An electrospun gastric perforation patch based on Ag / Zn bimetallic MOF and its preparation method

Abstract

This invention provides an electrospun gastric perforation patch based on Ag / Zn bimetallic MOF and its preparation method. The gastric perforation patch comprises a tissue integration layer, an antibacterial drug-loaded core layer, and an anti-adhesion layer integrally formed by electrospinning. The antibacterial drug-loaded core layer is composed of Ag / Zn bimetallic MOF loaded with antifungal drugs and a biodegradable polymer material. In the Ag / Zn bimetallic MOF, the molar ratio of zinc to silver is (8:1) to (12:1), and the antifungal drug is voriconazole or amphotericin B. This invention combines the broad-spectrum antimicrobial properties of Ag / Zn bimetallic MOF with a three-layer functional gradient design, enabling the patch to adhere firmly to tissue without sutures. It can actively prevent infection, inhibit adhesion, promote tissue regeneration, and gradually degrade and absorb postoperatively, significantly reducing the risk of foreign body reaction, infection, and recurrence, demonstrating excellent biocompatibility and broad clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to an electrospun gastric perforation patch based on Ag / Zn bimetallic MOF and its preparation method. Background Technology

[0002] Gastric perforation repair surgery is a common surgical procedure for treating gastric perforation. Traditional repairs widely use non-degradable synthetic patches such as polypropylene and polyester. While these materials provide mechanical support to the tissue, their surfaces also create conditions for the adhesion and proliferation of bacteria and fungi, easily leading to postoperative infection. In severe cases, patch rejection may occur, requiring a second surgery for removal. Furthermore, the mechanical properties of these materials differ significantly from those of human tissue, easily causing stress concentration and chronic pain. Their long-term presence can also trigger persistent inflammatory responses, affecting normal tissue healing.

[0003] In recent years, electrospinning technology has been widely used in tissue engineering repair due to its ability to prepare nanofiber scaffolds that mimic the extracellular matrix. These scaffolds have high specific surface area and tunable pore structure, which is beneficial for cell migration and tissue ingrowth. However, traditional electrospun patches have a single function, mainly providing physical support, and cannot simultaneously meet multiple biological requirements such as anti-infection, anti-adhesion, and promoting healing.

[0004] To enhance anti-infective properties, existing technologies have developed antibacterial patches that load silver ions or antibiotics through surface coatings or blending. However, these modifications suffer from problems such as narrow antibacterial spectrum, burst drug release, short duration of action, and susceptibility to inducing drug resistance. Metal-organic frameworks (MOFs), as an emerging porous nanomaterial, have shown great potential in controlled antibacterial ion release and drug loading, but how to stably and efficiently integrate them into fiber scaffolds and achieve synergistic regulation of structure and function remains a current technical challenge.

[0005] Therefore, existing gastric perforation repair materials still have significant shortcomings in terms of broad-spectrum antibacterial properties, anti-adhesion, stable mechanical support, and tissue integration. A novel composite gastric perforation patch that can systematically solve the above problems is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to overcome the deficiencies of the prior art and provide an electrospun gastric perforation patch based on Ag / Zn bimetallic MOF and its preparation method. The patch of this invention integrates active antibacterial, anti-adhesion, tissue integration promotion and drug controlled release, aiming to significantly reduce the risk of postoperative complications and recurrence.

[0007] This invention provides the following technical solution: This invention provides an electrospun gastric perforation patch based on Ag / Zn bimetallic MOF. The gastric perforation patch includes a tissue integration layer, an antibacterial drug-loaded core layer, and an anti-adhesion layer integrally formed by electrospinning. The antibacterial drug-loaded core layer is composed of Ag / Zn bimetallic MOF loaded with antifungal drugs and a biodegradable polymer material. In the Ag / Zn bimetallic MOF, the molar ratio of zinc to silver is (8:1) to (12:1), and the antifungal drug is voriconazole or amphotericin B.

[0008] Furthermore, the biodegradable polymer material is a mixture of polylactic acid-glycolic acid copolymer and polycaprolactone, wherein the mass ratio of polylactic acid-glycolic acid copolymer to polycaprolactone is (6:4) to (8:2).

[0009] Furthermore, the Ag / Zn bimetallic MOF loaded with antifungal drugs accounts for 8% to 12% of the mass of the antibacterial drug-loaded core layer.

[0010] Furthermore, the thickness of the tissue integration promoting layer is 40μm to 60μm, the thickness of the antibacterial drug-carrying core layer is 70μm to 90μm, and the thickness of the anti-adhesion layer is 20μm to 40μm.

