4.1 Characteristics and challenges of acute skin wounds

Acute skin wounds typically arise suddenly from events such as cuts, surgical procedures, and traffic accidents, often leading to significant skin trauma and bleeding. A rapid onset, predictable healing phases, short duration, and minimal complications characterize these wounds. However, several challenges persist in the healing process. Infection Risk: A potential for infection exists, particularly in wounds caused by lacerations, punctures, or burns. Immediate Care Needs: Timely and appropriate medical intervention is critical to prevent complications and promote healing. Pain Management: Effective pain management is essential for patient comfort and to facilitate healing. Scarring: Proper wound care is crucial for minimizing scarring, especially for deep or extensive wounds, which can be challenging. Acute skin wounds encompass various types, including incision wounds, partial-thickness injuries, and wounds involving significant tissue loss. While these different wound types may exhibit variations in the healing process, the fundamental phases of healing remain consistent.²⁰ Understanding and effectively managing each stage of healing is paramount. Acute skin wounds generally heal within a specific timeframe and are influenced by factors such as the size and depth of injury to the epidermis and dermis layers and the patient's age and overall health, including conditions such as diabetes or venous insufficiency. Personalized wound management and comprehensive treatment approaches can optimize the healing of different types of wounds, minimize complications, and improve patients' recovery outcomes.³⁴

4.2 Characteristics and challenges of chronic skin wounds

Chronic skin wounds deviate from the normal healing stages and remain open for extended periods, typically exceeding 4-6 weeks. These wounds commonly arise from underlying diseases, infections, immune dysfunction, or nutritional deficiencies, presenting significant challenges in management and treatment. The types of chronic skin wounds are described below. Pressure ulcers (bedsores), result from prolonged pressure on the skin and often occur in individuals with limited mobility, such as those who are bedridden or use wheelchairs. Diabetic ulcers are found on the feet of diabetic individuals due to poor blood circulation and nerve damage associated with the condition. Venous stasis ulcers arise from venous valve dysfunction in the legs, leading to increased pressure and fluid buildup, causing skin breakdown and ulceration. Arterial ulcers are caused by reduced blood flow due to arterial insufficiency and typically manifest as punched-out ulcers on the lower extremities. Infectious wounds are chronic infections that are prevalent in individuals with compromised immune systems and arise from cellulitis or infected surgical sites. Malignancy-related wounds arise from cancers invading the skin and underlying tissues; they are challenging to heal due to the aggressive nature of the malignancy.

The distinct features observed during the healing of these chronic skin wounds include several phases. Prolonged Inflammation: In contrast to acute wounds, chronic wounds often exhibit extended inflammation due to sustained pro-inflammatory cytokine activity, hindering progression towards the proliferative phase of healing. Impaired Angiogenesis: Chronic wounds frequently exhibit inadequate formation of blood vessels, resulting in reduced delivery of oxygen and nutrients to the wound bed, thereby impeding tissue regeneration. Excessive Protease Activity: Elevated levels of proteases, particularly matrix metalloproteinases, lead to the degradation of extracellular matrix components and growth factors, impeding healing progression. Biofilm Formation: Chronic wounds often harbor biofilms, resilient bacterial communities encased in a protective matrix, complicating infection control and diminishing treatment efficacy. Reduced Growth Factor Levels: Growth factors crucial for healing, such as platelet-derived growth factor and transforming growth factor-beta, are typically depleted in chronic wounds, thereby hindering tissue repair. Presence of Senescent Cells: Chronic wounds frequently contain senescent cells, which secrete inflammatory mediators and perpetuate a nonhealing state, contributing to delayed wound closure.^{35, 36}

Managing chronic wounds poses significant clinical challenges due to their increasing incidence and associated morbidity. The etiology, treatment outcomes, and prognosis vary widely, complicating their definition and management. While some chronic wounds are termed complex wounds, even traumatic and acute wounds can be complex. However, chronic wounds typically refer to superficial, partial, or full-thickness skin injuries that heal through secondary intention. In the UK, the prevalence of chronic wounds is 1.47/1000.³⁷ Some chronic wounds are complications of other diseases; for instance, diabetic foot ulcers are caused by diabetes. Individuals with diabetes are also predisposed to developing other chronic wounds, such as venous stasis ulcers.^{28, 38, 39} Despite undergoing a normal wound-healing process, chronic wounds are challenging to repair promptly and are highly susceptible to infection, which can lead to severe complications. In developed countries, an estimated 1-2% of individuals will experience chronic wounds during their lifetime, with approximately 6.5 million affected patients with chronic wounds in the U.S. alone.^{1, 40} In developing countries, the etiology of chronic wounds may differ significantly and is influenced by factors such as malnutrition, parasites, and chronic fungal infections.

