cleavage of polymeric chains through bulk or surface erosion and, following these mechanisms, the entrapped drug or tethered drug would be released from the hydrogels [104].

Because conventional treatments for burns and chronic wounds are expensive and sometimes ineffective, they represent a major public health problem. In chronic wounds, the wound-healing process is slowed down and becomes stuck in the inflammatory phase of the healing stages (hemostasis, inflammation, proliferation, and remodeling), which often causes major complications [106]. In this case, the anti-inflammatory role of a hydrogel designed for treating wounds represents a key factor in the wound-healing process. In this regard, the integration of bioactive molecules or biomaterials with anti-inflammatory effects in the hydrogel dressing can reduce or eliminate the free radicals, determine changes in macrophage activity, promote their transformation from M₁ to M_2, then reduce the excessive inflammation and facilitate the passage to the proliferation stage [22,107]. These dressings also promote angiogenesis, collagen synthesis and deposition, and cell migration (epithelial cells), reducing fibrosis and facilitating ECM remodeling. Due to the excess of reactive oxygen species (ROS), the wound healing process can be slowed down. Therefore, adding antioxidant compounds to the hydrogel composition could neutralize and enhance healing [108]. Thus, these compounds can be classified as shown in Figure 3.

On the other hand, chemokines (e.g., MCP-1 and IL-8) can influence wound healing and, when in excess, can lead to chronic inflammation. Some hydrogels that contain glycosaminoglycans (GAGs) and show a similar ECM morphology can accelerate healing by considerably reducing inflammation [109]. Direct growth factor (GF) and cytokine therapies are incompatible with normal wound care because they require specific delivery and frequent dressing changes. This might cause the patient to experience more pain and discomfort and prolong the healing process. Sustained delivery methods could improve usability and patient compliance, hence enhancing healing responses. In this context, biomaterials that imitate the ECM, such as hydrogels, can regulate the release of GFs and cytokines while protecting them from destruction. Although hydrogels have shown some efficacy in delivering biologics to improve wound healing in both animal models and human trials, there is limited capacity to control their physical, chemical, and mechanical properties, which are mostly determined by the type of polymer utilized [110,111]. By administering bioactive molecules such as growth factors, lactic acid, or bioactive glass, the hydrogels stimulate the transition from M₁ to M₂ macrophages, stimulating healing by promoting angiogenesis, epithelial repair, and fibrosis reduction [109].

3. Applications in Burn Treatment

Burns can occur when the skin is exposed to factors such as heat, chemicals, hot liquids, electric discharge, or radiation. Their severity (Figure 4) can range from first- to fourth-degree injury. In this case, managing burns is crucial to prevent the injury progression, infection, and associated complications [7,112,113].

The pathophysiology of burn wounds differs from other types of injuries (e.g., abrasions or lacerations) because of the heat that contributes to increased capillary permeability that causes plasma leaking from the interstitial space. This aspect prevents the formation of edema and local inflammation so that fluid is rapidly lost and inflammatory mediators are compromised [113]. The healing process of burns can vary according to their severity. While superficial burns covering the epidermis layer, though painful (second-degree), heal within a few weeks without leaving scars, a deep wound takes a long time to heal due to the destruction of the ECM and the degradation of GFs, a prolonged inflammatory phase, increases in pro-inflammatory cytokines, proteases, ROS, and possible infection [114].

Hydrogels are a great alternative for burn wound management and can be used as a first-aid dressing for burns. They can prevent bacterial infections and water infiltration due to their impermeable surface [115]. Also, hydrogel’s transparency represents an important property in burn management because the injury can be observed without the removal of the dressing, compared with the traditional approach that involves mafenide acetate cream in the morning and silver sulfadiazine cream in the evening, with gauze dressings used over the creams [113,116]. Additionally, hydrogels can promote burn cooling and reduce pain, promoting fibroblasts and epithelium migration [115]. Table 2 compares commercially available hydrogel dressings used for burn management. These hydrogels’ advantages are that they maintain moisture, absorb exudate, prevent bacterial infections, and ensure efficient wound healing. Additionally, these hydrogels allow for tissue rehydration and are easy to apply. However, there is limited information about their possible side effects and comparative studies of their effectiveness in large-scale clinical trials. Some manufacturers promise wound protection against bacterial infections, while others mention anti-inflammatory properties, but in principle, the effectiveness of hydrogel-based dressings varies depending on the formula and the patient’s needs. In this respect, comparative studies are necessary to establish an optimal hydrogel for wound treatment and to demonstrate rapid healing, infection control, and patient comfort.

Hydrogel’s three-dimensional nature promotes the integration of antimicrobial, growth factors, stem cell, and bioactive compounds and enhances hydrogels’ potential for DDS in burn management and efficient wound healing. Also, the moisture action of hydrogels on the skin improves therapeutic penetration through the skin, making transdermal drug delivery more effective [117]. Hydrogels cure burn wounds (superficial and moderate-thickness burns) faster than typical treatments like paraffin dressings and allow for good coverage and filling of the wounds. Furthermore, replacing conventional dressings with hydrogel dressings results in less pain and fewer dressing changes [115,118]. In vitro and in vivo evaluations of hydrogel-based dressings demonstrate promising potential in burn healing. They are suggested to have the potential to heal burns more quickly and effectively while safely removing them from the wound surface. It was observed that hydrogel-based dressings have the potential to reduce inflammation and promote complete re-epithelialization and complete tissue recovery. Thus, each type of hydrogel has specific advantages and disadvantages for burn healing. To obtain a better understanding of these aspects, Table 3 presents the key characteristics and outcomes of new approaches in burn healing. However, most of these studies remain in the preclinical stage. In this respect, standardized testing protocols and their applicability in clinical trials are needed to validate the results provided by preclinical tests and to validate the potential of these hydrogels in clinical practice.

Table 2

Commercially available hydrogel-based burn dressings.

