A multifunctional hydrogel precursor patch and a preparation method thereof

Abstract

The present application belongs to the technical field of wound dressing, and particularly relates to a multifunctional hydrogel precursor patch and a preparation method thereof. The patch is a fibrous hydrogel precursor obtained by chemical bonding of an organic polymer and a ferrocene derivative. The hydrogel precursor patch of the present application is triggered by exudate to form a 3D hydrogel in situ gelation, which is a wound healing strategy. No drug is needed, and no pre-crosslinking process of a solution-state matrix under acid-base, oxidation or light irradiation conditions is involved. In use, the solid patch is placed on the wound bed, and in a wet liquid environment, the sandwich structure ferrocene in the novel ferrocene-organic copolymer material promotes the rearrangement of the polymer chain through the "double-arm conjugation" effect, so that the irregular coil structure is mainly formed, the fluidity of the molecular chain is increased, and the hydrogel capacity is enhanced. In the gelation structure transformation process, the exudate is effectively absorbed in one direction, and the wound surface is kept clean.

Description

Technical Field

[0001] This invention belongs to the field of wound dressing technology, specifically relating to a multifunctional hydrogel precursor patch (containing an iron-organic polymer) and its preparation method. Background Technology

[0002] Skin abrasions are common pathological injuries in both military and daily life, impacting daily life and, in severe cases, even leading to death. Bleeding and exudate are common biological fluids in wounds. Massive, uncontrollable bleeding results in high mortality rates, while the accumulation of exudate on the wound surface provides a moist environment for bacterial growth, prolonging the inflammatory phase and causing chronic, non-healing wounds such as diabetic foot ulcers, pressure ulcers, and, in severe cases, even amputation. Therefore, hemostasis and exudate absorption are fundamental functions that ideal wound dressings should possess.

[0003] Currently, clinically used wound dressings include gauze, adhesive bandages, or cotton wool. However, their absorbency is limited, and they adhere to the skin, easily causing secondary skin damage during repeated changes. With the rise of technologies such as 3D printing and electrospinning, more mesh or sponge-like dressings are being used to improve exudate absorption and hemostasis. However, these dressings may have issues with incomplete skin adhesion and poor mechanical properties. Furthermore, wound healing is related to various biological functions, such as fibroblast migration promoting collagen deposition, angiogenesis to provide oxygen and nutrients for healing, and antibacterial activity to prevent infection. However, due to limitations in the fabrication processes of 3D printing and electrospinning, the structure of dressing materials is often restricted, making it difficult to perform these multiple functions.

[0004] In recent years, wound dressings have gradually evolved towards 3D design. Hydrogel wound dressings, with their 3D porous network structure and highly hydrophilic matrix materials, can maintain a moist environment, adhere closely to the skin, absorb exudate, and promote the transport of oxygen and nutrients. More advancedly, the porous structure can serve as a drug reservoir, allowing the dressing to exert its healing-promoting bioactive functions while absorbing exudate. However, most hydrogel dressings are achieved through a strategy of transforming a liquid matrix into a 3D structure, which reduces their exudate absorption capacity. The preparation and processing of drug-loaded hydrogels are complex, often requiring pre-induced gelation through in vitro oxidation and light exposure. The lack of readily available materials hinders the clinical application of these dressings, and the in vitro administration of oxidants poses potential safety risks to tissues and cells.

[0005] Therefore, adopting a simple strategy to prepare drug-free wound dressings and endowing them with more active properties through structural modification, allowing them to be directly transformed from a solid state to a hydrogel state, can simultaneously achieve the purpose of absorbing exudate and accelerating wound healing, and improve clinical usability, which has good development prospects. Summary of the Invention

[0006] To address the problem that existing wound dressings cannot meet the multifunctional requirements of antibacterial properties, exudate absorption, hemostasis, suitability for clinical application, and biocompatibility, the present invention aims to provide a multifunctional hydrogel precursor patch (containing an iron-organic polymer) and its preparation method.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A multifunctional hydrogel precursor patch, wherein the patch is a fibrous hydrogel precursor obtained by chemical bonding of an organic polymer and a ferrocene derivative.

[0009] The precursor patch is obtained by chemical bonding of the organic polymer and ferrocene derivative under the action of a condensing agent, wherein, by weight percentage, 9.9-93.5% is the organic polymer, 3.3-27.1% is the ferrocene derivative, and the balance is the condensing agent.