[0011] Furthermore, the anti-adhesion layer contains 1% to 3% hyaluronic acid by mass of the total polymer to enhance its lubrication and physical isolation effects.

[0012] This invention also provides a method for preparing the above-mentioned electrospun gastric perforation patch based on Ag / Zn bimetallic MOF, comprising the following steps: S1. Synthesize Ag / Zn bimetallic MOF and load it with antifungal drugs to obtain drug-loaded MOF powder; S2. Prepare a common base solution for biodegradable polymers and divide it into three equal parts, which are used to prepare electrospinning solutions for the tissue integration layer, the antibacterial drug-loaded core layer and the anti-adhesion layer, respectively. S3. Using a three-channel electrospinning device, the tissue integration layer, the antibacterial drug-loaded core layer, and the anti-adhesion layer are spun sequentially on the same receiving device to obtain a three-layer composite patch. S4. The obtained three-layer composite patch is subjected to vacuum drying and heat annealing to completely remove the solvent and enhance the interlayer bonding force. S5. Demolding, cutting, and terminal sterilization and packaging.

[0013] Further, in step S1, the method for synthesizing Ag / Zn bimetallic MOF is as follows: zinc nitrate, silver nitrate and 2-methylimidazole are dissolved in methanol and mixed, reacted at room temperature for 20 to 28 hours, and obtained by centrifugation, washing and drying, wherein the molar ratio of zinc to silver is (8:1) to (12:1).

[0014] Further, in step S2, the amount of drug-loaded MOF powder added is 8% to 12% (w / w) of the total mass of the biodegradable polymer, and it is ultrasonically treated for 30 to 60 minutes to make it uniformly dispersed.

[0015] Furthermore, in step S3, the process parameters for electrospinning are: spinning voltage 16-20 kV, receiving distance 12-18 cm, spinning solution propulsion speed 0.5-1.0 mL / h; ambient temperature controlled at 22-26℃, and relative humidity controlled at 40%-60%.

[0016] Furthermore, in step S4, the vacuum drying conditions are drying at 35-45°C for 36-60 hours; the heat annealing conditions are processing at 55-65°C for 3-8 minutes.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. Active and long-lasting anti-infection capability: This invention utilizes the controllable degradation characteristics of Ag / Zn bimetallic MOFs in the physiological environment to synergistically release Ag. + With Zn 2+ It produces a broad-spectrum and potent antibacterial effect and can release antifungal drugs in a long-lasting manner, achieving dual active prevention of bacterial and fungal infections and fundamentally reducing the risk of patch-related infections.

[0018] 2. Integrated gradient functional design: Through three-layer electrospinning integrated molding technology, the three functions of "promoting tissue integration", "antibacterial drug delivery" and "physical anti-adhesion" are precisely integrated into a single patch. This biomimetic gradient structure can simultaneously meet multiple clinical needs such as firm integration with gastric tissue, active defense against microbial invasion, and prevention of visceral adhesion.

[0019] 3. Excellent biocompatibility and biodegradability: The patch is based on the biodegradable polymer PLGA / PCL, which has good tissue compatibility with the human body. Its three-dimensional nanofiber structure facilitates cell ingrowth and tissue repair, and it can eventually be degraded and absorbed by the human body, avoiding the risk of chronic inflammation and pain caused by permanent foreign bodies.

[0020] 4. Stable mechanical fixation and good operability: The patch has good flexibility and mechanical strength, and can be biomechanically matched with the stomach tissue. Its macroscopic structure provides reliable mechanical support without relying entirely on suture fixation, simplifying surgical procedures and reducing tissue damage caused by sutures.

[0021] This invention provides a new generation of intelligent gastric perforation patch with active antibacterial, anti-adhesion, healing-promoting and biodegradable properties through synergistic innovation of materials and structure. Compared with traditional products, it has significant advantages in preventing postoperative complications and promoting functional repair, and has broad clinical application prospects and market value. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is a flowchart of the preparation process of Example 1 of the present invention; Figure 2 The graph shows the instant antibacterial test results of patches in Embodiment 1 and Comparative Examples 1-4 of the present invention. Figure 3 This is a graph showing the change in antibacterial rate of Staphylococcus aureus in patches of Examples 1 and 4 of the present invention. Figure 4 The graphs show the changes in the antibacterial rate of Candida albicans in patches of Examples 1 and 4 of the present invention. Detailed Implementation

[0024] 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.

