Functional hydrogel dressings for wound management: a comprehensive review

Hydrogels have gained significant attention as wound dressings due to their potential for rapid healing. Researchers have actively explored a range of techniques for antimicrobial applications, including incorporating drug payloads, utilizing inorganic nanometals, and harnessing the properties of natural cationic polymers. In terms of hemostasis and coagulation promotion, techniques such as drug delivery, adhesive physical hemostasis, and adhesive functional groups have been studied. To control inflammation, researchers have investigated the application of natural antioxidants and antioxidant functional groups, which have demonstrated anti-inflammatory effects. Furthermore, the smart responsiveness of hydrogel wound dressings to pH, temperature, and light has been explored. This review presents a summary of the research progress and application prospects in these areas and offers an outlook on the future development direction of hydrogel wound dressings.


Introduction
The wound healing process is highly intricate, requiring the coordination of multiple cell types and stages, including hemostasis, inflammation, proliferation, and remodeling [1].Wound healing is a dynamic and ongoing process that necessitates the collaboration of various cell populations, extracellular matrix, and mediators such as growth factors [2].Effective wound healing is crucial for minimizing infection risk, promoting tissue regeneration, and preventing complications like scarring.However, the rising prevalence of chronic wounds, often resistant to conventional treatments, has underscored the need for advanced wound dressings to enhance healing outcomes.These dressings play a pivotal role in maintaining optimal wound conditions, controlling exudate, preventing bacterial colonization, and promoting tissue regeneration.
The unique healing stages in different parts of a wound render wound healing a complex and intriguing topic.Hemostasis, inflammation, proliferation, and remodeling represent the four distinct stages involved in wound healing [3].Throughout this procedure, several points require special attention.First, keeping the wound moist allows for faster healing and reduces the chance of scarring [4].Secondly, it is a common practice to avoid mechanical stress and the risk of contamination from the external environment.In addition, it is crucial to maintain a high oxygen tension during wound healing.This is because oxygen is a crucial factor not only for cell replication and the synthesis of collagen but also because it contributes to the production of leukocytes, which are essential for killing bacteria [5].Therefore, the ideal wound dressing should have the following characteristics: (1) good histocompatibility and non-toxic [6]; (2) good moisture retention [7]; (3) adequate mechanical strength [8]; (4) good antibacterial properties [9]; and (5) some specific biochemical characteristics can facilitate the attachment, multiplication, and maturation of cells [10].
In recent years, numerous wound dressings have been successfully developed, including hydrogels [11], films [12], nanofibers [13], foams [14], and sponges [15].Of these advanced dressings, hydrogels have been the focus of most research in the field of rapid wound healing due to their biocompatibility, ability to maintain moisture, and antimicrobial properties at the interface between the dressing and the wound [16].Hydrogels possess distinctive properties as they are three-dimensional viscoelastic networks that are hydrophilic and selfsustaining, allowing for the diffusion and attachment of molecules and cells [17].These networks are formed from homopolymers or copolymers and rely on crosslinks, which can be either chemical or physical, to maintain their structural and physical integrity.Polymers with specific and unique properties can be produced using different crosslinking methods such as temperature, ions, or UV radiation [18].Hydrogels are soft and elastic, making them easy to apply and remove, which can increase patient comfort.Although hydrogels have been widely used as wound dressings, there are some drawbacks associated with their use.One of the primary concerns is that the accumulation of exudate can lead to the maceration of the wound and encourage bacterial growth.Another issue is that the low mechanical strength of hydrogels can make them challenging to handle [19].This paper summarizes and discusses various functional hydrogel dressings to provide reference and direction for wound dressing research.

