Preparation method and application of anion and cation hydrogel dressing for chronic wound treatment

Abstract

The application discloses a preparation method and application of a cationic and anionic hydrogel dressing for chronic wound treatment, and belongs to the field of biomedical materials; aiming at the problems of dynamic changes of a diabetic wound microenvironment and iron death hindering healing, the application provides a hydrogel containing cationic and anionic double components; the anionic component is loaded with an iron ion and a polyphenol coordination complex, is released in response to an alkaline microenvironment in an inflammation period, realizes antibacterial and anti-inflammatory effects, the cationic component contains an iron ion chelator grafted through a Schiff base bond, is released in response to a fracture of an acidic microenvironment in a proliferation period, and precisely chelates excessive Fe 2+ to reverse iron death; through hierarchical intelligent regulation, the application realizes full-stage synergistic repair from anti-infection, anti-inflammation to inhibition of iron death, significantly promotes wound healing, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and tissue engineering, specifically relating to a method for preparing and applying anionic and cationic hydrogel dressings for the treatment of chronic wounds. Background Technology

[0002] Diabetic refractory wounds are a serious and challenging clinical complication, placing a heavy burden on global public health. Unlike ordinary acute wounds, the healing of diabetic wounds is severely hampered by a variety of pathological factors, including irreversible vascular damage caused by persistent hyperglycemia, disordered inflammatory cascade responses, invasive bacterial infection, tissue hypoxia, and abnormal tissue remodeling. These adverse factors create a destructive vicious cycle in the hyperglycemic microenvironment. Specifically, the persistent infiltration of inflammatory cells leads to a prolonged and alkaline inflammatory phase, while the formation of bacterial biofilms and the outbreak of reactive oxygen species (ROS) jointly hinder the resolution of inflammation. In the later acidic proliferative phase, iron ions (Fe... 2+ Abnormal accumulation of fibroblasts induces lipid peroxidation through the Fenton reaction, activates the ferroptosis pathway, and leads to the failure of fibroblast and endothelial cell function, thereby severely inhibiting wound healing.

[0003] Currently, traditional treatment strategies for diabetic wounds, such as conventional nanomedicines and traditional dressings, often fail to address the complex and dynamic changes in the microenvironment of diabetic wounds, resulting in very limited therapeutic effects. In recent years, smart hydrogel materials have attracted widespread attention in the field of wound repair due to their excellent moisturizing properties, biocompatibility, and smart responsiveness. Among existing technologies, some studies focus on the antibacterial or anti-inflammatory effects of stimulus-responsive hydrogels (such as pH-responsive, ROS-responsive, or enzyme-responsive) in a single stage (such as the inflammatory phase), while other studies have proposed related iron chelation or antioxidant strategies to inhibit the ferroptosis pathway during the proliferative phase.

[0004] However, existing technologies have significant limitations, whether they target ferroptosis pathways or repair inflammation. Current treatment strategies mostly focus on a specific stage of diabetic wound healing or a single pathological problem, failing to properly understand the dynamic evolution of wound healing. Different healing stages require drastically different treatment strategies; excessive release of iron ions during the inflammatory phase can exacerbate inflammation, while failure to promptly remove iron ions during the proliferative phase can trigger ferroptosis. Existing technologies lack hydrogel dressings that can adapt to the spatiotemporal evolution of the wound microenvironment, enabling controlled graded drug delivery and matching repair across all stages. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing and applying anionic and cationic hydrogel dressings for the treatment of chronic wounds.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This application provides an anionic and cationic hydrogel dressing for the treatment of chronic wounds, comprising a first hydrogel component and a second hydrogel component; The first hydrogel component comprises an anionic polymer network and a first active ingredient loaded in the anionic polymer network. The first active ingredient comprises an iron ion-polyphenol coordination complex. The first hydrogel component swells in response to the alkaline microenvironment in the early stage of wound healing and releases the first active ingredient. The second hydrogel component comprises a cationic polymer network and a second active ingredient loaded in the cationic polymer network. The second active ingredient comprises an iron ion chelating agent. The second hydrogel component swells in response to the acidic microenvironment in the later stage of wound healing and releases the second active ingredient to chelate free iron ions.

