Wound healing is a complex, variable, and time-dynamic repair process. Wounds can be classified as acute wounds or chronic wounds, and effective wound management is still a major challenge in clinical nursing settings. The wound microenvironment is collectively regulated by internal biomolecules, external drugs, and external sanitation. Traditional wound dressings (powders, bandages, sponges, etc.) often have poor therapeutic effects during wound healing and repair processes because they cannot respond to the dynamic wound microenvironment changes over the long-term. Stimulus-responsive biomaterials, which are activated by various factors intrinsic to the wound microenvironment or external influences, hold great promise for precise drug delivery and controlled release. Various stimulus-responsive hydrogels have been developed in recent years, exhibiting a range of “smart” properties, such as interacting with the wound, sensing wound conditions or environmental changes, and responding accordingly, thereby effectively promoting wound healing. This review discusses the latest advancements in stimulus-responsive hydrogels used in wound healing. We introduce the design scheme of stimulus-response hydrogels in detail based on the local wound biological/biochemical peculiarities (pH, reactive oxygen species glucose, and enzymes, etc.) and physical microenvironments (temperature, light, ultrasound, and electric fields, etc.). Furthermore, we explore several promising tissue-engineered constructs (nanofibers, scaffolds, microneedles, and microspheres). Finally, summarize stimulus-responsive wound dressings on the basis of active research challenges, current research progress, and development trends in the field.

As the organ with the largest area, the skin performs multiple functions, including acting as a protective barrier, sensory system, temperature regulator, immune defense organ, excretory organ, and metabolic site, in addition to contributing to appearance.1–3 Acute and chronic skin injuries impose significant burdens on human health.4,5 Over the past several decades, wound care has depended mainly on drugs sprayed on local tissue, covering of the wound surface with bandages and gauze to prevent the invasion by external micro-organisms, and combined treatment with antibiotics to prevent infection. Nevertheless, the aforementioned treatments can be considered passive intervention approaches, which are unable to adapt to the complex and mutable microenvironments in various local wounds and are prone to secondary damage due to adhesion between dressing and wound. Recently, many researchers in tissue engineering have developed a series of multifunctional bioactive intelligent devices that can simulate the dynamic wound healing process.

Based on three-dimensional (3D) network structures, hydrogels are extremely flexible materials that can be used to customize various biomedical products.6,7 Besides their outstanding water absorption and storage capacity, hydrogels possess numerous biochemical and physical properties analogous to the natural extracellular matrix (ECM), providing ideal treatments for acute or chronic wounds.8,9 Similar to 3D carriers, hydrogels can easily load drugs or cytokines, such as glucose regulators, antibacterial agents, and angiogenic factors, specifically for wound treatment. Currently, numerous wound treatment strategies have been devised, and appropriate hydrogels for wound repair have been formulated.10 Nevertheless, conventional hydrogels applied as drug delivery systems depend mainly on the diffusion of the drug itself or its drug release, which is not controlled in a time-dependent or stage-specific manner and may fail to achieve the anticipated drug delivery outcomes.11 

In recent years, significant attention has been directed toward smart hydrogels with stimulus-response functions.12–15 The hydrogels are capable of responding to specific combinations of signals and can alter their physical properties or chemical structure in a reversible or irreversible manner, such as internal physiological signals [pH, reactive oxygen species (ROS), molecules or biological enzymes, etc.] and external stimuli (temperature, light, ultrasound, electric fields, etc.).16,17 Treatment strategies adopting intelligent-reactive hydrogels offer a more adjustable platform for managing the multi-variable and complex stages of acute or chronic wound healing. By employing precise stimulus-responsive design, hydrogels can be embedded with reactive copulants or chemically modified hydrogels, which can effectively detect abnormal signals in locally damaged tissues.18,19 This enables endogenous activation and active targeting of drugs. Compared with their endogenous counterparts, exogenous stimulus-responsive hydrogels aim for remote and non-invasive operations.20–22 The endogenous or exogenous stimulus-responsive units are integrated into a single hydrogel system, and programmable multi-stimulus response units are introduced to integrate multiple functions into a single hydrogel system.23–25 Therefore, hydrogels based on the stimulus-responsiveness of the wound microenvironment are promising for the improvement of wound management.

In this review, we discuss the ultramodern advancements in stimulus-responsive hydrogels in the wound microenvironment over the past five years. This review could guide researchers in the design of advanced stimulus-responsive hydrogels for wound healing. First, we introduce response strategies for trauma biological/biochemical microenvironments (pH, ROS, glucose, and enzymes) and exogenous environments (temperature, humidity, optics, electromagnetism fields). Subsequently, we briefly outline several smart wound-healing hydrogels as drug carriers (electrospinning, scaffolds, microneedles, and microspheres). Finally, we summarize and provide an outlook on stimulus-responsive hydrogel wound dressings, addressing key research areas and challenges to further enhance their wound treatment efficacy. In summary, this article explores the current research status of stimulus-reactive hydrogels as wound dressings and evaluates current market status and future development trends.

Acute wounds are caused mainly by accidental trauma and forced operations. In contrast, chronic wounds often occur in patients with underlying medical conditions and can take 2–3 weeks or more than a month to heal fully.11,26 Chronic wounds can be classified further into diabetic ulcers, immune-related ulcers, infectious wounds, and tumor-related wounds. Severe trauma is likely to lead to nutritional deficiencies and loss of body energy, or even high risks of infection, amputation, and death (Fig. 1).

FIG. 1.

Four basic processes during wound healing. (a) The earliest hemostasis phase. (b) and (c) The middle inflammation phase and proliferation phase. (d) The later tissue remodeling phase.27 [Reproduced with permission from Zhang et al., Int. J. Biol. Macromol. 248, 125949 (2023). Copyright 2023 Elsevier B.V. All rights reserved].

FIG. 1.

Four basic processes during wound healing. (a) The earliest hemostasis phase. (b) and (c) The middle inflammation phase and proliferation phase. (d) The later tissue remodeling phase.27 [Reproduced with permission from Zhang et al., Int. J. Biol. Macromol. 248, 125949 (2023). Copyright 2023 Elsevier B.V. All rights reserved].

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Although the wound healing process seems to simply involve the hemostasis, inflammation, proliferation, and remodeling stages, consecutively and overlapping, specific cells and factors are involved in each stage.28,29 In the early stages of hemostasis, the platelets, fibrin, and red blood cells rapidly fill the wound bed and form thrombus to achieve hemostasis. During the inflammatory phase, neutrophils, mononuclear macrophages, and immune lymphocytes infiltrate near the wound and secrete or recruit various inflammatory cytokines, growth factors, and bio-enzymes. In the proliferation phase, the epidermal cells and fibroblasts begin to migrate, proliferate, and differentiate, completing re-epithelialization, granulation, tissue repair, and angiogenesis. Finally, wound repair enters a prolonged tissue remodeling phase, which includes ECM remodeling, fibroblast/myofibroblast apoptosis, inflammation decrease, and vascular network development. The processes aim to restore the basic function and normal appearance of the wound area. However, if the four processes are not coordinated, pathological wound healing can occur, greatly extending overall healing time. Chronic wounds often impede the inflammatory process, resulting in prolonged healing and low response levels, hindering progression to the proliferative phase.30,31 If such challenges are not resolved in time during the proliferation period, hyperplastic scar tissue or keloid could occur in the local wound.

Over the past few decades, numerous wound dressings have been developed. Traditional wound dressings usually take a one-size-fits-all approach to control bleeding and promote wound healing. However, wound healing is a dynamic process. Each stage involves multi-circuit regulation of biomolecules and physiological states; therefore, different wound dressings are required for different repair stages to meet the specific repair needs.32,33 Temperature, pH, oxygen, and glucose in the local wound, etc., influence the wound healing process. Wound dressings that respond to these changes are desirable for wound healing because they can actively and directionally regulate the wound microenvironment to maintain a proper healing process.34 In the following chapters, we summarize and discuss recently developed stimulus-responsive wound dressings.

1. pH

pH is a critical indicator of wound status, and it is linked closely to numerous physiological processes, especially bacterial infection defense and angiogenesis.35 For normal skin or healing wounds, pH is usually in the slightly acidic range, between 4 and 6.35,36 This slightly acidic environment is essential for wound healing, as it inhibits harmful bacterial growth while promoting a normal cell repair process (≈7.44).37 As the epidermis regenerates and the stratum corneum covers the wound, the pH of the acute wound returns gradually to an acidic level. Conversely, chronic wounds maintain an alkaline pH in the 7.15–8.90 range.38 In the case of a bacterial infection, the pH around the wound tends to be elevated. This is because many harmful bacteria, such as Staphylococcus aureus, Helicobacter pylori, Klebsiella, Mycobacterium, and Proteus, break down urea to produce ammonia, which in turn raises the pH level in skin wounds.39 A change in wound pH has a direct impact on wound healing; it influences oxygen release, blood vessel formation, protease activity, and bacterial activity. Simply put, the alkaline environment is not conducive for wound healing; conversely, a slightly acidic environment can accelerate wound recovery.37,38 To treat wounds more effectively and promote healing, researchers have developed various pH-responsive biomaterials.

The key to pH-responsive biomaterial capacity to deliver drugs intelligently lies in their pH-sensitive chemical bonds.40,41 The chemical bonds are like smart switches that play a crucial role in a specific pH environment. When the pH of the surrounding environment changes, the chemical groups in the chemical bonds undergo protonation or deprotonation. The reactions directly lead to the breaking of chemical bonds, which in turn causes significant changes in the physical properties and chemical structure of drug molecules.42 Such change is like a key that opens the door to drug release so that the drug can be released at the right time and place. Notably, dynamic covalent chemistry has garnered significant attention for pH-responsive hydrogel development. Dynamic bonds can be established through either covalent or reversible permanent interactions. Due to the formation of these covalent bonds, such hydrogels exhibit greater stability compared to those crosslinked via non-covalent interactions.43 

Common pH-sensitive chemical bonds include hydrazine (C=NNHR), imine (–C=N-), borate/ortho ester bonds (R–C(O–R)3), amide (–CONH), and metal ion coordination bonds (such as Fe3+, Al3+, and Ca2+).44,45 The acid dissociation constant (pKa) is a critical parameter for pH-responsive groups. pH responsive and biodegradable polysaccharide hydrogels were prepared by Sharma et al. Polysaccharides, oxidized xanthan gum, and 8-armed poly(ethylene glycol) (PEG) hydrazine were bonded via dynamic, pH-responsive hydrazones.46 DOX was loaded onto the hydrogels, and release studies were carried out at pH 5.5 and 7.4. The cumulative release from 3%, 4%, and 5% hydrogels was 47.43%, 37.01%, and 35.34% at pH 7.4. While at pH 5.5, they significantly increased to 81.06%, 61.98%, and 41.67%. Zhang et al. synthesized a natural boron-based probe as a unit of a visual monitoring system using dynamic interactions between borax and tannic acid.47 Subsequently, these units were doped into guar gum and polyvinyl alcohol (PVA) networks to establish borate and hydrogen bonds, resulting in a dynamic hydrogel. This hydrogel dressing was used for visual monitoring and matching chronic wound healing. When in the initial chronic wound phase (alkaline), the hydrogel dressing is green in color and releases TA to reprogram macrophages and promote angiogenesis. During the wound healing phase (acidic), the hydrogel dressing gradually turns yellow and dissolves to promote tissue regeneration. Additionally, the color change and observation of the wound healing process can be monitored via a smartphone with instant feedback on the pH level. The visualization and intelligence system provides the basis for building a personalized, digital, and precise diagnosis and treatment platform. Haidari et al. prepared pH-responsive hydrogels by cross-linking N-isopropylacrylamide with acrylic acid and loaded them with silver nanoparticles (NPs) to provide on-demand release of Ag+ triggered by changes in the wound microenvironment.48 The hydrogel was demonstrated to limit Ag+ release at acidic pH (<5.5) and significantly promote release (>90% release) at alkaline pH (>7.4). pH-dependent release and antimicrobial efficacy were achieved at pH 7.4, eliminating >95% of pathogens. Fu et al. developed a series of tannin–europium coordination complex cross-linked bioadhesives for diabetic wound healing based on the combination of tannic acid and metal ions.49 The bioadhesives exhibited good shape adaptation and biocompatibility. The sensitive metal-phenol coordination also confers pH-responsive europium ion and TA release properties to the bioadhesive, which can be utilized for smooth attachment produced by the extracellular matrix of diabetic wounds with acidic pH conditions. This adhesive dressing provides an ideal regenerative strategy for diabetic wound management.

