CN112921659A

CN112921659A - Method for preparing medical wound dressing by micro-fluidic air-jet spinning method

Info

Publication number: CN112921659A
Application number: CN202110109623.2A
Authority: CN
Inventors: 陈苏; 王浩鹏
Original assignee: Janus New Materials Co ltd
Current assignee: Janus New Materials Co ltd
Priority date: 2021-01-26
Filing date: 2021-01-26
Publication date: 2021-06-08
Anticipated expiration: 2041-01-26
Also published as: CN112921659B

Abstract

The invention discloses a method for preparing a medical wound dressing by a micro-fluidic air-jet spinning method. In particular to a nano fiber scaffold with high biocompatibility, high flexibility, high porosity and controllable diameter, which is prepared by combining a micro-flow control method and a polymer air-jet spinning method. The MOF nano array is grown in situ on the obtained nano fiber scaffold, and the finally obtained medical wound dressing has the advantages of low cost, large-scale production, controllable diameter, good bactericidal performance and capability of effectively promoting wound healing. The invention has the advantages that extra energy is not needed to be introduced in the preparation process to maintain the forming of the fiber and the growth of the functional factors, and the composition and the shape of the material can be effectively regulated and controlled by combining the micro-fluidic chip and the air jet spinning. The whole preparation process is environment-friendly, efficient and energy-saving, can be used for large-scale production, and has good industrial prospect.

Description

Method for preparing medical wound dressing by micro-fluidic air-jet spinning method

Technical Field

The invention relates to the field of medical high polymer materials, in particular to a method for preparing a medical wound dressing by a microfluidic gas jet spinning method, which is used for preparing a high-performance nanofiber scaffold and functionally modifying the nanofiber scaffold so as to achieve the purpose of effectively promoting wound healing and skin regeneration.

Background

During the healing process of the wound, factors such as bacteria, microbial infection and ultraviolet radiation can cause complications, thereby prolonging the healing time of the wound. The wound dressing can play a role in preventing microbial penetration, sterilizing and diminishing inflammation, further protect open wounds, and promote wound healing and tissue regeneration.

The nanofiber scaffold as a wound dressing can provide a solid physical barrier for a wound, effectively prevents bacteria and external pollution from invading the wound, and meanwhile, the nanofiber scaffold can efficiently permeate moisture and air, so that the wound can heal in a stable environment. For the nano fiber scaffold, designability of preparation materials and functions also enables the nano fiber scaffold to play a positive role in the aspects of tissue regeneration, scar inhibition, extracellular matrix simulation and the like. However, as an external barrier to wounds, the composition and diameter of the fibers affect the water absorption, air permeability, and bacteria barrier properties of the nanofiber scaffold. The traditional nanofiber scaffold material is usually prepared by adopting an electrostatic spinning technology, but can only be used for small-area wounds, and has single component and uneven fiber diameter, so that the healing effect is not outstanding. Therefore, the preparation of the nanofiber scaffold with high specific surface area, good flexibility and good biocompatibility, the controllability of the components and the diameter and the large-scale industrialization of the scaffold are realized, the scaffold can effectively block bacteria in the wound healing process, and the promotion of tissue regeneration is a trend of the development of wound dressings.

In recent years, the biomedical applications of Metal Organic Frameworks (MOFs) have become more and more appreciated. The MOF material can be used as a reservoir of metal components and provide gradual release of metal ions, so that the MOF material has a certain antibacterial effect, and iron, manganese, zinc, silver, copper and the like have strong bactericidal capacity.

Disclosure of Invention

The invention aims to provide a method for preparing a medical wound dressing by a micro-fluidic air-jet spinning method. Provides a method for preparing a nano fiber scaffold with excellent performance, controllable diameter and high biocompatibility and capable of being prepared in a large scale. The provided functional modified nanofiber scaffold has good bactericidal performance and can effectively promote wound healing.

The technical scheme of the invention is as follows: a method for preparing medical wound dressing by a microfluidic gas jet spinning method comprises the following specific steps:

(1) dissolving a polymer in a corresponding solvent, fully stirring and dissolving to obtain a uniform polymer A solution, dissolving another polymer in the corresponding solvent, fully stirring and dissolving to obtain a uniform polymer B solution; respectively adding inorganic metal salt corresponding to the metal organic framework into the polymer solution A and the polymer solution B, stirring and dissolving uniformly again, and respectively transferring the mixed solution into two injectors provided with metal needles to be used as the polymer solution for preparing the nanofiber scaffold of the medical wound dressing;

(2) the nanofiber scaffolds were prepared using a microfluidics air jet spinning machine. The syringe containing the polymer solution was placed on a multi-stage micro-flow syringe pump to facilitate the start of the liquid and gas jet spinning operation. Controlling the composition and fiber diameter of the polymer by using different microfluidic chips, and controlling the conditions of temperature, humidity, receiving distance, air pressure, liquid outlet rate and the like in the spinning process to prepare a nano composite fiber bracket containing metal ions;

(3) mixing an organic ligand and water in a reactor to form a uniform solution, then placing the nanofiber scaffold in the solution, placing the reactor in a normal-temperature and normal-pressure environment, and growing the MOF nano array in situ to obtain a uniform and soft nano composite fiber scaffold;

(4) and washing and drying the obtained uniform and soft nano composite fiber scaffold, and removing unreacted monomers and free MOF particles to obtain the high-performance medical wound dressing.

