Metal organic framework / hydrogel composite material as well as preparation method and application thereof

Abstract

The invention belongs to the field of medical dressing materials, and particularly relates to a metal organic framework / hydrogel composite material and a method and application thereof. The hydrogel composite material contains hydrogel and a metal organic framework, and the hydrogel composite material has a hybrid structure formed by mutual intersection of the hydrogel and the metal organic framework. The preparation method of the hydrogel composite material comprises the following step: carrying out coordination reaction on a solution containing metal ions, small molecular ligands and hydrogel to obtain the hydrogel composite material. The hydrogel composite material has the flexibility of the hydrogel and the mechanical strength and long-acting antibacterial property of the metal organic framework, the hydrogel and the MOFs are compounded to organically combine a flexible material and a rigid material, the performance of the hydrogel and the performance of the MOFs are improved, and the application value of the hydrogel composite material in the medical field is expanded. In practical application, the hydrogel has the advantages of promoting wound healing, resisting bacteria and having biocompatibility.

Description

Technical Field

[0001] The present invention belongs to the field of medical dressing materials, and in particular relates to a metal organic framework / hydrogel composite material and a method and application thereof. Background Art

[0002] Wound healing and tissue repair are fundamental human health issues. To achieve rapid wound repair, a variety of biomedical materials, including electrospun fibers, porous sponges, and functionalized hydrogels, have been developed. Among these biomaterials, hydrogels have attracted much attention. They have many excellent properties, including maintaining a moist wound healing environment, reducing wound surface temperature, promoting cell proliferation and migration, and promoting the diffusion and penetration of nutrients. The wound healing process includes four stages: hemostasis, inflammation, proliferation, and remodeling. Although the hydrogels currently developed can only act on a single or two stages and have relatively simple functions, their clinical application has been greatly limited in recent years.

[0003] How to effectively inhibit the tissue deterioration caused by bacterial infection is a key problem in wound healing. Antibiotics are a common method for combating bacterial infection, but the use of antibiotics has many drawbacks. In recent years, new antibacterial hydrogels have great potential in actual anti-infection applications such as wound healing due to their good biocompatibility and resistance to drug. For example, in patent CN115300666A, a double network molecule (polyacrylamide and sodium alginate) was used to develop a composite hydrogel with antibacterial activity and light-assisted intelligent enhanced bactericidal activity, which has multiple functions such as hemostasis, anti-infection, and antioxidant. Although this composite hydrogel has good antibacterial activity, the silver nanoparticles as antibacterial components in this system are prone to aggregation, and the concentration and preparation process of the nanoparticles need to be strictly controlled, which requires relatively harsh experimental conditions.

[0004] Therefore, the development of a novel antibacterial hydrogel with uniform dispersion and sustained-release, long-term antibacterial efficacy is a technical challenge in this field. Furthermore, hydrogels are inherently soft, raising the question of how to create a hydrogel composite material that is both rigid and flexible, and thus expand its medical applications. Summary of the Invention

[0005] Metal-Organic Frameworks (MOFs) are porous materials with topological structures formed by self-assembly of metal ions and organic ligands. They are a type of crystalline porous material with a periodic network structure formed by self-assembly of inorganic metal centers (metal ions or metal clusters) and bridging organic ligands. They can fix metal ions in a three-dimensional framework structure through chemical bonds, effectively control the concentration and rate of metal ion release, and achieve long-lasting antibacterial effects. In recent years, some metal-organic framework compounds have been studied for use in the antibacterial field. For example, patent CN107823220A discloses a method of doping an iron-containing metal-organic framework with zinc ions that have antibacterial properties and can heal and repair skin wounds, thereby forming nanoparticles of a dual metal-organic framework antibacterial system containing iron ions and zinc ions. However, the resulting metal-organic frameworks are mostly bulk crystals or micro-nano particles, which are difficult to process, and thus greatly limit their application in medical dressings and other fields.

[0006] Through research, the inventors of the present invention have discovered that by mixing the precursors for forming metal-organic framework materials with a hydrogel solution and then growing the metal-organic framework material in situ within the hydrogel material, a hydrogel composite material can be obtained in which iron-based MOFs, shaped like mulberries, are grown in situ on a hydrogel network. The metal-organic framework material exhibits a single dispersed distribution without large-scale agglomeration. By compounding the hydrogel with MOFs, the flexible material and the rigid material are organically combined to obtain a hydrogel composite material that combines both rigidity and flexibility. This rigidity and flexibility hydrogel composite material can utilize the metal-organic framework to achieve a sustained-release, long-term antibacterial effect, avoiding the use of antibiotics, and can also utilize the softness, biocompatibility, and compliance of the hydrogel to improve the material's processability. This new hydrogel composite material combines hydrogel with MOFs to organically combine flexible and rigid materials, improving the performance of both and expanding its application value in the medical field.