Product	Hydrogel Composition	Purpose	Side Effects	Ref.
Aquacel Hydrogel	Sodium carboxymethylcellulose	Balances moisture, preventing fluid spread and macerationMicro-contours to the wound bed, leaving no gapsImmobilizes bacteria and MMPs to aid in tissue regenerationDraws fluid away from the wound bed through vertical wickingDe-sloughs the wound bed, reducing infection and inflammationAids autolytic debridement, creating a cleaner wound bed	Burning on initial applicationPossible allergic contact dermatitis	[119,120]
Derma-Gel Hydrogel	Polyethylene glycol (PEG)	Provides a moist environment to the injured skin site (wound, burn, etc.), through a water-based gel polymer that does not dry out.Forms a homogenous protective barrier on the surface of the damaged skin siteEasy wound management through hydrophilic properties and a long-term moist environment. Bacterial control, anti-inflammatory activity, protective film effect, absorbing wound exudatesIdeal for uncovered wounds or to allow for the removal of secondary dressings without adherence	n.r.	[121]
HydroTac	Polyacrylate, Polyurethane	Hydroactive polymer foam dressing with a hydrogel layerAccelerates the healing process Stimulate epithelialization process due to growth factor accumulationOptimizes pH values for epithelialization Reduces the potential for sticking to wounds and supports painless dressing changes High retention under pressure, including when used in combination with compression Protects wound edges against exudate, reducing the potential for maceration	Local skin reactions (irritation, redness, swelling)In rare cases, causes allergic reactions	[122]
Intrasite Gel	Carboxymethylcellulose (CMC)Propylene glycol	Applipak system provides simple, directable, and controlled applications even in awkward wound sitesAbsorbs slough and exudate without damaging fragile granulation tissueRange of sizes available for different wound sizesCreates a moist wound management environment Rehydrates necrotic tissue and aids debridementNon-adherent	Reddening of the skin may occur with lengthy exposureMay cause mild irritation to eyesIf it is accidentally ingested No significant signs or symptoms. Large amounts may case gastric disturbances	[123]
Purilon Gel	AlginateCarboxymethylcellulose (CMC)	Purilon® gel is indicated for dry and sloughy necrotic wounds as well as wounds with a mix of necrotic and granulated tissue such as leg ulcers, pressure ulcers, and non-infected diabetic foot ulcers, and it may be used on 1st- and 2nd-degree burns. May be used to provide a moist healing environment throughout the healing process. Purilon® gel should be used in conjunction with a secondary dressing.	n.r.	[124]
Solosite Gel	Sodium CarboxymethylcellulosePolyvinylpyrrolidone	Provides a moist environment for optimal wound healing. Protects the user against dehydration and bacterial contamination while absorbing exudates from the wound.	n.r.	[125]

Abbreviations: n.r.—not reported.

Table 3

In vitro and in vivo evaluation of hydrogel dressings for burn healing.

