A pH-responsive organic-inorganic composite nanofiber membrane and a preparation method and application thereof
By preparing a pH-responsive organic-inorganic composite nanofiber membrane, the problem that existing antibacterial materials cannot respond sensitively to pH changes and achieve synergistic effects of multiple antibacterial mechanisms has been solved, enabling efficient wound dressing applications with good biocompatibility and stability.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHANGZHOU NO 2 PEOPLES HOSPITAL
- Filing Date
- 2026-03-27
- Publication Date
- 2026-06-30
AI Technical Summary
Existing antibacterial materials cannot respond to pH changes with high sensitivity, and it is difficult to achieve the synergistic effect of multiple antibacterial mechanisms. They also have problems such as biocompatibility and complex preparation processes.
A pH-responsive organic-inorganic composite nanofiber membrane was prepared by loading pH-responsive ligand-modified inorganic antibacterial nanoparticles into the core layer and blending pH-responsive polymers with durable polymers in the shell layer to form a core-shell structure. The membrane was then prepared using coaxial electrospinning technology to achieve the conversion and synergistic effect of the antibacterial state.
It achieves a highly sensitive response to pH changes, possesses a dual antibacterial mechanism, improves therapeutic targeting and biosafety, reduces the risk of drug resistance, and has good structural stability, making it suitable for use as a wound dressing.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of antibacterial dressing technology, and specifically relates to a pH-responsive organic-inorganic composite nanofiber membrane, its preparation method and application. Background Technology
[0002] Bacterial infection is a major cause of wound healing failure and medical implant failure. Traditional antimicrobial materials (such as silver-containing dressings and quaternary ammonium salt coatings) typically release antimicrobial agents at a constant rate, which cannot respond to the dynamic changes in the infection microenvironment. This can lead to problems such as excessive early release that may cause toxicity and insufficient late release that may cause infection recurrence, while also easily leading to the development of bacterial resistance.
[0003] pH-responsive antibacterial materials have emerged. Commonly used organic polymer carrier technologies for pH response include polymethyl methacrylate (PMAA) and chitosan (CS). For example, antibiotics can be loaded into PMAA hydrogels, releasing the drug through carboxyl grouping and contraction in an acidic environment. However, this material suffers from poor mechanical strength and stability, and most only achieve "acid-triggered release," lacking active antibacterial components, resulting in limited antibacterial efficacy after response. Inorganic nanoparticle loading technologies modify pH-sensitive molecules onto the surface of mesoporous silica or layered double hydroxides (LDH). However, this technology suffers from poor biocompatibility and flexibility of inorganic carriers, making direct use as dressings difficult, and the preparation process is complex with limited loading rates. Simple physical blending techniques involve physically blending pH-sensitive polymers with inorganic antibacterial agents such as nano-zinc oxide. However, due to weak interfacial interactions, the response sensitivity and release controllability are poor, posing potential biotoxicity risks. In addition, existing materials are mostly focused on a single function (such as only releasing effective components or only changing surface charge), making it difficult to achieve synergistic antibacterial mechanism while responding to pH changes, thus failing to effectively deal with complex biofilm infections.
[0004] Therefore, there is an urgent need to develop a new type of material that can not only respond to pH changes with high sensitivity, but also exert multiple antibacterial mechanisms in the process, while possessing good biocompatibility and processability. Summary of the Invention
[0005] The purpose of this invention is to provide a pH-responsive organic-inorganic composite nanofiber membrane, its preparation method, and its application.
[0006] In a first aspect, the present invention provides a pH-responsive organic-inorganic composite nanofiber membrane, the composite nanofiber membrane comprising a core layer and a shell layer, wherein the shell layer is composed of a blend of a pH-responsive polymer and a durable polymer, providing initial cationic antibacterial properties and a fiber backbone; the core layer is loaded with inorganic antibacterial nanoparticles modified with pH-responsive ligands, wherein the ligands undergo protonation or cleavage under acidic conditions, thereby opening a "gating" and triggering synergistic antibacterial action of the inorganic nanoparticles.
[0007] The pH-responsive polymer is hydroxypropyltrimethylammonium chloride chitosan (HACC); the durable polymer is polyvinyl alcohol (PVA). Preferably, HACC accounts for 20-60% of the total weight of HACC and PVA.
[0008] The pH-responsive ligand-modified inorganic antibacterial nanoparticles are gallic acid-modified zinc oxide nanoparticles (GA-ZnO). Gallic acid (GA), as a weak acid ligand, stably binds to ZnO in a deprotonated form when pH > 7; when pH < 6.5, its carboxyl group is protonated, leading to a sharp decrease in the binding force with ZnO and dissociation from the surface. Preferably, the GA-ZnO loading accounts for 5% to 25% of the total dry weight of the fiber.