[0007] Based on the above research, the first aspect of the present invention is to provide a hydrogel composite material comprising a hydrogel and a metal organic framework, wherein the hydrogel composite material has a hybrid structure formed by the cross-linking of the hydrogel and the metal organic framework.

[0008] According to some preferred embodiments of the present invention, as determined by thermogravimetric analysis, the content of the metal-organic framework in the hydrogel composite material, calculated on a solids basis, is 2-12 wt%, preferably 3-9 wt%, such as 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, or any two values ​​or any range therebetween.

[0009] In the present invention, thermogravimetric analysis is performed as follows: Quantitative and qualitative thermogravimetric testing is performed by placing a sample in the sample chamber of a thermogravimeter using nitrogen at a flow rate of 150 ml / min. The temperature is raised from room temperature to 100°C at a rate of 10°C / min, held for 5 minutes, and then raised again to 500°C at a rate of 10°C / min for 5 hours until the reaction is complete. The metal-organic framework exhibits significant weight loss at approximately 280-300°C, which allows determination of the metal-organic framework content; the remainder represents the hydrogel content.

[0010] According to some preferred embodiments of the present invention, the hydrogel is selected from hydrogel materials containing at least one group of -NH2, -OH, and -COOH in the molecular chain. In this way, during the in situ combination of MOFs and the hydrogel, the side groups (-NH2, -OH, -COOH, etc.) of the polymer chains forming the three-dimensional network of the hydrogel are easily coordinated with the metal ions that construct the MOFs, so that the MOFs grow in situ on the hydrogel skeleton, which can effectively improve the agglomeration effect in the growth of MOFs and make the MOFs grown in situ on the hydrogel network present a single dispersion.

[0011] The water content in the hydrogel composite material of the present invention is not particularly limited. For example, in general, the water content in the hydrogel composite material is 80-92 wt%, where the total mass of the hydrogel composite material is 100 wt%.

[0012] As a medical material, in order to obtain a composite material having softness, biocompatibility and compliance, preferably, the hydrogel is selected from at least one of gelatin, agar, carboxymethyl hydroxyethyl cellulose and hydroxypropyl cellulose.

[0013] According to some preferred embodiments of the present invention, the metal element in the metal organic framework is selected from at least one of iron, cobalt, zirconium and zinc.

[0014] According to some preferred embodiments of the present invention, the MOF ligand in the metal organic framework is selected from at least one of 2-aminoterephthalic acid, 2-hydroxyterephthalic acid, 2,4-diaminoterephthalic acid, and 2,4-dihydroxyterephthalic acid.

[0015] According to some preferred embodiments of the present invention, the metal organic framework is selected from at least one of MIL-88, MIL-53, MIL-89, and MIL-101 metal frameworks.

[0016] In the present invention, the presence of the metal organic framework in the hydrogel composite material can be detected by electron microscopy and XRD spectrum analysis.

[0017] According to some preferred embodiments of the present invention, the hydrogel composite material has at least one of the following characteristics:

[0018] Mechanical strength greater than 40kPa;

[0019] According to the test of GB / T20944.3-2008, the antibacterial rate of the hydrogel composite material against Escherichia coli and Staphylococcus aureus is greater than 90%.

[0020] According to some preferred embodiments of the present invention, the metal organic framework in the hydrogel composite material is in situ grown on the hydrogel skeleton. Preferably, the hydrogel has a network structure.

[0021] More preferably, according to a preferred embodiment of the present invention, the method for preparing the hydrogel composite material comprises subjecting a solution containing metal ions, small molecule ligands and hydrogel to a coordination reaction to obtain the hydrogel composite material.

[0022] The second aspect of the present invention is to provide a method for preparing a hydrogel composite material, preferably the method for preparing the hydrogel composite material described in the first aspect, comprising:

[0023] A solution containing metal ions, small molecule ligands and hydrogel is subjected to coordination reaction, so that a metal organic framework is in situ grown on the hydrogel framework to obtain the hydrogel composite material.

[0024] As mentioned above, in this way, when metal ions and small molecule ligands form MOFs, the side groups (-NH2, -OH, -COOH, etc.) of the polymer chains that form the hydrogel three-dimensional network coordinate with the metal ions that construct the MOFs, so that the MOFs grow in situ on the hydrogel skeleton, which can effectively improve the agglomeration effect in the growth of MOFs and make the MOFs grow in situ on the hydrogel network with single dispersion.