[0010] The organic polymer is hyaluronic acid, carboxylated chitosan, collagen and its derivatives;

[0011] The hyaluronic acid or modified hyaluronic acid has a molecular weight of 1000 Da-100 KDa; the carboxylated chitosan or modified chitosan has a viscosity of 0.5-400 mPa·s; and the collagen or modified collagen is of the types of collagen I, collagen II, and collagen III.

[0012] The condensing agent is 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or N-hydroxysuccinimide (NHS).

[0013] The ferrocene derivative is an amino or carboxyl-modified ferrocene.

[0014] The fibrous hydrogel precursor dressing is placed on the wound bed. After the fibrous hydrogel comes into contact with the wound exudate, it can undergo in-situ gelation transformation and spontaneously form a 3D mesh structure hydrogel, which is then applied to the wound surface.

[0015] A method for preparing a multifunctional hydrogel precursor patch:

[0016] 1) Preparation of organic polymer solution: Dissolve the organic polymer in PBS buffer or a mixed solution of PBS and organic solvent, and set aside for use. The organic polymer shall be 0.2-20% by mass.

[0017] 2) Preparation of ferrocene derivative solution: Dissolve the ferrocene derivative in PBS buffer or a mixed solution of PBS and organic solvent to obtain a solution or suspension for later use, wherein the ferrocene derivative is 0.14-11% by mass.

[0018] 3) Condensation of 1) and 2): Add a condensing agent to the organic polymer solution obtained in step 1), dissolve it, and then add the ferrocene derivative solution from step 2). Stir at 10-40°C for 4-48 hours to carry out a chemical bonding reaction. The final system contains 9.9-93.5% organic polymer by weight, 3.3-27.1% ferrocene by weight, and the remainder is condensing agent.

[0019] In the preparation of the above-mentioned patch ferrocene-organic copolymer material, the ratio of polymer, ferrocene, and condensing agent in the reaction is controlled to achieve a certain grafting rate, resulting in a prominent patch effect. Specifically, under a certain polymer mass, ferrocene and condensing agent are added to the reaction together, and the bonding rate gradually increases with the increase of the amount of ferrocene and condensing agent. The preferred ratio is: polymer:ferrocene:condensing agent (mass ratio) = 1:0.23:0.27-1:0.69:0.8.

[0020] The bonding reactants were dialyzed with deionized water (8000-14000 Da), and the dialysate was then lyophilized after passing through a microporous membrane to obtain the hydrogel precursor patch.

[0021] The organic solvent in steps 1) and 2) is a mixed solution of PBS with pH 5-7 and DMF, DMSO or formamide, wherein the volume ratio of PBS to DMF, DMSO or formamide is 1:3-3:1.

[0022] The solid fibrous hydrogel precursor obtained by bonding and purification is placed on the wound surface and a 3D mesh structure that spontaneously forms after absorbing wound exudate is applied thereon.

[0023] Principle of this invention:

[0024] The multifunctional hydrogel precursor patch of this invention is obtained by covalently linking ferrocene derivatives with biocompatible polymers. The covalent bond effect refers to the one-step condensation of the substituted chains on the ferrocene ring in the ferrocene derivative and the amino, hydroxyl, and carboxyl groups in the polymer matrix structure to form amides, esters, etc. At the same time, iron-based polymers with arbitrary grafting ratios can be obtained by using the dosage ratio, and long-chain polymers have a positive promoting effect on meeting biocompatibility requirements.

[0025] The above covalent connection uses ferrocene as the core compound. In terms of synthetic structure, ferrocene contains an electron-rich cyclopentadiene ring, which can participate in a variety of electrophilic substitution reactions to graft and modify a variety of polymers. Compounds of various lengths and with one or more target groups can be attached to the four carbon positions on the ring.

[0026] Furthermore, ferrocene possesses a sandwich-like structure, with each of the two cyclopentadiene rings carrying a single negative charge, enabling them to form a stable coordination structure with the central ferrous ion. After chemical bonding with the polymer, one cyclopentadiene ring is chemically attached to the polymer molecular chain, while the other ring undergoes diene conjugation between adjacent molecules mediated by the stable sandwich structure. Therefore, ferrocene, as the structural center, can mediate the transformation of fiber patches into 3D network structures through this aforementioned "double-arm conjugation" effect.

