Skin architecture and function

The skin is the body’s largest organ and acts as a dynamic barrier against physical, chemical, and microbial insults while limiting trans epidermal water loss [3]. Structurally, it consists of the epidermis, dermis, and hypodermis, each of which contributes to barrier integrity, immune defense, and tissue homeostasis. Because the skin is both a barrier and a therapeutic target, its architecture is relevant not only to conventional transdermal delivery but also to wound-healing biomaterials. In hydrogel dressings, transport is directed primarily toward the injured tissue and wound microenvironment rather than across intact skin into the bloodstream. Nevertheless, skin structure, hydration, and local diffusion pathways remain important design considerations because they influence drug retention, tissue contact, and local therapeutic performance at the wound interface [4].

Physiology of wound healing

A wound can be broadly defined as any injury or disruption to the integrity of biological tissues, including the skin, mucous membranes, and internal organs. Damage occurs when the protective epithelial covering is broken, thereby impairing the structure and function of the underlying tissues. Prompt restoration of the injured barrier is essential for maintaining homeostasis because untreated wounds may lead to infection and other complications. Wounds range from minor tissue disruptions, such as incisions, to extensive tissue damage, such as burns. Accurate wound assessment is therefore essential for selecting appropriate treatment strategies [5]. Wounds can be classified according to their nature and healing pattern as either acute or chronic. Acute wounds usually heal within 8–12 weeks and typically result from mechanical injuries such as abrasions, avulsions, crush injuries, cuts, fishhook injuries, incisions, and lacerations [6]. By contrast, chronic wounds heal slowly, often lack a predictable healing timeline, and frequently recur. Delayed healing is associated with conditions such as diabetes, heavily exuding wounds, persistent infection, and antibiotic resistance [7].

Despite the high prevalence, complexity, and diverse causes of wounds, establishing a universally accepted classification system remains challenging. As summarized in Figure 1, wound classification remains important for diagnosis, management, and treatment because it helps anticipate infection risk and guides therapeutic selection [8]. Burn wounds represent a clinically important category of skin injury because they involve thermal, chemical, electrical, or radiation related tissue damage and may vary substantially in depth and severity. From a dressing-design perspective, burn wounds often require protection from infection, maintenance of a moist environment, absorption of exudate, pain reduction, and support for re-epithelialization [9]. Hydrogel dressings are therefore relevant to burn management because their high-water content can provide cooling, hydration, and a protective interface while enabling localized delivery of antimicrobial, anti-inflammatory, or regenerative agents. However, the selection of a hydrogel system should consider burn depth, exudate level, infection risk, and the need for mechanical stability.

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Figure 1. General classification of wounds.

Mechanism of wound healing

Healthy skin maintains a delicate balance between the epidermal and dermal layers. When this protective barrier is disrupted, the wound healing cascade is initiated and proceeds through hemostasis, inflammation, proliferation, and remodeling. These stages involve cell migration, angiogenesis, re-epithelization, collagen deposition, and extracellular matrix remodeling. Numerous growth factors in these events, as summarized in Table 1 [10]. Hemostasis begins with vasoconstriction, clot formation, and the release of mediators that promote subsequent healing events [11]. The inflammatory phase includes an early neutrophil dominated response followed by later monocyte and macrophage activity. During the proliferative phase, fibroblasts migrate to the wound bed, deposit extracellular matrix, and support new tissue formation. The final remodeling phase, illustrated in Figure 2, may last for weeks or longer and involves collagen synthesis, reorganization, and degradation under cytokine regulation [12]. Together, these tightly regulated events restore tissue integrity and improve the mechanical strength of healed skin. These biological events define the key design requirements for hydrogel wound dressings, including moisture regulation, exudate management, antimicrobial protection, inflammation control, oxygen permeability, mechanical flexibility, and support for re-epithelialization and tissue remodeling.

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Figure 2. Stages of wound healing. Adapted with permission from https://doi.org/10.3390/life11070665. © 2021 by the authors. Licensed under a CC-BY 4.0.

Chemical composition of hydrogels

Hydrogels can be prepared from natural biopolymers such as polysaccharides (alginate, chitosan, cellulose, and amylopectin) and proteins (collagen and gelatin), as well as from synthetic polymers such as poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), and poly(acrylic acid) [20]. Composite hydrogels that combine natural and synthetic polymers may offer the advantages of both classes, as summarized in Table 4. Selecting an appropriate polymer system remains challenging because the structural diversity of available materials must be balanced against the chemical, mechanical, biological, and interfacial properties required for a given wound application. Thus, the selection of natural, synthetic, or composite hydrogel matrices should be guided by the wound type, exudate level, infection risk, required residence time, mechanical demands, and intended therapeutic release profile.

