Stimuli-responsive Hydrogels: An Intelligent Tool for Wound Management

Stimuli-responsive Hydrogels: An Intelligent Tool for Wound Management | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 9 October 2025 V1 Latest version Share on Stimuli-responsive Hydrogels: An Intelligent Tool for Wound Management Authors : Debin Zheng 0009-0005-6826-5616 , Meiqi Zhu , Cuiping Zhang 0000-0003-0320-6226 , Di Wu , Tianyu Xie , Chen Li , Pei Zhao , Xi Liu 0000-0002-7968-0461 , Xiaobing Fu , and Xiaoxue Li [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176003520.04060772/v1 Published Interdisciplinary Medicine Version of record Peer review timeline 390 views 174 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Wound healing represents a well-coordinated and sophisticated biological process characterized by the need for precise regulation and spatiotemporal synergy of multiple cells, regulatory cytokines, and signaling pathways, ultimately achieving repair and functional reconstruction of damaged tissues. In complex situations such as war, disasters and diseases, how to carry out wound management in a truly effective manner still stands as a notable challenge. The microenvironment of wound is multi-dimensional, dynamic and complex, the wound healing process is collectively regulated by endogenous biochemical signals and exogenous physical, chemical, biological factors, which makes traditional dressings often fall short of expectations in the wound healing. Stimuli-responsive hydrogels, by sensing endogenous factors (like pH, reactive oxygen species, and glucose, along with specific enzymes) or exogenous factors (light, temperature, electric fields, etc.), exhibit various intelligent characteristics, such as interacting with wounds, monitoring wound conditions or microenvironment changes, achieving precise drug release control or dynamic assessment of the wound healing process, thereby effectively promoting wound healing. Stimuli-responsive hydrogel tissue engineering strategies (scaffolds, nanofibers, microneedles, microspheres, etc.) also provide more options for wound repair. Serving as a critical overview of stimuli-responsive hydrogels, this review delves into the recent application scenarios of these hydrogels in wound management, systematically summarizes the attendant challenges, and seeks to offer a useful reference for studies in this research field. Stimuli-responsive Hydrogels: An Intelligent Tool for Wound Management Debin Zheng 1,# ｜Meiqi Zhu 1,# ｜Cuiping Zhang 2 ｜ Di Wu 3 ｜Tianyu Xie 3 ｜Chen Li 1 ｜Pei Zhao 1 ｜Xi Liu 2 ｜Xiaobing Fu 2,* ｜Xiaoxue Li 1,* 1 Beijing Key Laboratory of Disaster Medicine, Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing 100853, P. R. China｜ 2 PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Medical Innovation Research Division of the Chinese PLA General Hospital Beijing,100853, P. R. China｜ 3 Department of General Surgery, First Medical Center of Chinese PLA General Hospital, Beijing 100853, P. R. China.Corresponding Author: Xiaobing Fu ( [email protected] )；Xiaoxue Li ( [email protected] ) Abstract Wound healing represents a well-coordinated and sophisticated biological process characterized by the need for precise regulation and spatiotemporal synergy of multiple cells, regulatory cytokines, and signaling pathways, ultimately achieving repair and functional reconstruction of damaged tissues. In complex situations such as war, disasters and diseases, how to carry out wound management in a truly effective manner still stands as a notable challenge. The microenvironment of wound is multi-dimensional, dynamic and complex, the wound healing process is collectively regulated by endogenous biochemical signals and exogenous physical, chemical, biological factors, which makes traditional dressings often fall short of expectations in the wound healing. Stimuli-responsive hydrogels, by sensing endogenous factors (like pH, reactive oxygen species, and glucose, along with specific enzymes) or exogenous factors (light, temperature, electric fields, etc.), exhibit various intelligent characteristics, such as interacting with wounds, monitoring wound conditions or microenvironment changes, achieving precise drug release control or dynamic assessment of the wound healing process, thereby effectively promoting wound healing. Stimuli-responsive hydrogel tissue engineering strategies (scaffolds, nanofibers, microneedles, microspheres, etc.) also provide more options for wound repair. Serving as a critical overview of stimuli-responsive hydrogels, this review delves into the recent application scenarios of these hydrogels in wound management, systematically summarizes the attendant challenges, and seeks to offer a useful reference for studies in this research field. Keywords ：Wound healing, Stimuli-responsive, Hydrogel, Dressing, Wound microenvironment 1. Introduction The effective management of wound has always been a significant challenge for humanity during wars, disasters, and diseases[1, 2]. A wound is an impairment of skin and tissue integrity resulting from external trauma (e.g., thermal, chemical, mechanical) or internal pathologies like localized ischemia [3, 4]. Wounds be classified into acute and chronic types based on their healing duration[5]. A typical wound healing process encompasses four stages that constitute its core response: hemostatic phase, inflammatory phase, proliferative phase, and remodeling phase[6, 7]. This is a highly complex and coordinated physiological process that involves the participation of various stem cells, inflammatory cells, immune cells, endothelial cells, growth factors, cytokines, and so forth[8-10]. If cellular function is impaired, growth factor secretion decreases, and severe infections or autoimmune dysfunctions cause the wound healing process to stagnate in the inflammatory phase, it typically results in a chronic wound[11]. In recent decades, conventional wound management has predominantly employed topical therapeutic agents coupled with passive barrier dressings[12]. This dual approach aims to create physical isolation against microbial invasion while relying on the adjunctive use of antibiotics for infection prophylaxis[13]. However, mounting evidence suggests that these conventional approaches are inherently passive interventions, exhibiting critical limitations in three key aspects: (1) limited microenvironmental responsiveness to dynamic wound conditions such as fluctuating pH, excessive exudate, and hypoxic states; (2) mechanical adherence to wound beds that induces traumatic re-injury during dressing changes; (3) inadequate modulation of biological processes crucial for healing, including angiogenesis and extracellular matrix (ECM) remodeling. Particularly concerning is the frequent occurrence of secondary tissue damage caused by dressing adhesion, which impedes wound repair and increases susceptibility to biofilm formation and prolonged inflammation[14].Hydrogels represent a class of hydrophilic polymer networks comprising 90-99.5% aqueous medium entrapped within three-dimensional matrices, categorized by cross-linking mechanisms into physical and covalent types. These biomimetic platforms exhibit several hallmark characteristics critical for wound healing applications, such as ECM mimetic viscoelasticity, tunable porosity, self-healing ability, injectable adaptability conforming to wound topography, degradation, electroconductivity[15-17]. Notably, their ECM-analogous architecture enable to mimic tissue environments and allow for the penetration of essential elements such as oxygen, ions, nutrients, and expulsion of metabolic products[18]. Typically, hydrogels have emerged as ideal platforms for bioactive cargo delivery (drugs, exosomes, stem cells) and tissue engineering, providing an advanced treatment method for acute or chronic wounds[19]. However, traditional hydrogels, used as therapeutic payload delivery platforms, are primarily dependent on the diffusion or release of the payloads, lacking the capability for spatiotemporal control release, which greatly limits the expected therapeutic effects on wounds[15].Over the past few years, stimuli-responsive hydrogels have garnered widespread concentration [20, 21]. These materials can respond to a specific combination of signals, including endogenous physiological stimuli (such as tissue pH, redox agent, and enzyme concentration) and external stimuli (like light, temperature, and electromagnetic field), and can change their behavior and network architecture reversibly or irreversibly[22-25]. Endogenous stimulus-responsive hydrogels can recognize and respond to pathological signals within locally damaged tissues, making active drug targeting possible. Exogenous stimulus-responsive hydrogels, on the other hand, are designed to enable remote and non-invasive operation[26]. Furthermore, integrating endogenous/exogenous stimulus-responsive moieties to create multifunctionally responsive hydrogels provides a more flexible and adjustable means of modulating multiparametric progression of wound repair[27]. Therefore, stimulus-responsive hydrogels, engineered to interact with the wound microenvironment, hold immense promise for advancing wound management[28]. This paper synthesizes recent advancements in responsive hydrogels for wound management, focusing on four key aspects: the wound healing process, microenvironment, stimulation-response strategies, and engineered hydrogel architectures. Finally, we will summarize the key research areas and main challenges of responsive hydrogels with the aim of further improving their effectiveness in wound repair. This review is expected to provide a theoretical framework to guide the rational design of next-generation stimuli-responsive hydrogels for advanced wound therapeutics. 