[0027] Specifically, the biocompatible polymers involved in this invention include chitosan, hyaluronic acid, collagen, and their derivatives. Carboxylated chitosan and hyaluronic acid contain carboxyl groups, while collagen has abundant amino groups in its structure, which can serve as reaction centers for the formation of ester or amide bonds. The reacted amide groups can interact with each other to form hydrogen bonds, or the ester bonds can form hydrogen bonds with the hydroxyl or amide groups on the original polymer chain, acting as a driving force for inducing in-situ gel structure transformation. Secondly, these chemical bonds can also provide adsorption sites for water molecules through hydrogen bonds, providing structural protection for the effective absorption of exudate.

[0028] Advantages of this invention:

[0029] The multifunctional hydrogel precursor patch of this invention is obtained by copolymer crosslinking of ferrocene and an organic polymer. It allows for the achievement of drug efficacy with a single material without the need for drug loading. This wound dressing spontaneously transforms from an iron-organic polymer upon contact with exudate, mitigating the risks associated with the content and duration of inducing crosslinking chemicals in clinical applications. Specifically:

[0030] 1. The multifunctional hydrogel precursor patch of the present invention selects hyaluronic acid, collagen and carboxylated chitosan as the main skeleton materials, which have good biocompatibility. At the same time, ferrocene derivatives (which have the effects of promoting coagulation, antibacterial, promoting microvascular angiogenesis and cell migration) are used as small molecule grafting materials to guide the polymer molecular chains to undergo structural rearrangement in response to the liquid environment, and play a core role in promoting in-situ gelation.

[0031] 2. In the stable "sandwich" structure of the ferrocene in the patch copolymer of this invention, the two ferrocene rings participate in chemical conjugation, forming a special "double-arm conjugated" structure. The presence of hydrogen bonding sites in the copolymer, either amide or ester bonds, not only promotes the formation of hydrogen bonds between molecular chains but also enhances hydrogen bonding with water molecules in the exudate. This "double-arm conjugation" and hydrogen bonding induce a rearrangement of polymer molecular chains in the liquid environment, often existing as random coils. Compared to the ordered double helix structure of the polymer chains before modification, the random coils increase the fluidity of the molecular chains, facilitating the entry and adsorption of liquid molecules. This "double-arm conjugation" and hydrogen bonding generate multiple microcrystalline regions in the polymer solution, which is conducive to the structural transformation to a gel state and enhances the in-situ gelation ability.

[0032] 3. The ferrocene-organic copolymer patch material obtained in this invention exhibits a certain grafting rate of ferrocene into the polymer, resulting in a superior patch formation effect. Ferrocene-organic copolymers with low grafting rates exhibit a strip-like fibrous structure after drying, with fewer amide groups and fewer water absorption sites. After water absorption, the resulting mesh structure is incomplete, leading to poor exudate absorption capacity. Ferrocene-organic copolymers with high grafting rates exhibit a film-like structure after drying, but excessive aggregation makes it difficult for water molecules to penetrate. After water absorption, a highly dense mesh is formed, resulting in poor exudate absorption capacity. Only ferrocene-organic copolymers with a moderate grafting rate exhibit a fibrous state where strips and small film-like structures coexist after drying. The introduction of a certain number of chemical bonds and a loose state ensure that a large number of liquid molecules can enter and be adsorbed. After structural transformation, an interconnected mesh structure is formed with intact mesh walls and a pore size of approximately 90 μm, effectively absorbing exudate and exudate waste.

[0033] 4. The patch of this invention avoids the pre-crosslinking of the hydrogel solution matrix before clinical use, thus solving the safety concerns of crosslinking agents on tissues. Furthermore, through in-situ gelation and structural transformation, the patch of this invention endows this novel wound dressing with absorbency far exceeding that of commonly used clinical gauze, bandages, cotton wool, and ordinary fibrous membranes. After in-situ gelation, it maintains a good wetting environment, and the release of iron ions from the wetting surface exerts various wound-healing functions. Compared with drug-loaded hydrogels, it exhibits stronger bioactivity.

[0034] 5. The patch of this invention does not involve a pre-gelling cross-linking process, making it simple and easy to use. It can be applied directly to the wound and adheres to the tissue upon contact with exudate. It will not fall off during movement, and after absorbing sufficient exudate, it can be easily peeled off and replaced without causing secondary damage. The patch has good breathability and strong exudate absorption capacity, preventing exudate from flowing back or spreading laterally to healthy tissue and causing chronic inflammation and infection. Attached Figure Description

[0035] Figure 1Fourier transform infrared (FT-IR) spectra of ferrocene-based hydrogel precursor patches with different grafting rates according to the present invention.