Antimicrobial agents for hydrogel dressings
Bacterial infection is a common challenge in wound treatment that can cause persistent inflammation and delay healing.While antibiotics have been widely used since the discovery of penicillin in 1928 [20], their administration can lead to bacterial resistance and cytotoxicity.Therefore, researchers are searching for better antimicrobial strategies.The incorporation of antimicrobial agents into hydrogels has demonstrated potential for the development of wound dressings.For instance, Jiang et al [21] loaded clindamycin onto glycerol hydrogels and made fibers for fabric dressings (figure 1).The prepared hydrogel fabric dressing showed excellent results in promoting the healing of infected wounds, completely closing the skin of rats within 14 days.This is impossible with conventional hydrogel dressings, providing a new avenue for development.Abegaz et al [22] encapsulated ibuprofen in a heparin-modified thermosensitive hydrogel to reduce pain and inflammation during healing.In vitro studies have verified that the hydrogel-released ibuprofen significantly mitigates lipopolysaccharide-induced inflammation by inhibiting the production of NO, PGE2, and TNF-α in RAW264.7 macrophages.

Inorganic nanometal for hydrogel dressings
In addition to drug loading, inorganic nanometals such as AgNPs [23], AuNPs [24], ZnONPs [25], and CuNPs [26] have been extensively studied as potential antimicrobial applications.Nanosilver has a well-established track record of use due to its broad-spectrum activity and compatibility with mammalian tissues.As a result, incorporating nanosilver into wound dressings has been proposed as a means to impart bactericidal properties.Early applications of nanosilver in hydrogel wound dressings were mainly based on physically coating silver nanoparticles (AgNPs) on a series of natural or synthetic polymers such as chitosan [27], alginate [28], gelatin [29], cellulose [30], and polyvinyl alcohol [31].Besides having antibacterial properties alone, nanosilver is often used with other antibacterial substances, such as curcumin [32] and graphene [33], to attain enhanced antibacterial efficacy.For example, Yang et al [34] developed a slow-release antimicrobial hydrogel combining polyethyleneimine (PEI), graphene oxide (GO), and nanosilver (AgNPs) with more stable and long-lasting antimicrobial effects.In addition to nanosilver, ZnO nanoparticles are the most widely used metal particles in wound dressings due to their low price.M et al [35] prepared a composite hydrogel using β-cyclodextrin dimer (bis-CD) as a novel main crosslinker with ZnO nanoparticles and sodium alginate as the principal polymer, which showed good antibacterial properties.
Meanwhile, this nanocomposite hydrogel exhibited rapid self-healing behavior in less than 5 seconds.In a study by Zhou et al [36], a hydrogel made from methacrylate gelatin (GelMA) and oxidized dextran (oDex) was developed.The hydrogel was loaded with black phosphorus (BP) nanosheets and zinc oxide nanoparticles (ZnO NPs).It showed a combined antibacterial effect from photothermal and zinc ions when exposed to 808 nm NIR laser irradiation.In addition, other metal particles have been used to prepare antimicrobial hydrogel wound dressings.Xu et al [37] developed a composite hydrogel (PDA/Cu-CS) composed mainly of polydopamine (PDA) and copper-doped calcium silicate ceramic (Cu-CS) (figure 2).PDA/Cu-CS composite hydrogels are formed by PDA complexed with Cu and acyl hydrazone bonds.The PDA generated on the macromolecular chain interacts with the Cu ions released from Cu-CS to form the PDA/Cu complex, which is the key to enhanced photothermal properties, antimicrobial activity and angiogenesis.The study confirmed that the PDA/ Cu complex within the composite hydrogel played a crucial role in boosting the photothermal properties and antimicrobial activity.Through photothermal action, the hydrogel rapidly and effectively inhibited methicillinresistant Staphylococcus aureus and Escherichia coli, utilizing the thermionic effect created by heating copper ions for long-term suppression.The complexation of PDA and Cu ions (PDA/Cu complexing) endows the composite hydrogel with enhanced photothermal performance, antibacterial properties, and angiogenesis.(C) Composite hydrogel with 'hot ions effect' for high-efficiency bacteria inhibition as well as accelerated tissue regeneration for infectious wound healing.Reprinted with permission from [37].Copyright (2020) American Chemical Society.