[0025] According to some preferred embodiments of the present invention, the preparation method comprises the following steps:

[0026] (1) mixing a soluble metal ion source, pluronic, a weakly acidic pH regulator, and a small molecule ligand to obtain a metal-organic framework precursor solution;

[0027] (2) mixing the metal organic framework precursor solution with the hydrogel solution to obtain a mixed precursor reaction solution;

[0028] (3) The mixed precursor reaction solution is subjected to coordination reaction under heating conditions, and then cooled and freeze-dried to obtain the hydrogel composite material.

[0029] According to some preferred embodiments of the present invention, the concentration of the soluble metal ion source in the metal organic framework precursor solution is 8-22 mmol / l, for example 8 mmol / l, 10 mmol / l, 12 mmol / l, 14 mmol / l, 16 mmol / l, 18 mmol / l, 20 mmol / l, 22 mmol / l, and any two values ​​or any interval between any two values. The inventors of the present invention have found through research that a suitable metal organic framework product can be obtained at this preferred concentration ratio, which is conducive to the uniform dispersion of the metal organic framework in the hydrogel material, has good mechanical strength, and has good antibacterial properties, and avoids the metal organic framework from agglomerating over a large area due to excessive concentration, which affects its performance.

[0030] In the present invention, the ratio of small molecule ligands to Pluronics can refer to the ratios used in the prior art for preparing MOFs. According to some preferred embodiments of the present invention, the molar ratio of the soluble metal ion source to the small molecule ligand is 1:(2-8), preferably 1:(4-6), based on the molar content of the metal element, and / or the molar ratio of the soluble metal ion source to Pluronics is 1:(0.1-0.3), preferably 1:(0.15-0.2). In this preferred embodiment, a composite material with better mechanical properties and better antibacterial properties can be obtained.

[0031] According to some preferred embodiments of the present invention, the weakly acidic pH regulator is selected from at least one of acetic acid, carbonic acid, and formic acid. More preferably, the amount of the weakly acidic pH regulator is such that the pH of the metal-organic framework precursor solution is 6-7. Specifically, the amount of the weakly acidic pH regulator can be flexibly adjusted depending on the type of weakly acidic pH regulator, for example, 5-7 L of acetic acid is used per mol of metal ion source.

[0032] According to some preferred embodiments of the present invention, the mass concentration of the hydrogel in the mixed precursor reaction solution is 5-20wt%, for example, 5wt%, 8wt%, 10wt%, 15wt%, 20wt%, and any two values ​​or any interval between any two values.

[0033] According to some preferred embodiments of the present invention, the hydrogel is selected from hydrogel materials containing at least one group of -NH2, -OH, and -COOH in the molecular chain; more preferably, the hydrogel is selected from at least one of gelatin, agar, carboxymethyl hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0034] According to some preferred embodiments of the present invention, the soluble metal ion source is selected from soluble metal salts, including but not limited to hydrochlorides, sulfates, and nitrates. As mentioned above, the metal element of the soluble metal salt is selected from at least one of iron, cobalt, zirconium, and zinc. For example, the iron salt includes but is not limited to one of ferric chloride, ferric sulfate, and ferric nitrate.

[0035] According to some preferred embodiments of the present invention, the small molecule ligand is selected from at least one of aminoterephthalic acid, 2-aminoterephthalic acid, 2-hydroxyterephthalic acid, 2,4-diaminoterephthalic acid, and 2,4-dihydroxyterephthalic acid.

[0036] According to some preferred embodiments of the present invention, the conditions of the coordination reaction include: a temperature of 100-150° C., and / or a time of 10-15 h.

[0037] As an example, the preparation method of the hydrogel composite material in the present invention includes the following steps:

[0038] Step 1: Weigh an appropriate amount of soluble iron salt and a certain proportion of Pluronic F127, add deionized water, and stir for a while. Then, add acetic acid and continue stirring for a while. Then, add the ligand solution aminoterephthalic acid and stir to obtain a metal organic framework precursor reaction solution.

[0039] Step 2: adding a certain amount of hydrogel and stirring for a period of time to prepare a mixed precursor reaction solution;

[0040] Step 3: Introduce the mixed precursor solution in step 2 into a suitable polymerization reactor. React at a suitable temperature for a period of time and then cool naturally;

[0041] Step 4: After the hydrothermal autoclave is cooled naturally, the hydrothermal autoclave is washed four times with ethanol and four times with deionized water, and freeze-dried for a period of time to obtain a composite medical antibacterial dressing.