2. Wound healing process and wound microenvironment 2.1 Wound healing process Following trauma, the wound healing cascade commences, progressing through four tightly orchestrated phases: hemostasis, inflammation, proliferation, and remodeling (Figure 1)[29]. During the hemostatic phase, the ruptured blood vessel contracts, and platelets form fibrin clots (blood clots) through the activation of pro-coagulant substances and the release of thrombin to hemostasis[30-32]. During the inflammatory phase, The permeability of blood vessels increases, inflammatory cells extravasate, and neutrophils can secrete reactive oxygen species (ROS) and lysozyme to clear dead tissues[33]. Monocytes are drawn to the site and mature into M1-polarized macrophages; these cells then release pro-inflammatory cytokines to clear microbial invaders. Subsequently, these M1 macrophages transition to an M2 phenotype, releasing anti-inflammatory mediators and facilitating neutrophil clearance[34, 35]. This process is essential for the inflammatory-to-proliferative phase progression[36]. At the wound site, recruited fibroblasts and skin stem cells become activated to play a multi-faceted role: they synthesize and deposit collagen, facilitate granulation tissue formation, promote angiogenesis, and drive wound contraction. This process constitutes the primary objective of the proliferative phase[37, 38]. In the terminal phase, the remodeling process of the ECM is initiated, with fibroblasts and keratinocytes working together to construct a new matrix[39]. During this process, matrix metalloproteinases (MMPs) participate in the degradation of specific types of collagen, modulating the ratio between type I collagen and type III collagen[40, 41]. Subsequently, these newly formed ECM components align along tension lines, gradually restoring the tensile strength of the tissue by reorganizing and degrading cells previously used for wound repair. This process marks a shift from a restorative structure/organization to a functional one[11]. Wound healing encompasses a cascade of biochemical reactions that drive dynamic alterations in the wound microenvironment[42]. Detailed understanding of the wound healing process holds substantial significance for deciphering the wound microenvironment and identifying novel therapeutic targets for tissue repair[43]. FIGURE 1 . Four processes involved in wound healing: ①hemostatic phase, ② inflammatory phase, ③proliferative phase, and ④ remodeling phase. Reproduced with permission[44]. Copyright 2024, Springer Nature. 2.2 Wound microenvironment The establishment of the theory of ”wound microenvironment” has promoted the rapid development of non-surgical wound treatment techniques. The wound microenvironment encompasses both the surface environment in direct contact with the external surroundings and the internal microenvironment of the wound, which is influenced by external factors and in turn affects the healing process[45-47]. Its endogenous influencing factors include aging, comorbidity, etc, while external factors encompass biological aspects such as bacterial load, microbiota, and immune responses; physical aspects like mechanical force, temperature, humidity, oxygen, light, electricity, and magnetism; as well as chemical aspects including pH, metal ions, and material degradation products(Figure 2)[48-50]. The stages of wound healing are not discrete but overlapping, unfolding as a dynamic process over time. When each stage is affected or interfered with, the microenvironment will immediately change, thereby altering the healing progression. The design of smart hydrogels that respond to pathological cues is directly informed by the evolving wound microenvironment, so the following factors can be paid attention to. FIGURE 2 . schematic illustration of wound microenvironment. pH change. The pH value in normal tissues and acute wounds typically ranges between 4 and 7, where a slightly acidic environment helps prevent bacterial colonization. However, due to improper immune response, the pH value of chronic wounds fluctuates between 7 and 9, and this alkaline environment makes bacteria invade and colonize the wound site susceptible to infection[51, 52]. (2) The level of uric acid. Uric acid predominantly exists as urate in wound exudate, with concentration levels ranging from 2.2 to 7.5 × 10-⁴ mol/L. The physiological removal of uric acid occurs exclusively through urinary excretion, due to the absence of enzymatic pathways for its catabolism in humans. Certain bacterial species, notably Pseudomonas aeruginosa, possess the unique ability to specifically break down uric acid, reducing its concentration in wound exudates to below 2.0×10−4 M[53]. (3) Temperature. The wound repair process is orchestrated by various chemical and enzymatic reactions that need to be occur at normal temperatures; When ulcers occur, the wound temperature is generally below 33°C, and reduced activity in crucial cells (fibroblasts, neutrophils, epithelial cells) leads to a subsequent decline in healing efficacy. Abnormal temperature fluctuation can serve as a predictor of early infection[54]. (4) ROS. ROS act as key signaling molecules in wound healing, and their roles are significantly stage-specific and dual[55]. During early wound formation, ROS released by damaged tissues will rapidly activate the inflammatory response, and through the recruitment of neutrophils, macrophages and other immune cells to the wound, clear necrotic tissue and invading pathogens[56]. However, excessive ROS production or an impaired scavenging mechanism can lead to persistently elevated levels of ROS, resulting in oxidative stress. This damages cell membrane integrity, causes DNA and protein impairment, and may even trigger chronic inflammation[57]. These effects contribute to delayed wound healing. Therefore, maintaining the dynamic balance of ROS within the wound is a central objective for regulating the process of tissue healing and enhancing the quality of healing[58]. (5) Blood glucose. Hypoxia inducer factor 1α (HIF-1α) is essential for capillary formation, and HIF-1α expression is upregulated during the initial phase of wound healing. However, its expression is impaired by high blood glucose concentration in chronic wounds, resulting in insufficient capillary network formation and further tissue necrosis[59, 60]. (6) Enzymes. Enzymes, as the core functional molecules in the process of wound healing, promote the orderly transformation of wound from injury to repair by accurately regulating the physiological reactions at various stages. The enzyme can degrade collagen, fibronectin and other ECM components in damaged tissues, and remove necrotic cells and pathogens. In addition, superoxide dismutase (SOD), catalase and other oxidoreductases can remove excess ROS from the wound surface and maintain the redox balance. If the enzyme activity is imbalanced, it will lead to excessive degradation of ECM and disorder of tissue repair, which will lead to delayed wound healing, chronic ulcer and other problems. Therefore, precise regulation of enzymes is the key to ensure efficient wound healing[47, 61]. 3. Stimulus-responsive hydrogels Conventional wound dressings typically adopt a ”one size fits all” method to achieve hemostasis and facilitate wound healing. While, wound healing process is complex and dynamic, with each phase necessitating the control of numerous biomolecules[62, 63]. Therefore, distinct repair phases require tailored dressing types to address specific healing requirements. The so-called ”stimuli-responsive” hydrogels refer to materials capable of undergoing changes in morphology, volume, properties, and degradation as a reaction to various stimuli, including pH, temperature, ROS, enzymes, glucose, and light exposure[64]. These changes can be used to achieve ”intelligent” controlled release of therapeutic drugs, cells, and growth factor within various microenvironments, and can even be used to dynamically monitor the wound healing process (Figure 3)[65]. The stimulus-responsive hydrogels are well suitable for wound healing, as they are able to positively and directionally modulate the wound microenvironment, thus maintaining the optimal healing process[66, 67]. In the present section, we systematically review and discuss the recent progress in the domain of stimulus-responsive hydrogels for wound management. FIGURE 3 . Stimulus-responsive hydrogel can deliver therapeutic effect through stimulation induction. 3.1 Endogenous stimulus-responsive hydrogels 3.1.1 pH responsive hydrogel The pH value undergoes dynamic changes throughout the wound healing process[68], so the pH-responsive hydrogels enable the monitoring of the healing status and on-demand drug release, which can be divided into two groups based on their chemical structure and response mechanism[69, 70]. The first category comprises polyelectrolyte-based hydrogel systems, in which protonation/deprotonation of charged pendant groups occurs upon contact with the wound microenvironment. This triggers macroscopic swelling/deswelling behavior that enables controlled and sustained substance release. For instance, Huang group prepared an antibacterial chitosan-based hydrogel dressing[71]. The cationic amino group in chitosan causes the hydrogel system with markedly higher swelling ratios in acidic media (pH 2.0) in comparison with neutral conditions (pH 7.0), which stems from the amino groups becoming protonated in acidic conditions, causing the polymer chains to relax and the network to expand (Figure 4A). In addition, Haidari et al. designed a dual-responsive (pH/temperature) hydrogel network. (Figure 4B), which was prepared through the crosslinking of N-isopropylacrylamide and acrylic acid, followed by the incorporation of ultrasmall silver nanoparticles (AgNPs). In acidic pH (7.4), the release of Ag + ions is significantly promoted (>90%) and the antibacterial effect is better (Figure 4C-4D)[72]. The second category comprises acid-labile bond-based hydrogels, incorporating borate ester/orthoester bonds (R-C(O-R) 3 ), imine linkages (-C=N-), hydrazone bonds (C=NNHR), amide bonds (-CONH), and metal-ion coordination complexes (e.g., Ca² + , Al³ + , Fe³ + ). Jiang group prepared mixed hydrogel of guar gum and polyvinyl alcohol (PVA) containing borate and tannic acid, and formed a