Composite hydrogels are particularly important in wound dressing design because they combine the biological advantages of natural polymers with the mechanical strength, tunability, and reproducibility of synthetic polymers. Natural components such as chitosan, alginate, collagen, gelatin, and hyaluronic acid can improve biocompatibility, biodegradability, cell adhesion, hemostasis, and intrinsic wound healing activity. Synthetic polymers such as PEG, PVA, polyacrylic acid, and PNIPAAM can improve mechanical stability, elasticity, swelling control, and controlled release behavior. In composite systems, the balance between natural and synthetic components allows modulation of porosity, degradation rate, adhesive strength, exudate absorption, and drug-release kinetics. Such hybrid networks are therefore useful for infected, exuding, diabetic, and irregular wounds where a single polymer hydrogel may not provide sufficient mechanical durability and biological activity. Natural polymer based hydrogels are often favored because of their biodegradability, biocompatibility, relatively low production cost, and environmental friendliness. Biodegradable systems can also provide improved flexibility and better control over drug stability and diffusion. In some cases, they enable site-specific delivery when the matrix is degraded by biological triggers such as microbial enzymes [33]. These systems may respond to enzymes, temperature, pH, and other cues while also exhibiting bioadhesive behavior, thereby supporting self-regulated delivery. Techniques such as grafting, physical blending, and block copolymerization can be used to improve mechanical performance and tune biodegradation rates. Naturally derived polymers typically show excellent biocompatibility, low cytotoxicity, minimal immunogenicity, and the ability to promote cell adhesion, tissue proliferation, and regeneration. In particular, polysaccharide-based hydrogels have emerged as attractive wound biomaterials, as illustrated in Figure 4 [34, 35].

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Figure 4. Properties of polysaccharide-based hydrogels and their mechanisms in wound dressing applications.

Synthesis of hydrogels

Hydrogel synthesis methods can generally be classified into physical crosslinking and chemical crosslinking. Physical crosslinking involves reversible interactions such as ionic interactions, hydrogen bonding, hydrophobic association, and complex coacervation. Chemical crosslinking involves covalent bond formation between polymer chains through chemical crosslinkers, enzymatic reactions, photo-polymerization, or irradiation induced free radical reactions. Therefore, irradiation crosslinking is best considered a chemical crosslinking method because high energy radiation generates reactive radicals that form covalent network structures. The choice of crosslinking method should balance mechanical stability, biocompatibility, sterilization compatibility, degradation behavior, and the ability to preserve the activity of incorporated therapeutic agents for wound dressing applications.

Drug loading strategies

The effective delivery of therapeutic agents from a hydrogel matrix depends strongly on the chemical and physical characteristics of both the cargo and the network. Three main drug-loading strategies are commonly used: diffusion, entrapment, and tethering. In the diffusion method, the hydrogel is immersed in a solution containing the therapeutic agent, and uptake depends on the size and chemical nature of the molecule as well as the mesh structure of the hydrogel network [35]. Entrapment occurs during gelation and is particularly suitable for large biomolecules, such as proteins and peptides, that cannot readily diffuse through small pores. Because both diffusion and entrapment allow relatively free movement of the drug within the network, they are often associated with an initial burst release. To reduce this effect, therapeutic agents may be linked covalently or physically to the hydrogel network in a strategy known as tethering. Tethering helps limit premature exposure and enables more controlled and sustained release [43]. Incorporating therapeutic agents such as antimicrobials, anti-inflammatory compounds, growth factors, enzymes, and stem cells can further enhance hydrogel efficacy. For example, a multifunctional chitosan/gallic acid glucomannan hydrogel promoted healing of antibiotic-resistant, bacteria infected wounds in diabetic models by scavenging reactive oxygen species and modulating inflammation [44]. Hydrogel systems can also help prevent microbial invasion and proliferation at the wound site [45].

Swelling behavior

Swelling capacity and moisture retention are key hydrogel properties that determine wound hydration and exudate absorption. Because swelling behavior is governed by the chemical and physical characteristics of the network, it is also an important determinant of drug-delivery performance. Hydrogels containing hydrophilic polymers generally exhibit high water uptake, whereas increasing the degree of crosslinking typically reduces swelling. Owing to their high-water content, often exceeding 90%, these materials closely resemble soft natural tissues and can be crosslinked through covalent bonds, van der Waals interactions, physical entanglements, or hydrogen bonding. An optimal degree of crosslinking enables sufficient swelling and fluid uptake while preventing premature degradation. For example, a hyaluronic acid/gelatin hydrogel with an 11-fold swelling capacity enabled sustained thrombomodulin release and promoted diabetic wound healing, whereas a pectin/Bletilla striata hydrogel with high moisture retention accelerated wound-fluid absorption [9].