Article Title	Treatment	Aim of the Study	Testing Stage	Results	Ref.
3D-Printed Gelatin-Alginate Hydrogel Dressings for Burn Wound Healing: A Comprehensive Study	3D-printed gelatin and alginate-based hydrogel	Evaluation of gelatin and alginate hydrogels	In vitroIn vivo	The hydrogel dressing based on 75% gelatin and 25% alginate showed the best balance between mechanical, hydration, and biological properties.3D-printed dressing in vivo tests, on Sprague Dawley rats, showed faster wound closure, follicular regeneration, and atraumatic removal.	[126]
In Vitro and In Vivo Evaluation of Metformin Hydrochloride HydrogelsDeveloped with Experimental Design in the Treatment of Burns	Hydrogel-based Poloxamer 407®, Carbopol 934®, and sodium carboxymethyl cellulose (Na-CMC)Metformin	Testing of different concentrations of Metformin (4 mg/g, 6 mg/g, and 8 mg/g) with optimization of the formulation on loading efficiency and release of the active substance.	In vitroIn vivo	In vitro tests analyzed Metformin’s physicochemical properties, pH, viscosity, and release profiles.For the in vivo evaluation, female Wistar rats were used to assess burn wound healing activity.Poloxamer® hydrogel with 8 mg/g metformin demonstrated the greatest reduction in burn size and the best results in tissue regeneration.Histopathologically, significant re-epithelialization and an increase in neovascularization were observed in the metformin hydrogel-treated groups.The beneficial effects were more pronounced in the acute phase of healing.	[127]
Hyaluronic acid hydrogel loaded by adipose stem cells enhances wound healing by modulating IL-1β, TGF-β1, and bFGF in burn wound models in rat	Hyaluronic acid-based hydrogel (HA)Adipose stem cells (ASCs)Acellular dermal matrix (ADM)	Efficacity investigation of hyaluronic acid (HA) hydrogel loaded with adipose tissue-derived stem cells (ASCs) in accelerating the healing of burn wounds.	In vitroIn vivo	In terms of cell viability, HA significantly increased cell viability in the culture medium.ADM-HA/ASCs accelerated wound closure compared to ADM and ADM-HA groups, reducing inflammation and stimulating angiogenesis.ADM-HA/ASCs had a significant impact on TGF-β1 (proliferation) and bFGF (maturation and angiogenesis) expression, as well as on reducing inflammation (decreased IL-1β).Wounds treated with ADM-HA/ASCs showed complete epithelialization at 14 days, with faster granulation tissue and blood vessels’ formation.	[128]
Hydrogel nanocomposite based on alginate/zeolite for burn wound healing: In vitro and in vivo study	Nanocomposite hydrogels based on alginate (Alg) and natural zeolite (clinoptilolite)	Evaluation of the antibacterial and regenerative characteristics of Alg/Zeolite (Alg/Zeo) composite hydrogel.Comparison of wound healing efficacy between plain hydrogel (Alg)- and composite hydrogel (Alg/Zeo)-treated groups versus the control group.	In vitroIn vivo	The hydrogels were biocompatible without inducing significant cytotoxicity at moderate concentrations.Alg and Alg/Zeo accelerated wound contraction and re-epithelialization process compared to the control group.There were no significant differences between the Alg and Alg/Zeo groups in terms of granulation tissue thickness, angiogenesis, and inflammatory cell recruitment.The Alg/Zeo group showed almost complete epithelialization (86%) and better collagen organization compared to the control group after 14 days	[129]
Conformable hyaluronic acid hydrogel delivers adipose-derived stem cells and promotes regeneration of burn injury	Injectable hydrogel based on hyaluronic acid (HA) and polyethylene glycol (PEG)Adipose-derived stem cells (ASCs)RGD short peptide	Developing a conformable hydrogel to deliver and protect stem cells in an inflammatory environment.Evaluating the hydrogel’s ability to accelerate burn healing and reduce scar formation.	In vitroIn vivo	The presence of RGD peptide promotes significative cell proliferation, and viability, and promotes secretion of factors such as PDGF, HGF, and MMP-9.Healing was accelerated and the hydrogel- and cell-treated group demonstrated a significantly higher healing rate than the control group.The average healing time was 11.8 days.The hydrogel + cells group showed increased vascularization and a significant reduction in fibroblasts involved in scar formation (α-SMA positive).The type III/I collagen type III/I ratio was higher, indicating reduced scarring.	[130]
Antibacterial polysaccharide-based hydrogel dressing containing plant essential oil for burn wound healing	Hydrogel-based carboxymethyl chitosan (CMC) and carbomer 940 (CBM) loaded with Eucalyptus (EEO), Ginger (GEO), and Cumin (CEO) essential oils	This study aimed to develop anantibacterial polysaccharide-based hydrogel with essential oil for burn skin repair.	In vitroIn vivo	The hydrogels did not exhibit obvious cytotoxicity on L929 cells up to a low extraction concentration (1000 mg/mL), while, at a low concentration, the cell viability decreased for all hydrogels.CBM/CMC/EEO hydrogel also induced significant migration of L929 cells, which was attributed to the presence of the essential oil. CBM/CMC/EEO hydrogel exhibited a minimal effect on apoptosis.Essential oils enhanced the antimicrobial effect of hydrogels. CBM/CMC/EEO hydrogel was observed to possess the highest antibacterial activity toward S. aureus and E. coli.The in vivo results illustrated that the CBM/CMC/EEO hydrogel treatment induced the regeneration of collagen fibers, epidermis, and appendagesThe histology staining, and analysis of IL6, TNF-α, TGF-β, VEGF, and EGF levels showed that the CBM/CMC/EEO hydrogel treatment significantly accelerated burn wound repair in a mouse model.	[119]
Thermo-responsive chitosan hydrogel for healing of full-thickness wounds infected with XDR bacteria isolated from burn patients: In vitro and in vivo animal model	Chitosan-based hydrogel cross-linked with different concentrations of β-glycerolphosphate disodium salt pentahydrate (β-GP)	Evaluation of thermo-responsive chitosan (TCTS) hydrogel potential for protection against full-thickness wounds containing extensively drug-resistant (XDR)bacteria isolated from burn patients. The hydrogel was evaluated both in vitro and in vivo in a rat model.	In vitroIn vivo	Cell viability assay showed no significant cytotoxicity of the TCTS hydrogel for Hu02 fibroblast cells.In vitro, antibacterial assay showed no antibacterial activity of TCTS hydrogel against standard strain bacteria.In hydrogel-treated wounds, a decrease in the number of bacterial colonies was observed, which was explained by the accelerated healing induced by the hydrogel. The wounds were completely re-epithelialized and closed on postoperative day 14.	[131]
Oxygen-releasing hydrogels promote burn healing under hypoxic conditions	Oxygen delivery system made of self-healing hydrogel (QGO) (gallic acid-grafted quaternized chitosan and oxidized hyaluronic acid)Oxygen-releasing microspheres (GC) (calcium peroxide (CaO2) and gelatin)	Using oxygen-releasing hydrogels to accelerate burn healing under hypoxic conditions	In vitroIn vivo	QGO/GC has stable mechanical properties and is self-healingConsistently releases oxygen over 10 daysPromotes the migration and proliferation of endothelial cells and the capillary formationStimulates angiogenesis by increasing VEGF expression and other GFWound healing was significantly accelerated compared to control groupsReduced inflammation (decreased TNF-α expression) and increased collagen deposition and granulation formationThe hydrogel showed no cytotoxicity and good tissue compatibility	[132]
Silk fibroin hydrogel promotes burn wound healing through regulating TLN1 expression and affecting cell adhesion and migration	Silk fibroin hydrogel	Silk fibroin hydrogel for grade II burns healing by regulating TLN1 (Talin1) expression and influencing cell adhesion and migration	In vitroIn vivo	Porous structure favors nutrient transport and cell proliferationIn the hydrogel-treated group, accelerated healing was observed compared to the other groups, with a complete regeneration of the epidermis in 12 days. Histologically, the hydrogel-treated burns showed faster re-epithelialization and a considerable reduction in inflammationHydrogel promoted cell proliferation and reduced cell apoptosis Hacat and HDF cells had a considerably higher migration rate TLN1 expression was significantly upregulated, promoting cell dehydration and migration	[133]

4. Applications in Chronic Wound Care

Chronic wounds can be defined as those wounds that are characterized by an inability to heal within an expected period of time (~4–6 weeks) so that, biologically and functionally, the skin can return to its anatomical integrity within 1–3 months. These wounds are becoming increasingly common, with high morbidity and a socio-economic impact on patients, which has led to their recognition as a global public health problem. The management of chronic wounds should present a similar approach to those intended for patients diagnosed with geriatric syndrome and consider several factors, such as age, comorbidities, medication use, functional and cognitive status, social support, and quality of life of patients [5,134]. A patient’s wound can become chronic if they do not receive the correct treatment in time. Some of the causes may be hypoxia, bacterial colonization, altered cellular responses, and ECM abnormalities, which can all cause delayed wound healing, but more studies are needed to determine the exact mechanism and the specific causes [134,135]. Also, chronic injuries are characterized by some abnormal microenvironment factors, such as edema, reduced blood perfusion, inflammation, infections, and tissue degeneration) [136]. Injuries often close during the inflammatory or granulation stages, compared with chronic wounds, which remain in an inflammatory phase characterized by low levels of GF, uncontrolled protease activity, and high bacterial infection risk, which can delay the wound healing process and create great discomfort to patients, such as increased pain, and a poor quality of life [134,135].

The main forms of chronic wounds include diabetic foot ulcers (DFU), venous leg ulcers (VLU), and pressure ulcers (PrU) [136,137]. To promote healing, wound dressings are commonly used to treat acute and chronic wounds without surgery [137]. Traditional wound dressings are made from cotton wool, bandages (natural or synthetic), plasters, gauze, or cotton strips, but they are limited by inconveniences such as lack of adherence to the wound, causing secondary wounds, and the need to change bandages as often as possible [137,138]. In this regard, hydrogels have gained popularity in chronic wound treatments, and some of them are clinically approved (Table 4) [139]. Similar findings as for burn dressings were also found when using hydrogels to treat chronic wounds. These hydrogels are designed to maintain a moist environment, which is essential in the healing process of chronic and acute wounds, with different compositions for different types of injuries. However, there are still concerns regarding the toxicity of some of the products (e.g., those containing honey or silver) and, in addition, the potential for the emergence of bacterial resistance to antimicrobial agents. However, there are still concerns regarding the toxicity of some of the products (e.g., those containing honey or silver) and, in addition, the potential for the emergence of bacterial resistance to antimicrobial agents.