pH-responsive dynamic hydrogel through borate ester bond and hydrogen bond, which was utilized for the visual observation and treatment of chronic wounds. In the early stage of a chronic wound, characterized by an alkaline environment, the hydrogel dressing turns green and releases tannic acid to alter macrophage behavior and promote new blood vessel formation. During the phase of wound healing, characterized by an acidic environment, the hydrogel dressing turns yellow over time and dissolves to support tissue regeneration (Figure 4E). In addition, wound healing process can be observed through color changes using smartphones, which offer real-time pH feedback[73]. FIGURE 4 . The preparation and application of representative pH-responsive hydrogels. ( A ) Chitosan-based proton-responsive hydrogel. Reproduced with permission[71]. Copyright 2023, Marine Life Science & Technology. ( B ) Synthesis of Pnipam-PAA Hydrogel. ( C ) Swelling behavior of the hydrogel in PBS buffers with varying pH (4 to 10). ( D ) Quantification of wound closure area (%) at various time points. Reproduced with permission[72]. Copyright 2022, ACS publications. ( E ) Design schematic of a theranostic hydrogel dressing that allows visual monitoring and matched treatment of chronic wounds via a boron-based probe. Reproduced with permission[73].Copyright 2023, Wiley.In the past few years, hydrogels that respond to pH changes have proven to be highly effective in managing gastric bleeding and wound care. For example, Guo team prepared a new pH-responsive hydrogel with injectability and boosted adhesive performance, which showed good hemostatic effect in a porcine gastric bleeding model. pH-responsive hydrogels enable precise drug delivery by leveraging the pH differential between pathological and normal tissues. However, However, pH-responsive hydrogels still face several challenges. Firstly, their response speed needs improvement. As the pH value of the wound microenvironment alters, if the hydrogel cannot react rapidly to release drugs or adjust its properties in a timely manner, treatment efficacy may be compromised. For instance, in acutely infected wounds where pH drops quickly due to bacterial proliferation, a delayed response from the hydrogel may hinder the prompt release of antibacterial agents, thereby exacerbating the infection. Secondly, stability remains a significant concern. In the complex and dynamic wound microenvironment, hydrogels are susceptible to influences from temperature, moisture, enzymes, and other factors, which can lead to structural degradation and reduced performance. For example, in chronic diabetic wounds characterized by prolonged exposure to high glucose levels, low pH, and oxidative stress, conventional pH-responsive hydrogels often struggle to maintain long-term stability, undermining their ability to provide consistent therapeutic effects. Lastly, designing high-performance pH-responsive hydrogels with improved functionality continues to pose major challenges. 3.1.2 ROS-responsive hydrogel ROS-responsive hydrogels represent a widely utilized intelligent wound healing strategy, enabling precise drug delivery and effective scavenging of excess ROS to mitigate toxicity and side effects. This material offers a promising solution for diseases associated with elevated local ROS levels[74]. Polymers that respond to ROS include those with sulfur, selenium/tellurium, and phenylboric acid/esters. These polymers, when exposed to ROS, shift from a hydrophobic state to a hydrophilic one or undergo chemical bond cleavage, resulting in the release of the drugs they encapsulate. Two primary design strategies have been developed for creating ROS-responsive hydrogels: Firstly, ROS response modules are embedded in the backbone structure of block copolymers, such as hydrogels formed by cross-linking ketone mercaptan (TK) (Figure 5A), and curcumin with antioxidant properties is encapsulated. When used to treat full-layer burn wounds in rat models, this material has demonstrated significant anti-inflammatory properties, efficient wound healing ability, and the effect of promoting angiogenesis (Figure 5B)[75]. The second method involves polymers with side chains that are sensitive to ROS. Wang team proposed an innovative ROS-responsive injectable glycopeptic hydrogel consisting of pBA-grafted oxidative glucan and CA-grafted CE. This design represents a significant advancement in addressing chronic wound treatment. CA is a naturally occurring polyphenol, rich in catechol and acrylic functional groups, with multiple effects of anti-oxidation, anti-apoptosis and promoting angiogenesis. Furthermore, the research team incorporated mangiferin (MF), which exhibits similar effects, into the hydrogel (Figure 5C). The cleavage of borate bonds in infectious diabetic wounds triggers the controlled release of MF, which subsequently inhibits inflammation and accelerates healing (Figure 5D)[76]. Additionally, Yu et al. developed a ROS-responsive antibacterial hydrogel (PAAg-PGFe) with PA and PG as composite materials. This system was composed of PA containing silver nanoparticles (AGNPS) and PG containing Fe 2+ /Fe 3+ (Figure 5E). It has excellent anti infection ability and strong inhibitory effect on pathogenic Pseudomonas aeruginosa. Animal experiments further verified that this hydrogel can facilitate rapid wound healing and pathogen clearance[77]. ROS-responsive hydrogels have achieved significant advancements in the realm of chronic wound repair. Nevertheless, its application in clinical settings has remained limited, primarily owing to the lack of a clear distinction in ROS concentrations between abnormal and normal tissues. Furthermore, the redox microenvironment is susceptible to interference from multiple factors including bacterial infection, blood glucose levels, and individual immune status, resulting in significant unpredictability in drug release. Future research should prioritize optimizing hydrogel degradation rates and ROS scavenger release kinetics to maintain physiologically appropriate ROS levels in wound sites. FIGURE 5. ROS-responsive hydrogels as intelligent carriers for controlled drug release to promote wound healing. ( A ) Fabrication and degradation processes of the Cur@CMCTS hydrogel. ( B ) Representative images showing H&E and Masson’s trichrome staining of normal cutaneous tissue and wounded cutaneous tissue. Reproduced with permission[75]. Copyright 2021, Frontiers. ( C ) Preparation process of POD/CE hydrogels encapsulating DS and MIC@MF. ( D ) Schematic of drugs release behavior of the hydrogel, and the underlying mechanism by which wound healing is accelerated in an infected wound model. Reproduced with permission[76]. Copyright 2022, Elsevier. ( E ) Synthesis process of the antibacterial PAAg-PGFe hydrogel. Reproduced with permission[77]. Copyright 2020, Elsevier. 3.1.3 Enzyme-responsive hydrogel In the wound healing microenvironment, a variety of specific enzymes are involved in biochemical reactions. Enzyme-responsive hydrogels, exhibit unique advantages and broad application potential within the domain of wound healing due to their precise responsiveness to specific enzymes in the wound microenvironment[25]. The core mechanism lies in the chemical design that incorporates enzyme-sensitive moieties into the hydrogel network structure. When the hydrogel encounters characteristic enzymes highly expressed in the local wound area (such as matrix metalloproteinases MMPs, hyaluronidase, thrombin, etc.), these enzymes specifically degrade the sensitive moieties, triggering structural changes in the hydrogel and thereby enabling on-demand modulation of the wound healing process[78].When inflammatory responses become excessive, pro-inflammatory cytokines undergo a marked rise; this increase is capable of disturbing the equilibrium between MMPs and TIMPs [79]. As a consequence of this disturbed equilibrium, MMPs are overproduced, and MMP-9 stands out among these overexpressed enzymes[80]. Fan team designed a hydrogel system that is both responsive to MMP-9 and glucose. The hydrogel was constructed through the crosslinking of CS-BA with PVA, forming borate ester bonds (Figure 6A). It contained celecoxib (GMs@Cel) gelatin microspheres and insulin (INS), which are uniformly distributed within the CS-BA-PVA hydrogel (CBP). The cleavage of glucose-sensitive borate bonds within the CBP network triggers the concurrent insulin and GMs@Cel release. Simultaneously, celecoxib is liberated due to the inherent MMP-9 responsiveness of gelatin. Through the regulation of glucose concentrations and MMP-9 levels in the local wound microenvironment, this hydrogel achieves effective promotion of chronic diabetic wound healing. (Figure 6E)[81]. Additionally, Sonamuthu et al. designed a silk protein hydrogel combining curcumin and L-carnosine dipeptide (Figure 6F). The hydrogel chelates the Zn 2+ in the center of MMP-9 through L-carnosine, which inactivates MMP-9 protein. Their results showed that the hydrogel significantly improved the therapeutic efficiency of streptozotocin- induced diabetic mice (Figure 6G)[82].Zhu et al. developed an innovative hydrogel spray with antibacterial, anti-inflammatory, and antibiofilm properties by encapsulating L-arginine and nanosheets (Au/Cu₁.