Schiff base synthesis is a very common strategy for preparing pH-responsive hydrogels. The Schiff base, which is a reversible imine structure sensitive to pH, can be formed by an ingenious condensation reaction of the aldehyde group and the nucleophilic amine group under suitable weak acidic conditions.50,51 Based on the principle, Wang et al. cleverly designed an injectable multifunctional hydrogel called FEMI to effectively address a range of challenges [Figs. 2(a) and 2(b)].52 The FEMI hydrogel was prepared through the Schiff base reaction between MnO2 nanosheets (EM) coated with ε-polylysine (EPL) and self-assembled aldehyde Pluronic F127 (FCHO) micelles loaded with insulin. The crosslinking cites of Schiff bases, which are disrupted in the acidic medium, facilitated the degradation of the FEMI hydrogel and accelerated insulin release. The findings suggest that the hydrogel is suitable for delivering drugs to tissues in an acidic microenvironment (such as diabetic wounds) without affecting non-target healthy tissues significantly. This demonstrates that the FEMI hydrogel is suitable for delivering insulin to the acidic microenvironment of diabetic wounds, thereby enhancing insulin bioavailability. Hu et al. carefully prepared a double-crosslinked smart hydrogel that combines excellent mechanical strength, excellent self-healing properties, good adhesion, and easy injection [Figs. 2(c)2(f)].53 The unique multifunctional double-cross-linked hydrogel is the result of a Schiff base reaction between the amino group (–NH2) in quaternized chitosan (HTCC) and the aldehyde group (–CHO) in oxidized d-amino–dopamine (OD–DA), which skillfully generates the catechol–catechol adduction, thus giving the hydrogel the remarkable properties. The dual-crosslinking mechanism imparted outstanding mechanical properties to the hydrogels. In the infected wound of diabetic patients, the system composed of double Schiff base bonds (specifically between DA and OD and HTCC and OD–DA) is able to respond rapidly to changes in pH value, thus enabling continuous and controlled release of silver nanoparticles (AgNPs). This characteristic not only accelerates the wound healing process but also effectively reduces the adverse effects of drugs on non-target tissues, providing a more accurate and efficient solution for the treatment of diabetic infected wounds. Kim et al. prepared an oxidized succinoglycan (OSG)-crosslinked chitosan (CS) hydrogel via a Schiff base reaction.54 The hydrogel exhibited a pH-controlled drug release curve at pH 7.4–2.0, which increased 5-fluorouracil release from 60% to 90%.

FIG. 2.

pH-responsive hydrogels based on Schiff bases. (a) Multifunctional FEMI hydrogels were prepared by reacting EM with insulin-encapsulated FCHO Schiff bases. (b) Insulin release profiles of FEMI under pH and redox dual reactivity. [Reproduced with permission from Wang et al., “Nanoenzyme-reinforced injectable hydrogel for healing diabetic wounds infected with multidrug resistant bacteria,” Nano Lett. 20(7), 5149 (2020). Copyright 2020 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (c) and (d) Schematic diagram of the formation and mechanism of double cross-linked hydrogels. (e) The pH-responsive behavior in double cross-linked hydrogel the right panel shows the shape of the hydrogel photographed after incubation with PBS (pH 5.0) for 6 h. (f) Cumulative release profile of AgNPs in double cross-linked hydrogels. [Reproduced with permission from Hu et al., Chem. Eng. J. 411, 128564 (2021). Copyright 2021 Elsevier B.V. All rights reserved].

FIG. 2.

pH-responsive hydrogels based on Schiff bases. (a) Multifunctional FEMI hydrogels were prepared by reacting EM with insulin-encapsulated FCHO Schiff bases. (b) Insulin release profiles of FEMI under pH and redox dual reactivity. [Reproduced with permission from Wang et al., “Nanoenzyme-reinforced injectable hydrogel for healing diabetic wounds infected with multidrug resistant bacteria,” Nano Lett. 20(7), 5149 (2020). Copyright 2020 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (c) and (d) Schematic diagram of the formation and mechanism of double cross-linked hydrogels. (e) The pH-responsive behavior in double cross-linked hydrogel the right panel shows the shape of the hydrogel photographed after incubation with PBS (pH 5.0) for 6 h. (f) Cumulative release profile of AgNPs in double cross-linked hydrogels. [Reproduced with permission from Hu et al., Chem. Eng. J. 411, 128564 (2021). Copyright 2021 Elsevier B.V. All rights reserved].

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Hydrogels containing Schiff base bonds not only exhibit excellent self-healing ability and biocompatibility but also promote the healing process of diabetic wounds considerably. Thanks to their excellent biocompatibility and self-healing properties, the hydrogels made of Schiff base bonds can be injected in situ in the body and be integrated quickly into a cohesive and stable structure, regardless of location or shape. Li et al. cleverly selected N-carboxyethyl chitosan (N-chitosan for short), hyaluronic aldehyde (HA-ALD), and dihydrazide adipate (ADH) as raw materials and successfully synthesized a pH-responsive hydrogel by constructing reversible dynamic acylhydrazone and imide bonds.55 Insulin glargine was favorably incorporated into the hydrogel, allowing it to be released continuously from the hydrogel for up to 14 d while responding to pH changes. In addition, the self-healing ability and injectable properties of the hydrogel make it very attractive in the field of skin wound repair. Even after external mechanical damage, it can effectively reduce gel fragments and reintegrate the broken gel structure at the target site, thus providing strong support for healing skin wounds. Notably, the Schiff base bond not only endows hydrogels with self-healing ability but also enables them to respond to external stimuli. However, its reversibility weakens the overall hydrogel mechanical strength and long-term stability to some extent. In general, hydrogels containing Schiff base bonds have broad application prospects in the field of skin tissue engineering due to their simple preparation, strong reversibility, and pH responsiveness.

In recent years, pH-responsive hydrogels have shown remarkable potential in the treatment of gastric bleeding and wounds. Considering the harsh gastric acid environment and the high risk of gastric bleeding and perforation due to surgery after mucosal barrier damage, such hydrogels can be formed in situ in the body in a very short time, respond rapidly to pH change, and efficiently cross-link with surrounding tissue at the wound site. As bioadhesive materials, they can bind tissue tightly, effectively sealing leaks and preventing bleeding. On that basis, He et al. successfully developed a new pH-responsive hydrogel by combining 6-aminocaproic acid (AA) with AA-G-N-hydroxysuccinimide (AA-NHS) through a clever radical polymerization method, with breakthroughs in related therapeutic fields.56 The hydrogel exhibits ideal gelling time, excellent self-healing capacity (efficient and autonomous), excellent hemostatic performance, and excellent biocompatibility. By introducing AA-NHS as a micro-crosslinking agent, the bonding strength of hydrogels has been improved significantly. In a pig stomach bleeding model, the hydrogel can not only effectively block acute arterial bleeding but also exert a significant hemostatic effect to prevent delayed bleeding. Its stable and long-lasting adhesion ensures that the hydrogel does not fall off the wound site, thus providing more complete and long-lasting protection against stomach acid wounds.

In the field of diabetes wound treatment, pH-reactive injection hydrogel application has been explored increasingly, with remarkable research results. The hydrogels can target the pH difference between pathological and normal tissue to achieve precise drug delivery. However, despite the progress, several issues persist. A key problem is that many pH-reactive hydrogels are not sensitive enough to changes in the pH of the local wound treatment area to trigger effective release of the drug, thus affecting the optimization of the therapeutic effect. Second, due to difficulty in clinical pH prediction at the disease site, the use of pH-reactive hydrogels may result in adverse local tissue reactions. Finally, the cost-effective synthesis of pH-responsive hydrogels with well-defined physical and chemical properties remains a major challenge.

pH-responsive hydrogels have been extensively explored for practical applications in the treatment of diabetic wounds, and significant progress has been made. pH-responsive hydrogels can be selected for drug delivery applications when the pH of the pathologic tissue is different from that of normal tissue. However, the pH changes in the localized wound treatment area are not significant, so precise control of drug release from pH-responsive hydrogels remains challenging to achieve the desired therapeutic effect.

2. Reactive oxygen species

Reactive oxygen species (ROS) are highly reactive ions and radicals produced within the human body, encompassing superoxides (O2−), hydrogen peroxide (H2O2), hydroxyl radicals (·OH), and singlet oxygen (1O2).57 They are predominantly generated by neutrophils and macrophages during the inflammatory phase of wound healing. ROS at moderate levels play a crucial role in regulating cellular signaling pathways, inflammation, and cellular proliferation. Infected and chronic wounds typically exhibit prolonged inflammatory responses, resulting in high ROS levels.58 Excessive ROS induces oxidative stress, which can damage proteins, DNA, and other active biomolecules, thereby hindering wound healing. Eliminating excess ROS can promote in vitro fibroblast growth and wound healing in animal models.59,60 Therefore, ROS-responsive hydrogels are a common intelligent wound healing strategy that aims to achieve targeted drug release at the injury site, reduce toxicity and side effects, and scavenge excess ROS.

ROS-responsive polymers encompass sulfur-containing polymers, selenium/tellurium-based polymers, and phenylboronic acid/ester-containing polymers. Upon exposure to ROS, these polymers undergo chemical bond disruption and/or a transition from a hydrophobic to a hydrophilic state, leading to the release of encapsulated drugs. Hydrogels represent a common platform for ROS-responsive polymers, capable of sensing oxidative stress in the local environment, modulating cellular behavior, facilitating the release of desired drugs, and counteracting excessive ROS production. Consequently, ROS-responsive hydrogels are promising tools for addressing diseases characterized by high local levels of ROS, such as diabetic wounds.