However, impaired healing occurs across all chronic wounds, sometimes called “nonhealing” wounds by clinicians.³⁵ Critical clinical issues in chronic wound treatment include impaired angiogenesis, prolonged inflammation, and persistent infection. New treatment modalities have been developed to address the complexities of chronic wounds, including bioactive wound dressings, skin equivalents for promoting epithelialization, matrix metalloproteinase inhibitors, and the topical application of growth factors. While attention to understanding and treating chronic wounds there has been renewed, significant gaps persist in comprehending their characteristics and mechanisms of impaired healing. Advances in basic research, improved wound dressings, and surgical techniques have led to progress in managing chronic wounds. However, challenges remain, necessitating further research to improve knowledge, develop effective treatments, reduce societal and economic burdens, and optimize health care management for chronic wounds, representing a potential silent epidemic.⁴¹

5.1 Traditional skin wound dressings

Over the years, traditional wound dressings such as gauze, bandages, and cotton wool have been commonly used to maintain wound cleanliness and prevent pathogen infection because of their low cost, convenience of use, and ease of manufacturing.⁴⁴ Gauze fibers are often employed to absorb exudate and fluids from open wounds but require frequent replacement to prevent the maceration of healthy tissues. Bandages, typically composed of natural cotton, cellulose fibers, or synthetic polyamide materials, are utilized to secure lighter dressings or as compression bandages. Due to wound exudation, traditional dressings necessitate frequent changes to prevent infection and are often prone to adhere to the wound site, resulting in secondary trauma upon removal.⁴⁵ Furthermore, traditional wound dressings tend to be dry and cannot provide the moist environment necessary for accelerating wound healing processes. Modern dressings can replace traditional dressings because of their more advanced functionalities, better suitability for diverse wound requirements, and ability to promote wound healing.

5.2 Modern wound dressings

Modern wound dressings have undergone significant advancements, offering exceptional performance and versatility in clinical applications. They exhibit excellent biocompatibility, facilitating seamless integration with human tissues and minimizing allergic reactions and irritation. Typically composed of degradable materials, these dressings help obviate the need for secondary surgeries and alleviate patient discomfort. Moreover, they excel in moisture retention, creating an optimal healing environment that fosters cell regeneration and tissue repair. These attributes have propelled the widespread use of modern synthetic dressings in medical settings, enhancing the efficacy and comfort of wound care practices. Modern dressings are categorized into various forms, such as films, foam sheets, and hydrogels, which are distinguished by their manufacturing materials and specific therapeutic properties.