₆O/P-C₃N₅) in hyaluronic acid (denoted as ACPCAH) (Figure 6H). This nanozyme system exhibits the activities of five enzymes, namely SOD, catalase (CAT), glucose oxidase (GOx), peroxidase (POD), and nitric oxide synthase (NOS), enabling a self-enhanced cascade reaction under ultrasound activation. Through synergistic sonodynamic and sonothermal effects, the material significantly modulates key pathological factors in DFU: scavenging ROS, alleviating hypoxia, reducing inflammatory cells (Figure 6I), promoting vascularization, and exerting antibacterial effects (Figure 6J). Both in vitro and in vivo studies confirmed its ability to accelerate wound healing in a streptozotocin-induced diabetic model, highlighting the potential of multimodal nanozyme hydrogels as all-in-one theranostic platforms for complex chronic wounds[83]. Enzyme-responsive hydrogels, known for their targeted reaction capabilities and high biocompatibility, offer significant potential for managing chronic wounds. Although these hydrogels have the ability to respond to specific enzymes, the complexity of the wound environment makes ensuring an effective enzyme response challenging, and gaining accurate control over both the temporal release and dosage of drugs remains a difficult issue. In addition, enzyme-responsive hydrogels have been the subject of relatively few studies, and a dearth of more extensive research and clinical information leaves their application in the biomedical field without sufficient validation. FIGURE 6. Preparation of enzyme-responsive hydrogels based on natural products or modified polymers to accelerate the healing of diabetic foot. ( A ) Fabrication of celecoxib-loaded gelatin microspheres (GMs@Cel). ( B ) Synthesis of the CBP/GMs@Cel&INS hydrogel and characterization of its thermoresponsive self-adaptation behavior. ( C ) The particle size distribution of GMs@Cel after a 72-hour treatment with MMP-9 was determined. ( D ) ELISA for the detection of MMP-9; ( E ) Wound closure rate measured on days 3, 7, 10, and 14. Reproduced with permission[81]. Copyright 2022, Elsevier. ( F ) Synthesis process of the SF hydrogel matrix encapsulating L-carnosine and curcumin. ( G ) Wound closure rate at different days. Reproduced with permission[82]. Copyright 2020, Elsevier. ( H ) to treat multidrug-resistant bacterial infections in DFU. ( I ) Analysis of inflammatory cell counts across different treatment groups. ( J ) Assessment of MRSA viability in wound tissue in various groups. Reproduced with permission[83]. Copyright 2023, ACS publication. 3.1.4 Glucose-responsive hydrogel Glucose-responsive hydrogels have opened new application pathways within the domain of wound healing owing to their precise responsiveness to changes in glucose levels within the wound microenvironment, offering innovative solutions particularly for the therapeutic intervention of diabetes-related wounds[84]. In the context of wound healing, the primary function of glucose-responsive hydrogels is the precise regulation of drug release: leveraging the characteristically elevated glucose levels in diabetic wounds, antibacterial agents, healing-promoting factors, or insulin can be loaded into the hydrogel[85]. When glucose concentrations in the wound exceed threshold levels, the hydrogel automatically degrades or swells through this responsive mechanism, releasing drugs to control infection, regulate blood glucose, and promote tissue repair[86].Among glucose-responsive hydrogels, the two classes that have been most extensively researched are those integrated with GOx or PBA motifs. For instance, Zhang et al. developed a novel glucose-responsive hydrogel for the treatment of diabetic wounds (Figure 7A). Specifically, they fabricated the HA-PBA-FA/EN106 hydrogel via the cross-linking of HA, PBA, and fulvic acid (FA), followed by the loading of EN106. This hydrogel exhibits antibacterial, antioxidant, and angiogenesis-promoting properties. Moreover, the authors confirmed the hydrogel’s ability to accelerate diabetic wound healing through the establishment of a mouse diabetic wound model (Figure 7B)[87]. Qu team developed a dual-functional glucose-responsive hydrogel dressing. This system was constructed by performing cross-linking between copper nanoclusters (CuNCs) and oxidized hyaluronic acid (OHA) in situ, with subsequent modification using GOx (Figure 7C). It conforms to irregular wound contours, lowers wound glucose, maintains a sterile environment, and promotes angiogenesis via electrical stimulation, so as to effectively treat complex diabetic wounds (Figure 7D-7E)[88]Diabetes is closely linked to increased ROS levels, and many studies have centered on using the condensation reaction of PBA with catecholins to generate hydrogels containing borate ester bonds, which exhibit responsiveness to both ROS and glucose. After the borate ester bond response is broken, the resulting PBA has a high hydrophilicity, which will induce the hydrogel to expand, degrade, and decompose, and then effectively release the loaded substance. The researchers prepared a a hydrogel dressing with dual responsiveness to ROS and glucose, incorporating hyaluronic acid (HA) alongside polyethylene glycol chitosan that bears grafted PBA and catechol side chains (Figure 7F-7H). Silver nanoparticles modified with tea polyphenols were embedded into the synthesized hydrogel (Figure 7I). These nanoparticles are incorporated into the hydrogel by imide bonds and phenylborate ester bonds on two polymer chains. The results show that the obtained hydrogels have both glucose and H 2 O 2 response degradation properties, which are confirmed by the enlargement of pore size and the destruction of network structure (Figure 7J). At the same time, its anti-oxidant function has also been verified, and it can use catechol and boric acid groups to remove ROS free radicals. Together with encapsulated silver nanoparticles, this novel hydrogel dressing demonstrates capabilities including antimicrobial infection resistance, anti-inflammatory effects, ROS scavenging, and tissue adhesion promotion, thereby shortening the healing time of diabetic wounds (Figure 7K)[89].Despite significant advances in glucose-responsive hydrogels, there are still many limitations that must be resolved before these materials can enter practical use. First of all, although GOx has advantages in biocompatibility and biodegradability, it is susceptible to environmental influence and denaturation, resulting in loss of activity. Meanwhile, although the hydrogels based on PBA show favorable stability, there are still obvious deficiencies in its glucose sensitivity and dynamic response rate. Consequently, the development of stimulus-response units with good biocompatibility, stability and high glucose responsiveness is still an important direction of current research. FIGURE 7 . Glucose-responsive hydrogels for visualizing the wound microenvironment and aiding wound repair. ( A ) Schematic of glucose-responsive hydrogel. ( B ) Wound closure rate of various treatment groups. Reproduced with permission[87]. Copyright 2023, Elsevier. ( C ) Synthesis of CGH hydrogel. ( D ) Representative images of infected wound beds in T1DM rats over the healing timeline. ( E ) Measurement of unhealed wound area. Reproduced with permission[88]. Copyright 2024, Elsevier. ( F ) Synthesis of TP@Ag NPs. ( G ) Synthesis of HAAPBA. ( H ) Synthesis of GCHCA. ( I ) Fabrication of hydrogel network. ( J ) Stimuli-triggered release behavior of TP@Ag NPs. ( K ) Analysis of wound area rate in different groups. Reproduced with permission[89]. Copyright 2023, ACS Pulications. 3.2 Exogenous stimulus-responsive hydrogels 3.2.1 Thermo-responsive hydrogel Temperature is the most commonly employed parameter for modulating hydrogel properties. Thermo-responsive hydrogels consist of functional groups with hydrophilic and hydrophobic properties. Temperature changes impact the hydrogen bonding within polymer chains and hydrophobic interactions, thereby bringing about alterations in the hydrogels’ structural form and dimensional properties [90]. Thermosensitive polymers are characterized by defined solution temperatures, including lower critical solution temperature (LCST) and upper critical solution temperature (UCST)[91]. The specific change process and main temperature-sensitive substances are shown in Figure 8. In the process of wound repair, temperature-responsive hydrogels provide great convenience to facilitate the mixing and delivery of therapeutic drugs. Various bioactive components, including drugs, stem cells, cytokine, and peptides, can be incorporated homogeneously into polymer solutions. These mixtures are then applied to skin wounds by injection or spray and are converted to a gel state triggered by temperature changes, enabling controlled release of the drug and facilitating wound healing. FIGURE 8. Classification of temperature sensitive hydrogels and their polymers.PNIPAm is a hydrogel material that has attracted much attention in the biomedical field[92, 93]. Its significant advantages are that the temperature at which it undergoes volume phase transition is near normal body temperature, and it can rapidly react to environmental changes. PNIPAm exhibits a LCST near 32°C owing to the interplay between its hydrophobic isopropyl segments and hydrophilic amide groups in aqueous environments, resulting in a distinct phase transition with thermo-responsiveness. Therefore, thermo-responsive hydrogels based on PNIPAm were developed to enable controlled drug delivery at normal body temperature and rapid drug release when locally heated. Through crosslinking between n-isopropylacrylamide and acrylic acid, Haidari et al. successfully prepared a temperature - and pH-responsive hydrogel and combined it with ultra-small silver nanoparticles. When the temperature rise exceeds LCST (36℃), the rearrangement of polymers leads to notable alterations in the physicochemical characteristics of hydrogels, with a sharp increase in their hydrodynamic diameter, and the hydrogels usually dehydrate and form a spherical structure, causing them to shrink and aggregate into larger particles, becoming a gelatine state on a macro level. This hydrogel responds to pathological temperature and pH value changes in the course of wound healing, thereby triggering the release of silver ions. This characteristic is well compatible with the biological demands of the wound repair and provides innovative solutions for wound treatment[72]. Hu team designed a temperature responsive hydrogel. they fabricated the HA/gel-R-Ag hybrid gel by incorporating a thiol HA/ gelatin polymer gel network within the rhein gel structure (Figure 9A), which has excellent bactericidal ability and can serve for the treatment of skin defects (Figure 9B). Using the mouse model of skin defects, the hybrid gel markedly