[0042] Preferably, based on the above technical solution, taking iron salt as an example, the concentration of the soluble metal salt of iron salt in the metal organic framework precursor reaction solution in step 1 is 0.3-2wt% by mass.

[0043] In step 1, the concentration of Pluronic F127 is 2-4 wt %, the concentration of acetic acid is 5-10 wt %, the concentration of aminoterephthalic acid is 1-3 wt %, and the stirring time is 1-2 hours;

[0044] In step 2, the hydrogel solution is one of gelatin solution, agar, carboxymethyl hydroxyethyl cellulose or hydroxypropyl cellulose, the hydrogel concentration in the mixed precursor reaction solution is between 5-20%, and the stirring time is 1-2 hours;

[0045] In step 3, the reaction temperature is 100-150° C. and the reaction time is 10-15 hours; in step 4, the freeze-drying time is 48-72 hours.

[0046] In summary, the preparation process of the present invention is simple. The hydrogel is placed in a metal organic framework precursor solution, and MOFs are grown in situ on the hydrogel skeleton, which can avoid MOFs agglomeration and obtain the target material of the present invention.

[0047] The third aspect of the present invention is to provide an application of the hydrogel composite material described in the first aspect or the hydrogel composite material prepared by the preparation method described in the second aspect in the medical field, preferably in the field of medical dressing materials.

[0048] Through the technical content described above, it can be seen that the present invention has obtained a hydrogel composite material that combines rigidity and flexibility. This hydrogel composite material can not only utilize the metal organic framework to slowly release long-term antibacterial effects, avoiding the use of antibiotics, but also utilize the softness, biocompatibility and compliance of the hydrogel to improve the processability of the material. The hydrogel composite material of the present invention has both the softness of the hydrogel and the mechanical strength and long-term antibacterial properties of the metal organic framework. This new hydrogel composite material combines hydrogel with MOFs to organically combine flexible and rigid materials, improving the performance of both and expanding its application value in the medical field. In practical applications, it has the advantages of promoting wound healing, antibacterial, and biocompatibility.

[0049] Specifically, compared with the prior art, the present invention has the following beneficial effects:

[0050] (1) The preparation process of the present invention is simple. The hydrogel is placed in a metal organic framework precursor solution, and MOFs are grown in situ on the hydrogel to avoid MOFs agglomeration.

[0051] (2) The composite dressing prepared by the present invention does not rely on antibiotics for new wound dressings. MOFs can store and slowly release metal ions, and the antibacterial effect is long-lasting and effective;

[0052] (3) The composite dressing prepared by the present invention can not only utilize the metal organic framework to release a long-term antibacterial effect, thus avoiding the use of antibiotics, but also achieve both rigidity and flexibility, utilizing the softness, biocompatibility and compliance of the hydrogel to improve the processability of the material;

[0053] (4) The active components selected in the process of the present invention are all low-toxic and environmentally friendly products with low cost and good economic and environmental benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1Electron micrograph of the novel metal-organic framework / hydrogel medical dressing (i.e., hydrogel composite material) in Example 1;

[0055] Figure 2 Electron micrograph of the novel metal-organic framework / hydrogel medical dressing in Comparative Example 1;

[0056] Figure 3 Schematic diagram of the in vitro antibacterial performance verification of the novel metal-organic framework / hydrogel medical dressing in Example 1;

[0057] Figure 4 In vitro antibacterial performance curve of the novel metal-organic framework / hydrogel medical dressing in Example 1. DETAILED DESCRIPTION

[0058] The present invention will be described in detail below with reference to specific embodiments. It is necessary to point out that the following embodiments are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art to the present invention based on the contents of the present invention still fall within the scope of protection of the present invention.

[0059] In the following embodiments:

[0060] Antibacterial performance test: According to the national standard of the People's Republic of China "GB / T20944.3-2008", the antibacterial performance of the hydrogel was characterized using common Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) as representatives of Gram-positive and Gram-negative bacteria respectively. The antibacterial performance of the composite dressing was tested using the agar plate diffusion method. First, the sample and the control group were sterilized under ultraviolet light for 30 minutes, and then immersed in 10 4 After culturing for 24, 48, and 48 hours, 100 ml of the culture medium was streaked onto nutrient agar plates. The plates were then incubated overnight at 37°C and observed for bacterial adhesion under an inverted fluorescence microscope. The number of colonies on each plate was calculated. The number of colonies obtained in the control was designated as NC, and the number of colonies obtained in the sample was designated as NS. The antibacterial rate (R, %) was calculated as follows: R = (NC – NS) / NC × 100%.