[0009] As one of the preferred embodiments of the pH-responsive organic-inorganic composite nanofiber membrane, the composite nanofiber membrane is prepared by coaxial electrospinning.
[0010] In a second aspect, the present invention provides a method for preparing the above-mentioned pH-responsive organic-inorganic composite nanofiber membrane, comprising the following steps: (1) GA-ZnO nanoparticles were uniformly dispersed in a solvent to obtain a core layer dispersion; (2) Mix the PVA aqueous solution with the acetic acid solution of HACC to obtain the shell solution; (3) Using a dual-channel injection pump, the shell solution and the core dispersion were loaded into two syringes respectively, and electrospinning was performed using a coaxial spinning needle to obtain a nascent nanofiber membrane. (4) The nascent nanofiber membrane was cross-linked, washed and dried to obtain a pH-responsive organic-inorganic composite nanofiber membrane.
[0011] As one of the preferred embodiments of the above preparation method, the preparation method of the GA-ZnO nanoparticles in step (1) is as follows: nano zinc oxide particles (ZnO NPs) are synthesized by hydrothermal method. ZnO NPs are dispersed in ethanol, and excess gallic acid (GA) is added. The mixture is stirred at 50-60°C. GA is bonded to the ZnO surface through esterification or coordination to form a GA-ZnO complex. After centrifugation, washing, and drying, GA-ZnO nanoparticles are obtained.
[0012] Optionally, the solvent in step (1) is selected from deionized water or dimethyl sulfoxide (DMSO).
[0013] As one of the preferred embodiments of the above preparation method, the mass concentration of the PVA aqueous solution in step (2) is 8-12 wt%.
[0014] The concentration of HACC in the acetic acid solution is 30-60 mg / mL, and the concentration of the acetic acid solution is 2-4 wt%.
[0015] The total mass fraction of HACC+PVA in the shell solution is 8-12 wt%.
[0016] As one of the preferred solutions of the above preparation method, the electrospinning in step (3) has the following specific process parameters: shell flow rate 0.8-1.2 mL / h, core flow rate 0.2-0.5 mL / h, voltage 15-25 kV, receiving distance 12-18 cm, temperature 25±3°C, and humidity <50%.
[0017] As one of the preferred embodiments of the above preparation method, the crosslinking treatment in step (4) involves placing the nascent nanofiber membrane in a crosslinking agent for 6-24 hours to impart water stability and mechanical strength. The crosslinking agent is a water-soluble crosslinking agent used to stabilize the fiber structure, such as glutaraldehyde vapor or genipin, and the amount of the crosslinking agent is 1% to 5% of the total weight of the shell polymer.
[0018] In a third aspect, the present invention provides the application of the above-mentioned pH-responsive organic-inorganic composite nanofiber membrane as a wound dressing and antibacterial dressing.
[0019] Compared with the prior art, the technical principles and beneficial effects of the present invention are as follows:
[0020] (1) The pH-responsive organic-inorganic composite nanofiber membrane prepared in this invention has a synergistic effect of intelligent dual antibacterial mechanisms. Antibacterial state I (pH≥7.0): The material surface is enriched with persistent cations provided by HACC, which destroy bacterial cell membranes through electrostatic adsorption, achieving contact antibacterial action. At this time, GA-ZnO is "locked in," releasing very little. Antibacterial state II (pH≤6.5, infection environment): On the one hand, GA is protonated and dissociates from the ZnO surface, triggering Zn... 2+ The rapid release of small amounts of ZnO nanoparticles interferes with bacterial metabolism; on the other hand, the dissociated GA itself is a phenolic acid, which reacts with free Zn in an acidic microenvironment. 2+It generates a Fenton-like reaction, co-catalyzing the production of high levels of reactive oxygen species (ROS), which cause oxidative damage to mature biofilms. Through a mechanism shift from "physical contact" to "chemical release," it achieves highly efficient clearance of both acute and chronic biofilm infections.
[0021] (2) The pH-responsive organic-inorganic composite nanofiber membrane material prepared in this invention is highly responsive to a narrow pH change window (6.5-7.0). It reaches a release peak in the acidic region of infection, while releasing very little in the pH region of normal tissue, which greatly improves the therapeutic targeting and biosafety, and reduces the risk of systemic toxicity and drug resistance.