[0007] Optionally, the anionic polymer network is a network structure formed by cross-linking of a polymer containing carboxyl groups; the iron ion and polyphenol coordination complex is a complex formed by coordination of tannic acid and ferrous ions.

[0008] Optionally, the cationic polymer network is a network structure formed by cross-linking a polymer containing primary amino, secondary amino, or quaternary ammonium groups; the iron ion chelating agent is a nitrogen-containing heterocyclic compound. The iron ion chelating agent is bound to the cationic polymer network through acid-unstable chemical bonds, which are Schiff base bonds, and the Schiff base bonds break in an acidic microenvironment to release the iron ion chelating agent.

[0009] Optionally, the first hydrogel component and the second hydrogel component form an integrated bilayer or bicontinuous phase structure through interfacial bonding or interpenetrating network.

[0010] Optionally, the swelling ratio of the first hydrogel component in an alkaline environment with a pH of 7.4-8.9 is greater than its swelling ratio in an acidic environment with a pH of 4.7-6.5; The swelling ratio of the second hydrogel component in an acidic environment with a pH of 4.7-6.5 is greater than that in an alkaline environment with a pH of 7.4-8.9.

[0011] Optionally, after the first active ingredient is released, the ferrous ions in the iron ion-polyphenol coordination complex react with reactive oxygen species in the wound microenvironment to generate hydroxyl radicals in a Fenton-like reaction to achieve antibacterial effect. Meanwhile, the polyphenolic components remove excess reactive oxygen species from the wound microenvironment to reduce oxidative stress and inflammatory response.

[0012] Optionally, after the second active ingredient is released, the iron ion chelating agent selectively binds to excess ferrous ions in the wound microenvironment, blocking iron-dependent lipid peroxidation, thereby inhibiting the ferroptosis pathway and promoting wound healing during the proliferative phase.

[0013] A method for preparing a smart responsive hydrogel dressing includes the following steps: A first prepolymer solution is provided, the first prepolymer solution comprising an anionic monomer or polymer precursor, a crosslinking agent, a photoinitiator, and an iron ion-polyphenol coordination complex; The first prepolymer liquid is placed in a mold to undergo the first stage of photocuring and cross-linking to form an incompletely cross-linked first hydrogel layer. A second prepolymer solution is provided, the second prepolymer solution comprising a cationic monomer or polymer precursor, a crosslinking agent, a photoinitiator and an iron ion chelating agent; The incompletely cross-linked first hydrogel layer is brought into contact with the second prepolymer liquid, and a second stage of photocuring cross-linking is performed, so that the second prepolymer liquid forms a cross-linked second hydrogel layer on the surface and / or inside the first hydrogel layer.

[0014] Optionally, the ultraviolet light wavelength for the first stage of photocuring crosslinking is 365nm, and the irradiation time is 3-10 minutes; The ultraviolet light wavelength for the second stage of photocuring crosslinking is 365nm, and the irradiation time is 5-15 minutes.

[0015] Application of a smart responsive hydrogel dressing in the preparation of drugs or medical devices for treating chronic, refractory, infected, or diabetic wounds.