Natural polymers for hydrogel dressings
Bacteria with negatively charged surfaces can be neutralized by cations, which results in the loss of their biological activity.Therefore, cationic substances have been explored as potential antimicrobial agents.Chitosan is the only known natural cationic polysaccharide and is often used in complexes with other polymers for its antimicrobial properties.Other cations such as quaternary amines and cationic peptides can be grafted onto polymers through chemical modification to enhance their antimicrobial activity.CA-pDA is a self-healing hydrogel created by Ling and colleagues [38], which comprises dihydroxyphenylalanine nanoparticles, L-arginine conjugated chitosan, and benzaldehyde functionalized polyethylene glycol.This hydrogel has dual angiogenesis and antimicrobial activity functions and can be used as a wound repair and antimicrobial dressing.Yuan et al [39] developed a salt-reactive hydrogel dressing based on cationic peptides by combining ε-polylysine, poly (glycoldiglycidyl ether), and poly(DVBAPS-co-GMA).These hydrogels can be further quaternized to improve their antimicrobial properties.The hydrogels showed good antimicrobial activity, biocompatibility, cell proliferation potency, and adhesion properties.In vivo and in vitro tests demonstrated that these hydrogels have suitable antifouling and sterilization ability, achieving a 96% sterilization rate.

Drug hemostasis for hydrogel dressings
Adequate hemostasis is a critical component of the initial phase of wound healing, underscoring the importance of developing hydrogel wound dressings that can rapidly promote this process.Recent research has revealed that the hemostatic properties of hydrogel dressings are not solely based on physical sealing but also on promoting coagulation by absorbing wound extracts [40,41].A foam gel wound dressing with quick hemostatic and antibacterial properties was developed by Xie and colleagues [42].The dressing comprised a calcium alginate foam matrix and chitosan-modified graphene oxide (CG) nanocomposites.CG was found to have a strong affinity for platelets, which aided in rapid hemostasis, enabling the dressing to halt bleeding within 10 seconds.Du and colleagues [43] developed a new hydrogel through photocrosslinking using gelatin methacrylate (GelMA) and hyaluronic acid aldehyde (HA-CHO).The hydrogel was loaded with either gentamicin sulfate (GS) or a combination of GS and lysozyme (LZM).First, SEBS was activated by pretreatment with oxygen plasma and photoinitiator BP.The GelMA and HA-CHO composite hydrogel was created through a Schiff base reaction between an amine and an aldehyde.The degree of cross-linking was adjusted by the ratio of HA-CHO and GelMA.Next, GS was added to the mixed solution to form drug-loaded hydrogels on the SEBS substrate after UV cross-linking.Finally, the drug release behavior and pH sensitivity of the resulting hydrogels were evaluated at pH 7.4 and 5.0.The combination of LZM and GS produced a synergistic effect, resulting in a hydrogel with effective hemostatic properties (figure 3).Song and colleagues [44] described a chitosan-based hydrogel (DCS-PEGSH gel) that possesses a unique multistage pore structure.This gel was created by cross-linking sebacic acid with 3-(3,4-dihydroxyphenyl)propionic acid-modified chitosan (DCS).The resulting biohydrogel exhibited favorable cytocompatibility and a stretchability of approximately 780%, with excellent blood absorption capacity (1300% ± 50%).Furthermore, these hydrogels demonstrated strong adhesion properties (up to ~68.5 kPa), firmly adhering to pig skin and bleeding wounds in static and dynamic humid environments and possessing an extended service life.