enhanced skin regeneration through suppressing inflammation, accelerating collagen deposition, and stimulating new blood vessel formation[94]. In addition, Liu et al. synthesized a temperature sensitive copolymer material- PECE, and prepared a kind of madecassoside (MA) preparation which is conducive to local administration (Figure 9C). Ma liposomes modified with PECE remained in a hydrogel state up to the point when the temperature reached 43 °C for better adhesion. In the experimental model of second degree burn in rats, Ma liposomes modified with PECE showed good surface adhesiveness and effective wound repair efficacy (Figure 9D)[95]. Qin group crosslinked the thermos-responsive copolymer with pectin hydrazide functionalized by dopamine (PDAH) to prepare an injectable hydrogel with both biodegradable and self-healing properties (Figure 9F). The hydrogel has favorable mechanical strength, good biocompatibility and thermos-responsive slow-release process[96]. A near-infrared (NIR)- responsive nanocomposite hydrogel was designed using nano graphene oxide (GO) to create a photothermally enhanced wound dressing incorporating vancomycin[96]. The hydrogel composite further displayed pH-responsive release behavior, the drug release rate was also significantly accelerated under near-infrared radiation due to a phase transition induced by photothermal effects. More importantly, Nanocomposite hydrogels loaded with vancomycin and possessing photothermal properties is capable of boosting burn wound repair rate by inhibiting the growth of bacteria (Figure 9G). FIGURE 9. LCST hydrogels for wound healing. ( A ) Synthesis of HA/Gel-R-Ag hydrogel. ( B ) Quantification of wound area closure rate. Reproduced with permission[94]. Copyright 2023, Elsevier. ( C ) PEG-PCL-PEG triblock copolymer. ( D ) Analysis of treatment effects. ( E ) in vitro release (n = 3); Reproduced with permission[95]. Copyright 2020, Elsevier. ( F ) Preparation of P(NIPAM-DAA-DMA). ( G ) statistical of skin healing rate. Reproduced with permission[96]. Copyright 2024, Elsevier.Agar and gelatin are thermologically responsive biopolymers with UCST properties. At temperatures above UCST, they dissolve in an aqueous solution, while when the temperature drops below UCST, they change to a gel state, which is opposite to the behavior of polymers with LCST. The UCST temperature range for agar is about 35-37℃, while the UCST for gelatin is 40℃. At high temperatures, gelatin dissolves in water in a random coiled conformation, and when cooled below UCST, it transforms into a triple helix structure. Agar, gelatin and carboxymethyl cellulose were combined to prepare a terpolymer bio-ink suitable for 3D-printed soft tissue constructs. During cooling, the agar molecules change from a random coiled state to a single or double helix conformation, where these helical structures interact and aggregate through hydrogen bonds. Subsequently, the hydrophilic gelatin and carboxymethyl cellulose chains permeate into the agar network, eventually forming a semi-interpenetrating network hydrogel. By optimizing the ratio of agar and gelatin, the water absorption, porous structure and mechanical performance of the product can be improved[97]. Temperature-responsive gels have significant targeting capabilities and minimal adverse effects, contributing to reduced treatment costs and improved patient compliance and quality of life. However, the application of passively temperature-sensitive hydrogels is often limited by their delayed response kinetics, resulting from the minimal thermal contrast between pathological and healthy tissues. To overcome this shortcoming, such thermos-responsive gels can serve as foundational matrices for constructing advanced hybrid platforms that respond to external stimuli such as light or magnetic fields. In addition, inadequate thermal stability continues to be a critical issue for temperature-responsive hydrogel systems. Significant temperature variations across seasons and climatic zones pose significant challenges to how temperature-sensitive hydrogels maintain stability and are stored. 3.2.2 Photo-responsive hydrogel On account of its non-invasive characteristic, excellent spatiotemporal resolution and low environmental pollution, the use of photo-responsive hydrogels to transform optical signals into multifunctional responses has attracted wide attention[98]. Photo-responsive hydrogels are mainly divided into two classes: the first class contains photosensitive components (such as nitrobenzoic acid and azobenzene), while the second class combines NIR absorbing elements (such as dopamine as photothermal nanomaterials). Photo-responsive behavior is engineered into these hydrogels via the encapsulation of photochromic particles using mechanical or chemical techniques, enabling controlled light-mediated responses. By precisely regulating chromophore, light intensity, wavelength and polymer network, the response ability can be adjusted. When stimulated by light, these hydrogels exhibit a transformation from gel to solution due to the fracture of the photosensitive part or the transformation of the configuration. In addition, the integration of photo-responsive groups into the thermally responsive hydrogel matrix induces chemical changes or photothermally induced expansion-contraction behavior.Azo compounds have photoisomerization properties and can be converted between trans and cis-isomers. The state of these isomers can be easily regulated by ultraviolet (UV) irradiation. Xu team have developed a straightforward yet efficient approach to accelerate wound healing by using supramolecular hydrogels to control the release of EGF. A novel photosensitive supramolecular polysaccharide hydrogel was constructed by leveraging the specific host-guest interaction between azobenzene molecules and β-cyclodextrin groups (Figure 10A). Wavelength-dependent azobenzene photoisomerization provides a means for precise modulation of the dynamic cross-linking density through photo-stimulation. Under UV irradiation, the relaxed hydrogel can release EGF quickly, thus improving the efficiency of EGF delivery to the wound site (Figure 10B-10C) [98]. However, the body penetration ability of UV is poor, so UV-responsive hydrogels are mainly used for epidermal wound repair. Kim et al. developed a photo-responsive hydrogel. This system connects CMC-Azo to CD dimers via disulfide bonds, with agarose serving as the structural support (Figure 10D). The multifunctional hydrogel has good drug control release effect under the stimulation of UV light and reduction reaction[99]. The penetration capacity of near-infrared light through biological tissues exceeds that of ultraviolet light, accompanied by significantly reduced phototoxicity. Hao et al. developed a new intelligent hydrogel dressing incorporating conductive MXene nanosheets and temperature-responsive PNIPAm (Figure 10G). It features high wear resistance and excellent biocompatibility, allowing for close adhesion to human skin, making it suitable for movement detection and health monitoring (Figure 10H). During the assessment of drug delivery carriers, the hydrogel prepared by near-infrared light is controlled to achieve the function of on-demand drug release (Figure 9I)[100]. In addition, Gao et al. designed an injectable hydrogel through the crosslinking of PDA NPs and GC molecules and loading the antibiotic ciprofloxacin (Cip) (Figure 10J). Their results demonstrated that this system could improve the efficiency wound healing of bacteria-infected mice (Figure 10K) [101]. In short, the drug release technology triggered by photothermal effect and NIR has the capacity to act as a promising strategy for versatile wound dressing applications. NIR-responsive multifunctional wound dressings exhibit angiogenic properties while holding notable advantages in addressing multidrug-resistant bacterial infections in wounds. However, ROS produced by heat and photosensitizers is a double-edged sword. Excessive heat and ROS, while killing bacteria, may also cause damage to cells. Hence, it is essential to accurately regulate phototherapeutic intensity and specifically target bacteria to reduce side effects on cells. In addition, photosensitive hydrogels are dependent on a light source for activation and subsequent therapy, a requirement that may elevate both the expense and complexity of product development and manufacturing scale-up. FIGURE 10. Light-controlled hydrogel drug system accelerates wound healing. ( A ) The fabrication process of supramolecular hydrogels. ( B ) Light-triggered release kinetics of EGF@S gel and EGF@PR-S gel. ( C ) Quantification of wound healing in different groups. Reproduced with permission[98]. Copyright 2020, Frontiers. ( D ) Schematic of CMC-Azo hydrogel based on host-guest interactions with CD-dimers. ( E ) Time-dependent absorption spectra of CMC-Azo hydrogels during 365 nm UV light exposure. ( F ) NPX release (%) triggered by UV light and DTT over a 3-hour period. Reproduced with permission[99]. Copyright 2020, Elsevier. ( G ) Fabrication process of K-M/PNIPAm hydrogel. ( H ) Relative resistance curve of the K-M2/PNIPAm hydrogel sensor under applied strain. ( I ) TC release profiles from hydrogels with varying KH570-MXene content under 0.5 W NIR irradiation. Reproduced with permission[100]. Copyright 2021, ACS Publications. ( J ) Schematic of the Gel-Cip fabrication process. ( K ) Analysis of wound area healing rates of mice. Reproduced with permission[101]. Copyright 2019, Elsevier. 