[0016] Compared with the prior art, this application has the following beneficial effects: This invention proposes a method for preparing and applying anionic and cationic hydrogel dressings for the treatment of chronic wounds. By constructing anionic and cationic dual-component intelligent hydrogel system, it achieves hierarchical intelligent regulation of the entire healing process of diabetic wounds: In the early alkaline inflammatory stage of wound healing, the anionic hydrogel swells in response to the alkaline microenvironment, releasing iron ions and polyphenol coordination complexes loaded within its network. The ferrous ions in these complexes react with reactive oxygen species (ROS) enriched in the wound microenvironment to undergo a Fenton-like reaction, catalyzing the generation of highly toxic hydroxyl radicals (·OH) to efficiently kill invasive bacteria. Simultaneously, the polyphenol component powerfully removes excess ROS, reduces oxidative stress, significantly inhibits inflammatory cascade reactions and tissue damage, and promotes the wound's passage through the difficult inflammatory phase. In the later acidic proliferation stage of wound healing, the cationic hydrogel swells in response to the acidic microenvironment. Iron ion chelating agents grafted onto acid-instable chemical bonds such as Schiff base bonds break and release under acidic conditions, precisely and selectively chelating excess free ferrous ions (including residual or abnormally accumulated Fe) in the wound microenvironment. 2+This process blocks iron-dependent lipid peroxidation, restores the function of glutathione peroxidase 4 (GPX4), effectively reverses ferroptosis-driven cell damage, significantly promotes the proliferation and migration of fibroblasts and endothelial cells, and ultimately accelerates wound closure and tissue regeneration.

[0017] This invention highly integrates multiple functions such as anti-infection, anti-inflammation, anti-oxidation, and reverse regulation of ferroptosis, effectively solving the key technical problems of traditional dressings being unable to dynamically match the wound microenvironment and difficult to achieve graded drug delivery, providing a promising clinical translation strategy for the efficient repair of chronic refractory wounds in diabetic patients. Attached Figure Description

[0018] Figure 1 These are scanning electron microscope (SEM) images of the anion and cation hydrogels prepared in Example 3 of this invention in deionized water and under different pH conditions.

[0019] Figure 2 This is a diagram showing the antibacterial plate test results of anionic hydrogel against Staphylococcus aureus and Escherichia coli in Example 3 of the present invention.

[0020] Figure 3 These are macroscopic photographs and statistical diagrams of wound healing diameters at 0, 3, 5, 8, and 14 days post-surgery in a diabetic rat back wound model using hydrogel dressings from Example 3 of this invention. Detailed Implementation

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Furthermore, in this invention, an element referred to as fixed to or disposed on another element may be directly disposed on the other element, or there may be an intermediate element. When an element is considered to be connected to another element, it may be directly connected to the other element, or there may be an intermediate element present simultaneously. The terms vertical, horizontal, left, right, and similar expressions used herein are for illustrative purposes only and do not represent the only possible implementation.

[0023] Example 1

[0024] This embodiment describes in detail the preparation of oxidized sodium alginate (OSA): First, dissolve 2g of sodium alginate (SA) in 100ml of deionized water.

[0025] Dissolve 0.55g of sodium periodate (NaIO4) in 8ml of deionized water under light-protected conditions.

[0026] Slowly add sodium periodate solution to sodium alginate solution and keep the reaction in the dark for 3 hours.

[0027] After the reaction is complete, add 1 ml of ethylene glycol (EG) and continue the oxidation reaction for 1 hour.

[0028] Finally, the product was transferred to deionized water for dialysis for three days. The molecular weight cutoff of the dialysis bag was 1000 Da. The deionized water was changed approximately every 4 hours during this period.

[0029] After dialysis, the solution was freeze-dried to obtain a white solid, which is sodium oxidized alginate (OSA).

[0030] Example 2

[0031] This embodiment describes in detail the preparation of quaternized chitosan (QP) grafted with iron ion chelating agents: Weigh 400 mg of quaternized chitosan (QCS) and dissolve it in 10 mL of deionized water.

[0032] Weigh 22.4 mg of 1,10-phenanthroline-2-carboxaldehyde (PTL22) and dissolve it in 10 mL of anhydrous ethanol.

[0033] Slowly add the PTL22 solution to the QCS solution and stir overnight.