At present, there are two main methods for endowing ROS responsiveness to hydrogels. The first method is integrating the ROS responsive part into the backbone structure of the block copolymer. The second approach is to use polymers with ROS responsive side chains. When the external ROS concentration rises, these ROS responsive units can respond to oxidation conditions by triggering controlled release of the drug through bond breaking, which is accompanied by a transition from hydrophobic to hydrophilic properties or a break in the polymer chain. In particular, phenylboric acid (PBA), as a common ROS reaction unit, can be combined with cis1, 2-diol, or 1, 3-diol to form a cycloborate through covalent bonds, and this binding structure can be degraded selectively by ROS.61 Wang et al. developed a DL-dithiothreitol (DTT)/poly(ethylene glycol) diacrylate (PEGDA)/poly(L-lysine)-PBA (EPL-PBA) hydrogel (DPP) [Figs. 3(a)3(c)].61 First, dithiothreitol (DTT) and polyethylene glycol diacrylate (PEGDA) are polymerized through the Michael addition reaction to form a polymer network structure containing numerous dihydroxyl functional groups. Functional groups in the polymer networks then react with PBA groups in EPL-PBA (a certain polymer containing phenylboric acid) to form cyclic borate ester bonds. This unique hydrogel not only has excellent water absorption properties but also exhibits good ROS (reactive oxygen species) response properties, providing the necessary moisture for wound healing as well as a suitable oxidation microenvironment. Zhao et al.57 used polyvinyl alcohol (PVA) crosslinked with ROS-responsive linkers [N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, and N3-tetramethylpropane-1,3-diaminium (TPA)] to develop an ROS-scavenging hydrogel for wound microenvironments.57 The hydrogel effectively scavenges ROS in wounds, reduces pro-inflammatory cytokine levels, enhances M2 macrophage polarization, promotes angiogenesis, and stimulates collagen production, thereby accelerating wound healing. Under ROS stimulation, the ROS response connectomes inside the hydrogel are broken, and then the hydrogel is degraded gradually. During the process, moxifloxacin and granulocyte-macrophage colony-stimulating factor (GM-CSF) loaded in the hydrogel are released to play antibacterial roles and promote wound repair function, respectively.

FIG. 3.

ROS response to hydrogels and drug release behavior. (a) DPE hydrogel preparation by stepwise polymerization via Michael addition reaction and formation of cyclic borate ester. Selective cleavage of ROS by cyclic borate esters. (b) ROS-scavenging properties of DPE. (c) EPL release from DPE in H2O2 at 37 °C. [Reproduced with permission from Chengwei et al., Chem. Eng. J. 450, 138077 (2022). Copyright 2022 Elsevier B.V. All rights reserved]. (d) Temporal and spatial release behavior of POD/CE hydrogels. (e) Macroscopic observation of hydrogel pH/ROS responsiveness. (f) Kinetics of MF release from hydrogels under different conditions. [Reproduced with permission from Wu et al., J. Controlled Release 341, 147–165 (2022). Copyright 2022 Elsevier B.V. All rights reserved].

FIG. 3.

ROS response to hydrogels and drug release behavior. (a) DPE hydrogel preparation by stepwise polymerization via Michael addition reaction and formation of cyclic borate ester. Selective cleavage of ROS by cyclic borate esters. (b) ROS-scavenging properties of DPE. (c) EPL release from DPE in H2O2 at 37 °C. [Reproduced with permission from Chengwei et al., Chem. Eng. J. 450, 138077 (2022). Copyright 2022 Elsevier B.V. All rights reserved]. (d) Temporal and spatial release behavior of POD/CE hydrogels. (e) Macroscopic observation of hydrogel pH/ROS responsiveness. (f) Kinetics of MF release from hydrogels under different conditions. [Reproduced with permission from Wu et al., J. Controlled Release 341, 147–165 (2022). Copyright 2022 Elsevier B.V. All rights reserved].

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As mentioned earlier, low ROS levels promote normal wound healing significantly. ROS accumulation can lead to prolonged inflammatory responses, rendering wounds fragile and inhibiting tissue regeneration around diabetic wounds. In recent years, with significant advances in antioxidant theory, a series of antioxidant hydrogels designed to promote chronic wound healing have emerged. These innovative hydrogels achieve their antioxidant function in two ways: loading antioxidant drugs and making antioxidant modifications. On that basis, Wu et al.17 carefully designed an ROS reactive injectable glycopeptic hydrogel based on pba grafted oxidative glucan (POD) and caffeic acid (CA) grafted ε-polylysine (CE), which was a breakthrough in the field of chronic wound healing [Figs. 3(d)3(f)].17 CA is a natural polyphenolic compound containing catechol and acrylic functional groups. Mangiferin (MF), which possesses antioxidant, anti-apoptotic, and angiogenic effects, was loaded into the hydrogel. During the healing of infected diabetic wounds, boronate–ester bonds undergo cleavage, leading to the continuous release of MF, thereby suppressing inflammation and promoting wound healing in infected diabetic wounds.

ROS hydrogels, as potential biomedical material, have been studied widely in the field of chronic wound healing because of their REDOX reaction mechanism to precisely regulate drug release. Nevertheless, the promotion of ROS reactive hydrogels in clinical applications still faces certain challenges, mainly because the clear distinction between ROS levels in pathological and normal tissues has not been fully elucidated. Additionally, achieving sufficient control over the redox state poses challenges, leading to significant uncertainties in drug release kinetics.62 

ROS-responsive hydrogel is one of the most promising biomaterials. It has been extensively studied in the healing of chronic wounds. However, the clinical application of ROS-responsive hydrogels is limited by insufficient ROS differences between pathological and normal tissues. In addition, the redox environment is affected by various factors such as bacterial infections, blood glucose, and individual immunity, leading to significant uncertainty in drug release.

3. Glucose

Diabetes is a metabolic disease characterized by persistent hyperglycemia, which poses a serious threat to human health.63,64 The treatment of chronic wounds such as diabetic ulcers has long been a formidable challenge for the medical community.65 In the wound healing process of diabetic patients, the hyperglycemic environment often leads to impaired angiogenesis and reduced growth factor secretion, which leads to delayed wound healing and increases the risk of complications. In addition, elevated blood sugar levels make the wound more susceptible to microbial attack. Therefore, wound dressings that can respond to changes in glucose levels have received widespread attention in diabetic wound management. Among the many proposed solutions, glucose-reactive hydrogels stand out with their self-regulating drug delivery system, capable of releasing the appropriate amount of drug in response to fluctuations in glucose concentration. Among them, glucose oxidase (GOx) and phenylboric acid (PBA) hydrogels are the two most widely studied glucose reactive hydrogels.

Under elevated blood sugar conditions, Gox catalyzes the conversion of glucose into gluconic acid, which in turn alters the pH of the surrounding environment. Based on this principle, a common strategy for synthesizing GOx hydrogels is adopting a pH-responsive hydrogel as a matrix framework and incorporating GOx as a glucose-sensitive component. Han et al.66 cleverly designed the GOx–MnO2 nanoenzyme system and successfully synthesized hyaluronic acid hydrogels by Schiff base reaction. They further encapsulated GOx–MnO2 nanomaterials and vascular endothelial growth factor (VEGF) in the hydrogel to achieve specific biomedical functions.66 The hydrogel exhibited good adhesion, self-healing ability, and injectability in vitro, with the loaded nanoenzymes depleting glucose rapidly in a diabetic wound microenvironment. Moreover, the generated H2O2 combines with manganese dioxide to produce Mn2+, enhancing magnetic resonance imaging (MRI) performance. Additionally, pH indicators have been used to develop smart wound dressings. Zhu et al.35 developed a versatile zwitterionic hydrogel with the ability to simultaneously monitor two key wound parameters—pH and glucose levels—to effectively assess diabetic wound status [Figs. 4(a) and 4(b)].35 In the design, the pH indicator dye (phenol red), GOx, and horseradish peroxidase (HRP) were embedded carefully in the matrix of the zwitterionic polycarboxylic beet alkali hydrogel, imparting the hydrogel with high sensitivity to changes in glucose. To monitor glucose and pH fluctuations at the wound site of diabetic mice in real time, the researchers cleverly used a smartphone equipped with a specific algorithm to capture and analyze visible red–green–blue (RGB) images of the wound site.

FIG. 4.

Glucose responsive hydrogels and visualization. (a) Scheme of PCB hydrogel for detecting pH and glucose concentration. (b) PCB hydrogel for detecting pH (under visible light) and glucose concentration (under ultraviolet light). (1) PBS and (2) artificial wound exudates. [Reproduced with permission from Zhu et al., Adv. Funct. Mater. 30, 1905493 (2020). Copyright 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim]. (c) Schematic diagram of the glucose-responsive antioxidant H-water MPC gel platform for diabetic wound healing. (d) Catechin release behavior of HMPC hydrogels. [Reproduced with permission from Xu et al., Adv. Funct. Mater. 147, 147–157 (2022). Copyright 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved].

FIG. 4.

Glucose responsive hydrogels and visualization. (a) Scheme of PCB hydrogel for detecting pH and glucose concentration. (b) PCB hydrogel for detecting pH (under visible light) and glucose concentration (under ultraviolet light). (1) PBS and (2) artificial wound exudates. [Reproduced with permission from Zhu et al., Adv. Funct. Mater. 30, 1905493 (2020). Copyright 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim]. (c) Schematic diagram of the glucose-responsive antioxidant H-water MPC gel platform for diabetic wound healing. (d) Catechin release behavior of HMPC hydrogels. [Reproduced with permission from Xu et al., Adv. Funct. Mater. 147, 147–157 (2022). Copyright 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved].

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At present, the glucose reactive delivery system based on PBA and its derivatives is one of the most widely used schemes. The excellent stability and durability of PBA under physiological conditions make it an indispensable glucose sensing element in glucose reactive hydrogels. Its unique PBA ester structure can react with ROS and glucose with a wide range of responsiveness. In particular, PBA is able to reversibly bind to diols, especially glucose, to form stable five-membered ring complexes. This property forms the core of a PBA-mediated glucose-sensitive drug delivery system that relies on a reversible and efficient reaction mechanism between PBA and cis-diol compounds. In the presence of glucose, the charged boronic acid ester forms stable complexes with glucose via reversible covalent bonds. Consequently, there is a shift toward increasing the hydrophilic forms of phenylboronate salts.

The improvement of hydrophilicity of PBA material will induce its expansion, degradation, and decomposition processes and then effectively release the loaded material. Jiang et al.68 successfully developed a multifunctional hydrogel with self-healing, antibacterial, antioxidant, and electrical conductivity properties that can be activated in response to a dual ROS/glucose reaction triggered by exosome release. The innovative hydrogel is composed of dopamine-modified MXene, chlorogenic acid, L-ascorbate-2-trisodium phosphate, and a synergistic complex of adipose-derived stem cell (ADSC) exosomes. In particular, flaxseed gum modified by phenyboric acid was introduced, and through its chemical crosslinking with polyvinyl alcohol (PVA), dynamic phenyboric acid ester bonds were formed, which gave the hydrogel unique properties. The carboxyl groups of chlorogenic acid facilitate its facile amidation with 3-aminophenylboronic acid, introducing PBA moieties while preserving its inherent advantages. Chlorogenic acid exhibits antioxidant and antimicrobial properties. In addition, dynamic phenylboronate esters and hydrogen bonding confer self-healing capabilities to the hydrogel, mitigating potential damage from gel rupture and healing sports-related wounds. Researchers have assessed the in vitro drug release performance of the hydrogel in response to ROS/glucose and its efficacy in healing diabetic wounds in a type I diabetes mouse model through ROS/glucose-responsive exosome release.