3.2.3 Electric field-responsive hydrogel Electric fields hold important significance in domains like tissue regeneration and drug delivery [102]. Electric field-responsive hydrogels represent a category of intelligent polymer materials that exhibit reversible physical/chemical property changes when subjected to an electric field, which serve a vital function in wound healing[103]. Electrical stimulation can regulate cell proliferation and differentiation, promote cell migration and epithelialization, and accelerate wound healing. Furthermore, electric field-responsive hydrogels can be combined with therapeutic drugs, achieving controlled release of these drugs under electrical stimulation[104]. This effectively prevents and treats wound infections, enhancing the quality of wound healing.Over the past few years, smart drug delivery platforms have provided creative strategies for precision wound treatment. Liu et al. developed an integrated system composed of a pulsed direct current piezoelectric nanogenerator (PENG) and a drug-loaded conductive hydrogel (BPV@PCP) (Figure 11A)[105]. This system utilizes the PENG to convert animal motion into electrical energy, which on one hand provides electrical stimulation to the wound, and on the other hand triggers the controlled release of the PTEN-inhibiting drug bpV (HOpic) from the hydrogel. The conductive composite hydrogel (Figure 11B) based on polyacrylamide/carboxymethyl chitosan/polypyrrole (PAM/CMCS/PPy) exhibits excellent electric field-responsive characteristics, enabling on-demand drug release only upon mechanical stimulation (such as movement), thereby avoiding the potential side effects associated with continuous drug release in traditional delivery systems. The results demonstrate that this self-powered system significantly promotes wound healing in a skin defect rat model (Figure 11C), offering a conditional and highly controllable new therapeutic approach for chronic wound treatment. Additionally, a representative effort is the design of conductive hydrogels derived from CP and OD polymers, which exhibit dual sensitivity to both electrical stimuli and pH changes (Figure 11D)[106]. These hydrogels are synthesized under physiological conditions and demonstrate inherent antibacterial properties（Figure 11E）, suitable conductivity, and tunable gelation time. Meanwhile, applying an external voltage significantly accelerated the drug release rate, demonstrating its excellent electrically-driven controlled release capability. Collectively, these findings position such injectable, conductive, and antibacterial hydrogels as promising candidates for next-generation smart wound dressings and controlled-release systems. FIGURE 11 . Representative electric field-responsive hydrogels for tissue repair. ( A ) SEM image of BPV@PCP hydrogel. ( B ) Conductivity of the hydrogels. ( C ) Statistical analysis of the remaining wound area. Reproduced with permission[105]. Copyright 2023, ACS. ( D ) Schematic of the CP/OD hydrogel. ( E ) Antibacterial effect of the CP/OD hydrogels. Reproduced with permission[106]. Copyright 2018, Elsevier. 3.3 Multiple stimulus-responsive hydrogel In the previous section, we discussed seven different types of single responsive hydrogels. Nevertheless, owing to the intricacy of the internal environment and the uncertainty of disease development, these single-responsive hydrogels have limitations in achieving the desired wound repair effect. In contrast to single-function hydrogels, multi-stimuli-responsive hydrogels have a core advantage: they can sense multiple physiological or pathological signals in the wound microenvironment, adapt precisely to the dynamic changes of the wound microenvironment, and thereby enable on-demand drug release. These hydrogels are capable of actively intervening in and accelerating all phases of wound healing, thus emerging as a research focus and key development direction in the current field of wound repair materials.Combination treatment strategies, through the synergies between multiple treatments, are often able to surpass the therapeutic effects of a single therapy. As mentioned earlier, near-infrared light and temperature control strategies have been extensively applied in a variety of wound management dressings. Guo’s group reported a physical dynamic double-network hydrogel dressing that can respond to changes in near-infrared light, temperature and pH value (Figure 12A). The dressing is prepared by modified gelatin, which has adaptive morphology, self-healing ability and temperature sensitivity. Under conditions of photothermal stimulation or pH change, the interaction of hydrogen bonds with catechol-Fe 3+ will be triggered, allowing the dressing to be easily detached from the skin by irradiation with near-infrared light or using a weakly acidic water solution (Figure 12B-12C)[107]. This innovative multi-responsive hydrogel system demonstrates notable hemostatic efficacy and a potent bactericidal effect on drug-resistant bacteria, thereby accelerating the healing process of skin incisions [108]. Additionally, Han et al. prepared a multi-responsive double-network gel system with antibacterial function (Figure 12D). This gel system is prepared by cross-linking the PNIPAAm and keratin, and is loaded with the antimicrobial drug CHX (Figure 12E). This CHX loaded hydrogel has multiple response characteristics (temperature, pH, and ROS). The findings demonstrated that the multiple stimulus-responsive hydrogel exhibited favorable tissue r egeneration ability in the SD rat skin defect model (Figure 12F)[109]. FIGURE 12 . Representative triple-responsive hydrogels for wound healing. ( A ) Synthesis of PEGSD/GTU hydrogel and scheme of its dual dynamic crosslinking network. ( B ) NIR-induced sol-gel transition of the hydrogel. ( C ) Degradation progression of the hydrogel over a 30-minute period. Reproduced with permission from Guo et al[107]. Springer Nature, 2023. ( D ) Schematic diagram of PNIPAAm/keratin DN gels for treating rats with skin defects. ( E ) Release kinetics of CHX across various physiological conditions. ( F ) Wound closure rates following treatment with various dressings. Reproduced with permission[109]. Copyright 2021. Engineering structure of hydrogels 4.1 Scaffold Given their three-dimensional porous architecture, scaffolds have become a research hotspot in wound healing, thanks to the capability to regulate cellular behavior, guide tissue growth, and optimize the healing microenvironment[110]. Acting as an artificial ECM, they provide a crucial three-dimensional supportive framework for wound repair. This framework can effectively guide and promote the migration of fibroblasts, keratinocytes, and other cells from surrounding tissues to the wound defect area, where these cells proliferate and differentiate[111]. Meanwhile, the porous structure of the scaffolds facilitates vascular ingrowth, delivering sufficient oxygen and nutrients for tissue regeneration. In addition, advanced scaffolds are capable of carrying various growth factors and antibacterial agents, with these components being released continuously to accelerate granulation tissue formation, inhibit infection, and regulate the inflammatory response[112]. Eventually, as the newly formed tissue gradually matures and remodels, the scaffold material is safely degraded and absorbed by the body, thereby successfully repairing the wound, effectively reducing scar formation, and achieving favorable structural and functional regeneration[113].3D printing technology plays a revolutionary role in the preparation of wound dressings, with its core value lying in precision customization and functional integration[114]. Compared to traditional dressings, it enables personalized printing based on the specific shape, depth, and size of a patient’s wound, achieving a perfect fit, minimizing gaps, and maximizing wound protection. More importantly, 3D printing allows engineers to precisely design the microstructure of the dressing, such as porosity and pore size, thereby optimizing oxygen permeability, nutrient exchange, and the management of wound exudate to establish an optimal moist wound healing environment[115]. For example, Jiang et al. have fabricated a multifunctional double-layered nanoscaffold using 3D printing technology. The upper layer consists of a pH-responsive hydrogel scaffold that is loaded with curcumin, while the lower layer is prepared by mixing GelMA with ApoEVs (Figure 13A)[116]. Experimental studies have shown that the ApoEVs in the lower-layer hydrogel scaffold possess the ability to neovascularization and collagen synthesis. Meantime, once released from the lower layer, the coacervates are able to inhibit bacterial growth (Figure 13D) and scavenge ROS. The scaffold prevented wound infection and accelerated wound healing using a rat model of full-thickness skin defects (Figure 13E). Furthermore, Chen et al. innovatively designed and fabricated a functional double-layer hydrogel using 3D printing technology (Figure 13F)[117]. The upper layer of the hydrogel scaffold consists of SFMA and GelMA, primarily serving to imitate the epidermis and offer a scaffold for cell attachment. HaCaT cells were embedded in this layer to promote epidermal regeneration and regulate wound moisture. The lower layer consists of GelMA and HAMA, designed to simulate the dermis. Cu-EGCG was integrated into this layer to confer antibacterial properties (Figure 13H), among other functions. Animal experiments demonstrated that DLS/c significantly enhanced epidermal formation and barrier function, effectively regulated the hydration level at the wound surface, and created an ideal moist healing environment. Most notably, the structure and proportion of collagen in the skin treated with DLS/c were similar to those in normal skin (Figure 13I). FIGURE 13 . Preparation of scaffold structure and their applications in controlled drug release and wound repair. ( A ) Fabrication of a bilayer scaffold via 3D printing technique. ( B ) Photographs of the Coa-ApoEV-GMA scaffold. ( C ) Microscopy of the scaffold’s upper and lower layers. ( D ) Antibacterial effect of this scaffold system. ( E ) Comparative analysis of unhealed wound areas among three groups. Reproduced with permission[116].Copyright 2025, Elsevier ( F ) Preparation of DLS and DLS/c. ( G ) SEM images of ULHs and LLHs. ( H ) Antibacterial effect of DLS. ( I) Wound closure rates in various groups. Reproduced with permission[117]. Copyright 2024, Elsevier. 