[0025] This invention provides an electrospun gastric perforation patch based on Ag / Zn bimetallic MOF and its preparation method. The gastric perforation patch includes a tissue integration layer, an antibacterial drug-loaded core layer, and an anti-adhesion layer integrally formed by electrospinning. The antibacterial drug-loaded core layer is composed of Ag / Zn bimetallic MOF loaded with antifungal drugs and a biodegradable polymer material. In the Ag / Zn bimetallic MOF, the molar ratio of zinc to silver is (8:1) to (12:1), and the antifungal drug is voriconazole or amphotericin B.

[0026] In a specific embodiment, the molar ratio of zinc to silver in the Ag / Zn bimetallic MOF can be any ratio between 8:1, 10:1, 12:1, or (8:1) to (12:1). The mass percentage of the Ag / Zn bimetallic MOF loaded with antifungal drugs in the antibacterial drug-loaded core layer is any value between 8%, 10%, 12%, or 8% to 12%. The thickness of the tissue integration promoting layer is 40 μm to 60 μm, the thickness of the antibacterial drug-loaded core layer is 70 μm to 90 μm, and the thickness of the anti-adhesion layer is 20 μm to 40 μm.

[0027] The present invention will be further illustrated below through specific embodiments: Example 1: The preparation method provided in this embodiment includes the following specific steps: Synthesis and Drug Loading of S10, Ag / Zn Bimetallic MOFs: 2.97 g of zinc nitrate and 0.17 g of silver nitrate (molar ratio 10:1) were dissolved in 50 mL of methanol; 3.28 g of 2-methylimidazole was dissolved in 50 mL of methanol. The two solutions were mixed under magnetic stirring and reacted at room temperature for 24 hours. The precipitate was collected by centrifugation (8000 rpm, 10 min), washed three times with methanol, and dried under vacuum at 60°C for 12 hours to obtain Ag / Zn bimetallic MOF powder. 100 mg of MOF powder was dispersed in 50 mL of methanol solution containing 50 mg of voriconazole, stirred in the dark for 48 hours, collected by centrifugation, and dried under vacuum at 40°C to obtain drug-loaded MOF powder.

[0028] S20. Preparation of the three-layer electrospinning solution: Prepare a 12% (w / v) DMF / THF (volume ratio 7:3) solution of PLGA / PCL (mass ratio 7:3) as a common substrate, and magnetically stir for 12 hours until completely dissolved. Divide the common substrate solution into three portions: Layer 1 (tissue integration layer) spinning solution: take the substrate solution without adding MOF; Layer 2 (antibacterial drug-loaded core layer) spinning solution: take the substrate solution, add 10wt% drug-loaded MOF, and ultrasonically disperse for 30 minutes; Layer 3 (anti-adhesion layer) spinning solution: take the substrate solution, add 2wt% hyaluronic acid.

[0029] S30, Three-layer sequential electrospinning: A three-channel electrospinning device is used, with parameters set as follows: voltage 18kV, receiving distance 15cm, feed speed 0.8mL / h, ambient temperature 25°C, and relative humidity 50%. First, Layer 1 (tissue integration layer) is spun for 2 hours, then Layer 2 (antibacterial drug-loaded core layer) is spun for 3 hours, and finally Layer 3 (anti-adhesion layer) is spun for 1 hour.

[0030] S40. Post-treatment and strengthening: The obtained three-layer composite patch was dried in a vacuum drying oven at 40°C for 48 hours, and then heat-annealed at 60°C for 5 minutes.

[0031] S50. Terminal processing: Remove the patch from the receiving device, cut it into a standard size of 10cm×15cm, sterilize it with ethylene oxide, and finally encapsulate it under aseptic conditions and store it at 4°C for later use.

[0032] The prepared patch was subjected to performance testing: (1) Antibacterial performance test: According to GB / T 15979-2002 standard, the inhibition rate against Staphylococcus aureus and Escherichia coli reached 99.2% and 98.7% respectively; the diameter of the inhibition zone against Candida albicans reached 12.5±0.5mm.

[0033] (2) Mechanical property test: The tensile strength of the patch was 4.5±0.3MPa and the elongation at break was 65±5% when measured by a universal testing machine; the interlayer bond strength was 0.85±0.05N / cm².

[0034] (3) Biocompatibility test: The relative proliferation rate of L929 cells after culturing in patch extract for 72 hours was 96.5±2.1% by CCK-8 method.

[0035] (4) Drug release test: Voriconazole showed a steady release trend after continuous monitoring in PBS buffer for 360 hours, with a cumulative release rate of 78.2±3.5% over 360 hours.