[0036] Figure 2 The X-ray diffraction (XRD) spectra of ferrocene-based hydrogel precursor patches with different grafting ratios according to the present invention.

[0037] Figure 3 The circular dichroism (CD) spectra of ferrocene-based hydrogel precursor patches with different grafting rates of the present invention are shown.

[0038] Figure 4 The images show the morphology of the ferrocene-based hydrogel precursor patches with different grafting rates before and after in-situ gelation transformation under scanning electron microscopy (SEM).

[0039] Figure 5 The present invention provides a ferrocene-based hydrogel precursor patch that improves the absorption capacity of biofluids compared to gauze, wound dressings, and hyaluronic acid gel.

[0040] Figure 6 This is a comparative diagram showing the adhesion of the ferrocene-based hydrogel precursor patch of the present invention to isolated rat skin tissue.

[0041] Figure 7 This invention demonstrates the ability of the ferrocene-based hydrogel precursor patch to promote wound healing in a rat model of full-thickness skin defects.

[0042] Figure 8 The biological functions of iron in the wound dressing of this invention are (A. antibacterial; B. angiogenesis; C. cell migration). Detailed Implementation

[0043] This invention discloses a method for preparing a ferrocene-organic copolymer hydrogel precursor patch wound dressing. The invention will be further described below with reference to the accompanying drawings and embodiments.

[0044] This invention employs a ferrocene-organic copolymer hydrogel precursor patch design. The hydrogel precursor patch gels in situ in vivo upon triggering with exudate, forming a 3D hydrogel that promotes wound healing. This addresses the potential biosafety concerns associated with antibacterial metal components and avoids the pre-gelation process required for clinical application, thus meeting the needs of various wound healing and care requirements. Furthermore, the material can be cut into any desired shape and size. Upon contact with wound exudate, it transforms into a hydrogel and adheres to the affected area. The interconnected 3D mesh structure enhances its exudate absorption capacity, and the iron evenly dispersed on the mesh surface induces ferroptosis-mediated antibacterial activity, further promoting cell migration and accelerating angiogenesis.

[0045] This invention eliminates the need for cross-linking agents or cross-linking processes in the patch, addressing the problem that existing hydrogel wound dressings require drug loading to achieve multifunctional effects. However, the drug loading process is affected by the content of gelation triggering agents and gelation time, resulting in poor clinical applicability. This invention, when laid flat on the wound bed, automatically transforms into a gel state upon absorbing exudate, further increasing exudate absorption. Simultaneously, the bonded metal components exert various wound-healing effects. The patch is suitable for a wide range of wound healing processes and various wound treatments and care. These wide-range wound healing processes include absorbing exudate, maintaining wound cleanliness, hemostasis, antibacterial properties, promoting angiogenesis, and promoting cell migration. Wound treatments and care include injuries leading to acute bleeding wounds, delayed surface wetting leading to infected wounds, and chronic, difficult-to-heal wounds with abundant exudate.

[0046] This invention's patch requires no drug loading and does not involve a pre-crosslinking process of the solution matrix under acidic, alkaline, oxidative, or light-irradiated conditions. In use, the solid patch is placed on the wound bed. In a moist liquid environment, the sandwich structure of the novel ferrocene-organic copolymer material promotes polymer chain rearrangement through a "double-arm conjugation" effect, resulting in a predominantly irregular coil structure. This increased molecular chain fluidity promotes the formation of more microcrystalline regions, thereby enhancing its gelation ability. During the gelation structure transformation, it effectively absorbs exudate unidirectionally, keeping the wound clean. Simultaneously, the release of iron-based materials from the hydrogel facilitates the performance of various biological functions.

[0047] Example 1:

[0048] Approximately 1 g of ferrocene carboxylic acid was weighed and suspended in 60 mL of dichloromethane. Three drops of N,N-dimethylformamide (DMF) were added dropwise under ice bath conditions, followed by 1 mL of oxaloyl chloride. The mixture was stirred at room temperature for 3 hours, and the organic solvent was removed by rotary evaporation under reduced pressure. The solution was then reconstituted in 30 mL of dichloromethane. While stirring, the solution was added dropwise to 30 mL of dichloromethane containing 3 mL of anhydrous ethylenediamine, and the mixture was stirred at room temperature for 48 hours. The solution was washed with 40 mL of 10% potassium hydroxide solution, allowed to stand for extraction, and the lower layer was collected. The crude product was obtained by rotary evaporation under reduced pressure. The crude product was then purified by column chromatography to obtain the pure target compound, amino-modified ferrocene, denoted here as Fc1.