6.1 Antibacterial hydrogel for skin wound dressings

Researchers are actively exploring advanced antibacterial materials in response to the increasing threat posed by drug-resistant pathogens. As porous 3D materials, antibacterial hydrogels have garnered considerable attention as viable alternatives for antibacterial applications.^{87, 98, 99} Depending on their matrix and antibacterial agent, antibacterial hydrogels are categorized into antibiotic-containing hydrogels, hydrogels incorporating inorganic nanoparticles, and hydrogels with inherent antibacterial properties.⁹⁹ The advent of antibiotics marked a significant milestone in combating infectious diseases such as skin and soft tissue infections. Antibiotics exert their therapeutic effects through four primary mechanisms: inhibition of bacterial cell wall synthesis, disruption of critical metabolic pathways, interference with protein synthesis, and inhibition of nucleic acid synthesis.¹⁰⁰ Despite the discovery of numerous antibiotics, less than 1% of antibiotics are currently utilized in clinical settings due to concerns regarding toxicity and limitations in host cell uptake.^{101, 102} To date, tetracycline,^103-105 ciprofloxacin,^106-110 gentamicin,^111-113 and sulfamethoxazole^114-116 have been widely used to prepare antibacterial hydrogel wound dressings. These antimicrobial agents are effectively incorporated into hydrogels through electrostatic interactions, hydrogen bonding, hydrophobic interactions, and van der Waals forces. These interactions critically influence the drug distribution, stability, release rate, and release mechanism within the hydrogel network. Understanding these interaction dynamics facilitates the optimization of hydrogels as drug carriers, enabling precise control over drug release kinetics and enhancing drug delivery efficacy. Furthermore, variations in hydrogel compositions and ratios significantly impact their physical and chemical properties, including mechanical strength, water absorption capacity, responsiveness to environmental stimuli (e.g., temperature and pH), and degradation rates. These properties, in turn, influence the release profiles of encapsulated drugs, thereby shaping the therapeutic efficacy of hydrogel-based wound dressings. For example, Ding et al.¹¹⁷ reported the fabrication of a dual-crosslinked interpenetrating network hydrogel based on poly(acrylic acid-co-hydroxyethyl methacrylate), synthesized via free radical polymerization of hydroxyethyl methacrylate and acrylic acid. This hydrogel was simultaneously loaded with the antibiotic gentamicin (Gen) as a dynamic physical crosslinker. The immobilization of Gen within the hydrogel matrix occurred through electrostatic interactions between the carboxyl groups of polyacrylic acid and the amino groups of gentamicin, thereby imparting pH-responsive characteristics to the drug release profile. This research documented sustained antibacterial efficacy against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria for a duration exceeding 28 days. Ji et al.¹¹⁸ reported a novel injectable and pH-responsive hydrogel wound dressing composed of oxidized sodium alginate and hyaluronic acid-ethylenediamine grafting. Tetracycline hydrochloride was incorporated into the hydrogel, attenuating the release rate of tetracycline and thereby exerting a substantial bacteriostatic effect that persisted throughout 120 h of antibacterial therapy. These antibiotics play a critical role in wound dressings, aiding in preventing and treating infections while promoting wound healing. However, the careful selection and use of antibiotics are essential to avoid the development of resistance and other potential adverse effects. Future research on antimicrobial hydrogel wound dressings should focus on identifying and evaluating novel antimicrobial agents, such as antimicrobial peptides (AMPs) and natural extracts.

Due to their unique physicochemical properties—their ultrasmall size and high surface reactivity—nanomaterials have emerged as alternative tools to overcome antibiotic resistance. Common nanomaterials include metal-based nanoparticles (such as AgNPs^{119, 120} and copper nanoparticles¹²¹), metal oxide nanoparticles (composed of zinc oxide,¹²² cerium oxide,¹²³ and yttrium oxide¹²⁴), and other substances with antibacterial activity. They disrupt bacterial membranes, penetrate cells, and interact with cellular components such as DNA, ribosomes, and enzymes, disrupting standard cellular mechanisms.¹²⁵ The bactericidal mechanisms of nanomaterials hinge on their core materials, size, and surface functionalization. AgNPs have been extensively applied in various wound dressings due to their broad-spectrum and efficient antibacterial activity. For instance, Mao et al.¹²⁶ developed an agarose-based hydrogel dressing by complexing the hydroxyl groups of carboxymethyl agarose with Ag⁺ that exhibited significant antibacterial activity (Figure 3A). Wang et al.¹²⁸ synthesized Gel-DA@AgNPs by reducing dopamine-modified gelatin, resulting in a hydrogel dressing with excellent hemostatic and antibacterial properties by combining it with agarose and borax. In addition to its inherent antibacterial properties, Ag can be combined or combined with various materials, such as nanoparticles. For example, Liu et al.¹²⁹ prepared an antibacterial and hemostatic hydrogel by loading AuNPs into the cavities of halloysite nanotubes and mixing them with chitin. Li et al.¹³⁰ prepared a chitosan-based hydrogel composite with Ag-Au NPs to treat bacteria-infected wounds. Despite the excellent antibacterial effects of these hydrogels, the physical and chemical instability of nanoparticles often limits their development. Surfactants such as polyvinylpyrrolidone and PVA can stabilize AgNPs but may also impact their size. Therefore, improving nanoparticle stability is crucial in designing antibacterial hydrogels based on AgNPs to control antibacterial activity while effectively minimizing toxicity.