[0034] During this reaction, the primary amino group inherent in the QCS molecular chain undergoes nucleophilic addition and dehydration reaction with the aldehyde group on the PTL22 molecule to form a dynamic covalent bond: a Schiff base bond, thereby covalently grafting the iron ion chelating agent 1,10-phenanthroline onto the quaternized chitosan molecular backbone.

[0035] These Schiff base bonds are easily hydrolyzed and broken in the acidic microenvironment of pH 4.7-6.5 during the proliferative phase of diabetic wounds, which is the key chemical basis for achieving the acidic microenvironment-triggered targeted release of this invention.

[0036] After the reaction was completed, the product was transferred to deionized water for dialysis for three days. The molecular weight cutoff of the dialysis bag was 1000 Da. The deionized water was changed approximately every 4 hours during this period.

[0037] After dialysis, freeze-drying yields an orange solid, which is quaternized chitosan (QP) grafted with an iron ion chelating agent.

[0038] Example 3

[0039] This embodiment describes in detail the preparation of anion and cation environmentally responsive smart hydrogel dressings: Preparation of prepolymer solution: Prepolymer solution I (anionic prepolymer solution): Weigh an appropriate amount of ferric chloride hexahydrate (FeCl3·6H2O) and dissolve it in deionized water to prepare a solution of 10 mg / ml.

[0040] Weigh an appropriate amount of tannic acid (TA) and dissolve it in deionized water to prepare a 40 mg / ml solution.

[0041] Weigh an appropriate amount of acrylic acid (AA) and dissolve it in deionized water to prepare a 15 wt.% solution. Add 10% N,N'-methylenebisacrylamide (MBA, crosslinking agent) and 2% photoinitiator 12959 (i.e., 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone) according to the mass of AA monomer.

[0042] Subsequently, a certain amount of OSA prepared in Example 1 was added to bring its final concentration to 18 wt.%.

[0043] In this mixed solution, add 200 μl of TA solution and 400 μl of FeCl3·6H2O solution to every 10 ml, mix thoroughly, and obtain prepolymer solution I.

[0044] Prepolymer solution II (cationic prepolymer solution): Weigh an appropriate amount of dimethylaminoethyl methacrylate (DE) and dissolve it in deionized water to prepare a 15 wt.% solution. Add 10% MBA and 2% photoinitiator 12959 according to the mass of DE.

[0045] A certain amount of QP prepared in Example 2 was added to make its final concentration 18 wt.%, and the mixture was stirred to obtain prepolymer liquid II.

[0046] Secondary photo-initiated crosslinking preparation of bilayer hydrogel: The above prepolymer liquid I was injected into the mold and irradiated with a UV lamp with a wavelength of 365nm for 5 minutes to carry out the first stage of photocuring crosslinking, resulting in an incompletely crosslinked first hydrogel layer (anion layer).

[0047] Remove the first hydrogel layer, divide it into two parts, and remove one part.

[0048] Place the other half of the mold into prepolymer liquid II, let it stand for 5 minutes, and then irradiate it with a UV lamp with a wavelength of 365nm for 10 minutes.

[0049] Through this secondary initiation method, a cross-linked second hydrogel layer (cationic layer) is formed on the surface and / or inside the first hydrogel layer by the prepolymer II, ultimately yielding a fully cross-linked anionic and cationic OSA / AA@FeTA / / QP / DE hydrogel.

[0050] Preparation of control samples: To facilitate subsequent experimental characterization, the same method described above was used to prepare OSA / AA / / QCS / DE hydrogels without FeTA and PTL22, and OSA / AA@FeTA / / QCS / DE hydrogels without PTL22, as control samples.

[0051] Example 4

[0052] This embodiment elaborates on the structural characterization and pH-responsive physicochemical property testing of the hydrogel: First, combined Figure 1 The microstructure and pH-responsive swelling behavior were verified: like Figure 1 As shown, the morphology of the hydrogels was characterized by scanning electron microscopy (SEM). The anionic hydrogels and cationic hydrogels were placed in deionized water (RO water), pH=6.4 and pH=8.0 environments, respectively.