Adhesives for hydrogel dressings
Hemostatic properties, as a fundamental function, are often combined with other functions in hydrogel wound dressings.Adhesive hydrogels provide physical closure to the wound for hemostasis and prevent infection by shielding it from the external environment.However, adhesive hydrogels used for wound dressings must possess good biocompatibility and degradability.Most adhesive hydrogels still suffer from limitations such as poor mechanical properties, low bioactivity (i.e., antibacterial and hemostatic ability), and low biocompatibility, which significantly restrict their practical applications.To overcome these limitations, Zhao et al [45] proposed a simple preparation method for PAM-Lignin-CS-Laponite-SA hydrogels suitable for wound dressings.Hydrogen bonding and electrostatic interactions within the system were identified as the key factors responsible for the hydrogels' robust self-healing properties and consistent adhesive properties.Furthermore, the hydrogels exhibited low cytotoxicity, good antibacterial activity, and excellent hemostatic properties.
In addition to incorporating adhesives, introducing functional groups with adhesion properties into the structure is another approach to achieving high adhesion properties by interacting and binding to the surrounding tissue.Among these methods, the Schiff base reaction is one of the most effective ways of introduction.The Schiff base reaction is a highly effective approach for introducing tissue adhesion.A robust tissue adhesion effect can be achieved by cross-linking the aldehyde group with the amino group on the tissue.In their study, Hao et al [46] developed an injectable and self-healing four-arm PEG-CHO/polyethyleneimine (PEI) tissue adhesive for liquid first aid applications in trauma first aid, utilizing the dynamic Schiff base reaction (figure 4).The hydrogel adhesive exhibited short and controlled gelation time (9-88 seconds), strong adhesive strength, and excellent antimicrobial created a self-healing, injectable tissue adhesive composed of four-arm PEG-CHO and polyethyleneimine (PEI) that utilizes the dynamic Schiff base reaction for use in liquid first aid applications for trauma.The resulting hydrogel adhesive exhibited fast and controlled gelation times ranging from 9 to 88 seconds, strong adhesive properties, and potent antimicrobial effects.In vivo testing demonstrated that the hydrogel adhesive was highly effective in achieving rapid hemostasis and showed superior resistance to infection when compared to commercially available Prontosan gels.Liu et al [47] developed an injectable hydrogel for soft tissue adhesion and hemostasis through the Schiff base reaction using biocompatible and biodegradable materials.The researchers oxidized hydroxyethyl starch to produce aldehyde hydroxyethyl starch (AHES) and grafted ethylenediamine onto carboxymethyl chitosan to obtain more amino groups, creating amino carboxymethyl chitosan (ACC).By combining these two components through the Schiff base reaction between the aldehyde and amino groups, a two-component AHES/ACC hydrogel was formed.This hydrogel exhibited efficient hemostatic ability.

Inflammation control using hydrogel dressings
The second phase of wound healing, inflammation, is crucial for eliminating harmful bacteria and debris [48].While inflammation is necessary for proper wound repair, it is important to control it through dressings [49].Excessive inflammation can result in high levels of oxidative stress, leading to an increase in reactive oxygen species that can cause cell damage by triggering chain reactions like lipid peroxidation, DNA damage, or protein oxidation [50].Several hydrogel dressings with antioxidant properties have been developed to speed up the healing process of chronic wounds.These dressings are effective in promoting regular wound repair.As a result, developing hydrogels with antioxidant properties is a promising new approach for treating chronic regular injuries and is of great importance to maintaining human health [51].
Numerous natural compounds exhibit antioxidant properties, including thiol compounds like GSH and γglutamyl-cysteinyl-glycine, non-thiol compounds such as anthocyanins and polyphenols, vitamins like ascorbic acid and vitamin A, and enzymes such as catalase, GSH reductase, and GSH-peroxidase.Polyphenols have been extensively researched due to their excellent antioxidant capabilities [52].Slight molecule phenols, such as catechins, quercetin, anthocyanins, gallic acid, ellagic acid, arbutin, and other natural phenols, are included in this category of polyphenols [53].Tea polyphenols, gallic acid, anthocyanins, and theaflavins have been particularly well-studied among them.For example, M et al [54] functionalized an alginate hydrogel dressing with natural antioxidants such as curcumin and tertiary resveratrol to give it anti-inflammatory and antibacterial effects.The hydrogel dressing maintained excellent mechanical properties and oxygen permeability over time.
Meanwhile B et al [55] synthesized a poly(2-hydroxyethyl methacrylate) (pHEMA)-based hydrogel and then functionalized it using an interpenetrating polymer network (IPN) structure containing cross-linked chitosan and p(HEMA) networks.The hydrogels were further modified by amide coupling reaction using polyphenols such as gallic acid and dopamine to obtain antioxidant hydrogels.B et al [56] conducted a study where they created a hydrogel using poly(2-hydroxyethyl methacrylate) p(HEMA), which they then modified using an interpenetrating polymer network (IPN) structure made from methacrylamide chitosan through free radical polymerization.To create an antioxidant hydrogel, they functionalized the surface of the chitosan-IPN hydrogels with gallic acid through an amide coupling reaction (figure 5).The results of the study suggest that antioxidant hydrogels have the potential to be used for treating chronic wounds, which is an essential aspect of human health.In addition to introducing natural antioxidants into hydrogel dressings to act as anti-inflammatory agents, antioxidant functions can be achieved by synthesizing groups with antioxidant functions.One of the commonly used methods is the Biginelli reaction [57] for the preparation of monomers containing phenylboronic acid (PBA) and 3,4-dihydropyrimidine-2(1H)-one (DHPM) moieties.Water-soluble copolymers were synthesized by Yang et al [58] through free radical polymerization of PBA-DHPM monomers with poly(ethylene glycol methyl ether) methacrylate (PEGMA).These copolymers were capable of promptly cross-linking polyvinyl alcohol (PVA) through borate ester bonds, leading to the creation of self-repairing hydrogels in mild conditions at around pH 7.4 and 25 °C.The prepared hydrogels have an inherent antioxidant capacity attributed to the DHPM fraction in the hydrogel structure.