Antimicrobial hydrogels with inherent activity generally refer to hydrogels containing natural antimicrobial components that exhibit fewer side effects than traditional antimicrobial hydrogels.¹³¹ CS, a natural cationic hydrophilic polymer, is characterized by its excellent biocompatibility, hemostatic properties, and antimicrobial activity.^132-134 Its antimicrobial efficacy primarily stems from the amino and hydroxyl groups within its molecular structure that interact with anionic components on bacterial cell membranes, leading to membrane disruption and subsequent bacterial death. Additionally, chitosan can chelate metal ions within bacterial cells, interfering with metabolic processes. CS synergistically interacts with other natural polymers, such as HA, gelatin, and cellulose, commonly utilized in developing composite wound dressings and tissue engineering scaffolds. For example, Peng et al.¹³⁵ developed a polysaccharide-based bioadhesive hydrogel using carboxymethyl chitosan and acrylic fiber, leveraging the inherent antimicrobial properties of CMSCs to achieve effective antimicrobial activity without the need for antibiotics. Chen et al.⁵⁵ designed a non-cross-linked CS/HA hybrid antimicrobial hydrogel that exhibited excellent antibacterial effects against MRSA. In vivo, studies of the wounds of diabetic mice infected with MRSA indicated that CS/HA hydrogels significantly facilitated wound healing by eliminating MRSA infections and promoting epidermal regeneration, collagen deposition, and vascularization.

Furthermore, AMPs are abundant, short, cationic biomolecules produced by tissues and cells of various plant and invertebrate species.¹³⁶ Over 880 different AMPs have been identified or predicted from nucleic acid sequences. AMPs are widely believed to bind to membranes, leading to bacterial destruction.¹³⁷ AMPs exhibit broad-spectrum bactericidal activity against gram-positive bacteria, gram-negative bacteria, and fungi, making them a promising choice for developing antimicrobial composite materials.^{138, 139} For instance, Zhu et al.¹⁴⁰ designed an antimicrobial hydrogel dressing composed of oxidized β-glucan and the AMPs CH₃(CH₂)₆C(O)-GIKKIIKKI-NH₂ (C₈G₂) through a Schiff base reaction. C₈G₂ is released in the mildly acidic environment of bacteria-infected wounds, inhibiting bacterial growth and reducing inflammation in vitro and in vivo, thereby accelerating the healing of MRSA-infected skin wounds. Wang et al.¹²⁷ utilized the self-assembly of the natural AMPs Jelleine-1 nanofibers to develop an AMPs-based hydrogel that exhibited excellent antimicrobial activity and biodegradability. ε-Polylysine (ε-PL), a natural peptide formed by lysine residues linked via ε-amine and α-carboxyl groups, is widely utilized in the development of antimicrobial hydrogels due to its broad-spectrum antimicrobial activity, low toxicity, and excellent biocompatibility. The abundant functional groups on ε-PL facilitate chemical modification and customization for designing antimicrobial hydrogels with various functionalities, such as injectability, photocuring, and adhesion (as shown in Figure 3B). For instance, Qian et al.¹⁴¹ synthesized an injectable photocurable hydrogel by modifying ε-PL with methacrylic acid glycerol ester and γ-poly(glutamic acid), which possessed outstanding antimicrobial properties and biocompatibility.

6.2 Antioxidant hydrogel for skin wound dressings

ROS are byproducts of cellular oxidative metabolism produced by inflammatory cells such as neutrophils and other white blood cells,^{142, 143} playing a crucial role in wound healing. They are involved in regulating the inflammatory response, promoting the clearance of inflammatory cells, and resolving inflammation, thereby creating a favorable microenvironment for wound healing.¹⁴² However, excess ROS can lead to oxidative damage, apoptosis, and inflammation, ultimately hindering angiogenesis and inhibiting wound healing. In the case of a ROS imbalance, the addition of antioxidants can effectively promote enzyme repair and improve metabolism, ultimately restoring the average growth of cells.²⁴ Common natural antioxidants include non-thiol compounds (plant polyphenols), thiol compounds, vitamins (ascorbic acid and vitamin A), and various enzymes (glutathione reductase and glutathione peroxidase) (as shown in Figure 4). These antioxidants exhibit excellent properties that help protect the body from ROS-mediated damage. Antioxidant hydrogels can eliminate excess ROS in wounds, reduce cellular oxidative stress, improve the pathological microenvironment of wounds, and achieve rapid wound healing. Plant polyphenols are a class of secondary metabolites with polyphenolic structures that are renowned for their potent antioxidant properties and are widely used in wound healing treatments. Common polyphenols include dopamine, tannic acid (TA), catechins, GA, and theaflavins.¹⁴⁴ The phenolic hydroxyl groups in their structures have a strong ability to scavenge ROS and other free radicals, making them widely used in the preparation of antioxidant hydrogels.¹⁴⁵