Drug release

Drug release from hydrogels commonly occurs by passive diffusion, although diffusion-controlled, chemically controlled, and swelling controlled mechanisms may each become rate-limiting depending on the system. Hydrogel mesh size is a key determinant of drug diffusion because it is influenced by the chemical structure, degree of crosslinking, and responsiveness of the network to external stimuli. Important physical properties such as mechanical strength, diffusivity, and degradability are all linked to mesh size, which typically ranges from 5 to 100 nm in swollen biomedical hydrogels [9]. Drug release from hydrogel wound dressings is controlled by several interrelated mechanisms. In diffusion controlled systems, the therapeutic agent migrates through water filled pores of the hydrogel network, and the release rate depends on mesh size, polymer concentration, crosslinking density, drug molecular weight, and drug polymer interactions. In swelling controlled systems, water uptake expands the polymer network and increases chain mobility, thereby allowing drug molecules to diffuse more readily from the matrix. In degradation controlled systems, hydrolytic, enzymatic, or oxidative breakdown of the network gradually releases entrapped or conjugated agents. Chemically controlled release may also occur when drugs are linked to the hydrogel through cleavable covalent bonds or reversible physical interactions. In stimuli responsive systems, wound-specific triggers such as acidic pH, elevated glucose, bacterial enzymes, matrix metalloproteinases, reactive oxygen species, or temperature changes can accelerate network swelling, bond cleavage, or matrix degradation. Therefore, release performance is influenced not only by the hydrogel composition and crosslinking strategy but also by wound pH, exudate level, enzyme activity, infection status, and the physicochemical properties of the loaded drug.

Infection-responsive drug delivery systems

Prolonged infection with resistant organisms such as Pseudomonas aeruginosa, Staphylococcus aureus, and Enterobacter species remains a major barrier to chronic wound healing. Infection-responsive carriers therefore offer an attractive strategy for on-demand delivery directly at the wound site. For example, a hyaluronic acid-based antibacterial hydrogel was designed to release the antimicrobial peptide epsilon-poly-L-lysine in response to hyaluronidase produced by pathogenic bacteria [46]. In another study, a glucose responsive hydrogel treated methicillin-resistant Staphylococcus aureus-infected diabetic wounds in rats by combining glucose oxidase activity, pH-triggered release of copper nanoclusters, and enhanced conductivity to improve antibacterial action and tissue repair [47].

Stimuli-responsive hydrogels for diabetic wound healing

A variety of stimuli responsive hydrogels have been explored for diabetic wound treatment, including pH responsive hydrogels containing acidic or basic groups that swell or deswell in response to pH changes; temperature responsive hydrogels such as poly(N-isopropylacrylamide), which undergo phase transitions around their critical solution temperature; glucose-responsive hydrogels based on glucose oxidase, phenylboronic acid, or concanavalin A; reactive oxygen species responsive hydrogels with bonds that degrade in oxidative environments to release drugs; matrix metalloproteinase-responsive hydrogels that are degraded by enzymes overexpressed in wounds; and dual or multi stimuli responsive systems that combine pH, glucose, reactive oxygen species, or thermal sensitivity to better match the complex wound environment. Collectively, these systems demonstrate the strong potential of smart hydrogels that sense pathological microenvironments and regulate therapeutic delivery to accelerate healing [48]. Hu et al. reported a photo-enzyme-polymerized hydrogel with photo-switchable redox behavior based on flavin adenine dinucleotide-centered dihydrolipoamide dehydrogenase [49].

Growth factor delivery systems

Hydrogel-based carriers that enable sustained and localized delivery of regenerative growth factors such as EGF, FGF, and VEGF represent an expanding area of research aimed at addressing the growth factor deficiency associated with chronic wounds. For example, PDGF loaded hydrogel systems developed for neuropathic diabetic foot ulcers have been reported to promote substantial granulation tissue formation [50].

Delivery of antimicrobial peptides

Hydrogels loaded with naturally derived antimicrobial peptides, such as cathelicidins and defensins, can disrupt critical bacterial processes while also promoting innate immune responses, making them promising for the prevention and treatment of wound infection [51]. For example, a patented chitosan hydrogel containing temporin antimicrobial peptides exhibited broad-spectrum activity against commonly isolated multidrug-resistant wound pathogens [52].

Self-healing hydrogels

Liu et al. developed an ultra-stretchable, tissue-adhesive, shape-adaptive, self-healing, and on-demand removable PBOF hydrogel dressing for infected wounds in highly mobile skin regions [53]. The hydrogel was prepared through multiple reversible interactions among polyvinyl alcohol, borax, oligomeric procyanidin, and ferric ions. The incorporation of ferric ion/polyphenol chelates endowed the hydrogel with photothermal antibacterial activity, while the dynamic network provided tissue adhesion, stretchability, shape adaptability, and self-healing behavior. Under near-infrared irradiation at 808 nm, the PBOF hydrogel showed strong antibacterial activity against both Staphylococcus aureus and Escherichia coli, representing Gram-positive and Gram-negative bacteria, respectively [53].