4.2 Microneedle Microneedles, consisting of micron-scale needle-like arrays, are non-invasive tools. Microneedles are typically made of polymer materials and can be prepared through 3D printing and electrospinning methods[118]. Microneedles are critical for facilitating the wound healing process. Firstly, microneedles can break through the physical barrier of the wound surface, penetrate blood scabs/biofilms, and achieve efficient drug delivery[119]. Secondly, microneedles can load growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), etc., and precisely deliver these growth factors to the wound surface, stimulating cell proliferation and migration[120]. In addition, microneedles can also load drugs and precisely deliver them to the wound surface, promoting wound healing.Lu et al.[121]designed a microneedles system rely on HA-hydrazide/quaternized–aldehyde-modified HA (HA-ADH/HA-QA-ALD), referred to as HAQA, which exhibits excellent biocompatibility, self-healing properties, a three-dimensional porous network, and controlled drug release capability, making it an ideal drug carrier (Figure 14A). Owing to its high plasticity, the HAQA was further fabricated into microneedles (MNs) with robust mechanical strength, enabling easy penetration of the epidermis and promoting the delivery of the drug KD into deep tissue (Figure 14B). Additionally, by coating KD with a macrophage membrane (forming M-KD), the target cell affinity was significantly enhanced, and the KD-induced mitigation of macrophage inflammation was further strengthened through reprogramming glucose metabolism. In a diabetic mouse model, this novel M-KD@HAQA-MN system demonstrated multiple therapeutic effects: effectively suppressing inflammatory responses, inhibiting bacterial proliferation, neutralizing oxidative damage stress, and promoting endothelial angiogenesis, thereby notably accelerating wound healing (Figure 14C). Yao et al.[122]proposed a therapeutic strategy targeting mitochondrial dysfunction to treat radiation-induced chronic wounds. Owing to the critical role of mitochondria-containing extracellular vesicle (EVs) derived from adult stem cells in paracrine-mediated repair, the authors utilized metformin to enhance mitochondrial biogenesis in stem cells derived from adipose tissue, thereby obtaining mitochondria-rich EVs (designated “Met-EVs”). These Met-EVs significantly ameliorated radiation-induced mitochondrial dysfunction in vitro and in vivo by restoring mitochondrial membrane potential, elevating ATP production, and reducing ROS through functional mitochondrial transfer. To achieve sustained delivery, a microneedle patch (MNP) system made from DAM and HAMA was developed to sustained release of Met-EVs into wound tissue (Figure 14D). This system not only alleviated mitochondrial defects but also promoted macrophage polarization, consequently enhancing anti-inflammatory responses and tissue repair in a murine model of combined radiation–skin injury (Figure 14E). In addition, Fan et al. designed a spatially compartmentalized multifunctional microneedle patch for synergistically promoting wound healing (Figure 14F)[123]. The microneedle system consists of two distinct functional parts. The needle tips are composed of GelMA, while the base is fabricated from silk fibroin-methacryloyl (SilMA). The needle tips, loaded with VEGF, can penetrate the stratum corneum and enable subsequent drug delivery into the subcutaneous tissue, effectively facilitating cell proliferation and angiogenesis. The backing layer was incorporated with silver nanoparticles (AgNPs) exhibiting potent antimicrobial properties, acting as a barrier that covers the wound and prevents microbial infection. Through this compartmentalized loading strategy, the patch simultaneously achieves dual functions of antibacterial protection and tissue regeneration (Figure 14H). In the treatment of infected wounds in rats, this microneedle system markedly accelerated wound closure and tissue repair (Figure 14I). FIGURE 14 . Microneedle hydrogel for promoting skin wound healing. ( A ) Synthesis diagram of M-KD@HAQA-MN. ( B ) Stereomicrograph of the MN patch. ( C ) Wound closure rate. Reproduced with permission.Copyright 2025, Wiley. ( D ) Stereoscopic DAM/HAMA-MNP images; ( E ) Wound healing curves of the dorsal wounds of mice among the groups. Reproduced with permission.Copyright 2024, ACS. ( F ) Scheme of fabrication of MMN patches. ( G ) Micrograph of the MMN patch. ( H ) Antibacterial effects of different microneedles. ( I ) Analysis of wound area among groups at day 9. Reproduced with permission. Copyright 2025, Wiley. 4.3 Nanofiber Nanofibers are a novel class of biomaterial, featuring large specific surface area, excellent mechanical properties, and a structure resembling the ECM[124]. They provide a favorable microenvironment to support cell proliferation, adhesion and migration [125]. The diameter of nanofibers is typically less than 1000 nanometers and can be fabricated via techniques like electrospinning, self-assembly, and template synthesis[126]. The high specific surface area increases the contact area between nanofiber hydrogels and wound tissues, enhancing the adhesion and spreading of cells in wound healing[127]. Additionally, this system facilitates the loading of more bioactive molecules including therapeutic drugs and growth factors, enabling precise regulation of the wound repair process[128]. He et al. successfully developed a functionalized nanofiber membrane loaded with OI (P/G-CS-OI)[129]. Initially, OI was covalently conjugated to chitosan (CS), and then the CS-OI complex was grafted onto a nanofibrous membrane (P/G) fabricated by blend electrospinning of polycaprolactone (PCL) and gelatin, ultimately yielding the functionalized P/G-CS-OI membrane (Figure 15A). Favorable mechanical properties, biocompatibility, and anti-inflammatory and antioxidative activities were observed in the P/G-CS-OI membrane (Figure 15B-F). By triggering the KEAP1/NRF2 signaling pathway, the dressing reprogrammed macrophage function, transforming the inflammatory microenvironment of diabetic wounds into a pro-regenerative one, thereby effectively accelerating the healing process (Figure 15G). Compared with single-layer wound dressings, bilayer dressings exhibit a synergistic effect of multiple functions to promote wound healing. Tavakoli et al. developed a novel bilayered wound dressing. The top layer (TL) is composed of a porous sponge, which is made from PAAc and Hny. The bottom layer (BL) comprises nanofibers loaded with VEGF (Figure 15H)[130]. In this dual-layer design, the TL acts as a supportive layer with both antibacterial and high absorbency properties. The BL mimics the morphology of the ECM, creating a bioactive interface that promotes cell adhesion and accelerates angiogenesis through the controlled release of VEGF. To further optimize performance, three variations of the BL were fabricated using nanofibrous systems based on Hny, Hny−Kr, and Hny−Kr−VEGF (Figure 15I). Finally, the bilayered material demonstrated excellent capabilities in reducing inflammatory responses and promoting tissue regeneration in a model of full-thickness skin defects in rats (Figure 15J).Microfluidic technology is a platform that enables precise manipulation of fluids at the microscale, allowing accurate control over the concentration gradients and spatiotemporal distribution of drugs such as growth factors and antibiotics, thereby achieving targeted delivery. Combined with nanofiber scaffolds fabricated through techniques like electrospinning, it provides a favorable three-dimensional supportive environment for cell growth and angiogenesis. For instance, Dong et al. innovatively designed a multifunctional artificial skin using microfluidic spinning technology (MST)[131]. This system consists of a core-shell structure, where the shell is fabricated from CMC-Fe and the core is made from PCL-Cur (Figure 15K). Relying on the fast chelation between carboxymethyl cellulose (CMC-Na) and Fe³⁺, the artificial skin exhibits outstanding mechanical properties and strain sensitivity. Furthermore, the material demonstrates biocompatibility, biodegradability, drug release capability, and antibacterial properties (Figure 15L-M). Finally, the authors verified that this artificial skin can efficiently promote wound healing using a rat full-thickness skin defect model (Figure 15N). FIGURE 15. Anti-inflammatory, promoting angiogenesis and antibacterial dressing based on nanofiber structures. ( A ) Fabrication process of the electrospun nanofiber membrane. ( B-D ) Analysis of TNF-α, IL-1β, and IL-6 level. ( E-F ) Statistical analysis of NO production and SOD activity ( G ) Wound closure rate. Reproduced with permission[129]. Copyright 2024, Springer Nature. ( H ) Schematic of the Bilayer Wound Dressing. ( I ) Three types of nanofibers as the BL. ( J ) Wound closure rates. Reproduced with permission[130]. Copyright 2023, ACS. ( K ) Fabrication process for core–shell gel NFSs using MST technology. ( L-M ) Bacterial colony counts in various samples. ( N ) The wound area was measured over time after treatment with different samples. Reproduced with permission[131]. Copyright 2024, Wiley. 