Typically, antioxidant properties are imparted to hydrogels through the direct addition of polyphenolic substances or by modifying polymers. For example, Gao et al.¹⁴⁶ developed an antioxidant hydrogel wound dressing using TA, PVA, agarose, and hyperbranched polylysine. In studies of MRSA-infected wounds, this hydrogel exhibited excellent antioxidant and antibacterial capabilities, effectively killing bacteria in vivo, reducing inflammation, and promoting tissue regeneration. Additionally, Gou et al.¹⁴⁷ developed an antioxidant hydrogel (OBGTP) loaded with tea polyphenols based on oxidized polysaccharides and adipic acid dihydrazide-modified gelatin. In a rat skin injury model, OBGTP exerted significant antioxidant effects, reducing the expression of inflammatory factors and promoting rapid wound healing. Additionally, phenolic groups (such as tyrosine, catechol, and hydroquinone) can undergo oxidative coupling under the influence of HRP/H₂O₂, hemin/H₂O₂, laccase, tyrosinase, sodium periodate, and sodium hydroxide to form injectable antioxidant hydrogels. The type and concentration of the oxidant, as well as the content of phenolic groups, affect the gelation rate, gelation time, and gel strength of phenolic-crosslinked hydrogels. For example, Tan et al.¹⁴⁸ utilized HRP/H₂O₂ to catalyze the formation of antioxidant hydrogels (HA-DA@rhCol) from dopamine-modified hyaluronic acid (HA-DA) loaded with recombinant human type III collagen (rhCol). Their study indicated that a concentration of 1.5% HA-DA@rhCol resulted in a suitable gelation time (30 s) and injectability at 37°C. Furthermore, DPPH radical scavenging assays confirmed the in vitro antioxidant capacity of the HA-DA@rhCol hydrogel. Additionally, it effectively scavenged ROS, alleviated oxidative stress in chronic wound tissues, and promoted wound healing. Due to the mild reaction conditions, high specificity, and good biocompatibility of enzymatic crosslinking, it is particularly suitable for preparing hydrogel wound dressings. However, the activity of enzymes is susceptible to factors such as temperature and pH, necessitating specific storage and usage conditions.

6.3 Hemostatic and adhesive hydrogel for skin wound dressings

Wounds resulting from major trauma or surgery can lead to serious consequences such as hemorrhage, infection, shock, organ failure, and even death.^{2, 87} Therefore, achieving efficient and rapid hemostasis is crucial in wound treatment.^{149, 150} Hemostasis occurs in the early stages of wound repair, and hemostatic hydrogel dressings can facilitate rapid bleeding control, positively promoting wound healing. Current research indicates that hemostatic hydrogels physically seal wounds and enrich coagulation factors by absorbing wound exudates.¹⁵¹ Additionally, hemostatic and adhesive hydrogels can adhere seamlessly to the wound area for extended periods, reducing the risk of infection from the external environment. Numerous hemostatic dressings (such as HemCon, Surgicel®, and fibrin bandages) have been extensively developed for clinical treatment. However, weak adhesion to wet tissue surfaces often limits the hemostatic effectiveness of these materials.

Inspired by the strong adhesion properties of marine mussels, researchers have developed a variety of phenolic-based adhesive hydrogel wound dressings. One of the most extensively studied adhesives from marine organisms is 3,4-dihydroxyphenylalanine, which is found in mussel foot proteins. DA can interact with various surfaces through physical (hydrogen bonding, π–π interactions, electrostatic interactions, and coordination) or chemical interactions (Michael addition and Schiff base reactions). Notably, during the free radical polymerization process, introducing high concentrations of DA may affect the polymerization of the hydrogel. Common strategies for preparing adhesive hydrogel wound dressings involve introducing functional groups or small molecules with adhesive properties to enable multiple interactions between the hydrogel and surrounding tissues. For instance, phenol hydroxyl and aldehyde groups can crosslink with thiol and amino groups on tissues via Michael addition and Schiff base reactions, resulting in stable tissue adhesion. Hemostatic hydrogels developed using a caffeic acid-modified gel (CaG), ODEX, and ZnO have shown excellent hemostatic performance in rat liver and heart bleeding models.¹⁵² Furthermore, Zn²⁺-catechol chelation endows the hydrogel with sustained anti-infection, anti-inflammatory, and antioxidant properties. Chen et al.¹⁵³ developed a novel adhesive hydrogel using PVA, DA, and Cu²⁺, which possesses injectable and strong adhesive capabilities, serving as a physical barrier for hemostasis at wound sites. Similarly, Dai et al.⁹³ reported a DA-based collagen–starch hydrogel (CoSt). In models of rat tail amputation, skin incisions, severe liver injury, abdominal aorta injury, and nerve transection injury, this hydrogel exhibited superior hemostatic efficiency compared to fibrin glue. The removal of adhesive hydrogels often causes discomfort, such as pulling and pain; damages newly regenerated skin tissue; and potentially leads to bleeding and infection (as shown in Figure 5). Moreover, the residual hydrogel may hinder wound repair. Emerging stimulus-responsive detachable adhesive hydrogels have garnered significant attention from researchers to mitigate these issues.