[0036] In this embodiment, the Ag / Zn bimetallic MOF uses Zn 2+ With Ag + The synergistic effect of these components not only significantly broadens the antibacterial spectrum and enhances antibacterial efficacy, but its porous structure also enables efficient loading and long-lasting sustained release of antifungal drugs. The three-layered electrospun structure, after thermal annealing, forms a stable interfacial bond. Its biomimetic fiber network structure is highly similar to the extracellular matrix of gastric tissue. This gradient functional design allows the patch to simultaneously achieve multiple objectives after implantation, including mechanical support, active anti-infection, physical barrier against adhesion, and promotion of targeted tissue regeneration, thereby significantly improving the overall therapeutic effect of gastric perforation repair.

[0037] Example 2: The remainder is the same as in Example 1, except that: the molar ratio of zinc to silver in the Ag / Zn bimetallic MOF is 8:1; the amount of drug-loaded MOF added to the antibacterial drug-loaded core layer is 8% (w / w); the mass ratio of PLGA to PCL in the common substrate solution is 6:4; the electrospinning voltage is 16kV and the receiving distance is 12cm; and the thermal annealing condition is 55°C for 8 minutes.

[0038] Example 3: The remainder is the same as in Example 1, except that the molar ratio of zinc to silver in the Ag / Zn bimetallic MOF is 12:1. The amount of drug-loaded MOF added to the antibacterial drug-loaded core layer is 12% (w / w). The mass ratio of PLGA to PCL in the common substrate solution is 8:2. The electrospinning voltage is 20kV, and the receiving distance is 18cm. The thermal annealing conditions are 65°C for 3 minutes.

[0039] Comparative Example 1: The three-layer PLGA / PCL electrospun patch without loading any drugs or MOFs differs from Example 1 in that all three layers are made by electrospinning together with a 12% (w / v) DMF / THF (volume ratio 7:3) solution of PLGA / PCL (mass ratio 7:3) as a common substrate.

[0040] Comparative Example 2: Except for replacing the Ag / Zn bimetallic MOF with an equal amount of pure Zn-MOF (ZIF-8), the preparation steps of the three-layer drug-loaded patch are completely the same as those in Example 1.

[0041] Comparative Example 3: A three-layer patch was made by directly adding the same amount of antifungal drug (voriconazole) and silver nitrate as in Example 1 to the spinning solution through physical mixing.

[0042] Comparative Example 4: Commercially available ordinary polypropylene gastric perforation patch (Prolene) ® ).

[0043] The patches from Example 1 and Comparative Examples 1-4 were all cut into 50mm diameter round pieces, sterilized with ethylene oxide, and then used for antibacterial testing. The model microorganisms were Staphylococcus aureus (ATCC 6538, Gram-positive bacteria), Escherichia coli (ATCC 25922, Gram-negative bacteria), and Candida albicans (ATCC 10231, fungus).

[0044] Immediate antimicrobial test: Each patch was placed in a sterile petri dish, and antimicrobial / antifungal tests were performed according to ISO 22196 standard. The simplified procedure is as follows: A certain concentration of bacterial suspension / spore suspension was inoculated onto the patch surface, covered with a polyethylene film, and incubated for 24 hours at 37°C and relative humidity >90%. Afterward, the patches were eluted with SDS neutralization solution, and the number of viable colonies was counted. The antimicrobial rate / antifungal rate was calculated.

[0045] Long-lasting antimicrobial test: The patch was pre-immersed in phosphate-buffered saline (PBS, pH 7.4) and continuously shaken in a shaker (100 rpm) at 37°C. Antimicrobial / antifungal tests were performed at preset time points (days 1, 7, 14, 21, and 28) according to the ISO 22196 method described above.

[0046] For the test results, see Figures 2-4 : (1) Immediate antibacterial / antifungal properties (Day 1, without PBS pre-soaking): The patch in Example 1 showed antibacterial / antifungal rates greater than 99.9% against Staphylococcus aureus, Escherichia coli, and Candida albicans, demonstrating excellent immediate broad-spectrum activity. The patch in Comparative Example 1 showed no antibacterial effect. The patch in Comparative Example 2 showed good inhibition of bacteria (>99%), but the inhibition rate against Candida albicans was only 85.2%. The immediate antibacterial effect of the patch in Comparative Example 3 was comparable to that in Example 1. The patch in Comparative Example 4 showed no antibacterial or antifungal ability.

[0047] (2) Long-lasting antibacterial / antifungal properties (after PBS pre-soaking): With prolonged soaking time, the antibacterial / antifungal properties of the patch in Example 1 decreased the slowest. By day 28, its antibacterial rate against the three test microorganisms remained above 99.5%. The inhibitory rate against Candida albicans in Comparative Example 2 patch (monometallic MOF) had decreased to 78.1% by day 14. The inhibitory rate against Candida albicans in Comparative Example 3 patch (physical mixture) exhibited significant drug burst release and rapid deactivation; its antibacterial activity decreased significantly by day 7 and was essentially lost by day 28 (antibacterial rate <30%).