Smart response technologies in hydrogel dressings
Stimulus-responsive hydrogels, commonly called 'smart hydrogels,' have emerged as a promising solution for wound healing [6].Smart hydrogels have the exceptional capacity to modify their mechanical properties, hydrophilicity, swelling capacity, and permeability to bioactive substances in reaction to different stimuli, including variations in pH, temperature, proteases, and other biological factors [59].Smart hydrogels can improve therapeutic effectiveness and decrease toxicity, depending on the wound's specific features.

pH-responsive for hydrogel dressings
pH is a crucial parameter to assess the status of a wound, as it influences various physiological processes, such as bacterial infection and angiogenesis [60].Typically, the pH of normal skin or healing wounds is slightly acidic (pH: 4-6) due to keratin-forming cells' release of fatty acids and amino acids.However, chronic wounds tend to remain alkaline (pH: 7-9) for extended periods, promoting the growth and colonization of pathogenic microorganisms and making the damage more susceptible to bacterial infection [61].pH-responsive hydrogel wound dressings are mainly used for controlled drug release.For instance, Yang and colleagues [62] developed a novel pH-responsive hydrogel (RPC/PB) by combining polyvinyl alcohol-borax (PB) with natural antibiotic resveratrol-grafted cellulose nanofibers (RPC) for wound management of bacterial infections.The RPC/PB hydrogel exhibited pH-responsive drug release behavior, with significantly higher cumulative release of resveratrol at pH 5.4 than at pH 7.4, making it well-suited for the acidic wound microenvironment.
Similarly, M et al [63] prepared a non-toxic orthosilicate (TEOS) hybrid CS/PVA/GG hydrogel for sustained release of paracetamol, which swelled maximally at acidic pH and minimally at pH 7 or higher, making it pH-sensitive and suitable for controlled drug release.Besides drug release, pH-responsive hydrogel wound dressings can also monitor wound healing.For instance, F et al [64] incorporated the pH indicator phenol red dye into a hydrogel to monitor wound healing through color changes due to pH shifts.O et al recently demonstrated a novel approach for incorporating pH-sensing capabilities into a cutting-edge hydrogel wound dressing composed of bacterial nanocellulose (BC) [65].In their study, they utilized mesoporous silica nanoparticles (MSN) to create a high surface area material in BC and then incorporated pH-responsive dyes into MSN to produce continuous pH-sensing wound dressings with spatiotemporal resolution.Additionally, Qiao et al [66] developed hydrogels by physically cross-linking polyvinyl alcohol (PVA) and UV-cleavable poly excipients (GS-Linker-MPEG), which were loaded with Cyanine3 (Cy3) and Cyanine5 (Cy5)-modified silica nanoparticles (SNP-Cy3 / Cy5).These silica nanoparticles functioned as pH-responsive fluorescent probes through the FRET effect between Cy3 and Cy5, allowing for the detection of bacterial infections.The Cy5 release curves of SNP-Cy3/Cy5 in different pH solutions are shown in figure 6(a).We can clearly see that SNP-Cy3/Cy5 exhibits a two-step release.During the first 3 h, Cy5 release was faster at pH 5.5 than at pH 7.4 because the Schiff base bond was cleaved at the acidic pH, and after 3 h, Cy5 release was still slower according to the Higuchi model.In addition, the amount of Cy5 released from SNP-Cy3/Cy5 significantly increased to 33% within 12 h at pH 5.5, whereas very little Cy5 was released at pH 7.4; this can be attributed to the physical absorption on the surface of the nanoparticles.The release behavior of Cy5 is good proof of the pH responsive property of SNP-Cy3/Cy5.SNP-Cy3/Cy5 was found in PB buffer (pH 5.5 and pH 7.).The Cy5 fluorescence at 673 nm was weakened with the increase of soaking time in the buffer (pH 5.5) while the Cy3 fluorescence at 587 nm was restored upon excitation at 540 nm (figure 6(b)).