6.4 On-demand detachable hydrogel for skin wound dressings

Adhesive hydrogel wound dressings can function as moisturizers and hemostatic agents, stabilizing adhesion to irregular wounds and preventing interference from the external environment. The adhesion of nonbiodegradable adhesive hydrogel dressings is often irreversible, making their separation from the wound site during replacement difficult and potentially causing secondary injury or new infections.¹⁵⁴ Even hydrogel dressings with relatively weak adhesion can cause varying degrees of damage to sensitive tissues, significantly limiting their application in treating skin wounds.¹⁵⁵ Hydrogels with on-demand removal or dissolution capabilities can minimize adverse effects on wounds. Techniques such as pH, temperature, ion-induced phase separation, grafting of polymer chains with cleavable disulfide bonds, and terminal NHS esters can endow adhesive hydrogels with on-demand removal properties.

Additionally, the chemical composition of these hydrogels can be customized according to the type and condition of the wound, imparting unique physical and chemical characteristics to the on-demand adhesive hydrogels. For instance, Weng et al.¹⁵⁶ developed an on-demand removable, adhesive, bioinspired hydrogel based on catechol chemistry that can be easily separated from porcine skin with the assistance of a 5 wt.% aqueous urea solution (as shown in Figure 6A). Zhou et al.¹⁶⁰ created an on-demand, removable hydrogel using gelatin, TA quinone, and borax that effectively treated MRSA-infected wounds. The pH-sensitive borate ester (polyphenol-B) and Schiff base bonds crosslinked within the gel network enable on-demand removal and dissolution. However, the design and manufacturing of such on-demand removable or dissolvable hydrogel dressings can be complex and may result in low-toxicity byproducts, which could negatively impact tissues.

6.5 Stimulus-responsive hydrogel for skin wound dressings

Traditional hydrogels exhibit unique functionality and passively act at specific stages of wound healing. Modifying the chemical structure to impart various responsive characteristics (stimulus-responsiveness, injectability, self-healing, and conductivity) to hydrogels has emerged as a promising strategy for addressing antimicrobial, anti-inflammatory, and angiogenic needs throughout the wound healing process.^161-164 Among these, stimulus-responsive hydrogels have garnered significant attention due to their abilities to respond to physical, chemical, or biochemical stimuli (such as temperature, pH, light, electric field, or magnetic field) by altering their physicochemical properties (e.g., solubility, shape, swelling behavior, network structure, and mechanical properties).^{17, 165, 166} Stimulus-responsive hydrogels can control the release of bioactive molecules (anti-inflammatory agents, epidermal growth factors, hemostatic agents, and antimicrobial substances) or adjust their physicochemical properties within the wound microenvironment, thereby accelerating the wound healing process. The pH of the skin plays a crucial role in maintaining normal function. The pH fluctuates during different stages of wound healing, gradually increasing from the surface to deeper layers. This variation can indicate the wound status, helping to predict the likelihood of healing or deterioration. Healthy skin maintains a slightly acidic pH (pH 4-6), chronic wounds exhibit a pH of around approximately 7.3–10, and acute wounds have a pH of approximately 7.4. As the wound heals, the pH returns to an acidic state.^{166, 167} Hydrogels with pH-responsive functionality can adapt to changes in the pH of the wound microenvironment by releasing loaded drugs or cytokines to promote wound healing. For instance, Schiff-base crosslinked hydrogels can dissociate under acidic conditions to release insulin, aiding in healing diabetic wounds.^{63, 86} Similarly, pH-responsive hydrogels that release TA achieve this property by deprotonating chitosan under alkaline conditions, thereby reducing its binding strength with TA.¹⁶⁸ Tao et al.¹⁶⁹ prepared a multifunctional hydrogel dressing loaded with zinc oxide nanoparticles through the use of phenylboronic acid-grafted CS, dibenzaldehyde-grafted polyethylene glycol, and TA. Due to the pH-responsive release of Zn²⁺ and TA, the hydrogel effectively killed MRSA, scavenged reactive oxygen and nitrogen species, mitigated oxidative stress, and induced the M2 polarization of macrophages.