[0053] The results showed that the hydrogels possessed a porous and dense network structure. The anionic hydrogels exhibited significant swelling and a marked increase in porosity in an alkaline environment (pH=8.0), while in an acidic environment (pH=6.4), the pores became dense and the hydrogels shrank significantly. The cationic hydrogels, however, displayed distinctly different swelling behavior. These results precisely validated that the anionic and cationic components of this invention possess ideal pH responsiveness.

[0054] Furthermore, swelling rate tests were conducted: after freeze-drying and weighing each group of hydrogels, they were immersed in the corresponding solutions for equilibration and then weighed again for calculation. The results showed that in deionized water, the swelling rates of anionic and cationic hydrogels were basically the same, at 180% and 160%, respectively. The swelling rate of anionic hydrogels was 330% in an alkaline environment and 80% in an acidic environment. The swelling rate of cationic hydrogels was 200% in an alkaline environment and decreased by -20% in an acidic environment. These results accurately corresponded to the microenvironmental changes during the inflammatory phase (alkaline) and proliferative phase (acidic) of the wound.

[0055] Furthermore, mechanical property tests were conducted: compression and rheological tests were performed using a rheometer and a universal testing machine. The results showed that OSA / AA@FeTA / / QCS / DE exhibited the highest fracture strain (approximately 91%) but the lowest compressive strength (approximately 160 kPa); OSA / AA / / QCS / DE had the highest compressive strength (approximately 280 kPa) and the highest compressive modulus (approximately 310 kPa); the introduction of FeTA reduced the modulus of OSA / AA@FeTA / / QCS / DE by approximately 180 kPa; notably, OSA / AA@FeTA / The modulus of / QP / DE recovered to approximately 230 kPa, indicating that the introduction of PTL22 effectively restored and optimized the mechanical properties reduced by the introduction of FeTA. In the stress scan results, OSA / AA / / QCS / DE had the highest initial G' (approximately 10,000 Pa), and the introduction of FeTA reduced G'. However, the G' of OSA / AA@FeTA / / QP / DE recovered slightly and maintained modulus stability within the test range. The strain scan test showed that OSA / AA@FeTA / / QP / DE maintained G'>G'' even under high strain, exhibiting excellent structural integrity.

[0056] Example 5

[0057] This embodiment elaborates in detail on the verification of reactive oxygen species (ROS) scavenging ability and in vitro antibacterial effect: ROS scavenging test: ABTS free radical scavenging experiment and superoxide anion (·O2) were used. - The scavenging efficiency of OSA / AA@FeTA hydrogel was evaluated using ABTS· scavenging and hydroxyl radical (·OH) scavenging experiments. The results showed that the scavenging efficiency of OSA / AA@FeTA hydrogel significantly increased with increasing FeTA content. Taking the optimal group OSA / AA@FeTA10 as an example, its scavenging efficiency for ABTS· was 64.8%, and for ·O2... - The scavenging rate was 74.1%, and the scavenging rate for ·OH was 38.9%, indicating that FeTA endowed the hydrogel with excellent antioxidant capacity.

[0058] In vitro antibacterial test: such as Figure 2 As shown, we conducted a colony count plating experiment. The experiment confirmed that the OSA / AA@FeTA hydrogel utilizes its peroxidase-like activity to catalyze the production of highly toxic ·OH from H2O2. The colony count results showed that the inhibition rate of Staphylococcus aureus and Escherichia coli co-cultured with OSA / AA@FeTA was close to 100%. The live / dead bacteria staining results also showed that almost all bacteria in the control group survived, while the OSA / AA@FeTA group showed a significant bactericidal effect. This demonstrates that the hydrogel can effectively prevent and inhibit bacterial infection of diabetic wounds.