Temperature-responsive for hydrogel dressings
Temperature-responsive hydrogels are widely used to regulate hydrogel properties due to their adjustable switching temperature, simple operation, and short response time.These hydrogels contain both hydrophilic and hydrophobic groups, and temperature changes can alter the structure and volume of the hydrogel by affecting hydrophobic interactions and hydrogen bonding between polymer chains [67].For instance, Hu et al [68] developed a new thermosensitive hydrogel that disperses Nano-CeO2 uniformly on the surface of mesoporous silica (MSN) and physically cross-links the nanocomposite particles with poly(N-isopropyl acrylamide) (PNIPAM) to create a temperature-sensitive hydrogel (PMCTH).The hydrogel is dominated by hydrophilic hydrogen bonds at temperatures below the critical point, making it liquid.Conversely, when the ambient temperature exceeds the required point, the hydrophobic effect of isopropyl in the hydrogel becomes dominant, causing it to solidify.In diabetic chronic wounds, healing can be hindered by excessive expression of matrix metalloproteinase 9 (MMP-9).Therefore, effective wound dressings that can inhibit MMP-9 expression are crucial for diabetic wound healing.A hybrid hydrogel dressing that combines topical application with continuous delivery of MMP-9 siRNA (siMMP-9) was developed by Lan et al [69].They achieved this by complexing siMMP-9 with Gly-TETA (GT) and loading the GT/siMMP9 complex into a thermosensitive hydrogel made from Pluronic F-127 (PF) and methylcellulose (MC).The hydrogel can undergo reversible gelation and transforms into a gel at body temperature (37 °C) (figure 7) while remaining in a liquid state below body temperature.This feature enables targeted wound treatment and facilitates drug delivery to the affected area.

Light-responsive for hydrogel dressings
The use of light as a tool in modern medicine has gained popularity in recent years [6], and it has various applications, such as drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), and tissue engineering [70].In wound healing, photosensitive hydrogel wound dressings have gained significant attention.Li et al [71] developed an all-light-operated hydrogel dressing for rapid and remotely controllable dressing changes for chronic wounds.This hydrogel gels in just 30 seconds and dissolves after 4 min of light exposure, providing an effective solution for chronic wounds that require long-term and repeated dressing changes while minimizing the possibility of secondary injury (figure 8).Molybdenum oxide nanomaterials with structural defects are currently a subject of extensive research in the field of biomedical applications, particularly for phototherapy, antibacterial, and antitumor treatments.These materials offer several advantages, including efficient near-infrared (NIR) photothermal conversion, catalytic activity similar to enzymes (in terms of scavenging/generating reactive oxygen species), and excellent biocompatibility [72].Recently, Wang et al [73] developed a novel nanocomposite hydrogel using poly(vinyl alcohol) (PVA) and polyethylene glycol (PEG), which was loaded with molybdenum oxide nanoparticles and the photosensitizer methylene blue (MB).This hydrogel can potentially serve as a photoactivated wound dressing that can be used for synergistic photothermalphotodynamic therapy, combining the benefits of NIR-II 1064 nm and 660 nm lasers.