Temperature-responsive hydrogels release drugs, antimicrobial agents, or cytokines through volume changes, resulting in short response times, simple operation, and adjustable response temperatures.^{89, 170-172} These properties have led to extensive research and application in wound healing and other fields. Temperature changes affect the interactions between hydrophobic and hydrophilic groups within the hydrogel, causing structural changes that result in volume expansion or contraction.^{173, 174} For instance, hydrogels with a lower critical solution temperature (LCST) contract when the temperature exceeds the LCST, aiding in the localized loading of substances and preventing accumulation in healthy tissues.¹⁷¹ Common thermosensitive polymers used in biomedicine include PNIPAM,¹⁷⁵ poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide),^{176, 177} and poly(D, l-lactide)-poly(ethylene glycol)-poly(D, l-lactide).^{178, 179} For example, Haidari et al.¹⁸⁰ developed a temperature-responsive hydrogel by copolymerizing NIPAM with AA and subsequently embedding AgNPs. Blacklow et al.⁷⁷ created a temperature-responsive hydrogel dressing (AAD) using PNIPAM, alginate, and AgNPs. This AAD was attached to skin tissue via chitosan and carbodiimide-mediated reactions and contracted upon temperature triggering to facilitate active wound closure and AgNP release, thus accelerating wound healing. Similarly, Guo et al.¹⁸¹ designed a thermoresponsive hydrogel dressing based on quaternized chitosan, polydopamine-coated reduced graphene oxide (rGO-PDA), and PNIPAM. This hydrogel dressing can stably adhere to tissues and promote wound closure through contraction. However, PNIPAM hydrogels are typically nonbiodegradable and may cause localized inflammatory responses, impeding tissue repair. Therefore, many studies have attempted to use natural polymer crosslinkers (such as GelMA and SFMA) or incorporate natural polymers into the PNIPAM framework to enhance its biocompatibility.¹⁸²

Diabetes has a high prevalence worldwide, with approximately 19%–34% of diabetic patients estimated to develop complications such as chronic wounds, posing a severe threat to their quality of life and safety.^183-185 Due to the high glucose microenvironment in diabetic wound areas, which serves as a stimulus for controlled drug release, glucose-responsive hydrogel dressings have displayed unique advantages in treating chronic wounds. Currently, the glucose-responsive hydrogels developed include glucose oxidase (GOx) systems,^{186, 187} lectin systems,^{188, 189} and phenylboronic acid systems.^{190, 191} GOx is an endogenous redox enzyme that catalyzes the conversion of glucose into gluconic acid and H₂O₂, rapidly consuming glucose at the infected site while lowering the pH of the wound microenvironment.^{192, 193} However, GOx, a protein-like substance sensitive to the external environment, is prone to immune reactions in the human body. In the phenylboronic acid system, boronate ester bonds respond to high concentrations of glucose and H₂O₂, consistent with the microenvironment of diabetic wounds. Additionally, phenylboronic acid can bind to the diol structure in glucose to form boronic esters. In the high-glucose environment of diabetic wounds, glucose can competitively react with phenylboronic acid, leading to hydrogel dissociation or promoting drug release from the hydrogel. Currently, glucose-responsive hydrogel dressings based on the phenylboronic acid system offer advantages such as low toxicity, good stability, and no immune rejection reactions, and thus they are widely used for treating chronic diabetic wounds.^194-196 For example, Zhou et al.¹⁵⁷ developed a functional hydrogel utilizing dynamic boronate bonds that adaptively react with high glucose concentrations and hydrogen peroxide to alleviate oxidative stress and release deferoxamine in the early stages of wound healing. Sun et al.¹⁹⁷ also designed a photocrosslinked GelMA hydrogel loaded with (-)-epigallocatechin-3-gallate (EGCG) through boronate bonds. This hydrogel releases more EGCG as glucose levels increase, thereby reducing inflammation, promoting angiogenesis, and facilitating tissue remodeling (as shown in Figure 6B). Additionally, phenylboronic acid esters exhibit responsiveness to both pH and ROS.¹⁹⁸ Leveraging this characteristic, various responsive hydrogels have been developed to achieve more precise drug release within pathological microenvironments. For instance, Wang et al.¹⁹⁹ constructed an injectable glycopeptide hydrogel with dual pH/ROS-responsiveness, enabling spatiotemporal drug release in response to these stimuli. Similarly, Yao et al.²⁰⁰ formulated a dual pH/ROS-responsive hydrogel loaded with platelet-rich plasma via hydrogen bonding and Schiff base formation. The Schiff base in the hydrogel dissociates in acidic and oxidative wound environments, releasing growth factors to effectively promote wound healing.