[0022] (3) This invention uses coaxial electrospinning technology to encapsulate GA-ZnO within fibers, avoiding direct exposure and premature loss of nanoparticles. The cross-linked network further stabilizes the shell structure, ensuring the integrity and functional durability of the material during use.
[0023] (4) The nanofiber membrane prepared by the present invention has a high specific surface area, high porosity and a structure that mimics the extracellular matrix, which is very conducive to gas exchange, exudate absorption and cell growth. It is an ideal form of wound dressing, and the preparation process is mature and easy to scale up. Attached Figure Description
[0024] Figure 1 This is a scanning electron microscope image of GA-ZnO nanoparticles. Detailed Implementation
[0025] The present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.
[0026] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.
[0027] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.
[0028] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.
[0029] Unless otherwise specified, all reagents and materials mentioned in the examples are commercially available products.
[0030] The preparation method of GA-ZnO used in the following embodiments of the present invention is as follows: ZnO nanoparticles (ZnO NPs) are synthesized by hydrothermal method. 0.5 g of ZnO NPs are dispersed in 100 mL of ethanol, and 2.0 g of gallic acid (GA) is added. The mixture is reacted at 60°C for 12 h to form a GA-ZnO complex. After centrifugation and washing, the complex is dried under vacuum at 60°C for later use.
[0031] Example 1
[0032] (1) Dissolve 1.6g PVA (99% degree of hydrolysis) in 18.4g water and stir at 90°C for 4h. After cooling, mix with 2.0g hydroxypropyltrimethylammonium chloride chitosan (HACC) solution (dissolved in 50mL 2% acetic acid) and concentrate to adjust the total polymer content to about 8wt% to obtain shell liquid.
[0033] (2) 0.4g GA-ZnO was ultrasonically dispersed in 5g DMSO to obtain the core layer liquid.
[0034] (3) Electrospinning was performed using a coaxial needle (outer diameter 0.9 mm, inner diameter 0.4 mm). The shell flow rate was 1.0 mL / h, the core flow rate was 0.3 mL / h, the voltage was 20 kV, and the receiving distance was 15 cm. The collected membrane was crosslinked in glutaraldehyde vapor for 12 h, then soaked in ethanol to remove residual glutaraldehyde, and then vacuum dried. Finally, a pH-responsive organic-inorganic composite nanofiber membrane was obtained.
[0035] Example 2
[0036] (1) Dissolve 1.6g PVA (99% degree of hydrolysis) in 18.4g water and stir at 90°C for 4h. After cooling, mix with 3.0g hydroxypropyltrimethylammonium chloride chitosan (HACC) (dissolved in 50mL 2% acetic acid) solution, concentrate to adjust the total polymer content to about 12wt%, and obtain shell liquid.
[0037] (2) 0.4g GA-ZnO was ultrasonically dispersed in 5g DMSO to obtain the core layer liquid.
[0038] (3) Electrospinning was performed using a coaxial needle (outer diameter 0.9 mm, inner diameter 0.4 mm). The shell flow rate was 1.0 mL / h, the core flow rate was 0.3 mL / h, the voltage was 20 kV, and the receiving distance was 15 cm. The collected membrane was crosslinked in glutaraldehyde vapor for 12 h, then soaked in ethanol to remove residual glutaraldehyde, and then vacuum dried. Finally, a pH-responsive organic-inorganic composite nanofiber membrane was obtained.
[0039] Example 3
[0040] (1) Dissolve 1.6g PVA (99% degree of hydrolysis) in 18.4g water and stir at 90°C for 4h. After cooling, mix with 3.0g hydroxypropyltrimethylammonium chloride chitosan (HACC) (dissolved in 50mL 2% acetic acid) solution, concentrate to adjust the total polymer content to about 12wt%, and obtain shell liquid.
[0041] (2) 0.6g GA-ZnO was ultrasonically dispersed in 5g DMSO to obtain the core layer liquid.
[0042] (3) Electrospinning was performed using a coaxial needle (outer diameter 0.9 mm, inner diameter 0.4 mm). The shell flow rate was 1.0 mL / h, the core flow rate was 0.3 mL / h, the voltage was 20 kV, and the receiving distance was 15 cm. The collected membrane was crosslinked in glutaraldehyde vapor for 12 h, then soaked in ethanol to remove residual glutaraldehyde, and then vacuum dried. Finally, a pH-responsive organic-inorganic composite nanofiber membrane was obtained.
[0043] Comparative Example 1
[0044] Except for using unmodified ZnO NPs instead of GA-ZnO, the rest is the same as in Example 1.