In most cases, ROS production plays a defensive role, effectively defending against bacterial attack and preventing wound infection. However, in diabetic wounds, excess ROS is released constantly due to a persistent hyperglycemic microenvironment. The phenomenon causes abnormal upregulation of inflammatory factors and impinges on hematopoietic function, resulting in a continuous inflammatory phase in most chronic diabetic wounds, which is difficult to heal. Therefore, the delayed wound healing problem in chronic diabetes caused by abnormally elevated ROS levels remains a global medical challenge.67 Xu et al. developed a HA-based hydrogel platform with responsive antioxidant activity for rapid diabetic wound repair [Figs. 4(c) and 4(d)].67 In the study, the researchers first modified methyl methacrylate modified hyaluronic acid (HAMA) with PBA groups and successfully synthesized a glucose-responsive HA derivative (HAMA-PBA). Subsequently, they prepared hyaluronic-based hydrogel precursors by forming borate bonds between HAMA-PBA and catechins, a natural polyphenol with strong antioxidant activity. Afterward, using ultraviolet radiation technology, they constructed a glucose-responsive HMPC hydrogel platform. Stimulated by a high-sugar environment, borate ester bonds are specifically disrupted by glucose molecules, resulting in the release of catechins, a design that exhibits glucose-responsive antioxidant activity in diabetic wound treatment. The study shows that the HMPC hydrogel platform has significant potential in promoting diabetic wound healing. In addition, in another study, Xu et al.69 used a one-step synthesis method to modify glucose-sensitive PBA directly onto the hyaluronic acid chain and cleverly incorporated it into a PEGDA hydrogel matrix, providing another innovative strategy for diabetic wound treatment.69 Subsequently, they fixed quercetin (MY) with strong antioxidant activity in the hydrogel and formed a dynamic boric acid bond between the polyphenol group of MY and the PBA group of HA-PBA, thus constructing a novel glucose-responsive antioxidant complex hydrogel. The hydrogel achieved glucose-triggered quercetin release, effectively clearing more than 80.0% of ROS and reshaped the oxidative microenvironment at the wound site.

Indeed, significant progress has been made in the development of glucose-reactive hydrogels, offering new hope for diabetes treatment and other related fields. However, several key limitations in the field need to be addressed before it can be used widely in clinical practice. Despite the biocompatibility and biodegradability of GOx, its stability is compromised due to potential denaturation and loss of activity under varying environmental conditions. Additionally, hydrogels containing GOx can rapidly remove glucose, leading to H2O2 accumulation, which may disrupt the redox balance of the wound microenvironment, resulting in excessive ROS production and potential toxic side effects. Although PBA-based materials have demonstrated multifunctional reactivity and high stability under physiological conditions compared to protein-based systems such as glucose oxidase GOx, which makes them ideal, PBA reactive hydrogels still face some challenges. The glucose selectivity is not ideal, the biodegradability needs to be improved, and the reaction rate is relatively slow. Therefore, to advance its progress in practical applications, further research is required to improve and optimize such aspects.

Although glucose-responsive hydrogels have advanced considerably, many limitations in the field remain to be addressed before their real-world application. GOx has advantages in terms of biocompatibility and biodegradability, but may be subject to denaturation and loss of activity due to environmental changes. PBA-based hydrogels have good stability, but PBA is deficient in glucose selectivity and response rate. Therefore, the development of a stimuli-responsive unit with good biocompatibility and stability with efficient glucose responsiveness is still expected.

4. Enzymes

Proteases are the most extensively studied enzymes involved in acute and chronic wound healing. These enzymes and their specific inhibitors play a vital role in wound repair, covering almost all key stages from ECM degradation and deposition, cell proliferation, apoptosis, migration, differentiation, angiogenesis, to damaged tissue clearance, and bacterial load control. Among them, serine proteinases and matrix metalloproteinases (MMPs) are particularly critical, which can degrade most ECM components, thereby fine-tuning the dynamic wound repair process.70 Human neutrophil elastase (HNE) is a serine protease specific for small uncharged amino acids such as alanine and valine. Aimetti et al. doped HNE-sensitive peptides into hydrogels to achieve HNE-triggered, controlled, and localized drug release.71 The hydrogel facilitated precise control of delivery kinetics and has potential applications in cell-responsive delivery systems for inflammation.

Excessive inflammatory responses in diabetic wounds can lead to a significant increase in the secretion of pro-inflammatory cytokines, which can upset the delicate balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). This imbalance promotes the overproduction of MMPs, especially MMP-9, which has been shown to be up to 14 times higher in diabetic ulcers than in traumatic wounds. High levels of MMPs relentlessly degrade growth factors and matrix proteins that are critical for wound healing, a chain reaction that significantly exacerbates the chronic progression of diabetic wounds.65 Targeting both glucose and MMP-9 with a dual-stimuli-responsive drug delivery hydrogel is a promising approach for the treatment of chronic diabetic wounds. Zhou et al.65 developed a glucose and MMP-9 dual-responsive hydrogel [Figs. 5(a)5(c)].65 The hydrogel, constructed using PBA-modified chitosan (CS-BA) and PVA via boronate–ester bonds, incorporates gelatin microspheres loaded with celecoxib (GMs@Cel), an anti-inflammatory drug, and insulin (INS). These components are dispersed evenly in the CS-BA-PVA hydrogel (CBP). The CBP network releases insulin and GMs@Cel upon glucose-induced boronate–ester bond cleavage, facilitated by the inherent susceptibility of gelatin to MMP-9 degradation, leading to celecoxib release. This hydrogel system accelerates the healing of chronic diabetic wounds by regulating local glucose and MMP-9 levels in the wound environment. Shao et al. developed an adaptive multifunctional hydrogel for use in wound microenvironments [Figs. 5(d)5(f)].72 Based on quaternized chitosan functionalized with 3-carboxy-4-fluorophenylboronic acid (QCSF) grafted onto PVA, the hydrogel maintained stability at diabetic wound sites. The hydrogel contained deferoxamine-loaded gelatin microspheres (DFO@G) that responded to high glucose and overexpressed ROS via boronate ester bonds, regulating the microenvironment and releasing DFO@G microspheres. These microspheres respond to elevated MMP-9 levels to control deferoxamine release. Owing to its adaptive properties, dynamic response, on-demand release, and reduction of oxidative stress, the hydrogel accelerates diabetic wound healing.

FIG. 5.

Enzyme-responsive hydrogels and drug release behavior. (a) Schematic diagram of drug release from hydrogel via glucose and MMP-9 dual reaction system. (b) Cumulative release of celecoxib, and (c) Photograph of hydrogel after treatment with different concentrations of glucose and MMP-9. [Reproduced with permission from Zhou et al., “Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing,” Bioact. Mater. 17, 1–17 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (d) Hydrogel reduces oxidative stress and releases DFO. (e) Degradation profile in a simulated wound microenvironment. (f) DFO released after MMP-9 addition. [Reproduced with permission from Shao et al., “Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing,” Bioact. Mater. 20, 561–573 (2023). Copyright 2023 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 5.

Enzyme-responsive hydrogels and drug release behavior. (a) Schematic diagram of drug release from hydrogel via glucose and MMP-9 dual reaction system. (b) Cumulative release of celecoxib, and (c) Photograph of hydrogel after treatment with different concentrations of glucose and MMP-9. [Reproduced with permission from Zhou et al., “Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing,” Bioact. Mater. 17, 1–17 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (d) Hydrogel reduces oxidative stress and releases DFO. (e) Degradation profile in a simulated wound microenvironment. (f) DFO released after MMP-9 addition. [Reproduced with permission from Shao et al., “Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing,” Bioact. Mater. 20, 561–573 (2023). Copyright 2023 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

Enzyme reactive hydrogels can be obtained either directly from natural polymers with inherent sensitivity, such as hyaluronic acid, gelatin, collagen, and fibronectin, or indirectly by modifying biological materials that do not otherwise possess the property using enzyme reactive linkers. Among them, HA enzyme reaction hydrogels have shown very broad application potential in the biomedical field. This potential stems from the properties of hyaluronic acid as a substrate for hyaluronidase, which is not only overexpressed in aggressive malignancies but also excreted by pathogenic micro-organisms at the site of infection. Shang et al. innovatively proposed a hydrogel spray that artfully combined L-arginine coated with hyaluronic acid and hybrid nanocases [i.e., ultra-small gold nanoparticles (NPs) and CuO NPs co-loaded on phosphate-doped graphite carbon nitrides nanosheets], opening up new potential biomedical applications.73 ACPCAH spray exhibits multifunctional properties, including anti-inflammatory, antimicrobial, oxygen-supplying, and cell growth-promoting effects, and it is suitable for treating diabetic foot ulcers. The encapsulation strategy of hyaluronic acid not only significantly improves the biocompatibility and stability of the nanase but also subtly utilizes the hyaluronidase (HAase) on the biofilm for specific degradation, thereby accurately releasing L-arginine and the nanase, which greatly enhances the interaction with bacteria. The designed ACPCAH system is activated in response to the unique microenvironment of the diabetic wound and participates in a five-enzyme cascade consisting of superoxide dismutase (SOD), catalase (CAT), GOx, peroxidase (POD), and nitric oxide synthase (NOS). This complex biochemical reaction network effectively promotes the treatment process of chronic wounds and offers a novel therapeutic strategy for diabetic wound management.

Enzyme-responsive hydrogels with specific responses and good biocompatibility offer many advantages in the treatment of chronic wounds. Although enzyme-responsive hydrogels can respond to specific enzymes, the complex microenvironment of wounds makes it difficult to ensure an effective enzymatic response, and precise control of drug release time and dose remains challenging. In addition, reports on enzyme-responsive hydrogels are scarce, and more comprehensive studies and clinical data are lacking to support the use of enzyme-responsive hydrogels in biomedical applications.

1. Temperature

Temperature is the most common factor used to regulate hydrogel performance. Temperature-sensitive hydrogels exhibit fast response, ease of use, and adjustable switching temperature, which greatly broadens their application range. They are composed of functional groups that possess both hydrophobic and hydrophilic properties. Therefore, temperature fluctuation will act on the hydrophobic interaction force between polymer chains and hydrogen bonding connections, thus adjusting the structural morphology and volume size of hydrogels. Such thermosensitive polymers exhibit specific critical solution temperature characteristics, namely lower critical solution temperature (LCST) or upper critical solution temperature (UCST). Specifically, when the ambient temperature rises above LCST, such polymers tend to undergo phase separation. When the temperature drops below LCST, it tends to return to a single-phase state. In contrast, UCST polymers exhibit a tendency toward phase separation at temperatures below UCST, and once the temperature exceeds the threshold, they return to a single-phase state.

Poly(N-isopropylacrylamide) (PNIPAm) is one of the many hydrogel materials studied widely in the biomedical field, which benefits from its volume phase transition temperature approaching the normal temperature of the human body at the critical dissolution temperature and its ability to quickly respond to environmental changes. The hydrophilic amide group in the PNIPAm molecular structure interacts with the hydrophobic isopropyl side chain, allowing the polymer to exhibit sensitive phase transition characteristics to temperature changes in aqueous solution when the LCST is ∼32 °C. Therefore, PNIPAm-based thermoresponsive hydrogels are designed for customized drug delivery at normal body temperature (36–37 °C), where drugs are released rapidly upon local external heating. Haidari et al. synthesized pH- and temperature-sensitive hydrogels by crosslinking N-isopropylacrylamide with acrylic acid and loaded them with ultra-small AgNPs.48 Copolymerization of PNIPAm with acrylic acid facilitates easy adjustment of LCST. When the temperature rises above 36 °C, significant changes in the physicochemical properties of the hydrogel occur due to polymer rearrangement, resulting in a sharp increase in hydrogel hydrodynamic diameter. Above the LCST, the hydrogel is often dehydrated and organized into small spherical structures, leading to its contraction and aggregation into larger particles. The hydrogel can respond to the pathological fluctuations of pH and temperature during wound infection, thus stimulating the release of silver ions, which is highly consistent with the physiological requirements of the wound healing stage.