4.4 Microspheres Microspheres play multifaceted key roles in wound healing due to their controllable particle size, excellent biocompatibility, and versatile loading capacity[132]. Firstly, as precision drug delivery carriers, microspheres enable sustained release of antibacterial drugs and growth factors by modulating the material degradation rate[133]. Secondly, in terms of physical barrier and wound protection, microspheres can form porous scaffold structures through self-assembly or combination with hydrogels. After covering the wound, they not only isolate external mechanical stimuli and microbial invasion but also maintain a moist wound microenvironment.It is worth mentioning that the microsphere preparation can be made into an injection or oral dosage form, which greatly improves the convenience of medication for patients. Hydrogel microspheres exhibited excellent biocompatibility, controllable biodegradability, adjustable porosity, regulated mechanical strength, and the capability to carry and deliver bioactive molecules within the realm of tissue engineering research[134]. Xiao et al. developed a novel hydrogel microsphere mPDA-PEI@GelMA to promote diabetic wound healing(Figure 16A)[135]. Studies have shown that the excessive production of Neutrophil Extracellular Traps (NETs) prolongs the duration of inflammatory responses during wound healing, thereby slowing down the wound healing process. The hydrogel microspheres can effectively alleviate the pro-inflammatory response by clearing NETS and ROS (Figure 16B-16C). Moreover, the authors verified that this hydrogel microsphere can promote wound healing by establishing a diabetic mouse model. (Figure 16D). Additionally, Chen et al. developed a hydrogel microsphere system (i-Lyso@Alg) that can alleviate inflammatory reactions and possess antibacterial capabilities (Figure 16E)[136]. This microsphere fabricated from alginate and loaded with lysozyme and MXene was prepared by a revised microfluidic technique. MXene endows i-Lyso@Alg with excellent thermal effects and enables it to effectively inhibit bacterial viability when exposed to near-infrared light. In vitro antibacterial experiments showed an inhibition rate exceeding 98% against Staphylococcus aureus (Figure 16F). Using a rat skin defect model, this system was found to significantly accelerated wound healing by suppressing the expression of inflammatory factors, preventing bacterial infection, and inducing the expression of pro-angiogenic factors (Figure 16G). FIGURE 16. Preparation of composite hydrogel microspheres for wound repair. ( A ) Fabrication of the NETs-scavenging ’micro-cage’ mPDA-PEI@GelMA. ( B-C ) Wound NETs and ROS level in different groups. ( D ) Wound closure rates across various groups at days 0, 3, 7, and 12. Reproduced with permission[135]. Copyright 2024, Wiley. ( E ) Schematic of the i-Lyso@Alg microsphere fabrication process. ( F ) Analysis of bactericidal viability in different groups. ( G ) Wound area healing rate in various treatment groups. Reproduced with permission[136]. Copyright 2024, Elsevier. 5. Summary and prospect Wound healing represents a complex process centered on the regeneration of tissue. With the deepening of research on the mechanisms of different microenvironments in this process, a variety of innovative biomaterials have been designed as ’smart’ tools to respond to and manage the wound microenvironment. This review centers on the primary stimulus-responsive hydrogels, which exhibit responsiveness to microenvironments: the biochemical microenvironment (including pH, glucose, ROS, and specific enzymes) and the physical microenvironment (encompassing light, magnetic and electric fields), and multiple response modes of the wound to induce changes in morphology, structure, degradation, and properties, ultimately fulfilling their biomedical function. In addition, we briefly outline several novel engineering structures, including scaffolds, nanofibers, microneedles, and microspheres. By reviewing the design strategies of various representative ”intelligent” hydrogels and their effects in wound repair, these materials’ potential for application in wound repair is demonstrated.As an advanced concept, stimulus-responsive wound dressing combines sensing technology and smart materials to establish a dynamic feedback loop with the wound. This allows for precise monitoring of the surrounding environment, facilitating subsequent adaptive modifications, showing considerable intelligent potential. Central to the design of these dressings is their excellent stimulus response. Specifically, pH-responsive hydrogels can be primarily categorized into two types: the first type uses polyelectrolyte, whose expansion and contraction depend on the dissociation constant and the pH value of the medium; Schiff base imine crosslinks are employed in the second design for acid-triggered degradation and drug release. The synthesis of thermosensitive hydrogels and biopolymers showed LCST or UCST characteristics. These polymers undergo a transition from solution to gel as they approach physiological temperatures, allowing them to gelate in situ and adapt to different wound locations and geometry. Dynamic covalent bonds, including borate bonds, disulfide bonds and thioketones, have become popular crosslinkers for glucose and ROS -responsive hydrogels. Such dynamic bonds further give the hydrogel system injectable, self-repairing property and adjustable mechanical performance. Additionally, the use of proteinase-digestible polymers is currently the main method for preparing enzyme-responsive hydrogel wound dressings, and the irritants mainly include matrix metalloproteinase, phosphatase and esterase. Photo-responsive hydrogels chemically modify polymers to respond to UV, NIR, and visible light, triggering photoinduced crosslinking, photothermal therapy, or hydrogel degradation for drug delivery and wound repair. Electric field responsive hydrogels provide a flexible means for the development of wearable wound dressings, which can help realize effective wound repair and dynamic monitoring. Furthermore, it is becoming a developing trend to integrate functional modules into a single hydrogel system to build dual or multi-responsive hydrogels, is capable of responding more intelligently to the dynamic changes in wound microenvironment. According to their wound repair effects, multi-responsive hydrogels are superior to single responsive hydrogels.In spite of substantial research progress in the domain of stimulus-responsive wound dressings, this area still faces numerous significant challenges that urgently need to be addressed. First, biosafety remains a major obstacle. For dressings containing nanoscale components, nanoparticles may be released into wound tissues and even enter the circulatory system, leading to long-term biosafety concerns. For instance, nanoparticle accumulation may increase the risk of thrombosis. Additionally, small-molecule materials used during hydrogel dressing preparation may undergo passive diffusion, causing toxic side effects on Homo sapiens and tissue damage. Therefore, enhancing material biosafety evaluations and adopting green, safe, and highly biocompatible hydrogel materials are inevitable trends for future development. Second, in terms of large-scale production, the current laboratory-developed smart hydrogels may face limitations in preparation costs and industrial scalability, hindering the translation of research outcomes. Third, the clinical translation gap remains difficult to bridge. The majority of intelligent dressings remain in the initial phases of research and development, with their wound repair efficacy primarily validated utilizing established animal models like mice and rats. Studies that validate the therapeutic effects of hydrogel wound dressings using large animal models are still scarce. Moreover, unified quality control standards have not yet been established, resulting in significant batch-to-batch variations in hydrogel products. Finally, closer collaboration between clinical and fundamental research is still necessary, and interdisciplinary cooperation must be strengthened. Smart hydrogels must ultimately serve clinical needs, accelerating the clinical validation and regulatory approval processes for intelligent wound dressings.Looking forward, advancements in stimulus-responsive hydrogel wound dressings is anticipated to prioritize enhanced functionality and customization, facilitating more precise and intelligent wound monitoring and therapeutic interventions. For instance, we can construct integrated sensing-therapeutic devices that can monitor in real time the biochemical indicators of wounds and precisely release drugs on demand to promote wound healing. This advancement represents a significant progression in wound care, moving towards intelligent management and telemedicine integration. With the continuous deepening of research and ongoing innovation in technology, stimuli-responsive hydrogels are expected to bring revolutionary breakthroughs to wound healing, particularly for the the treatment of complex and refractory wounds, significantly improving patients’ therapeutic outcomes and quality of life. Declaration of interests: The authors confirm that they have no known competing financial interests or personal relationships that might have influenced the work presented in this paper. Acknowledgments: This work was supported by the National Natural Science Foundation of China (Grants 32301103, 22205260), National Key Research and Development Program of China (Grant No. 2023YFC3011902) and the ”Eagle Plan” Talent Cultivation Project of the Medical Innovation Research Division of the Chinese PLA General Hospital. References [1] M.S. Sangha, F. Deroide, R. Meys, ”Wound healing, scarring and management.” Clinical and experimental dermatology 49 (2024):325-336.[2] R. 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Keywords hydrogel stimuli-responsive ： wound healing Authors Affiliations Debin Zheng 0009-0005-6826-5616 Chinese PLA General Hospital View all articles by this author Meiqi Zhu Chinese PLA General Hospital View all articles by this author Cuiping Zhang 0000-0003-0320-6226 Chinese PLA General Hospital View all articles by this author Di Wu Chinese PLA General Hospital View all articles by this author Tianyu Xie Chinese PLA General Hospital View all articles by this author Chen Li Chinese PLA General Hospital View all articles by this author Pei Zhao Chinese PLA General Hospital View all articles by this author Xi Liu 0000-0002-7968-0461 Chinese PLA General Hospital View all articles by this author Xiaobing Fu Chinese PLA General Hospital View all articles by this author Xiaoxue Li [email protected] Chinese PLA General Hospital View all articles by this author Metrics & Citations Metrics Article Usage 390 views 174 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Debin Zheng, Meiqi Zhu, Cuiping Zhang, et al. 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