[0061] Mechanical properties of hydrogels were tested at room temperature using a WDW-05 electronic universal testing machine (Time Group Inc., China). At least three samples were tested for each mechanical property. For the tensile properties test, hydrogel samples were cut into trouser shapes (7.5 mm wide, 50 mm long, 20 mm cut length, and 2 mm thickness) according to the standard (GBT 529-2008A). The tensile rate was set at 50 mm min. -1 .

[0062] In the following examples, the composite medical antibacterial dressing was confirmed to contain a metal organic framework by the following specific detection methods: on the one hand, it can be analyzed by electron microscopy, because the morphology of the metal organic framework is unique and not an ordinary spherical nanoparticle. For example, the metal organic framework in the present invention is a spindle shape; on the other hand, the metal organic framework is analyzed by XRD, i.e. powder X-ray diffraction (X Pert Pro diffractometer). Using CuKα radiation, the main component is a wavelength of The test range is 10-80°. The structure of the medical antibacterial dressing can be determined by comparing the XRD pattern with the crystallographic information file (CIF).

[0063] In the following examples, the content of MOFs and hydrogel materials in the composite medical antibacterial dressings was quantitatively and qualitatively determined using thermogravimetric analysis. The sample was placed in the sample chamber of a thermogravimetric analyzer, and nitrogen was used at a flow rate of 150 ml / min. The temperature was raised from room temperature to 100°C at a rate of 10°C / min. After a 5-minute dwell, the temperature was again raised to 500°C at a rate of 10°C / min and allowed to react for 5 hours until the reaction was complete. The metal-organic framework (MOF) content was clearly detectable at temperatures between 280 and 300°C, with the remainder representing the hydrogel content.

[0064] Content of metal organic framework (wt%) = m1 / m0×100wt%

[0065] m1 is the weight loss of the sample at 280-300 °C;

[0066] m0 is the weight of the initial sample placed in the sample chamber.

[0067] In the following examples, all the raw materials used are conventional commercially available products.

[0068] In the following examples and comparative examples, unless otherwise specified, the temperature condition is room temperature (20-25° C.).

[0069] In the following examples and comparative examples, the pH of the metal organic framework precursor reaction solution was in the range of 6-7.

[0070] Example 1

[0071] Step 1: Weigh 0.049 g of Fe(NO₃)₃·6H₂O and 0.32 g of Pluronic F127, add 10 mL of deionized water, and stir for 1 hour. Then, add 0.7 mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120 mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0072] Step 2: Add 1 g of gelatin and stir for a period of time to prepare a mixed precursor reaction solution;

[0073] Step 3: Introduce the mixed precursor solution in step 2 into a 20ml polymerization reactor, react at 120°C for 12 hours, and then cool naturally;

[0074] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing (ie, the hydrogel composite material of the present invention).

[0075] The electron microscopy and XRD spectrum analysis methods confirmed that the composite medical antibacterial dressing contained a metal organic framework, which was MIL-88-Fe-NH2.

[0076] like Figure 1 As shown in the figure, the iron-based MOFs shaped like mulberries are in situ grown on the hydrogel network and show single dispersion. It can be seen that the method of in situ growth of MOFs on the hydrogel skeleton adopted in the present invention can effectively improve the agglomeration effect in the growth of MOFs. This is because in the process of in situ combination of MOFs and hydrogel, the side groups (-NH2, -OH, etc.) of the polymer chains forming the three-dimensional network of the hydrogel are easy to coordinate with the metal ions that construct the MOFs.

[0077] Thermogravimetric analysis confirmed that the content of MOFs in the composite medical antibacterial dressing was 5wt%, and the rest was hydrogel content.

[0078] Example 2

[0079] Step 1: Weigh 0.049 g of Fe(NO₃)₃·6H₂O and 0.32 g of Pluronic F127, add 10 mL of deionized water, and stir for 1 hour. Then, add 0.7 mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120 mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0080] Step 2: Add 1 g of agar and stir for a while to prepare a mixed precursor reaction solution;

[0081] Step 3: Introduce the mixed precursor solution from step 2 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0082] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0083] It was confirmed that the composite medical antibacterial dressing contained a metal organic framework, which was MIL-88-Fe-NH2. The content of MOFs in the composite medical antibacterial dressing was close to that in Example 1.