The temperature responsive hydrogel system, based on the development of natural and synthetic polymers, has been adopted and applied widely in the biomedical field. Because of their phase transition at physiological temperatures, gelatin-based thermosensitive hydrogels have been utilized to treat diabetic wounds. Jiang et al. developed a skin-friendly adhesive hydrogel by complexing poly(glycolic acid) (PGA) with methacrylated gelatin (GelMA) [Fig. 6].74 PGA GelMA hydrogel shows unique temperature responsive adhesion and detachment characteristics with its rich non-covalent bond network. When it makes contact with the skin and under the action of body temperature, the GelMA chain segment will break and transform into a soft and easy-to-fit hydrogel shape on the skin surface. In addition, the GelMA molecular chain inside the hydrogel can move freely and expose a large number of active groups, such as amino and carboxyl groups, which form multiple chemical bonds on the skin interface, thus giving the hydrogel extremely strong adhesion. Upon cooling, the reformation of hydrogen bonds between the GelMA chains restricts chain mobility and disrupts adhesive bonds. This painless adhesion and detachment capability, triggered by body heating and cooling, enables epidermal electronics to detach and reattach seamlessly to infant skin, facilitating reliable and long-term healthcare applications.

FIG. 6.

Temperature-responsive hydrogel dressing in skin adhesion and removal. (a) Body temperature-triggered mild adhesion and ice-cold-induced painless dislodgement. (b) Hydrogel adheres tightly to the surrounding tissues of the wound to withstand stretching. (c) The adhesive strength. [Reproduced with permission from Jiang et al., “Infant skin friendly adhesive hydrogel patch activated at body temperature for bioelectronics securing and diabetic wound healing,” ACS Nano 16(6), 8662–8676 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 6.

Temperature-responsive hydrogel dressing in skin adhesion and removal. (a) Body temperature-triggered mild adhesion and ice-cold-induced painless dislodgement. (b) Hydrogel adheres tightly to the surrounding tissues of the wound to withstand stretching. (c) The adhesive strength. [Reproduced with permission from Jiang et al., “Infant skin friendly adhesive hydrogel patch activated at body temperature for bioelectronics securing and diabetic wound healing,” ACS Nano 16(6), 8662–8676 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

Recently, temperature-switchable reversible adhesion has shown tremendous potential in promoting wound closure. Traditional wound closure strategies, such as sutures and staples, are typically invasive and can lead to trauma, insufficient tissue integration, and incomplete closure, resulting in leakage of tissue contents. Liang et al. developed a biomimetic dynamic crosslinking functional hydrogel with adhesive and mechanical strength sufficient for tissue sealants, injectable and responsive adhesion capabilities, and the capability of repeatedly closing or reopening wounds for post-closure treatment.75 The hydrogel is composed of gelatin, alginate, pyrogallol (PA), and Fe3+. Aldehyde and quinone groups are located on top of PA and can crosslink dynamically with amino groups in gelatin through dynamic Schiff base reactions or Michael addition mechanisms. The dual dynamic bonding characteristics within the network endow materials with excellent injectability and self-healing capabilities, especially in terms of mechanical strength and adhesive strength. In addition, gelatin forms ordered helical structures through hydrogen bonding at 25 °C while it transforms into disordered coil states at 37 °C, which endows the material with temperature sensitive properties. Under body temperature conditions, the high fluidity exhibited by the adhesive promotes sufficient adhesion with the small surface of the tissue, increases the probability of surface interaction, and significantly improves the bonding effect. The developed adhesive sealant combines excellent biocompatibility, biodegradability, photothermal antibacterial performance, hemostatic function, and the ability to promote wound healing and closure.

Temperature-responsive gels have the advantages of strong targeting and few toxic side effects, which can effectively reduce the cost of patient treatment and improve the quality of patient compliance survival. However, the response rate of passive temperature-responsive hydrogels has a delay from the drug rate due to the small temperature difference between pathological and normal tissues in vivo. To address this deficiency. Thermo-responsive gels can be used as basic actuators designed for advanced hybrid external stimulus (light, magnetic, etc.) response platforms.

2. Light

Owing to its non-invasive nature, excellent spatiotemporal resolution, and low environmental pollution advantages, light is a highly promising triggering tool in numerous applications and fields. The conversion of light signals into multifunctional responses using photoresponsive hydrogels has garnered considerable attention. Photoresponsive hydrogels can be categorized broadly into two: the first type encapsulates photosensitive components (e.g., nitrobenzyl and azobenzene), whereas the second incorporates near-infrared (NIR)-absorbing elements (e.g., dopamine and MXene as photothermal nanomaterials). These polymer hydrogels act as photoresponsive systems by embedding photochromic particles into their structures, which can be achieved mechanically or chemically. This capability can be modulated through the precise characterization of chromophores, light intensity, wavelength, and polymer communication. Upon exposure to light stimuli, these hydrogels exhibited sol-to-gel transitions owing to the cleavage of the photosensitive part that is connected to the hydrogel platform. Furthermore, the integration of elements within a thermoresponsive hydrogel matrix results in chemical changes or light-thermally induced swelling-deswelling behavior.

Azo compounds exhibit photoisomerization properties (trans- and cis-isomers). Exposure to ultraviolet UV light can easily manipulate these isomers. The trans-azo compound has an affinity for the hydrophobic cavity of β-cyclodextrin (CD), forming a host–guest complex. This affinity is light-switchable, meaning that the application of UV light generates an affinity-disrupting cis isomer, whereas the removal of the UV light restores complexation with the CD host.76 

Zhao et al. proposed a simple and effective method using supramolecular hydrogels to manipulate epidermal growth factor (EGF) release to accelerate wound healing [Figs. 7(a) and 7(b)].76 The study explored the preparation of a novel photosensitive supramolecular polysaccharide hydrogel, which was constructed based on unique host–guest recognition between the azobenzene molecule and the β-cyclodextrin (β-CD) group (the latter covalently combines with the HA chain). A dynamically cross-linked network density can be achieved via light stimulation by leveraging the photoisomerization properties of azobenzene at different wavelengths. Under UV light, the relaxed hydrogel releases EGF rapidly, which enhances its delivery to the wound site. Kim et al. developed a multifunctional hydrogel composed of carboxymethyl cellulose-grafted azobenzene and β-CD dimer.77 The dimer was linked to agarose via disulfide bonds to provide structural support. The resulting hydrogel exhibited self-healing properties through host–guest complexation and sol–gel phase transitions under UV light. Additionally, drug release from the hydrogel could be accelerated to 80% within 3 h using UV light or a reducing agent.

FIG. 7.

Photoresponse properties of supramolecular hydrogels. (a) Photographs of reversible hard-soft state transitions of supramolecular hydrogels and their corresponding storage moduli. (b) Release profiles of EGF@S gels (photoresponsive) and EGF@PR-S gels (non-responsive) under UV and visible light irradiation. [Reproduced with permission from Zhao et al., J. Controlled Release 323, 24–35 (2020). Copyright 2020 Elsevier B.V. All rights reserved]. (c) Drug release scheme of MXene–PNIPAm hydrogel under near-infrared (NIR) irradiation. Temperature change profiles of MXene–PNIPAm by NIR irradiation. (d) and (e) Curves of tetracycline release from hydrogels after 10 and 70 min of NIR laser irradiation. [Reproduced with permission from Hao et al., “Bifunctional smart hydrogel dressing with strain sensitivity and NIR-responsive performance,” ACS Appl. Mater. Interfaces 13(39), 46938–46950 (2021). Copyright 2021 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 7.

Photoresponse properties of supramolecular hydrogels. (a) Photographs of reversible hard-soft state transitions of supramolecular hydrogels and their corresponding storage moduli. (b) Release profiles of EGF@S gels (photoresponsive) and EGF@PR-S gels (non-responsive) under UV and visible light irradiation. [Reproduced with permission from Zhao et al., J. Controlled Release 323, 24–35 (2020). Copyright 2020 Elsevier B.V. All rights reserved]. (c) Drug release scheme of MXene–PNIPAm hydrogel under near-infrared (NIR) irradiation. Temperature change profiles of MXene–PNIPAm by NIR irradiation. (d) and (e) Curves of tetracycline release from hydrogels after 10 and 70 min of NIR laser irradiation. [Reproduced with permission from Hao et al., “Bifunctional smart hydrogel dressing with strain sensitivity and NIR-responsive performance,” ACS Appl. Mater. Interfaces 13(39), 46938–46950 (2021). Copyright 2021 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

NIR light offers better skin penetration and is safer than UV. Hao et al. have created a novel smart hydrogel dressing that combines conductive MXene nanosheets and temperature responsive PNIPAm [Figs. 7(c)7(e)].78 In its application as a soft strain sensor, this hydrogel sensor exhibits high strain sensitivity, wide working range, fast response speed, and excellent cycle durability. The hydrogel sensor exhibited high abrasion resistance and biocompatibility and adhered well to human skin for human motion detection and real-time health monitoring applications. Furthermore, when tested as a drug delivery vehicle, the prepared hydrogel was controlled using NIR light to achieve on-demand drug release. Tao et al. mixed curcumin-loaded polydopamine NPs (PDA@Cur) with PEGDA and lauric acid-terminated chitosan (Chi-LA) polymers to develop NIR-responsive hydrogels via Schiff base and/or Michael addition reactions.79 Curcumin is a natural polyphenol with antioxidant, anti-inflammatory, and antimicrobial properties. Under NIR laser irradiation, PDA@Cur exhibits a “switch-on/off” release characteristic for curcumin. Therefore, the laser irradiation accelerated the release of Cur from the PDA@Cur gel. In addition, photothermal therapy induces localized thermal healing, effectively killing the surrounding bacteria. In vivo studies using a full-thickness skin defect model infected with Staphylococcus aureus demonstrated the antimicrobial activity and wound healing efficacy of the NIR-induced PDA@Cur hydrogel system.

The light-mediated antibacterial treatment method, with its excellent immediate sterilization ability, has attracted considerable attention. Li et al. have developed a unique hybrid hydrogel, ingeniously combining food grade additives with the affordable photosensitizer Rose Red (RB).80 This new material not only has improved mechanical strength but also demonstrates extraordinary abilities in photoactive antibacterial performance. Combining the photothermal and photodynamic effects has enhanced its antibacterial performance significantly. Under visible light excitation at a specific wavelength of 550 nm, RB can effectively transition to its triplet state and generate ROS through energy transfer pathways. Although RB is easy to blend into hydrogel because of its good water solubility, it also introduces a series of new challenges to the design and application of materials.

The photothermal effect and NIR-triggered drug release can be a multifunctional wound dressing solution. NIR-responsive multifunctional wound dressings show the potential to promote angiogenesis and the advantage of treating wounds infected with multidrug-resistant bacteria. However, heat and photosensitizer-generated ROS are double-edged swords. High levels of heat and ROS not only kill bacteria but also cause cellular damage. Therefore, precise control of phototherapy intensity and targeting of bacteria to limit adverse cellular damage is critical.