However, there is a continued need to develop better-performing hydrogels that lead to faster and more efficient wound healing [150].

In DFU, a complication of patients diagnosed with diabetes, the risk of severe complications such as infection, amputation of the affected limb, and death rates are increased. Although the affected limb is amputated, the chances of recurrence are increased. Thus, DFU is a serious, multifactorial condition that affects a large percentage of patients with diabetes who suffer from ulceration, neuropathy, and infection, leading to damage to the skin layers and the formation of lesions throughout the skin. Moreover, amputation-based treatments impose a heavy burden on the health and economic resources of diabetes patients [151]. In this pathology, the wound-healing process is obstructed, generating disorders that need continuous treatment. Also, chronic wounds are generally characterized by an inflammatory phase and neutrophil’s continuous production of metalloproteinases (MMPs) that decompose the ECM. As a result, the re-epithelialization and remodeling are unable to occur because of the degradation of collagen types IV, V, VII, and X, and laminin in the ECM. Additionally, the production of ROS is increased, resulting in an increased secretion of MMPs, which inhibits the action of growth factors and limits angiogenesis and tissue oxygenation, resulting in a hypoxic environment that maintains the wound open [152,153].

On the other hand, VLU represents a manifestation of long-term chronic venous disease (CVD), or its advanced stage of the disease, called chronic venous insufficiency (CVI), with a high prevalence among older people and an 80% chance of recurrence [154,155]. VLU are chronic injuries defined as skin defects localized mainly in the lower tibia due to high venous tension and limb edema. VLU characteristics are represented by heavy limbs, pain, varicose veins, stasis dermatitis, dermal weeping, skin hyperpigmentation, and subcutaneous fibrosis [154]. In the case of VLU, the healing time varies from several months to several years, but 25% of cases do not heal. VLU can be associated with diabetes mellitus and can be caused by its complications, such as neuropathy and local ischemia, but it can also be associated with obesity, sedentary, thrombophilic disorders, vascular dysfunction, rheumatoid arthritis, etc. [154]. This condition can also come with numerous risks, especially for geriatric patients, such as infections, ischemia, and gangrene, which can lead to complications or even the need for amputation of the affected limbs [156].

PrU is defined as an injury that occurs on the skin’s surface or the underlying tissue in the bone-prominence area, caused by continuous pressure or shearing forces, or related to medical devices. Both injure the soft tissue and cause cell death due to deformation, ischemia, or prolonged moisture, which produces maceration and tissue distraction [157,158,159,160]. In general, this condition appears in people with reduced activity and mobility, and can occur in areas such as the heels, the ankles, the foot, the hips, the coccyx, the shoulders, the elbows, and the ear flaps [157]. Diabetes mellitus represents a major risk factor for developing PrU, together with factors such as smoking, malnutrition, and immobilization in bed for long periods [161]. In general, PrU treatment is focused on preventing this condition from progressing to advanced or infected stages and consists of healing the wound in the shortest time at the lowest cost. Injuries caused by PrU show an increased risk of infections conducive to a high risk of mortality in long-term patients [160].

Considering the complexity of chronic wounds, hydrogels can represent an innovative treatment strategy for chronic wounds because of their biocompatibility, hydration, and flexibility. However, novel studies should focus on the complex wound environment, which involves multiple factors such as pH, high levels of ROS, and specific enzyme expression [162]. Table 5 provides an overview of recent studies on the use of hydrogels as dressings for chronic wounds. Thus, an acceleration of healing in all types of chronic wounds was observed, with high biocompatibility, showing the potential to reduce inflammation, with an effective antimicrobial effect, and promote angiogenesis and collagen synthesis, making them promising for future clinical applications. These studies showed the incorporation of nanoparticles, bioactive agents, and stem cells, highlighting their effect in the wound healing process. Still, their manufacturing process, scalability, and regulatory approval present a challenge, as well as patient comorbidities, such as diabetes, which influence the treatment outcome.

5. Innovations and Advanced Technologies

Regarding facile wound healing, its management represents a key factor in an optimal healing process, reducing complications and improving patient outcomes. Therefore, hydrogels represent an emergency approach, providing a versatile tool in wound care.

However, hydrogels still need improvements to enhance the wound-healing process. In this respect, one of the main approaches to obtaining a hydrogel dressing with enhanced properties is represented by 3D printing technology, fabricating dressings with customizable properties for wounds with irregular shapes and sizes, improved efficacity, and better treatment for wounds. These hydrogels can cover and better adhere to the wound bed, improving the healing outcomes by printing complex structures [171,172]. 3D printing technology can be implemented in hydrogel-based dressing fabrication because hydrogels are potentially printable materials that can be extruded through nozzles and needles. They can regain properties such as viscosity once on the printing platform. Also, when using an algorithm, it is possible to realize micro- and macro-hydrogel structures resembling ECM that can contribute to improved cell activity and much easier tissue repair [172]. Figure 5 shows the 3D printing methods suitable for hydrogel dressings fabrication.

The use of 3D printing technology, together with biocompatible hydrogels, provides a promising approach for producing smart wound dressings, combating several challenges. Additionally, 3D-printed dressings can be loaded with different substances, such as antibiotics, antibacterial nanoparticles, and other biological substances that facilitate wound healing and skin regeneration. The main benefit of using this technology to obtain hydrogel wound dressings is its cost-effectiveness and rentability compared with conventional manufacturing methods such as casting, molding, machining, and forming, which are effective in mass production but not for complicated and multi-material designs [173].

Smart hydrogels are another approach to enhance the effectiveness of hydrogel-based dressings. Smart hydrogels can change their network structures, mechanical properties, and permeability in response to various stimuli, such as pH, temperature, electric and magnetic fields, light, and biological molecules, producing modifications such as swelling or collapse. Thus, temperature-sensitive hydrogels go through a transition between monophasic and biphasic states depending on the critical solution temperature, while pH-sensitive ones change their protonation state in response to pH variations [173,174,175]. Additionally, enzyme-responsive types modify their properties upon interaction with specific biomolecules [173,174,175].