[0048] In summary, the patch of this invention, through an Ag / Zn bimetallic MOF carrier, achieves stable loading and slow, controlled release of antimicrobial components. It exhibits highly effective bactericidal activity against Gram-positive bacteria, Gram-negative bacteria, and fungi, demonstrating its broad-spectrum activity. Its long-lasting antibacterial performance is significantly superior to single-metallic MOF drug-loading systems and physically mixed drug-loading systems, proving the synergistic enhancement effect of the bimetallic carrier and the crucial role of the MOF carrier in achieving long-lasting efficacy. The patch of this invention can provide full-cycle, broad-spectrum infection protection after gastric perforation repair surgery, solving the key problems of narrow antibacterial spectrum and short effective duration in existing technologies.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An electrospun gastric perforation patch based on Ag / Zn bimetallic MOF, characterized in that, The gastric perforation patch comprises an integrated tissue integration layer, an antibacterial drug-loaded core layer, and an anti-adhesion layer, all integrally formed by electrospinning. The antibacterial drug-loaded core layer is composed of an Ag / Zn bimetallic MOF loaded with an antifungal drug and a biodegradable polymer material. In the Ag / Zn bimetallic MOF, the molar ratio of zinc to silver is (8:1) to (12:1), and the antifungal drug is voriconazole or amphotericin B.

2. The electrospun gastric perforation patch based on Ag / Zn bimetallic MOF as described in claim 1, characterized in that: The biodegradable polymer material is a mixture of polylactic acid-glycolic acid copolymer and polycaprolactone, wherein the mass ratio of polylactic acid-glycolic acid copolymer to polycaprolactone is (6:4) to (8:2).

3. The electrospun gastric perforation patch based on Ag / Zn bimetallic MOF as described in claim 1, characterized in that: The mass percentage of Ag / Zn bimetallic MOF loaded with antifungal drugs in the antibacterial drug-loaded core layer is 8%~12%.

4. The electrospun gastric perforation patch based on Ag / Zn bimetallic MOF as described in claim 1, characterized in that: The thickness of the tissue integration promoting layer is 40μm to 60μm, the thickness of the antibacterial drug-carrying core layer is 70μm to 90μm, and the thickness of the anti-adhesion layer is 20μm to 40μm.

5. The electrospun gastric perforation patch based on Ag / Zn bimetallic MOF as described in claim 1, characterized in that: The anti-adhesion layer contains hyaluronic acid at a mass of 1% to 3% of the total polymer mass.

6. The method for preparing the electrospun gastric perforation patch based on Ag / Zn bimetallic MOF according to any one of claims 1 to 5, characterized in that, Includes the following steps: S1. Synthesize Ag / Zn bimetallic MOF and load it with antifungal drugs to obtain drug-loaded MOF powder; S2. Prepare a common base solution for biodegradable polymers and divide it into three equal parts, which are used to prepare electrospinning solutions for the tissue integration layer, the antibacterial drug-loaded core layer and the anti-adhesion layer, respectively. S3. Using a three-channel electrospinning device, the tissue integration layer, the antibacterial drug-loaded core layer, and the anti-adhesion layer are spun sequentially on the same receiving device to obtain a three-layer composite patch. S4. The obtained three-layer composite patch is subjected to vacuum drying and heat annealing. S5. Demolding, cutting, and terminal sterilization and packaging.

7. The preparation method according to claim 6, characterized in that: In step S1, the method for synthesizing Ag / Zn bimetallic MOF is as follows: zinc nitrate, silver nitrate and 2-methylimidazole are dissolved in methanol and mixed, and reacted at room temperature for 20 to 28 hours. After centrifugation, washing and drying, the product is obtained, wherein the molar ratio of zinc to silver is (8:1) to (12:1).

8. The preparation method according to claim 6, characterized in that: In step S2, the amount of drug-loaded MOF powder added is 8% to 12% (w / w) of the total mass of the biodegradable polymer, and it is ultrasonically treated for 30 to 60 minutes to make it uniformly dispersed.

9. The preparation method according to claim 6, characterized in that: In step S3, the electrospinning process parameters are as follows: spinning voltage 16-20kV, receiving distance 12-18cm, spinning solution propulsion speed 0.5-1.0mL / h; ambient temperature controlled at 22-26℃, and relative humidity controlled at 40%-60%.

10. The preparation method according to claim 6, characterized in that: In step S4, the vacuum drying conditions are drying at 35-45°C for 36-60 hours; the heat annealing conditions are processing at 55-65°C for 3-8 minutes.

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