3. Ultrasound

Through adjustment of the intensity, frequency, and duration of ultrasound, thermal effects, acoustic streaming, cavitation, and acoustic radiation forces can be generated on tissues and cells. Ultrasound-responsive hydrogels respond to sound or ultrasound stimulation and have significant application potential in drug delivery. Contact and non-contact low-frequency (20–30 kHz) ultrasound may directly promote chronic wound healing. In addition, ultrasound can produce thermal, acoustic flow, cavitation, and acoustic clustering effects on tissues and cells, depending on intensity, frequency, and duration.70 

Zhang et al. innovatively prepared high-density platinum nanoparticle assembly structures (PNAs) based on a combination of metal organic coordination polymers and dynamic covalent bonds.81 The compact PNAs not only successfully simulate the functions of antioxidant enzymes such as CAT and POD but also enhance the polarization effect of electrons under ultrasound by exploiting their surface plasmon resonance properties. This characteristic enables them to efficiently simulate the enzymatic activity of glutathione reductase, thereby promoting glutathione (GSH) production. In summary, PNAs not only effectively catalyze hydrogen peroxide by simulating CAT and POD activity to combat hypoxia but also generate GSH with ultrasound assistance, further enhancing their ability to scavenge ROS. What is particularly prominent is that PNAs can regulate macrophage responses in the inflammatory microenvironment, thereby achieving this goal without the need for additional substances.

Piezoelectric materials refer to a type of dielectric material with an asymmetric crystal structure. Once subjected to external mechanical forces, they can generate dynamic electric field effects internally and form potential differences on the surface, causing electrons and holes to be pulled to opposite surfaces, thereby triggering redox reactions. Xu et al. successfully created a viscous piezoelectric antibacterial hydrogel with high swelling properties, biodegradability, and adjustable rheological properties using a simple assembly method containing carboxymethyl chitosan, tannic acid, and piezoelectric material FeWO4.82 Under ultrasound stimulation, the hydrogel showed excellent rheological stability, swelling capacity, degradation characteristics, and antibacterial properties. The synergistic effect of ultrasonic cavitation and the internal electric field of FeWO4 piezoelectric material greatly promote the generation, separation, and migration of charge carriers, thereby generating a large amount of ROS. In vivo experiments have shown that the combination of piezoelectric hydrogel and ultrasound could greatly accelerate the healing process of full-thickness skin wounds caused by bacterial infection in mice. This promoting effect is achieved mainly by regulating the inflammatory response, accelerating collagen deposition, and promoting angiogenesis. It is particularly notable that the excellent efficacy of piezoelectric hydrogel in wound healing is confirmed further through the analysis of histomorphology and the detection of the expression level of inflammatory factors.

Sonodynamic therapy (SDT) is a promising antibacterial and antitumor treatment strategy. It uses external ultrasound to trigger the production of highly toxic ROS using sonosensitizers. Compared to traditional photodynamic therapy (PDT), sonodynamic therapy (SDT) demonstrates higher soft tissue penetration ability when using photosensitizers systemically while effectively avoiding severe skin photosensitivity reactions. During SDT, sonosensitizers generate high amounts of ROS under ultrasound irradiation, exhibiting excellent bactericidal capabilities and significantly reducing the likelihood of antibiotic resistance.

BaTiO3 is a well-known wide bandgap ferroelectric semiconductor material that can induce internal electric fields and surface charges upon encountering external mechanical stress, thereby triggering ROS-mediated redox processes. Liu et al. developed a hydrogel system integrating ultrasonic activated piezoelectric catalysis technology with the aim of accelerating the recovery process of bacterial infectious wounds [Fig. 8].83 In the system, when exposed to ultrasonic vibration, BaTiO3 NPs embedded in the hydrogel generate ROS rapidly due to the strong internal electric field, giving the hydrogel excellent antibacterial properties. Compared with classical photodynamic therapy, this novel therapy exhibits unique advantages such as excellent soft tissue penetration and avoidance of severe skin photosensitivity caused by systemic use of photosensitizers. In addition, the Schiff base aqueous gel based on oxidized hyaluronic acid showed remarkable self-healing ability and bioadhesiveness, which accelerated the healing of full-thickness skin wounds. It is particularly critical that this viscous hydrogel can effectively fix BaTiO3 NPs on the wound site and, under ultrasound action, locally trigger the piezoelectric catalytic process to remove bacteria, thus greatly reducing the potential side effects. Given the excellent soft tissue penetration performance of ultrasound, this study not only provides new ideas for the treatment of superficial infected wounds but also provides conceptual validation and possibilities for remote treatment of deep and persistent infections, such as deep muscle abscesses, paraspinal, and gastrointestinal infections.

FIG. 8.

Ultrasound-triggered response behavior. (a) Schematic diagram of an ultrasonic piezoelectric antibacterial treatment strategy. (b) Schematic diagram of BT-mediated piezoelectric effect catalyzed by ultrasound-triggered generation of –OH and –O2. UV–visible absorption spectra in (c) control and (d) BT gel at different times. The inset shows the rhodamine B solution after ultrasound-triggered piezoelectric catalysis at different times. (e) Electron spin resonance spectra of each group for detection signals. [Reproduced with permission from Liu et al., “Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing,” Bioact. Mater. 24, 96–111 (2023). Copyright 2023 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 8.

Ultrasound-triggered response behavior. (a) Schematic diagram of an ultrasonic piezoelectric antibacterial treatment strategy. (b) Schematic diagram of BT-mediated piezoelectric effect catalyzed by ultrasound-triggered generation of –OH and –O2. UV–visible absorption spectra in (c) control and (d) BT gel at different times. The inset shows the rhodamine B solution after ultrasound-triggered piezoelectric catalysis at different times. (e) Electron spin resonance spectra of each group for detection signals. [Reproduced with permission from Liu et al., “Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing,” Bioact. Mater. 24, 96–111 (2023). Copyright 2023 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

4. Electric field

An electric field is the fundamental physical microenvironment of skin wounds. Normally, the skin surface is charged negatively; however, once a wound forms, the central surface of the wound becomes positively charged.70 As the wound heals, the positive charge decreases gradually, returning to the normal state. Exogenous electric fields generated by wearable devices or specialized wound dressings can significantly promote wound healing and alleviate infections. Among the various external stimuli, electrical stimulation is particularly attractive because of its ease of generation and control, with potential applications including the development of wireless implants.

Conductive polymers, such as polyaniline, polythiophene, and polypyrrole, along with their various derivatives, have shown great potential in the biomedical field, especially in controlled release systems, due to their excellent electroactivity. Among these materials, polyaniline has become the focus of research due to its excellent biocompatibility. Qu et al. innovatively developed an injectable conductive hydrogel, which not only has electrical responsiveness and pH sensitivity but also has natural antibacterial properties.84 The hydrogel is composed of CS grafted polyaniline (CP) copolymer and oxidized dextran (OD). The study successfully verified the electrical response of the hydrogel by implementing the “switching” pulse release strategy. Specifically, with an increase in the applied voltage, the release rate of amoxicillin and ibuprofen loaded in the hydrogel significantly increased. Under the no voltage condition, drug release remains at the lowest level, which strongly demonstrates the effectiveness of the “on–off” mechanism. In addition, the hydrogel shows biocompatibility and biodegradability. The findings indicate that this injectable conductive hydrogel with antibacterial properties is an ideal drug delivery platform in the field of precise drug delivery for chronic diseases.

In view of the complex and diverse causes of acute and chronic wounds, the effectiveness of traditional single response hydrogel dressings in promoting comprehensive wound healing is limited. To overcome the challenge, researchers have started developing multi-responsive dressings aimed at optimizing the wound healing process by responding to multiple external stimuli. With the growing demand for precise drug delivery in the medical field, the coordinated regulation of drug release combined with various stimuli has become a key way of improving the efficacy of drug loaded hydrogels. The combination therapy strategy, with its synergistic effects among multiple treatment methods, often surpasses the therapeutic effect of a single therapy. In such a context, multi-responsive hydrogel dressings have emerged. They have been carefully constructed as a platform integrating multiple treatments, designed to meet the needs of complex wound healing.

In view of the complex and changeable physiological environment in vivo, especially the low pH environment and hyperglycemia state involved in diabetes foot ulcer, it is a challenging task to design an advanced delivery system that can respond to changes in metabolic state. The Schiff base structure is sensitive to pH and decomposes easily under acidic conditions, leading to accelerated drug release. This characteristic can be integrated with the glucose responsive phenylboronic acid ester structure. Liang et al. ingeniously combined the two dynamic chemical bonds of Schiff base and phenyl borate to develop a novel hydrogel dressing [Fig. 9].64 The hydrogel not only has multiple functions such as promoting healing, tissue adhesion, and antibacterial and antioxidant effects, but also the benzaldehyde functionalized polymer in its composition can form a Schiff base structure with the aldehyde group and amino group in chitosan. Meanwhile, the catechol structure and PBA group can form a dynamic phenylboronic acid ester structure. Therefore, when the two are combined, a hydrogel dressing that can respond to both pH changes and glucose levels is generated, which is particularly beneficial for the treatment of diabetes wounds under low pH and high glucose conditions. In addition, this dual dynamic combination imparts hydrogels with excellent self-healing ability, effectively avoiding the risk of hydrogel damage, with significant advantages in the dynamic wound repair process. Especially when metformin is loaded on hydrogel, it can dynamically regulate drug release according to the glucose concentration in the wound microenvironment of diabetes, thus accelerating the healing process of foot ulcers in type II diabetes.

FIG. 9.

pH and glucose dual stimulus response behavior. (a) pH and glucose response mechanism. (b) pH and (c) glucose response to metformin release. (d) Dynamic bonds: (1) self-healing mechanism and (2) and (3) representative display pictures of removability. [Reproduced with permission from Liang et al., “pH/glucose dual responsive metformin release hydrogel dressings with adhesion and self-healing via dual-dynamic bonding for athletic diabetic foot wound healing,” ACS Nano 16(2), 3194–3207 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 9.

pH and glucose dual stimulus response behavior. (a) pH and glucose response mechanism. (b) pH and (c) glucose response to metformin release. (d) Dynamic bonds: (1) self-healing mechanism and (2) and (3) representative display pictures of removability. [Reproduced with permission from Liang et al., “pH/glucose dual responsive metformin release hydrogel dressings with adhesion and self-healing via dual-dynamic bonding for athletic diabetic foot wound healing,” ACS Nano 16(2), 3194–3207 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

Alternating magnetic fields (AMFs) and NIR have unique advantages, including tissue penetration, high sensitivity for remote control, and thermal effects. Yang et al. developed an intelligent, responsive hydrogel drug delivery system composed of MXene–Fe3O4 magnetic colloids and a PNIPAM-alginate double network hydrogel.85 MXene–Fe3O4 served as a nanounit responsive to NIR and AMF, exhibiting unique thermal effects. As a temperature-responsive polymer, PNIPAM undergoes dehydration and contraction near its LCST. In other words, the hydrogel system contracts with increasing temperature, precisely controlling the release of AgNPs from hydrogel. In the treatment of deep wounds in diabetes rats, MXene–Fe3O4 hydrogels demonstrated excellent cell compatibility, biocompatibility, and effective performance. The characteristics of the compounds suggest that they are promising candidates for treatment of deep chronic wounds.