6.6 Hydrogel wound dressings for monitoring the skin wound status

Traditional wound dressings are physical barriers that maintain a moist environment. In contrast, hydrogels integrated with smart sensors enable real-time monitoring of wound conditions. These monitoring capabilities are crucial for the timely detection of infections, inflammation, and other complications, facilitating targeted wound management and treatment. The pH is a critical indicator of the wound status and is associated with various physiological processes, such as bacterial infection, angiogenesis, and collagen formation.²⁰¹ Due to the release of fatty acids and amino acids by keratinocytes, the pH of healing wounds or normal skin is slightly acidic.^{202, 203} In acute skin wounds, neutrophils can lower the pH to prevent bacterial colonization. In chronic skin wounds, alkaline conditions may persist for months, increasing susceptibility to bacterial infections. Therefore, monitoring changes in the pH of skin wounds can be an effective method for assessing the wound status, providing alerts for the infection risk and assisting in wound management and treatment. Additionally, redox sensors can monitor oxidative stress levels at the wound site, providing critical information on the wound healing process. For example, Zhang et al.²⁰⁴ developed an amphiphilic ionic hydrogel wound dressing by incorporating GOx and HRP, enabling the simultaneous monitoring of pH and glucose levels in the treatment of diabetic wounds. Lu et al.²⁰⁵ crosslinked carboxymethyl cellulose with europium–ethylenediaminetetraacetic acid to prepare a functional hydrogel capable of monitoring the pH of diabetic wounds. The fluorescence intensity of this hydrogel has a linear relationship with pH, allowing real-time measurement of the wound pH.

Wound healing at joints, such as the fingers, elbows, and knees, is significantly affected by motion.²⁰⁶ Due to the frequent movement of joints, these wounds often exhibit slower recovery, posing more significant challenges for treatment. Traditional hydrogel dressings for joint wounds are prone to rupture and bacterial infection, and thus matching and monitoring irregular wounds is difficult. Hydrogels with self-healing and motion-sensing properties can autonomously repair damage and detect joint wound movement, effectively addressing these challenges.^{207, 208} For instance, Liu et al.²⁰⁹ developed a self-healing hydrogel dressing through dynamic borate ester bonds and supramolecular interactions that can effectively promote wound healing while simultaneously monitoring wound tearing at body joints in real time. Similarly, John et al.²¹⁰ developed a bacteria-responsive hydrogel that reacts to bacterial enzyme-induced changes in dielectric properties, enabling the detection of the wound infection status.

Temperature is considered a crucial parameter for evaluating the wound healing status because it influences a range of chemical and enzymatic reactions and cytokine activities in the body.²¹¹ Monitoring the wound temperature can provide essential information related to healing, such as local blood flow, infection, and inflammation, thus providing a reference for developing personalized treatment plans.²¹² Previous studies have shown that local vasodilation, angiogenesis, and infiltration of inflammatory cells can increase the temperature of the wound area.²¹³ Therefore, wound dressings with temperature-monitoring capabilities can help promptly detect the wound healing status, and intervention measures can be taken to prevent wound deterioration. For instance, Ma et al.¹⁵⁸ designed an intelligent, flexible, electronic integrated wound dressing capable of real-time wound temperature monitoring, which is an early predictor of pathological infection (as shown in Figure 6C). In another study, Fan et al.¹⁵⁹ developed a PNIPAM-based flexible wireless wound dressing with properties of conductivity, stretchability, antibacterial activity, and wireless temperature monitoring of the wound (as shown in Figure 6D). However, hydrogel wound dressings with monitoring capabilities also have certain limitations. For instance, their complex manufacturing process restricts their large-scale production and application. The sensitivity and stability of wound monitoring need to be improved in complex wound environments to ensure the accuracy of monitoring data. Additionally, the mechanical strength and biocompatibility of hydrogel materials require further enhancement to prevent damage or adverse reactions during use.