The best-known and most-studied thermal-responsive polymer is poly(N-isopropyl acrylamide) (pNIPAAM) [173,176]. However, studies demonstrated that acrylamide polymers present toxicity at physiological temperatures due to unreacted monomeric residues. Also, poly(diethylene glycol monomethyl ether methacrylate-co-poly(ethylene glycol) methyl ether methacrylate) (p(MEO₂MA-co-OEGMA) (PMO)) represents another thermal-responsive polymer, being nontoxic, uncharged, and biocompatible [176]. Liu et al. [176], obtained a thermo-responsive composite hydrogel based on PMO-carboxymethyl cellulose (CMC), poly(vinyl alcohol) (PVA) (PMO-CMC-PVA) with a two-stage drug release effect. Thus, this hydrogel showed excellent effects in the process of chronic wound healing, with controlled and extended drug delivery and optimal physiochemical properties. Another thermo-responsive hydrogel was obtained by Bei et al. [177], with antimicrobial and antioxidant effects, to promote the rapid healing of diabetic wounds. The researchers used NIPAM, polyacrylic acid grafted with N-hydroxysuccinimide (NHS) ester, and dopamine-modified gelatin (GelDA) as the primary cross-linking network, loaded with Ag-coated clay antibacterial nanoparticles (Ag@Clay-TA). This hydrogel exhibits excellent thermostimulated contraction and adhesive, antibacterial, and antioxidant properties. As a result of its thermoresponsive properties, the hydrogel enables the release of nanoparticles, facilitating accelerated wound closure. Li et al. [178] obtained a self-healing injectable hydrogel for DFU, with pH-responsive long-term insulin release. The hydrogel is composed of N-carboxyethyl chitosan (N-chitosan) and adipic acid dihydrazide (ADH), which are crosslinked in situ via hyaluronic acid–aldehyde (HA-ALD). In vivo studies confirmed that the insulin-loaded hydrogel dressing reduced inflammation, promoted granulation tissue formation and collagen deposition, and accelerated re-epithelialization and angiogenesis, representing a promising DFU treatment. Li et al. [179] proposed hydrogel loaded with polyhexamethylenebiguanide (PHMB) into a zeolitic imidazolate framework (ZIF-8) aiming to obtain novel pH-responsive ZIF (P-ZIF) nanoparticles with a high antimicrobial effect. Then, P-ZIF was loaded into an injectable hydrogel constructed from sodium alginate (SA) and 3-aminophenyl boronic acid-modified human-like collagen (H-A) to obtain the H-A/SA/P-ZIF (HASPZ) hydrogel dressing for deep second-degree burn treatment. The obtained HASPZ hydrogel dressing has dual pH responsiveness to avoid the overuse of drugs (ZIF-8 and PHMB). The researchers demonstrated that the hydrogel promoted angiogenesis and infection, while H-A and SA facilitated cell proliferation and migration, thus enhancing wound healing, especially in burn treatment.

6. Limitations, Challenges, and Future Directions

Hydrogels are a good alternative to traditional wound dressings for wound healing. Their porous nature and high compatibility with various drugs can promote the efficient delivery of biologically active substances to the wound. At the same time, they have great flexibility and elasticity, which allows for them to be removed without causing pain or secondary injury, providing a suitable microenvironment for wound recovery [180,181].

Among the reviewed hydrogels, most formulations rely either on natural (e.g., collagen, alginate, chitosan) or synthetic biocompatible polymers (e.g., PEG, PVA, polyacrylate). Natural polymers offer high biocompatibility and bioactivity, while synthetic ones provide improved mechanical stability and tunability. However, hybrid hydrogels that combine both material types are emerging as a preferred alternative [182].

Even though hydrogels have significant advantages, there are still disadvantages and limitations that must be overcome. Hydrogels possess poor mechanical properties due to their high water content (up to 90%), which limits their applicability, making it necessary to use a second dressing. Additionally, natural hydrogels, when used alone, have a fast degradation rate and poor stability, while synthetic ones are biologically inert and lack endogenous factors, which can be solved by preparing composite or co-polymeric hydrogel dressings. Their combination improves the individual disadvantages of natural and synthetic hydrogels in 3D cell cultures [181,183].

Although hydrogels generally exhibit good biocompatibility, their long-term safety and degradation profiles remain a concern. Some formulations degrade too quickly, requiring frequent reapplication, while others may accumulate in tissues, raising concerns about prolonged exposure to synthetic components. Henceforth, future studies should focus on developing hybrid materials, considering the needs of patients to obtain customized treatments and overcome the barrier imposed by the findings of laboratory tests and clinical applications.

A strategy to manufacture advanced hydrogel dressings is represented through the use of multifunctional hydrogels that promote simultaneous healing, control infections, and can administer personalized treatments for different types of wounds [171]. Most recent studies have already tackled this approach, as innovative hydrogel compositions incorporate antimicrobial agents (e.g., silver nanoparticles, honey, zinc-doped ceria), bioactive molecules, and anti-inflammatory compounds [44,170].

Another strategy is to incorporate sensors in the hydrogel matrix to follow the evolution of wound healing, conferring constant real-time feedback. Specifically, temperature and pH sensors can provide valuable information on the wound state, aiding in establishing whether there is infection, inflammation, or engorgement of affected tissues. With this information available in real-time, therapeutic interventions can be enhanced, offering personalized treatment for patients [184,185].

Advancements in fabrication methods can also enhance hydrogel-based wound care technologies. Four-dimensional bioprinting is emerging as the next-generation fabrication technology, representing a novel concept that enhances the 3D patterned biological matrices from synthesized hydrogel-based bioinks with the ability to change the structure and stimulate [186,187]. An advantage of using 4D printing is represented by the fact that the material used changes its properties, such as shape, following exposure to stimuli (e.g., temperature, humidity, pH, and light exposure), so stimuli-responsive biomaterials can be great candidates for 4D bioprinting [186,188]. This mimics the sophisticated structures of native tissues [187]. However, 4D bioprinting can be used to obtain DDS, which can be used to prevent infections and enhance wound healing. In this regard, the bio-inks used in 4D bioprinting must have properties such as shape memory, self-healing abilities, and stimuli-responsive application activities [188].