Conclusion and outlook
In recent years, the field of wound healing has made rapid progress.Thanks to the three-dimensional viscoelastic network of hydrogels, which allows the diffusion and attachment of molecules and cells, hydrogels have become the hottest research object in wound healing.Hydrogel wound dressings are a highly effective therapeutic tool widely used in the medical field, and this paper explores their functionalized applications in antibacterial, hemostatic, procoagulant, inflammation control, and smart response.Drug loading, inorganic nanometals, and natural cationic polymers have been used to enhance their antimicrobial capabilities.Techniques such as drug delivery for hemostasis, adhesive physical hemostasis, and adhesive functional groups are applied to promote hemostasis.Natural antioxidants and antioxidant functional groups are used for anti-inflammation and control of inflammation.Meanwhile, smart response technologies such as pH response, temperature response, and light response are used to enhance their therapeutic effects.Overall, the functionalized application of hydrogel wound dressings provides new directions for developing innovative wound treatment methods.
Amid these advancements, it is imperative to acknowledge the limitations and challenges associated with the practicality and safety of functionalized hydrogel dressings.Integrating substances like drug-loaded hydrogels and inorganic nanometals while offering enhanced therapeutic potential necessitates meticulous scrutiny.Of paramount concern is the potential toxicity linked to these materials, which demands comprehensive investigation to ensure their harmlessness and long-term stability.Therefore, it is crucial to emphasize the urgent need for rigorous research to address these concerns.The safety profile of functionalized hydrogel dressings must be established through systematic toxicity assessments and thorough biocompatibility evaluations.Long-term effects, potential interactions with bodily systems, and environmental impact must be comprehensively explored.In particular, incorporating drug-loaded hydrogels and inorganic nanometals demands heightened vigilance, as any compromise in safety could undermine the advantages these innovations promise.
Moreover, achieving effective and accurate intelligent responses within these dressings requires dedicated research.The intricate interplay of pH, temperature, light responsiveness, and their successful translation into clinical scenarios remains a challenge that necessitates sustained investigation.In the trajectory of future research, it is pivotal to dedicate attention and resources to address these intricate limitations.This comprehensive exploration will underscore the practicality and safety of functionalized hydrogel dressings and usher in a new era of innovative wound treatment modalities.As this field gains momentum, a steadfast commitment to research excellence will be pivotal in unlocking the full potential of functionalized hydrogel dressings to advance medical care.

Figure 1 .
Figure 1.Preparation process of hydrogel loaded with clindamycin.This glyhydrogel textile dressing features excellent breathability, antibacterium, antifreezing property, stretchability and outstanding performance in treating infected wounds, which are hard to achieve in existing dressings.Reproduced from [21].CC BY 4.0.

Figure 2 .
Figure 2. Design and application of the PDA/Cu-CS composite hydrogel.(A) Structures of prepared composite hydrogel networks.(B)The complexation of PDA and Cu ions (PDA/Cu complexing) endows the composite hydrogel with enhanced photothermal performance, antibacterial properties, and angiogenesis.(C) Composite hydrogel with 'hot ions effect' for high-efficiency bacteria inhibition as well as accelerated tissue regeneration for infectious wound healing.Reprinted with permission from[37].Copyright (2020) American Chemical Society.

Figure 6 .
Figure 6.(a) Percentages of released Cy5 from SNP-Cy3/Cy5 at different time points in PB buffer (pH 5.5 and pH 7.4).(b) Fluorescence spectra of SNP-Cy3/Cy5 after being immersed in buffer (pH 5.5) at different times.Reproduced from [66] with permission from the Royal Society of Chemistry.

Figure 7 .
Figure 7. Characterization of PM hydrogels.(a) The sol-gel transition of PM hydrogels with temperature rose from 4 to 37 °C.(b) SEM images of PM hydrogels exhibiting the porous morphology.(c) Rheological characterization of PM hydrogels from 5 to 45 °C.(d) In vitro release profiles of GT/siFAM10 from PM hydrogels in PBS at 37 °C.(e) The viability of HaCaT cells was assessed by CCK-8 assay after treatment with released GT/siMMP-910 from PM hydrogels on Day-1, Day-7, and Day-14.* P < 0.05.Reproduced from [69].CC BY 4.0.