[0049] Preparation of ferrocene-hyaluronic acid copolymer: 200 mg of hyaluronic acid (HA, molecular weight 90 kDa) was dissolved in 40 mL of a mixed solution of pH 6.5 PBS and DMF (3:2, V:V), and stirred until completely dissolved. Three hyaluronic acid solutions were prepared in this manner and used to prepare three hydrogel precursor patch dressings with different grafting rates, respectively. These formulations were designated A, B, and C. A certain mass of DMTMM was weighed into the above-mentioned mixed solution of pH 6.5 PBS and DMF (3:2, V:V) containing dissolved hyaluronic acid, and stirred at room temperature until completely dissolved. A certain mass of Fc1 was weighed into 5 mL of a mixed solution of pH 6.5 PBS and DMF (3:2, V:V), and after complete dissolution, it was added dropwise to the mixed solution of pH 6.5 PBS and DMF (3:2, V:V) containing both hyaluronic acid and DMTMM. After stirring at room temperature for 24 hours, the mixture was dialyzed with deionized water for 2 days, filtered through a 0.8 μm microporous membrane, and then lyophilized to obtain ferrocene-hyaluronic acid hydrogel precursor patches with different grafting ratios. Specific formulations are shown in Table 1.

[0050] Table 1. Formulation quantities for each hydrogel precursor patch preparation

[0051]

[0052] Hydrogen NMR spectroscopy was performed on each prescription hydrogel precursor patch. 1 Based on the spectral data obtained from H NMR detection, the grafting rates of each formulation are shown in Table 2.

[0053] Table 2 Grafting rates of hydrogel precursor patches for each formulation

[0054]

[0055] Test 1: Structural characterization of hyaluronic acid, Fc1, their physical mixture, and lyophilized hydrogel precursor patch samples. IR spectra are shown below. Figure 1 As shown, with the increase of Fc1 grafting rate, the vibrational stretching peaks attributed to amide II and amide III shift to lower wavenumbers, indicating an enhancement in hydrogen bond formation from the amide bond. The XRD spectrum is as follows: Figure 2 The results show that bonding Fc1 creates two new microcrystalline regions in the polymer molecular chain, which is beneficial for the transformation to a 3D structure. For example... Figure 3 As shown, each sample was prepared into a 0.5 mg / mL solution for CD characterization. The fitting results showed that hyaluronic acid molecular chains mostly exist in α-helical structures, while after bonding with ferrocene, they mostly exist in random coils, and the configuration change was the greatest in HF(5).

[0056] Test 2: Approximately 10 mg of each formulation of ferrocene-hyaluronic acid copolymer hydrogel precursor patch dressing was weighed and added to 200 μL of water and anticoagulated whole blood respectively to induce 3D structural transformation in a liquid environment. SEM morphology results of the dressings before and after structural transformation were shown... Figure 4 In the middle. By Figure 4 As can be seen, hydrogel precursor patches with different grafting ratios exhibit different morphologies at the microscopic level. With the increase of grafting ratio, the molecules become more tightly aggregated. HF(11) shows a banded structure, HF(5) is a combination of bands and short sheets, while HF(3) shows a membrane-like structure. After absorbing liquid, the patch transforms into a 3D mesh structure. With the increase of grafting ratio, the degree of gel cross-linking increases, and the mesh pore size gradually decreases. HF(5) and HF(3) have more blood cells adsorbed on their mesh walls, indicating that an increased grafting ratio is beneficial for the mesh structure to adsorb and retain blood cells and platelets. In addition, HF(5), due to its larger mesh diameter, can retain the largest number of cells.

[0057] Simultaneously, 10 mg of each prescription ferrocene-hyaluronic acid copolymer hydrogel precursor patch was weighed and added to water, FBS solution, and anticoagulated whole blood until saturation. The swelling rate was calculated, and the results are as follows: Figure 5 As shown.