As mentioned previously, synergistic NIR and temperature strategies have been developed extensively for various wound dressings. A recent study reported a hydrogel dressing that responds to NIR, temperature, and pH.42 In detail, a new type of hydrogel was created by using modified gelatin, which has morphological adaptability, self-healing ability, and temperature sensitivity. Under the condition of photothermal stimulation or pH fluctuation, the interaction between the hydrogen bond and catechol–Fe3+ will be activated, so that the hydrogel can be removed easily from the skin by NIR light irradiation or washing with weak acid aqueous solution. Compared with traditional medical glue and surgical sutures, this innovative hydrogel shows excellent hemostatic effects, and it has a high killing ability against methicillin-resistant Staphylococcus aureus (MRSA), thus accelerating the effective healing process of skin incision.

The nanofiber membrane formed by random or ordered arrangement of nanofibers not only has macroscopic morphology and mechanical strength but also responds rapidly to external stimuli, so it has a broad application prospect in the field of biomedicine. Electrostatic spinning can prepare nano-diameter polymer fibers, which have the advantages of simple operation, wide range of application, and high production efficiency. Electrospun nanofibers are characterized by high specific surface area, diverse structures, wide sources of prepared materials, unique physical and chemical properties, and flexible surface modification. In addition, electrospun nanofibers can mimic the structure of extracellular matrix (ECM), promote cell adhesion, proliferation, differentiation, and guide tissue repair and regeneration.86 Therefore, electrospun nanofibers have attracted considerable attention in tissue repair.

Jin et al. developed a near-infrared response dressing combining the advantages of nanofiber and dopamine modified hyaluronic acid hydrogel (MNF@HADA) [Figs. 10(a)10(c)].87 MNF ink is composed of MXene nanosheets, VEGF-loaded SiO2 NPs, and polylactic-co-glycolic acid. This type of MNF nanofiber as a functional framework can provide photothermal performance. Adjusting the NIR irradiation time can control the release behavior of VEGF from the MNF nanofiber framework, avoiding excessive vascularization and ECM deposition at the wound site. Compared to traditional strategies, MNF@HADA meets the complex requirements of a wider range of clinical wound care. This multifunctional dressing based on nanofibers has great potential in scar-free wound care.

FIG. 10.

Morphology, photothermal properties, and drug release behavior in NIR of nanofibers. (a) SEM images of nanofibers. (b) Photothermal properties and (c) drug release profile under NIR. [Reproduced with permission from Jin et al., “An NIR photothermal-responsive hybrid hydrogel for enhanced wound healing,” Bioact. Mater. 16, 162–172 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (d) NFES fibers and photographs, and (e) SEM images 50 μm (left) and 15 μm (right). Survivability of (f) S. aureus and (g) E. coli. [Reproduced with permission from Kong et al., Adv. Funct. Mater. 34, 2310544 (2024). Copyright 2024 Wiley‐VCH GmbH].

FIG. 10.

Morphology, photothermal properties, and drug release behavior in NIR of nanofibers. (a) SEM images of nanofibers. (b) Photothermal properties and (c) drug release profile under NIR. [Reproduced with permission from Jin et al., “An NIR photothermal-responsive hybrid hydrogel for enhanced wound healing,” Bioact. Mater. 16, 162–172 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (d) NFES fibers and photographs, and (e) SEM images 50 μm (left) and 15 μm (right). Survivability of (f) S. aureus and (g) E. coli. [Reproduced with permission from Kong et al., Adv. Funct. Mater. 34, 2310544 (2024). Copyright 2024 Wiley‐VCH GmbH].

Close modal

Kong et al. used a high-precision 3D printing near-field electrospinning (NFES) to establish a square microfiber lattice reinforced with polycaprolactone (PCL) [Figs. 10(d)10(g)].88 NFES technology can achieve flexible layout of submicrometer fiber arrays to simulate the orthogonal structure of natural corneal stroma. NFES fiber patches can enhance the mechanical stability of hydrogels. The special orthogonal structure can stimulate the directional growth of human keratinocytes. In addition, experimental gold NPs modified barium titanate (BTO@Au) disperse in the hydrogel matrix. BTO@Au piezoelectric NPs are fascinating ultrasound sensitizers. Under ultrasound intervention, BTO@Au is activated to convert the mechanical force of sound waves into an electric field, followed by the release of electrons, catalyzing the ROS production from oxygen and water to eliminate bacteria. A study using a rat model of corneal wound infection confirmed this load BTO@Au. The superior therapeutic effect of the NFES fiber patch.

Extensive and deep wound defects often require transplantation of autografts or allografts to close the wound, which can lead to donor tissue shortages, a risk of infection, and immunogenic rejection. Unfortunately, conventional techniques make it difficult to fabricate hydrogel structures with customized dimensions that adequately cover wounds of varying depth or morphology.89 In biology, materials science, and emerging additive manufacturing technologies, 3D printing has made significant advances in tissue engineering and regenerative medicine. 3D printing, an advanced biofabrication technology, can generate patient-specific scaffolds with complex geometries that carry cells and bioactive agents to promote tissue regeneration. 3D printed tissue-engineered scaffolds have been developed for the treatment of a variety of wounds and are particularly useful in treating chronic wounds, such as diabetic foot, which has great potential.90 Liu et al. prepared core/shell fiber scaffolds by 3D printing.91 The inner phase is alginate gelatin gel, and the outer shell is coated evenly with polycaprolactone (PCL). PCL coating effectively prevents the free diffusion of drugs. Subsequently, PDA was coated on the core/shell scaffold to endow it with a photothermal effect. The system achieved drug release triggered by NIR through the thermal response of the core gelatin sol–gel transformation. The released drugs and photothermal therapy effectively promote wound healing both in vitro and in vivo.

Integrating microfluidic systems with traditional extrusion-based 3D printing platforms allows for precise control of the composition and structural features of the scaffold. Microfluidic based 3D printed scaffolds have been used in tissue engineering. Especially, the biomimetic channel structure of vascular scaffolds has been demonstrated to be particularly effective in promoting the formation of vascular networks and new tissue regeneration. Wang et al. proposed a capillary assembly microfluidic printing strategy for preparing hydrogel scaffolds to promote vascular formation and flap regeneration [Figs. 11(a)11(e)].92 The MX-HF scaffold is manufactured in a microfluidic coaxial channel. The main components of printable bioink are MXene nanosheets, NIPAM, and alginate. By exploiting the photothermal conversion performance of MXene and the temperature responsiveness of NIPAM, the MX-HF scaffold exhibits NIR responsive contraction/expansion behavior, which can promote cell enrichment within the channel. Additionally, the incorporation of VEGF into the scaffold matrix achieved controlled delivery, facilitating HUVEC migration, proliferation, and pro-angiogenic effects under near-infrared irradiation. This microfluidic 3D printing strategy can be used to easily manufacture MXene-incorporated channel scaffolds with photothermal-responsive properties, and the channel structure and controllable release capability are expected to significantly promote angiogenesis and enhance flap wound repair. To promote wound closure, the team also used in situ 3D printing technology to directly deposit live algae-filled microalgal hollow fiber (MA-HF) scaffolds at defect sites.93 Owing to the embedded live Chlorella and their oxygen-producing photosynthetic properties, the scaffold exhibited light-responsive properties, producing sustainable oxygen under light exposure, even under hypoxic conditions, thereby promoting cell proliferation, migration, and differentiation. When the live algae scaffold is printed directly on the wound and exposed to light, the scaffold accelerates wound closure significantly by providing local oxygen, increasing angiogenesis, and promoting ECM synthesis.

FIG. 11.

Temperature responsive scaffold. (a) Schematic diagram of microfluidic 3D printed dynamically responsive scaffolds. The scaffolds exhibited photothermally responsive contraction/expansion behaviors under NIR. (b) Photographs and (c) SEM of the scaffolds. (d) Volume shrinkage of scaffolds. (e) The VEGF release profiles with or without NIR irradiation. [Reproduced with permission from Wang et al., “Dynamically responsive scaffolds from microfluidic 3D printing for skin flap regeneration,” Adv. Sci. 9(22), 2201155 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (f) SEM images of silica colloidal crystal templates and antiproteinite structures. (g) Schematic diagram of the temperature response characteristics of NNH patches. (h) The drug release profile of NNH patches under 37 or 25 °C. (i) Deformation of NNH patches. (j) Skin pH was measured using pH strips. [Reproduced with permission from Chen et al., “Responsive and self-healing structural color supramolecular hydrogel patch for diabetic wound treatment,” Bioact. Mater. 15, 194–202 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 11.

Temperature responsive scaffold. (a) Schematic diagram of microfluidic 3D printed dynamically responsive scaffolds. The scaffolds exhibited photothermally responsive contraction/expansion behaviors under NIR. (b) Photographs and (c) SEM of the scaffolds. (d) Volume shrinkage of scaffolds. (e) The VEGF release profiles with or without NIR irradiation. [Reproduced with permission from Wang et al., “Dynamically responsive scaffolds from microfluidic 3D printing for skin flap regeneration,” Adv. Sci. 9(22), 2201155 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license]. (f) SEM images of silica colloidal crystal templates and antiproteinite structures. (g) Schematic diagram of the temperature response characteristics of NNH patches. (h) The drug release profile of NNH patches under 37 or 25 °C. (i) Deformation of NNH patches. (j) Skin pH was measured using pH strips. [Reproduced with permission from Chen et al., “Responsive and self-healing structural color supramolecular hydrogel patch for diabetic wound treatment,” Bioact. Mater. 15, 194–202 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

Structural color is a coloring generated by the unique interaction between light and inherent periodic nanostructures, which has attracted considerable attention in optical displays, anti-counterfeiting labels, and wearable electronic products. Inverse opal scaffolds with unique optical properties have great potential for wound monitoring, management, and clinical treatment guidance. Chen et al. proposed a novel structurally colored supramolecular hydrogel inverse opal scaffold for diabetic wound treatment [Figs. 11(f)11(j)].94 This scaffold was composed of supramolecular and PNIPAM hydrogels loaded with VEGF. The supramolecular hydrogels endowed the hydrogel patches with excellent mechanical properties, whereas N-acryloylglycine and 1-vinyl-1,2,4-triazole exhibited self-healing and antibacterial properties, respectively. In addition, due to the existence of PNIPAM, hydrogels show thermal responsiveness, releasing active substances in response to temperature stimuli. Due to the unique optical properties of the inverted opal structure, the hydrogel has color sensing behavior, which is suitable for wound monitoring and guiding clinical treatment.

Microneedles are composed of needle arrays at the micrometer scale, which are non-invasive.95 Compared to injection or other medication methods, microneedles can reduce patient pain.96 Microneedles have unique advantages in tissue regeneration applications: microneedles can penetrate the physical barriers of wounds, such as blood clots, exudate, and biofilms, thereby enhancing drug utilization and significantly enhancing drug delivery efficiency. Moreover, the application is painless and non-intrusive, improving patient compliance when compared with traditional subcutaneous injections. Microneedles can be fabricated from various natural materials and synthetic polymers, featuring uniform nano- or microstructures that enable easy transdermal delivery of drugs to target sites. Smart drug delivery systems based on microneedles, therefore, promote wound healing.