[0059] Example 6

[0060] This embodiment elaborates in detail on the anti-inflammatory effect of macrophage polarization regulation in vitro: RAW264.7 macrophages were induced with 100 ng / mL lipopolysaccharide (LPS) to simulate the inflammatory microenvironment associated with diabetes. The expression levels of pro-inflammatory factors (IL-1β, TNF-α) and anti-inflammatory factors (IL-4, IL-10) were detected by real-time quantitative PCR. The results showed that IL-1β and TNF-α were significantly increased and IL-4 and IL-10 were significantly decreased after LPS induction. After treatment with OSA / AA@FeTA hydrogel, IL-1β and TNF-α were significantly decreased and IL-4 and IL-10 were significantly increased, demonstrating that the hydrogel can effectively induce macrophages to change from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype.

[0061] Example 7

[0062] This embodiment provides a detailed description of the in vitro verification of ferroptosis reversal activity: In a simulated acidic microenvironment of diabetic wounds, Erastin combined with FeSO4 was used to induce ferroptosis in cells.

[0063] Key gene and protein expression detection: qPCR results showed that after Erastin@FeSO4 treatment, the anti-ferroptosis genes GPX4 and SLC7A11 were significantly downregulated, while the pro-ferroptosis genes TFRC and ACSL4 were significantly upregulated; the QP / DE group significantly reversed this trend; flow cytometry detection of GPX4 protein confirmed that the proportion of GPX4 positive cells in the control group was 94.6%, which dropped sharply to 20.3% in the Erastin@FeSO4 group, and significantly rebounded to about 40% in the QP / DE group (only about 30% in the QCS / DE group); the immunofluorescence staining results were consistent with the above.

[0064] Intracellular Fe 2+ Concentration and iron accumulation detection: Prussian blue staining showed a large amount of blue iron accumulation in the Erastin@FeSO4 group, while blue staining was significantly reduced in the QP / DE group. Quantitative analysis of intracellular ferrous ions confirmed that the Erastin@FeSO4 group had high levels of Fe... 2+ The concentration surged to approximately 35 μmol / L, while the QP / DE group effectively reduced it to approximately 5 μmol / L (comparable to the control group); this demonstrates that in the system of this invention, the Schiff base bond breaks under acidic conditions, and the precisely released chelating agent achieves targeted Fe... 2+ Cleared, restored GPX4 functionality, and reversed Iron Death.

[0065] Example 8

[0066] This example illustrates in detail the full-thickness skin defect wound healing model in diabetic rats: A rat dorsal diabetic wound model was established to investigate the in vivo efficacy of OSA / AA@FeTA / / QP / DE hydrogel; the wound area changes in each hydrogel group were recorded on postoperative days 0, 3, 5, 8, and 14. Figure 3 As shown: Before day 5, both groups containing FeTA showed better results than the group without FeTA; after day 5, the healing process of the OSA / AA@FeTA / / QCS / DE group slowed down, while the OSA / AA@FeTA / / QP / DE group accelerated wound closure; by day 14, the wounds in the present invention group were almost completely epithelialized, and the skin had basically regenerated; quantitative analysis of wound area and diameter ( Figure 3 The right side also confirms this conclusion.

[0067] This perfectly confirms the timing cascade logic of this invention: during the inflammatory phase, the anionic hydrogel is antibacterial and anti-inflammatory, while during the proliferation phase, the cationic hydrogel precisely captures residual Fe through Schiff base bond cleavage. 2+ This reverses ferrodeogenesis. It proves that this invention truly achieves collaborative intelligent repair of diabetic wounds throughout the entire lifecycle and across multiple stages, breaking through the bottleneck of single-stage treatment.

[0068] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention; no reference numerals in the claims should be construed as limiting the scope of the claims.