While 3D and 4D printing technologies are promising, their integration into commercial-scale hydrogel manufacturing remains a challenge due to the high production costs, complexity, and regulatory hurdles. Before their widespread clinical adoption, hydrogel dressings must meet stringent regulatory requirements and demonstrate consistent performance in diverse patient populations. Thus, improving their scalability and cost-effectiveness is critical for bringing these advanced wound dressings into routine clinical use.

Also, comparative studies between clinically approved dressings are necessary to establish their side effects and effectiveness. While many hydrogels demonstrate promising preclinical results, large-scale clinical trials comparing their effectiveness are still limited. The available literature often lacks head-to-head comparisons between different formulations, making it difficult to determine the optimal hydrogel for specific wound types.

7. Conclusions

The skin is the largest organ of the human body and has numerous biological functions (e.g., moisturizing, homeostasis, thermal regulation, providing a barrier against external factors), so it is prone to damage. Thus, when the skin is damaged, biological functions are disrupted, and patients’ quality of life is considerably reduced. In this regard, this review highlighted the properties of hydrogels, which are used to obtain new dressings due to their superior properties that facilitate the healing of chronic wounds and burns. Thus, although there is a multitude of hydrogel-based products on the market, they can be improved in order to obtain much better healing without any adverse effects, as well as to obtain better mechanical properties and an improved antimicrobial effect, and to ensure the cumECM is as close as possible to that of the skin, promoting wound healing and skin regeneration. It should also be taken into account that wounds do not only occur in fixed areas of the body but also in moveable areas, such as the wrists, where hydrogel-based dressings need to be adaptable, with increased adhesion and flexibility. In this respect, the review aims to highlight recent advances by describing in vitro and in vivo studies on both burns and chronic wounds, highlighting the remarkable evolution in this field. At the same time, it can be observed that there is ongoing research in this field to discover more efficient methods to obtain more effective hydrogel-based dressings (e.g., 4D printing, the use of stimuli-responsive polymers, and the introduction of sensors to the hydrogel matrix). However, there is a need for further studies and innovative elements so that patients’ wounds heal uniformly and without complications and the quality of life of patients is improved.

Author Contributions

A.A., E.-T.M., A.-G.N., and A.M.G. participated in the review’s writing and revision. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Figure 1. Wound dressing characteristics. Created based on the information from [10,11].

Figure 2. Functionalities of hydrogel-based wound dressings. Created based on the information from [29] Abbreviations: ROS—reactive oxygen species.

Figure 3. Overview of antioxidant compounds that, when incorporated in hydrogels, lead to an improved wound healing process. Created based on information from [108].

Figure 4. Burn classification and their implications for wound management. Created based on information from [7,112,113].

Figure 5. Overview of advanced 3D printing methods for manufacturing hydrogel dressings. Adapted from an open-access source [29].

Table 1

Classification of polymers used in hydrogel-based wound dressings.

Polymer Type	Polymer Name	Advantages	Disadvantages	Ref.
Natural	Collagen (Col)	most abundant structural protein in animalsmain component of ECMbiocompatible and non-toxic polymerstable good capacity to retain watercan be loaded with therapeutic agentsenhances the activity of therapeutic agentsallows cell adhesion, proliferation, and differentiationrepresents an ideal microenvironment for angiogenesislow-cost and versatile polymer	its properties depend on fabrication parameters (e.g., Col source, pH, gelation)poor long-term stabilityexhibits poor mechanical properties (e.g., low stiffness)not easy to functionalizehas a high rate of proteolytic degradation that limits its applicabilityinsoluble in water	[36,37,38,39,40,41,42,43,44]
	Chitosan (CS)	biocompatible and biodegradable polymerstimuli-responsive polymercan be modified by both physical and chemical crosslinkingdoes not induce toxic or immunological effectspresents bioadhesive and antimicrobial effectscan act as a chelating, hemostatic, antioxidant, and pain-relief agentcan accelerate homeostasis and epidermal cell growthcan be used as a drug delivery systemcan maintain the moisture of injuries that is necessary for the wound-healing process	low blood compatibilitylow angiogenic activitypoor mechanical propertieshigh rate of degradabilitypoor solubility in aqueous solutions	[38,45,46,47,48,49,50,51]
	Alginate (ALG)	has a great biocompatibility and biodegradability soluble and stablehas multiple obtaining sources, with easy gelationstimuli-responsive polymerdoes not produce toxic or immunological effectscan form gels in the presence of divalent cationscan be easily functionalized with drugs and cells, and the degradation rate can be modified	poor cell adhesion propertieshas weak mechanical strength and needs to be combined with other polymers	[52,53,54,55,56,57,58,59]
	Gelatin (Gel)	high biocompatibility and biodegradability, and low toxicitycost-effectivegood water absorption propertiescan mimic the natural dermal EMCcan promote erythropoiesis and increase the quantity of platelets and white blood cells to prevent bleeding	not thermostablemust be coated with another material to improve its low mechanical strengthhas a high degradation rate	[60,61,62,63,64]
	Hyaluronic Acid (HA)	biocompatible polymer with great biodegradabilitypromotes cellular adhesion and can provide sufficient biological activity that stimulates the microenvironment destined for cell survivalcan act as a space-filler and lubricanthas high hydrophilicity, containing a high amount of water	insufficient mechanical strengthsusceptibility to degradation by hyaluronidasehas poor degradation rates	[57,65,66,67]
	Cellulose	biocompatible, biodegradablelow-cost materialnon-toxic polymerexcellent hydrophilicitygood mechanical propertiesexcellent capacity to absorb fluids	cannot be used in its natural form because of its high number of hydroxyl groupshigh costs and energy consumption for fabricating dressings	[68,69,70]
	Silk Fibroin (SF)	biocompatible, non-toxic, and safe to uselow immunogenicitydegradation rate can be easily controllablecan be combined with other polymers or materialssimilar structure to ECMgreat viscoelastic, swelling, and morphological propertiesexcellent tissue repair functionsenhances cell adhesion, adaptation, and proliferationcost-effective polymer that has a stable source to provide	lacks mechanical strengthvery brittle, which makes it difficult to use in scaffold fabricationneeds purification because of the residual sericin that can create problems with biocompatibility unstable in an aqueous environmentdegrades at a slower rate, inhibiting tissue renewal, which can be a disadvantage when considering resorbable hydrogelsinsoluble in most organic solvents and water	[71,72,73,74,75,76]
	Polydopamine (PDA)	polymerized form of dopaminecan be easily integrated into tissues and promotes healingcan provide a reliable and suitable tissue adhesionhas antioxidant properties due to its numerous catecholsbiocompatiblecan confer stability to drugs and biomoleculeshas great photothermal properties	still has biosecurity issuesrequires further studies to determine its effectiveness in hydrogel manufacturing	[77,78,79]
	Agarose	biocompatible and non-toxiclow-cost polysaccharideease of controllable gelationcapable of forming physically cross-linked hydrogels in aqueous mediumhigh water-absorption capacitycan mimic the ECMhas favorable and tunable mechanical properties can be used as drug-delivery systemscan be mixed with other polysaccharides, peptides, and magnetic nanoparticles	exhibits brittleness and contractilitydoes not support cell adhesion and must be combined with other polymers	[80,81,82,83,84]
Synthetic	Polyethylene glycol (PEG)	biocompatible and non-toxicresistant to protein adsorptioncan be easily modified with other polymers has a high drug encapsulation ratehas high hydrophilicity, tunable physicochemical properties, and anti-fouling propertiescan undergo rapid clearance from the body	because of its bioinert properties, it cannot provide an adhesive effect to cellsdoes not promote tissue formationshould be combined with other polymers to enhance its properties	[85,86,87,88]
	Poly-ε-caprolactone (PCL)	biocompatible and biodegradable has high hydrophobicity and a slow degradation ratesoluble in chlorinated solventscan be easily combined with other polymers	has low hydrophilicity; this disadvantage can be altered through combination with hydrophilic materialshas a slow rate of resorption	[89,90,91]
	Polyvinyl alcohol (PVA)	has a low toxicity, high biocompatibility, and biodegradable propertieshas a great absorption capacity and tunable mechanical propertieschemically stable in the presence of body fluids, stimuli-responsive, and resistant to aging	provides a weak network with low endurance at high temperatures and is incompatible with the human body networkunable to support cell attachment	[92,93,94,95,96]
	Poly-N-vinylpyrrolidone (PVP)	biocompatible and non-toxichydrophilic and soluble in water and organic solvents can be combined with both hydrophobic and hydrophilic polymers improves bioavailability of poor water-soluble incorporated drugs	has poor mechanical properties and bioactivityhas poor self-healing performance	[97,98,99,100]