For instance, Chi et al. combined an antimicrobial CS hydrogel with a microneedle array to create a multifunctional patch for enhancing wound healing.97 This CS imparts a porous structure to the patch, and it possesses antimicrobial and hemostatic activities, allowing direct and controlled delivery of drugs to the damaged area. The microstructure of the needle can deliver drugs transdermally to the target tissue. For example, VEGF encapsulated in CS and pNIPAM microneedles achieved temperature responsive on-demand release. Drug release is induced by increased surface temperature, which is associated with inflammatory responses at the wound site. Research has demonstrated that CSMNA patches accelerate cell migration and distribution, facilitate the effective transport of nutrients and oxygen, and promote the removal of metabolic waste. The multifunctional CSMNA patch, an excellent drug carrier, holds tremendous potential for enhancing wound healing. Therefore, microneedles are an advanced drug delivery system that improves local drug delivery efficiency and accelerates wound healing processes through smart design and multifunctional capabilities, offering new possibilities and choices for various medical treatments.

In chronic infections, biofilm formation enhances bacterial resistance to antibiotics. Microneedles can pierce dense biofilms and uniformly deliver antibiotics and other drugs into bacterial communities, thereby eradicating the biofilm [Fig. 12].98 Wu et al. developed an HA enzyme-responsive core–shell microneedle system using HAMA/carboxymethyl SC.99 The microneedles were stabilized on the wound using a CS adhesive layer, providing sufficient strength to penetrate the biofilm. Staphylococcus aureus secretes the HA enzyme to degrade the HAMA shell of the microneedles, facilitating drug release and triggering potent antimicrobial activity through drug intervention and physical cutting effects. The multifunctional microneedle patch is a potential strategy for accelerating healing.

FIG. 12.

Structure and transdermal drug delivery properties of microneedles. (a) Design strategy for microneedles. (b) The appearance of Dox MS-loaded MN patches as viewed under stereo-fluorescence microscopy. Red arrows indicate the tips containing Dox MS. Image of MN patch inserted into pig skin. (c) Dox release profiles of microsphere. (d) Live/dead stained images treated with the same concentration of free Dox and Dox MS. [Reproduced with permission from Yang et al., Small 20, e2307104 (2024). Copyright 2024 Wiley‐VCH GmbH].

FIG. 12.

Structure and transdermal drug delivery properties of microneedles. (a) Design strategy for microneedles. (b) The appearance of Dox MS-loaded MN patches as viewed under stereo-fluorescence microscopy. Red arrows indicate the tips containing Dox MS. Image of MN patch inserted into pig skin. (c) Dox release profiles of microsphere. (d) Live/dead stained images treated with the same concentration of free Dox and Dox MS. [Reproduced with permission from Yang et al., Small 20, e2307104 (2024). Copyright 2024 Wiley‐VCH GmbH].

Close modal

Microneedles penetrate barriers in chronic wounds, creating hundreds of micrometer-sized pores that serve as rapid pathways to tissues. However, wound closure during microneedle treatment has been neglected. In treating chronic wounds, most microneedles cannot easily provide a moist and closed repair environment for wounds. The flexible use of the tip and back layer of microneedles can enhance their synergistic therapeutic effect in wounds. Yang et al. encapsulated Dox in microspheres with lipase reaction characteristics and loaded them onto the tip of microneedles. Dopamine modified HA (HA–DA) hydrogel backing replaces the traditional microneedle backing, which can adhere to wounds and maintain a humid environment. By using microneedles to break through the wound barrier and deliver microspheres into the biofilm, they are then degraded by lipase secreted by pathogens, releasing Dox and achieving biofilm eradication. This process produces numerous micropores, which facilitate the rapid diffusion of drugs from hydrogels to tissues. This multifunctional dressing integrates hydrogel backing and needle tip, offering a novel scheme for wound treatment.

Microspheres have numerous advantages as drug carriers.100 Their small size and large surface area allow them to accommodate more drugs, thereby increasing their drug-loading capacity.101 Microspheres confine drugs to target areas without affecting other tissues, thereby reducing drug toxicity and adverse effects. Notably, microspheres can be formulated in injectable and oral dosage forms, enhancing patient convenience.

Hydrogel microspheres have significant advantages in tissue engineering. These include excellent biocompatibility, biodegradability, tunable porosity, adjustable carrier stiffness, and the ability to load and release bioactive substances. Hydrogel microspheres ensure biocompatibility and avoid severe immune and toxic reactions. Cui et al. developed smart microsphere assemblies that regulate wound microenvironment pH [Fig. 13].102 Gel 1 and 2 contain –COOH and –NH2 groups, respectively, which react with alkaline and acidic environments, allowing for dynamic pH regulation in a moist wound environment. When used in combination therapy for wounds, Gel 1 initially releases more H+ ions than Gel 2 during the hemostasis and inflammation stages, thereby lowering the pH. Subsequently, the swelling of Gel 2 exposes the increasing number of –NH2 groups, leading to higher pH during the later stages of proliferation and remodeling. These two hydrogel microspheres have been assembled into various macroscopic structures (e.g., linear, planar, and 3D hydrogel integrations) to achieve specific wound surface morphologies using microfluidic assembly techniques.

FIG. 13.

Microgels prepared by microfluidics and pH-adjusting properties. (a) Schematic representation of microgel assemblies prepared by microfluidics. (b) The molecular structure of microgel assemblies. (c) Construction of planar and 3D ordered assemblies. (d) pH regulation by microgel integration. (1) In vivo pH profiles with healing time for infected, uninfected, and normal skin wounds. (2) In vitro pH-time profiles for Gel 1, microgel integration, and Gel 2. (3) In vitro pH-time profiles for Gel 1 and 2 microbeads. (c) In vivo curves of wound over healing time for Gel 1, microgel integration, and Gel 2. [Reproduced with permission from Cui et al., “Micro-gel ensembles for accelerated healing of chronic wounds via pH regulation,” Adv. Sci. 9(22), 2201254 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

FIG. 13.

Microgels prepared by microfluidics and pH-adjusting properties. (a) Schematic representation of microgel assemblies prepared by microfluidics. (b) The molecular structure of microgel assemblies. (c) Construction of planar and 3D ordered assemblies. (d) pH regulation by microgel integration. (1) In vivo pH profiles with healing time for infected, uninfected, and normal skin wounds. (2) In vitro pH-time profiles for Gel 1, microgel integration, and Gel 2. (3) In vitro pH-time profiles for Gel 1 and 2 microbeads. (c) In vivo curves of wound over healing time for Gel 1, microgel integration, and Gel 2. [Reproduced with permission from Cui et al., “Micro-gel ensembles for accelerated healing of chronic wounds via pH regulation,” Adv. Sci. 9(22), 2201254 (2022). Copyright 2022 Author(s), licensed under a Creative Commons Attribution (CC BY) license].

Close modal

The inverse opal structure is based on the ordered stacking of NPs in space, presenting a unique porous structure and nanochannels, resulting in a larger specific surface area. Microspheres based on inverse opal structure are suitable for loading and delivering bioactive substances. Zhang et al. used microspheres with inverse opal structure for wound healing. Microspheres are composed of silk fibroin and gelatin, containing black phosphorus quantum dots (BPQDs), which can achieve controlled drug release under NIR stimulation.103 Different protein hydrogels can be easily and progressively integrated using the inverse opal structure while preserving their inherent properties. With sufficient mechanical strength, silk fibroin doped with BPQDs is a rigid scaffold, incorporating nanopores filled with a mixture of growth factors and antimicrobial peptides in gelatin within the inverse opal structure. Black phosphorus, known for its high photothermal conversion capability, is also a smart and responsive component. When exposed to NIR light, BPQDs rapidly convert light energy into heat, elevating local temperatures and controlling the release of both drugs by melting the external gelatin hydrogel. Studies have demonstrated that responsive inverse opal-structured microspheres could promote angiogenesis and inhibit bacterial infection in wounds using NIR light, offering innovative prospects for drug delivery and wound healing.

Perfect wound regeneration and scarless repair, including the epidermis, dermis, and appendages, is one of the relentless pursuits of physicians and scientists. With in-depth studies on the roles and mechanisms of various microenvironments in wound healing, emerging biomaterials have been developed to respond to and modulate the biological, biochemical, and pathological microenvironments of wounds. In this review, we present smart hydrogel dressings that respond to biological/biochemical wound microenvironments (pH, ROS, glucose, and enzymes), physical microenvironments (temperature, light, ultrasound, and electric fields), and combinatorial modalities. We then briefly summarize several novel tissue engineering processing modalities (nanofibers, scaffolds, microneedles, and microspheres) that hold promise in wound healing. We focus on reviewing design strategies for smart hydrogels and then present classic and interesting examples in the field of wound healing.

With the in-depth study of wound healing mechanisms, the field of wound care has ushered in a variety of dressing innovations for different healing stages. Among them, stimuli-responsive wound dressings, as an emerging concept, not only integrate sensor technology and smart materials but also interact with the wound to accurately sense its state and changes in the external environment and make adaptive adjustments accordingly, demonstrating a high potential for intelligence. At the heart of the design of these dressings lies a high degree of stimulus responsiveness, especially sensitivity to key factors such as pH, glucose concentration, temperature, and light. These properties make them ideal for the manufacture of advanced smart wound dressings that can flexibly respond to the complex dynamics of the wound healing process.

However, despite the significant research progress that has been made in this field, stimuli-responsive wound dressings still face a number of key challenges that need to be addressed. The primary issue lies in biosafety and compatibility, especially for those dressings containing nanoscale components. The potential release of nanoparticles into the wound tissue and even into the circulatory system may raise long-term biosafety concerns, such as the risk that the accumulation of nanoparticles may lead to thrombosis. Therefore, enhancing the biosafety assessment of materials and developing low-toxicity and highly biocompatible nanocomposites is an inevitable trend for future development. In addition, although smart wound dressings perform well in the laboratory, the road to their clinical translation is still long and challenging. Most smart dressings are still in the early stages of research and development, and there is still some way to go before they become clinically useable medical devices. This requires researchers to not only continue to deepen basic research but also strengthen interdisciplinary cooperation to promote a close match between technological innovation and clinical needs and accelerate the clinical validation and registration process of smart dressings.

Looking ahead, the design of stimuli-responsive wound dressings will focus more on functionality and personalization, aiming to achieve more accurate and smarter wound monitoring and treatment. For example, dressings incorporating electrically responsive materials can not only monitor changes in the wound microenvironment in real time but can also be wirelessly connected to mobile medical devices for remote monitoring and immediate therapeutic feedback, marking a significant step forward in wound management toward intelligent, remote medical care. Through continuous technological innovation and clinical application exploration, future smart wound dressings are expected to greatly enhance the efficiency and safety of wound treatment, provide healthcare providers with unprecedented remote treatment control capabilities, and open up a new era of wound healing management.

This study was supported by the Wenzhou Science and Technology Project of China (Grant No. Y20240232) and the medical and health research project of Zhejiang Province (No. 2025KY318).

The authors have no conflicts to disclose.

W.Z. and J.H. contributed equally to this work.

Wei Zhang: Data curation (equal); Investigation (equal); Methodology (equal); Software (equal); Writing – original draft (equal); Writing – review & editing (equal). Jun Hu: Methodology (supporting); Software (supporting); Writing – review & editing (supporting). Hao Wu: Conceptualization (equal); Formal analysis (equal); Supervision (equal); Validation (supporting); Visualization (supporting); Writing – review & editing (equal). Xiufei Lin: Funding acquisition (lead); Project administration (lead); Visualization (supporting); Writing – review & editing (supporting). Limei Cai: Conceptualization (equal); Formal analysis (equal); Resources (equal); Supervision (equal); Writing – review & editing (equal).

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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