[0058] Depend on Figure 5 It is evident that compared to commonly used clinical gauze, wound dressings, and hyaluronic acid hydrogels, the three hydrogel precursor patches exhibit significantly increased biofluid absorption, highlighting the liquid absorption effect of in-situ hydrogel structural transformation. HF(11) and HF(3) show significantly weaker liquid absorption capacity than HF(5). Combined with SEM images, it is clear that an appropriate grafting ratio significantly impacts exudate absorption capacity. A grafting ratio that is too low results in fewer absorption sites, an incomplete mesh structure, and poor liquid absorption capacity; a grafting ratio that is too high leads to high fiber material density, hindering liquid entry and adsorption, and resulting in a smaller transformed 3D mesh, thus reducing liquid absorption capacity.

[0059] Test 3: Approximately 10 mg of each formulation of ferrocene-hyaluronic acid copolymer hydrogel precursor patch was weighed and placed on isolated rat skin slices. FBS was applied to the contact surface to simulate exudate. The patch was pulled with forceps at the beginning and late stages of structural transition to compare its adhesion to the skin (see [link to test 3]). Figure 6 ).Depend on Figure 6 It is evident that HF(11), due to its poor cohesion, is prone to structural collapse when absorbing a large volume of liquid. HF(3), with its strong mechanical mesh structure, adheres strongly to the skin, potentially causing skin tearing during secondary dressing changes. HF(5), with moderate adhesion to the skin, is less likely to cause structural collapse when absorbing liquid, and does not cause skin damage during secondary dressing changes.

[0060] Test 4: Rats were general anesthetized by inhalation of isoflurane. Three circular full-thickness skin defects, each 8 mm in diameter, were cut along the midline of the back, extending to the fascia. The wounds were covered with PBS, HA hydrogel, and HF(5) wound dressings, and then covered with medical waterproof wound dressings. Rats were fed separately post-surgery. The wounds were photographed and their area was recorded periodically (1, 4, 6, 10, and 14 days). Figure 7 As shown in the figure. The results showed that the wound area had shrunk to 27% of its initial size by day 4, and was basically healed after 14 days. The strategy of transforming the hydrogel precursor patch into a 3D structure significantly accelerated skin healing.

[0061] Test 5: The inhibition zone method was used to conduct antibacterial experiments on Staphylococcus aureus and Escherichia coli with HF(5); skin tissue from days 6 and 14 of the wound healing efficacy experiment was collected, and the angiogenesis-promoting ability of HF(5) was evaluated by immunofluorescence staining of sections; the cell migration-promoting ability of HF(5) was verified by scratch assay. The results are as follows: Figure 8 As shown, HF(5) exhibits significant antibacterial activity, promotes early microvascular angiogenesis in wound healing, and significantly promotes fibroblast migration, which is beneficial for accelerating collagen deposition. HF(5) demonstrates significant multi-biological activity that promotes wound healing.

[0062] Example 2:

[0063] Approximately 1 g of ferrocene carboxylic acid was weighed and suspended in 60 mL of dichloromethane. Three drops of N,N-dimethylformamide (DMF) were added dropwise under ice bath conditions, followed by 1 mL of oxaloyl chloride. The mixture was stirred at room temperature for 3 hours, and the organic solvent was removed by rotary evaporation under reduced pressure. The solution was then reconstituted in 30 mL of dichloromethane. While stirring, the solution was added dropwise to 30 mL of dichloromethane containing 3 mL of anhydrous ethylenediamine, and the mixture was stirred at room temperature for 48 hours. The solution was washed with 40 mL of 10% potassium hydroxide solution, allowed to stand for extraction, and the lower layer was collected. The crude product was obtained by rotary evaporation under reduced pressure. The crude product was then purified by column chromatography to obtain the pure target compound, amino-modified ferrocene, denoted here as Fc1.

[0064] Preparation of iron-carboxylated chitosan: 200 mg of carboxylated chitosan (degree of deacetylation ≥95%, viscosity 10-200 mPa·s) was dissolved in a mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) and stirred until completely dissolved. 80 mg of DMTMM was weighed and added to a mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) containing dissolved carboxymethyl chitosan, and stirred until completely dissolved. Approximately 68 mg of Fc1 (as described in Example 1 above, or commercially available) was weighed into 5 mL of a mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) and completely dissolved. This solution was then added dropwise to the above mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) containing dissolved carboxylated chitosan and DMTMM, and stirred at room temperature for 24 hours. After dialyzing with deionized water for 2 days, the solution was filtered through a 0.8 μm microporous membrane and then lyophilized.