[0084] Example 3

[0085] Step 1: Weigh 0.074g of Fe(NO₃)₃·6H₂O and 0.48g of Pluronic F127, add 10mL of deionized water, and stir for 1 hour. Then, add 1mL of acetic acid and continue stirring for another hour. Then, accurately weigh 180mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0086] Step 2: Add 1 g of gelatin and stir for a period of time to prepare a mixed precursor reaction solution;

[0087] Step 3: Introduce the mixed precursor solution from step 2 into a 120ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0088] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0089] It has been confirmed that the composite medical antibacterial dressing contains a metal organic framework, which is MIL-88-Fe-NH2.

[0090] Thermogravimetric analysis confirmed that the content of MOFs in the composite medical antibacterial dressing was 8 wt%, and the rest was hydrogel content.

[0091] Example 4

[0092] Step 1: Weigh 0.074g of Fe(NO₃)₃·6H₂O and 0.48g of Pluronic F127, add 10mL of deionized water, and stir for 1 hour. Then, add 1mL of acetic acid and continue stirring for another hour. Then, accurately weigh 180mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0093] Step 2: Add 1 g of agar and stir for a while to prepare a mixed precursor reaction solution;

[0094] Step 3: Introduce the mixed precursor solution from step 2 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0095] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0096] It was confirmed that the composite medical antibacterial dressing contained a metal organic framework, which was MIL-88-Fe-NH2. The content of MOFs in the composite medical antibacterial dressing was close to that in Example 3.

[0097] Example 5

[0098] Step 1: Weigh 0.035g Co(NO₃)₂·6H₂O and 0.32g Pluronic F127, add 10mL of deionized water, and stir for 1 hour. Then, add 0.7mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0099] Step 2: Add 1 g of gelatin and stir for a period of time to prepare a mixed precursor reaction solution;

[0100] Step 3: Introduce the mixed precursor solution from step 2 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0101] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0102] It has been confirmed that the composite medical antibacterial dressing contains a metal organic framework, which is MIL-88-Co-NH2.

[0103] Thermogravimetric analysis confirmed that the content of MOFs in the composite medical antibacterial dressing was 4 wt%, and the rest was hydrogel content.

[0104] Example 6

[0105] Step 1: Weigh 0.051 g of Zr(NO₃)₄·5H₂O and 0.32 g of Pluronic F127, add 10 mL of deionized water, and stir for 1 hour. Then, add 0.7 mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120 mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0106] Step 2: Add 1 g of gelatin and stir for a period of time to prepare a mixed precursor reaction solution;

[0107] Step 3: Introduce the mixed precursor solution from step 2 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0108] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0109] It has been confirmed that the composite medical antibacterial dressing contains a metal organic framework, which is MIL-88-Zr-NH2.

[0110] Thermogravimetric analysis confirmed that the content of MOFs in the composite medical antibacterial dressing was 4 wt%, and the rest was hydrogel content.

[0111] Example 7

[0112] Step 1: Weigh 0.036g of Zn(NO₃)₂·6H₂O and 0.32g of Pluronic F127, add 10mL of deionized water, and stir for 1 hour. Then, add 0.7mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0113] Step 2: Add 1 g of gelatin and stir for a period of time to prepare a mixed precursor reaction solution;

[0114] Step 3: Introduce the mixed precursor solution from step 2 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0115] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0116] It has been confirmed that the composite medical antibacterial dressing contains a metal organic framework, which is MIL-88-Zn-NH2.

[0117] Thermogravimetric analysis confirmed that the content of MOFs in the composite medical antibacterial dressing was 5wt%, and the rest was hydrogel content.

[0118] Comparative Example 1

[0119] Step 1: Weigh 0.049 g of Fe(NO₃)₃·6H₂O and 0.32 g of Pluronic F127, add 10 mL of deionized water, and stir for 1 hour. Then, add 0.7 mL of acetic acid and continue stirring for another hour. Then, accurately weigh 120 mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0120] Step 2: Introduce the mixed precursor solution from step 1 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0121] Step 3: Add 1 g of gelatin solution to the prepared MOFs skeleton and stir for a period of time to prepare a mixed precursor reaction solution;

[0122] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0123] Comparative Example 2

[0124] Step 1: Weigh 0.074g of Fe(NO₃)₃·6H₂O and 0.48g of Pluronic F127, add 10mL of deionized water, and stir for 1 hour. Then, add 1mL of acetic acid and continue stirring for another hour. Then, accurately weigh 180mg of 2-aminoterephthalic acid to obtain a metal-organic framework precursor reaction solution.