Table 4

Commercially available hydrogel-based wound dressings.

Product	Hydrogel Composition	Applications	Side Effects	Refs.
ActivHeal®	Calcium sodium alginate	Used as a primary dressing on dry and sloughy wounds with nil to low exudate:Pressure ulcersCavity woundsLeg ulcersGraft and donor sitesDiabetic ulcersPost-op surgical woundsLacerations and abrasions	Potential issues for patients with sensitivity to calcium alginate or other known allergic skin conditions	[22,24,107,140,141]
AquaDermTM	2-Acrylamido-2-methyl-1-propanesulfonic acid sodium Propylene GlycolPoly(ethylene glycol) dimethacrylate2-Hydroxy-2-methylpropiophenonePurified water	For the management of partial and full-thickness wounds that are dry or have minimal exudate, including:Pressure ulcersMinor burnsRadiation tissue damage	Potential allergic reactions in patients with sensitivity to dressing componentsPropylene glycol component may cause allergic reactions in older people	[22,24,107,142,143,144]
MEDIHONEY	Active Leptospermum honey in combination with a hydrogel sheet dressing	Indicated for non-draining to lightly exuding wounds such as:Diabetic foot ulcersLeg ulcers (venous insufficiency ulcersArterial ulcers Leg ulcers of mixed etiology)Pressure ulcers (partial- and full-thickness)	Slight transient stingingIncrease in exudatePotential issues for patients with sensitivity to honeyMay raise blood glucose in diabetic patients	[22,24,107,141,145]
Neoheal® Hydrogel	PolyvinylopyrrolidonePolyethylene glycolAgar	Recommended for treatment of:UlcerationsBedsoresAll kinds of skin damage in which a humid medium is favorable	n.r.	[22,24,107,146]
NU-GEL	Sodium Alginate	Indicated for the autolytic debridement of necrotic and sloughy wounds.	n.r.	[22,24,107,147]
Restore Hydrogel	Deionized water, glycerin USP 99.7%, sodium polyacrylate, propylene glycol USP, hyaluronic acid, sodium metabisulfite FCC, methylparaben NF, propylparaben NF	It promotes a moist environment in a variety of wounds:Stages I-IV pressure ulcersDiabetic skin ulcersVenous ulcersSkin tearsCutsAbrasionsConditions associated with peristomal care	Propylene glycol component may cause allergic reactions in older people	[22,24,107,144,148]
Suprasorb G	Hydrogel: water, acrylic polymers based on a taurate derivative, polyethylene, phenoxyethanolCarrier film: polyethyleneWhite application aid: polyethylene	Indicated for the management of dry to moderately exuding chronic and acute wounds, including but not limited to: Venous leg ulcersDiabetic foot ulcers Arterial ulcers Moderate skin tears Malignant wounds and palliative care Extravasation injury	n.r.	[22,24,107,149]

Abbreviations: n.r.—not reported.

Table 5

Novel studies on the use of hydrogels as dressings for chronic wound healing.