[0065] Example 3:

[0066] Iron-collagen preparation: 100 mg of collagen (type II, molecular weight 2000 Da, commercially available) was dissolved in a mixed solution of pH 6.5 PBS and N,N-dimethylformamide (3 / 2, v / v) and stirred until completely dissolved. 80 mg of DMTMM was weighed and added to the same mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) containing dissolved collagen, and stirred until completely dissolved. Approximately 68 mg of amino-modified ferrocene was weighed and added to 5 mL of a mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v), and after complete dissolution, it was added dropwise to the same mixed solution of dissolved collagen and DMTMM in the same solution. The mixture was stirred at room temperature for 24 hours. After dialyzing with deionized water for 2 days, the solution was filtered through a 0.8 μm microporous membrane and then lyophilized.

[0067] Example 4:

[0068] Preparation of iron-hyaluronic acid-collagen: 200 mg of hyaluronic acid (molecular weight 90 kDa) and 50 mg of collagen (type II, molecular weight 2000 Da, commercially available) were dissolved in a mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) and stirred until completely dissolved. 80 mg of DMTMM was weighed and added to the mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) containing hyaluronic acid and collagen, and stirred until completely dissolved. Approximately 68 mg of amino-modified ferrocene was weighed and added to 5 mL of a mixed solution of pH 6.5 PBS and N,N-dimethylformamide (3 / 2, v / v), and after complete dissolution, it was added dropwise to the above mixed solution of pH 6.5 PBS and DMF (3 / 2, v / v) containing hyaluronic acid, collagen, and DMTMM, and stirred at room temperature for 24 hours. Dialyzed with deionized water for 2 days, filtered through a 0.8 μm microporous membrane, and then lyophilized.

Claims

1. A multi-functional hydrogel precursor patch, characterized by: The patch is a fibrous hydrogel precursor obtained by chemical bonding of an organic polymer and a ferrocene derivative; The chemical bonding of the organic polymer and the ferrocene derivative under the action of a condensing agent obtains the precursor patch, wherein the organic polymer is 9.9-93.5% by weight, the ferrocene derivative is 3.3-27.1% by weight, and the rest is the condensing agent; The organic polymer is hyaluronic acid, carboxymethyl chitosan or collagen; the condensing agent is 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM); The ferrocene derivative is an amino or carboxyl modified ferrocene.

2. The multi-functional hydrogel precursor patch according to claim 1, wherein: The fibrous hydrogel precursor patch is placed on the wound bed and can undergo in situ gelation transformation after contacting the wound exudate to form a 3D grid structure hydrogel spontaneously, and is applied to the wound surface.

3. A preparation method of the multifunctional hydrogel precursor patch of claim 1, characterized in that: 1) Preparation of an organic polymer solution: dissolve the organic polymer in a mixed solution of PBS and an organic solvent, and use it, wherein the organic polymer is 0.2-20% by mass fraction; 2) Preparation of a ferrocene derivative solution: dissolve the ferrocene derivative in a mixed solution of PBS and an organic solvent to obtain a solution or suspension, and use it, wherein the ferrocene derivative is 0.14-11% by mass fraction; 3) Condensation of 1) and 2): add the condensing agent to the organic polymer solution obtained in step 1), dissolve it, then add the ferrocene derivative solution in step 2), and stir at 10-40°C for 4-48 hours to obtain the chemical bonding reaction; the final system contains 9.9-93.5% by weight of organic polymer, 3.3-27.1% by weight of ferrocene, and the rest is condensing agent.

4. The method of claim 3, wherein the multi-functional hydrogel precursor patch is prepared by: The bonded reactants are dialyzed against deionized water to 8000-14000 Da, the dialysate is filtered through a microporous filter membrane, and then freeze-dried to obtain the hydrogel precursor patch.

5. The method for preparing the multifunctional hydrogel precursor patch according to claim 3, characterized in that: The mixed solution in steps 1) and 2) is a mixed solution of PBS and DMSO, DMSO or formamide, with a pH of 5-7, and the volume ratio of PBS to DMSO, DMSO or formamide is 1:3-3:

1.

6. A method of producing a multi-functional hydrogel precursor patch according to any one of claims 3 to 5, characterised in that: The fibrous hydrogel precursor patch is placed on the wound surface to absorb wound exudate and form a 3D grid structure spontaneously.

Images