[0125] Step 2: Introduce the mixed precursor solution from step 1 into a 20ml polymerization reactor. Incubate the reaction at 120°C for 12 hours and then cool naturally.

[0126] Step 3: Add 1 g of gelatin solution to the prepared MOFs skeleton and stir for a period of time to prepare a mixed precursor reaction solution;

[0127] Step 4: After the hydrothermal autoclave is cooled naturally, the mixture is washed four times with ethanol and four times with deionized water, and freeze-dried for 48 hours to obtain a composite medical antibacterial dressing.

[0128] Test example

[0129] The antibacterial performance test and mechanical performance test were performed on the composite medical antibacterial dressings obtained in the examples and comparative examples. Some of the results are shown in Table 1.

[0130] Table 1

[0131] name Mechanical strength (kPa) Antibacterial rate after 24 hours (%) Example 1 46 96 Example 2 43 95 Example 3 78 97 Example 4 79 97 Comparative Example 1 31 71 Comparative Example 2 32 75

[0132] Taking Example 1 as an example, we designed a new dressing with MIL-88-Fe-NH2 as the antibacterial component and combined with common hydrogels such as gelatin. 3+ Ions inhibit bacterial growth by depriving bacteria of the iron ions they need. In this invention, we systematically evaluated the antibacterial effect of the sample in Example 1 using two common bacteria found in skin wounds: Staphylococcus aureus and Escherichia coli, using the plate colony counting method and quantitative calculation of the antibacterial rate. Figure 3 and Figure 4 It can be seen that due to the positive interaction between the metal organic framework and the hydrogel, the sample of Example 1 effectively inhibited the adhesion and reproduction of bacteria on the surface of the material. Figure 3 In the example 1, the number of bacterial colonies on the surface is very small. After calculation, the average antibacterial rate of the example 1 can reach more than 95%. Figure 3 and Figure 4 ) showed that the dressing could significantly inhibit the growth of drug-resistant Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus.

[0133] It is worth noting that compared with Comparative Example 1 ( Figure 2 ), in Example 1, as Figure 1As shown in Figure 2, the mulberry-shaped iron-based MOFs were grown in situ on the hydrogel network and showed a single dispersion. Figure 2 In the hydrogel, the metal organic framework undergoes large-scale agglomeration. It can be seen that the method of in situ growth of MOFs on the hydrogel skeleton in the present invention can effectively improve the agglomeration effect during the growth of MOFs.

[0134] The same method was used to perform antibacterial tests and mechanical strength tests on the composite medical antibacterial dressings in the examples and comparative examples. The results are shown in Table 1. The tests showed that Examples 5-7 had similar effects to Example 1.

[0135] In summary, the composite dressing (hydrogel composite material) obtained by the in situ method of the present invention has both the softness of hydrogel and the mechanical strength and long-term antibacterial properties of metal-organic frameworks. This new hydrogel composite material combines hydrogel with MOFs, organically combining flexible materials and rigid materials, improving the performance of both and expanding its application value in the medical field. In practical applications, it has the advantages of promoting wound healing, antibacterial properties, and biocompatibility.

[0136] It should be noted that the embodiments described above are only used to explain the present invention and do not constitute any limitation of the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present invention may be modified as specified within the scope of the claims of the present invention, and the present invention may be revised without departing from the scope and spirit of the present invention. Although the present invention described therein relates to specific methods, materials and embodiments, it does not mean that the present invention is limited to the specific examples disclosed therein. On the contrary, the present invention can be extended to all other methods and applications with the same function.

[0137] All publications, patent applications, patents, and other references mentioned in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used in this specification have the meanings conventionally understood by those skilled in the art. In the event of conflict, the definitions in this specification shall prevail.

[0138] When this specification uses the prefix "well known to those skilled in the art", "prior art" or similar terms to introduce materials, substances, methods, steps, devices or components, the objects introduced by the prefix include those commonly used in the art when this application is filed, but also include those that are not commonly used at present but will become generally recognized in the art to be suitable for similar purposes.

[0139] The endpoints and any values ​​of the ranges disclosed in this application document are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and a separate point value, and the separate point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article. Hereinafter, in principle, each technical solution can be combined with each other to obtain a new technical solution, which should also be considered as specifically disclosed in this article.

[0140] In the context of this specification, any matters or items not mentioned are directly applicable to those known in the art without any changes except those explicitly stated.

[0141] Moreover, any embodiment described herein may be freely combined with one or more other embodiments described herein, and the technical solutions or technical ideas thus formed shall be deemed as part of the original disclosure or original record of the present invention, and shall not be regarded as new content that has not been disclosed or anticipated herein, unless a person skilled in the art considers that the combination is obviously unreasonable.