Article Title	Treatment	Aim of the Study	Testing Stage	Results	Ref.
A bioactive composite hydrogel dressing that promotes the healing of both acute and chronic diabetic skin wounds	Carboxymethyl chitosan (CMCS) hydrogel loaded with chitosan nanoparticles, Mesenchymal Stem Cell (MSC)-derived exosomes, bioglass (BG) and TiO2	Development of a bioactive composite hydrogel bioactive wound dressing for the treatment of acute and chronic wounds, including diabetic lesions and burns.	In vitroIn vivo	Hydrogel loaded with exosomes, chitosan, BG, and TiO2 provides a sustained release of bioactive substances, stimulating healingThe hydrogel promotes cell proliferation via the migration of endothelial cells and fibroblasts due to its optimal porosityPromotes angiogenesis by increasing VEGFA and VEGFR2 expressionReduces inflammation by decreasing TNF-α, IL-1β and IL-6, and increasing IL-10In vivo tests demonstrated accelerated healing in ratsIn diabetic wounds, the hydrogel promoted granulation formation and collagen synthesisShowed significant antimicrobial activity against E. coli and S. aureus strainsThe hydrogel prevented complications associated with burns and promoted epidermal regeneration	[163]
Piezoelectric hydrogel for prophylaxis and early treatment of pressure injuries/pressure ulcers	Electroactive hydrogel of polyacrylonitrile-acrylamide-styrene sulfate-poly (vinylidene fluoride) (PAAN-PVDF)	Obtaining a piezoelectric hydrogel for the prevention and early treatment of PrU	In vitroEx vivo	Hydrogel promotes L929 cell proliferationThe hydrogel is biocompatible and also shows high blood compatibilityIn vitro tests demonstrate that the hydrogel stimulated angiogenesis via piezoelectric stimulationFresh pig skin was used to simulate the effect of the hydrogel on pressure distribution in bony protrusive areas. Results showed that the hydrogel reduced the pressure applied to these areas	[164]
Immunomodulatory gallium/glycyrrhizic acid hydrogels for treating multidrug-resistant Pseudomonas aeruginosa-infected pressure ulcers	Gallium and glycyrrhizic acid (Ga/GA)-based immunomodulatory hydrogel (Ga/GA)	Development of (Ga/GA)-based immunomodulatory hydrogel for the treatment of pressure ulcers infected with antibiotic-resistant P. aeruginosa (MRPA)	In vitroIn vivo	The Ga/GA hydrogel has demonstrated a water-holding capacity that can facilitate the maintenance of a humid environmentThe hydrogel has a great antimicrobial effect, preventing bacterial biofilm formation and eliminating pre-existing biofilmsStimulates fibroblast and macrophage proliferationFacilitates the transition of macrophages from M1 to M2 phenotype, thereby reducing inflammation and accelerating tissue regenerationNeutralizes reactive oxygen species (ROS), protecting cells against oxidative stressIn MRPA-infected PrU models, the hydrogel promoted healing by reducing inflammation and wound contraction, facilitating the synthesis of collagen and angiogenesis	[165]
Asymmetric natural wound dressing based on porous chitosan-alginate hydrogel/electrospun PCL-silk sericin loaded by 10-HDA for skin wound healing: In vitro and in vivo studies	Asimetric hydrogel dressing based on chitosan-alginate (CS-Alg) with PCL-silk sericin (PCL-SS) membrane loaded with 10-hydroxy-2-decenoic acid (10-HAD)	The development of an asymmetric natural wound dressing based on a porous CS-Alg hydrogel and an electrospun PCL-SS membrane loaded with 10-HAD with enhanced antimicrobial, anti-inflammatory, wound healing, and regenerative properties	In vitroIn vivo	CS-Alg-based hydrogel demonstrated excellent biocompatibilityThe hydrogel promoted fibroblast proliferation and metabolic cellular activityIn Wistar rats, the dressing significantly accelerated wound healing by preventing the formation of granulation tissue10-HDA is released gradually, followed by a sustained releaseThe hydrogel has great antimicrobial efficiency against S. aureus and E. coli strains	[166]
Hyaluronic acid/alginate-based biomimetic hydrogel membranes for accelerated diabetic wound repair	Biomimetic hyaluronic acid (HA) and alginate (Alg), Polyvinyl alcohol (PVA)-based hydrogel loaded with cefotaxime (CTX)	Development of a biomimetic HA-Alg-PVA hydrogel biomimetic membrane to accelerate diabetic wound healing through the controlled release of CTX.	In vitroIn vivo	The hydrogel allows oxygen to pass through and regulates humidityPrevents the build-up of exudateIt has a great antimicrobial effect on the S. aureus and P. aeruginousa strains because of the CTXIt does not have a toxic effect on fibroblastsThe in vitro cytotoxicity assay demonstrates a cell viability of over 80%In a diabetic rat model, the membrane significantly accelerated the healing processThe group treated with CTX-loaded membrane showed complete epidermal and dermal formation without signs of necrosis	[167]
A platelet-derived hydrogel improves neovascularization in full thickness wounds.	Paletels, fibrin, and thrombin-based hydrogel	Development of a hydrogel derived from platelets and fibrin using expired platelets to stimulate wound repair.	In vivo	The hydrogel promotes angiogenesis and collagen synthesis The healing was accelerated by collagen fibers deposition, with a faster re-epithelization	[168]
Lutein-loaded multifunctional hydrogel dressing based on carboxymethyl chitosan for chronic wound healing	Hydrogel based on carboxymethylated chitosan (CMC), polyvinylpyrrolidone (PVP) loaded with lutein and tannic acid (TA)	Development of a multifunctional lutein/CMC/PVP/TA-based hydrogel wound dressing for chronic wounds, especially diabetic wounds.	In vitroIn vivo	Hydrogels with moderate lutein concentration (5 mg/mL) supported cell proliferationThe hydrogel has demonstrated effective removal ROSThe hydrogel prevented the development of biofilm biofilms and showed a good antimicrobial effectWound sizes were significantly reduced in the group treated with 5 mg/mL lutein concentration, with faster wound closure and formation of well-organized epithelial tissue.Hydrogels with moderate lutein concentration (5 mg/mL) promoted collagen synthesis and its uniform depositionHydrogels with moderate lutein concentration (5 mg/mL) promoted angiogenesisHydrogels with moderate lutein concentration (5 mg/mL) reduced the inflammation	[169]
Gelatin/dopamine/zinc-doped ceria/curcumin nanocomposite hydrogels for repair of chronic refractory wounds	Methylacrylated gelatin modified with dopamine (GelMD) with zinc-doped hollow mesoporous cerium oxide nanoparticles loaded with curcumin-based nanocomposite hydrogels (gelmd-Cur@zhmce)	Development of biocompatible multifunctional nanocomposite (GelMD-Cur@ZHMCe) for chronic wounds treatment	In vitroIn vivo	Curcumin is effectively released in an acidic environment such as infected woundsThe hydrogel supported free radical scavengingGelMD-Cur@ZHMCe significantly inhibited the growth of bacteria such as E. coli and S. aureus, preventing biofilm formationThe hydrogel stimulated endothelial cell migration and angiogenesisThe healing time was 14 daysGelMD-Cur@ZHMCe con led to epithelial regeneration, increased collagen deposits, and reduced inflammation	[170]

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