[0069] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A cationic and anionic hydrogel dressing for the treatment of chronic wounds, characterized in that, It includes a first hydrogel component and a second hydrogel component; The first hydrogel component comprises an anionic polymer network and a first active ingredient loaded in the anionic polymer network. The first active ingredient comprises an iron ion-polyphenol coordination complex. The first hydrogel component swells in response to the alkaline microenvironment in the early stage of wound healing and releases the first active ingredient. The second hydrogel component comprises a cationic polymer network and a second active ingredient loaded in the cationic polymer network. The second active ingredient comprises an iron ion chelating agent. The second hydrogel component swells in response to the acidic microenvironment in the later stage of wound healing and releases the second active ingredient to chelate free iron ions.

2. The smart responsive hydrogel dressing according to claim 1, characterized in that, The anionic polymer network is a network structure formed by cross-linking of a polymer containing carboxyl groups; the iron ion and polyphenol coordination complex is a complex formed by coordination of tannic acid and ferrous ions.

3. The smart responsive hydrogel dressing according to claim 1, characterized in that, The cationic polymer network is a network structure formed by cross-linking polymers containing primary amino, secondary amino, or quaternary ammonium groups; the iron ion chelating agent is a nitrogen-containing heterocyclic compound. The iron ion chelating agent is bound to the cationic polymer network through acid-unstable chemical bonds, which are Schiff base bonds, and the Schiff base bonds break in an acidic microenvironment to release the iron ion chelating agent.

4. The smart responsive hydrogel dressing according to claim 1, characterized in that, The first hydrogel component and the second hydrogel component form an integrated bilayer or bicontinuous phase structure through interfacial bonding or interpenetrating network.

5. The smart responsive hydrogel dressing according to claim 1, characterized in that, The swelling ratio of the first hydrogel component in an alkaline environment with a pH of 7.4-8.9 is greater than its swelling ratio in an acidic environment with a pH of 4.7-6.

5. The swelling ratio of the second hydrogel component in an acidic environment with a pH of 4.7-6.5 is greater than that in an alkaline environment with a pH of 7.4-8.

9.

6. The smart responsive hydrogel dressing according to claim 1, characterized in that, After the first active ingredient is released, the ferrous ions in the iron ion and polyphenol coordination complex react with reactive oxygen species in the wound microenvironment to generate hydroxyl radicals, thereby achieving antibacterial effect. Meanwhile, the polyphenolic components remove excess reactive oxygen species from the wound microenvironment to reduce oxidative stress and inflammatory response.

7. The smart responsive hydrogel dressing according to claim 1, characterized in that, After the second active ingredient is released, the iron ion chelating agent selectively binds to excess ferrous ions in the wound microenvironment, blocks iron-dependent lipid peroxidation, thereby inhibiting the ferroptosis pathway and promoting wound healing during the proliferative phase.

8. A method for preparing a smart responsive hydrogel dressing according to any one of claims 1-7, characterized in that, Includes the following steps: A first prepolymer solution is provided, the first prepolymer solution comprising an anionic monomer or polymer precursor, a crosslinking agent, a photoinitiator, and an iron ion-polyphenol coordination complex; The first prepolymer liquid is placed in a mold to undergo the first stage of photocuring and cross-linking to form an incompletely cross-linked first hydrogel layer. A second prepolymer solution is provided, the second prepolymer solution comprising a cationic monomer or polymer precursor, a crosslinking agent, a photoinitiator and an iron ion chelating agent; The incompletely cross-linked first hydrogel layer is brought into contact with the second prepolymer liquid, and a second stage of photocuring cross-linking is performed, so that the second prepolymer liquid forms a cross-linked second hydrogel layer on the surface and / or inside the first hydrogel layer.

9. The preparation method according to claim 8, characterized in that, The ultraviolet light wavelength for the first stage of photocuring crosslinking is 365nm, and the irradiation time is 3-10 minutes; The ultraviolet light wavelength for the second stage of photocuring crosslinking is 365nm, and the irradiation time is 5-15 minutes.

10. The use of the smart responsive hydrogel dressing according to any one of claims 1-7 in the preparation of a medicament or medical device for treating chronic, refractory wounds, infected wounds or diabetic wounds.

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