Claims

1. A hydrogel composite material comprising a hydrogel and a metal organic framework, wherein the hydrogel composite material has a hybrid structure formed by the cross-linking of the hydrogel and the metal organic framework.

2. The hydrogel composite material according to claim 1, wherein: The content of the metal organic framework in the hydrogel composite material is 2-12 wt %, preferably 3-9 wt %, based on solid content, as determined by thermogravimetric analysis; and / or The hydrogel is selected from hydrogel materials containing at least one group of -NH2, -OH, and -COOH in the molecular chain; preferably, the hydrogel is selected from at least one of gelatin, agar, carboxymethyl hydroxyethyl cellulose, and hydroxypropyl cellulose.

3. The hydrogel composite material according to claim 1, wherein: The metal element in the metal organic framework is selected from at least one of iron, cobalt, zirconium and zinc; and / or, The MOF ligand in the metal organic framework is selected from at least one of 2-aminoterephthalic acid, 2-hydroxyterephthalic acid, 2,4-diaminoterephthalic acid, and 2,4-dihydroxyterephthalic acid; Preferably, the metal organic framework is selected from at least one of MIL-88, MIL-53, MIL-89, and MIL-101 metal frameworks.

4. The hydrogel composite material according to claim 1, wherein: The hydrogel composite material has at least one of the following characteristics: Mechanical strength greater than 40kPa; According to the test of GB / T20944.3-2008, the antibacterial rate of the hydrogel composite material against Escherichia coli and Staphylococcus aureus is greater than 90%.

5. The hydrogel composite material according to any one of claims 1 to 4, characterized in that: The metal organic framework in the hydrogel composite material is in situ grown on the hydrogel skeleton; preferably, The preparation method of the hydrogel composite material comprises the steps of carrying out coordination reaction on a solution containing metal ions, small molecule ligands and hydrogel to obtain the hydrogel composite material.

6. A method for preparing a hydrogel composite material, preferably the method for preparing a hydrogel composite material according to any one of claims 1 to 5, comprising: A solution containing metal ions, small molecule ligands and hydrogel is subjected to coordination reaction to obtain the hydrogel composite material.

7. The preparation method according to claim 6, characterized in that The following steps are involved: (1) mixing a soluble metal ion source, pluronic, a weakly acidic pH regulator, and a small molecule ligand to obtain a metal-organic framework precursor solution; (2) mixing the metal organic framework precursor solution with the hydrogel solution to obtain a mixed precursor reaction solution; (3) The mixed precursor reaction solution is subjected to coordination reaction under heating conditions, and then cooled and freeze-dried to obtain the hydrogel composite material.

8. The preparation method according to claim 7, characterized in that: The concentration of the soluble metal ion source in the metal organic framework precursor solution is 8-22 mmol / l; and / or, The molar ratio of the soluble metal ion source to the small molecule ligand is 1:(2-8), preferably 1:(4-6), based on the molar content of the metal element, and / or the molar ratio of the soluble metal ion source to the pluronic is 1:(0.1-0.3), preferably 1:(0.15-0.2); and / or, The weakly acidic pH regulator is selected from at least one of acetic acid, carbonic acid and formic acid; preferably, the amount of the weakly acidic pH regulator is such that the pH of the metal organic framework precursor solution is 6-7.

9. The preparation method according to claim 7, characterized in that: The mass concentration of the hydrogel in the mixed precursor reaction solution is 5-20 wt%; and / or, The hydrogel is selected from hydrogel materials containing at least one group of -NH2, -OH, and -COOH in the molecular chain; preferably, the hydrogel is selected from at least one of gelatin, agar, carboxymethyl hydroxyethyl cellulose, and hydroxypropyl cellulose.

10. The preparation method according to any one of claims 7 to 9, characterized in that: The soluble metal ion source is selected from soluble metal salts; and / or, The small molecule ligand is selected from at least one of aminoterephthalic acid, 2-aminoterephthalic acid, 2-hydroxyterephthalic acid, 2,4-diaminoterephthalic acid, and 2,4-dihydroxyterephthalic acid; and / or, The conditions of the coordination reaction include: a temperature of 100-150° C., and / or a time of 10-15 hours.

11. Use of the hydrogel composite material according to any one of claims 1 to 5 or the hydrogel composite material prepared by the preparation method according to any one of claims 6 to 10 in the medical field, preferably in the field of medical dressing materials.

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