[0045] Comparative Example 2
[0046] Except for not using HACC (using only PVA), the rest is the same as in Example 1.
[0047] Comparative Example 3
[0048] HACC, PVA and GA-ZnO were simply blended and then subjected to uniaxial electrospinning (non-core-shell structure), and the rest was the same as in Example 1.
[0049] The pH-responsive release performance was evaluated as follows: Membrane samples were placed in phosphate-buffered saline (PBS) solutions of different pH values, and Zn was detected by ICP-MS. 2+ Release. The results are shown in Table 1. The Zn in Example 1 material was released at pH 5.5 for 24 hours. 2+The release rate was 8.2 times that at pH 7.4, showing a significant response. The release difference in Comparative Example 1 was less than 2-fold at different pH levels. Table 2 shows the changes in the antibacterial rate against Staphylococcus aureus of the materials prepared in each example and comparative example at different pH levels. Table 3 compares the 15-day wound healing rates of full-thickness skin defects in rats using Example 1, commercial silver-containing dressings, and commercial gauze. Table 4 compares the tensile mechanical properties of the materials prepared in each example and comparative example.
[0050] Table 1. Materials prepared in the Examples and Comparative Examples (24h Zn) 2+ Cumulative release (μg / mg)
[0051]
[0052] Table 2. Changes in the antibacterial rate (%) of the materials prepared in the examples and comparative examples against Staphylococcus aureus at different pH values.
[0053]
[0054] Table 3 Comparison of wound healing rates (%) of full-thickness skin defects in rats using Example 1 and commercial materials at 15 days
[0055]
[0056] Table 4. Fracture stress and fracture strain results of the materials prepared in the examples and comparative examples.
[0057]
[0058] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A pH-responsive organic-inorganic composite nanofiber membrane, characterized in that, The composite nanofiber membrane comprises a core layer and a shell layer; the shell layer is composed of a blend of a pH-responsive polymer and a durable polymer, and the core layer is loaded with inorganic antibacterial nanoparticles modified with pH-responsive ligands.
2. The pH-responsive organic-inorganic composite nanofiber membrane according to claim 1, characterized in that, The pH-responsive polymer is hydroxypropyltrimethylammonium chloride chitosan (HACC); the durable polymer is polyvinyl alcohol (PVA); and the pH-responsive ligand-modified inorganic antibacterial nanoparticles are gallic acid-modified nano-zinc oxide (GA-ZnO).
3. The pH-responsive organic-inorganic composite nanofiber membrane according to claim 2, characterized in that, HACC accounts for 20-60% of the total weight of HACC and PVA.
4. The pH-responsive organic-inorganic composite nanofiber membrane according to claim 2, characterized in that, The GA-ZnO loading accounts for 5% to 25% of the total dry weight of the fiber.
5. The pH-responsive organic-inorganic composite nanofiber membrane according to claim 1, characterized in that, The composite nanofiber membrane was prepared using a coaxial electrospinning process.
6. The method for preparing the pH-responsive organic-inorganic composite nanofiber membrane according to any one of claims 1-5, characterized in that, Includes the following steps: (1) GA-ZnO nanoparticles were uniformly dispersed in a solvent to obtain a core layer dispersion; (2) Mix the PVA aqueous solution with the acetic acid solution of HACC to obtain the shell solution; (3) Using a dual-channel injection pump, the shell solution and the core dispersion were loaded into two syringes respectively, and electrospinning was performed using a coaxial spinning needle to obtain a nascent nanofiber membrane. (4) The nascent nanofiber membrane was cross-linked, washed and dried to obtain a pH-responsive organic-inorganic composite nanofiber membrane.
7. The method for preparing a pH-responsive organic-inorganic composite nanofiber membrane according to claim 6, characterized in that, The mass concentration of the PVA aqueous solution in step (2) is 8-12 wt%.
8. The method for preparing a pH-responsive organic-inorganic composite nanofiber membrane according to claim 6, characterized in that, The concentration of HACC in the acetic acid solution is 30-60 mg / mL.
9. The method for preparing a pH-responsive organic-inorganic composite nanofiber membrane according to claim 6, characterized in that, The electrospinning process in step (3) has the following specific parameters: shell flow rate 0.8-1.2 mL / h, core flow rate 0.2-0.5 mL / h, voltage 15-25 kV, receiving distance 12-18 cm, temperature 25±3°C, and humidity <50%.
10. The application of the pH-responsive organic-inorganic composite nanofiber membrane according to any one of claims 1-5 as a wound dressing or antibacterial dressing.