Preferably, the polymer in step (1) is one or a combination of polycaprolactone, polylactic acid, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyurethane, gelatin, silk fibroin, chitosan, hyaluronic acid and tannic acid.

The solvent for dissolving the polymer in the step (1) is preferably not only capable of dissolving the polymer but also friendly to the human body and safe or easily removable. Can be one or the combination of water, ethanol, glacial acetic acid, formic acid, N-dimethylformamide and N, N-dimethylacetamide; the mass concentration of the polymer A solution is 5-60%, and the mass concentration of the polymer B solution is 5-12%.

Preferably, in the step (1), the inorganic metal salt is one or a combination of zinc acetate, copper acetate, manganese acetate, zinc nitrate hexahydrate or manganese sulfate-water; the mass concentration of the inorganic metal salt in the polymer solution A and the polymer solution B is 3-7 percent.

Preferably, the material of the microfluidic chip in the step (2) is polydimethylsiloxane or polymethyl methacrylate; the inner diameter of the micro-fluidic chip is 0.2-0.8mm, and the shape of the micro-channel is one of Y-shaped, T-shaped and sleeve-type or the combination thereof.

Preferably, the parameters of the microfluid gas jet spinning in the step (2) are as follows: the liquid inlet amount of the polymer solution A is 3-10mL/h, and the liquid inlet amount of the polymer solution B is 2-6 mL/h; the air pressure is set to be 0.1-0.3 MPa; the distance from the spinning nozzle to the receiver is 20-50 cm; the environmental temperature is 25-35 ℃; the environmental humidity is 55-65%; the spinning time is 2-6 h.

Preferably, the organic ligand in the step (3) is 2-methylimidazole; the mass concentration of the organic ligand in the solution is 20-33%; the in situ growth time is 16-24 hours.

Preferably, the washing solvent of the nano composite fiber scaffold in the step (4) is one or two of water and ethanol; the washing times are 8-10 times in total, the drying mode is vacuum drying (generally-0.1 MPa), and the drying temperature is 40-60 ℃.

Has the advantages that:

(1) the nanofiber wound dressing prepared by the method disclosed by the invention has the advantages that the fibers are randomly arranged, the structure of natural extracellular matrix can be simulated, and a good support is provided for cell growth and wound healing;

(2) the invention uses the micro-fluidic air jet spinning technology to replace the traditional electrostatic spinning technology to prepare the nano-fiber bracket, can realize the large-scale industrialization of the nano-fiber bracket, and can accurately control the diameter and the direction of the fiber by adjusting the spinning parameters and the design of a special micro-fluidic chip;

(3) the nanofiber scaffold prepared by the method can introduce bacteriostatic metal factors in a mode of in-situ growth of the MOF nano array, can effectively retard bacteria, and compared with the traditional wound dressing, the prepared composite medical wound dressing can effectively promote wound healing and can enhance the regeneration capacity of skin tissues.

Drawings

FIG. 1 is a schematic representation of a polymer fiber in example 1;

FIG. 2 is an SEM photograph of the polymer fiber in example 1;

fig. 3 is an SEM image of the composite nanofiber wound dressing in example 1;

FIG. 4 is a diagram showing the wound healing process in mice in example 1.

Detailed Description

The present invention will be described below with reference to specific examples, but the present invention is not limited to these examples.

Example 1

16g of thermoplastic polyurethane (from Basff) was dissolved in 84g of N, N-dimethylformamide to give a 16% by weight solution of Polymer A, and 4.5g of zinc acetate were added to the solution of Polymer A to give a 4.5% by weight solution. The mixed solution was transferred to a syringe equipped with a metal needle. 5g of tannic acid was dissolved in 95g of N, N-dimethylformamide to give a 5% by mass polymer B solution, and 4.5g of zinc acetate was added to the polymer B solution to give a 4.5% by weight mixed solution. Respectively transferring the A and B mixed solutions into two 20mL syringes provided with metal needles, mixing the A and B in the spinning process by adopting a Y-shaped polydimethylsiloxane micro-fluidic chip with the inner diameter of 0.8mm, setting the liquid outlet rate of a micro-flow pump to be 5mL/h and 2mL/h respectively, setting the distance from the needle to a receiver to be 35cm, blowing air from the needle hole by an air pump under the pressure of 0.1MPa, and spinning for 3h to obtain a polyurethane/tannic acid fiber support on the receiver, wherein the ambient temperature is 28 ℃ and the humidity is 58%. As shown in fig. 1, the resulting nanofiber scaffold was white in appearance and had good flexibility. As shown in FIG. 2, the fiber diameter is around 200 nm.

32.8g of 2-methylimidazole were dissolved in 100g of water to form a 25% strength by weight organic ligand solution, and the fiber membrane was then placed in the solution. Standing at normal temperature and pressure for 24h to obtain a white flexible composite nanofiber scaffold, washing the obtained nanofiber scaffold with deionized water for 5 times, then washing with ethanol for 5 times, then carrying out vacuum drying at 50 ℃ (-0.1MPa), and removing unreacted monomers and free particles to obtain the composite medical wound dressing. The functionalized fiber scaffold has similar appearance to the original fiber scaffold. As shown in FIG. 3, MOF nano-arrays are uniformly grown on the surface of the fiber, and the diameter is about 3 μm. As shown in fig. 4, compared to the conventional medical wound dressing, the composite medical wound dressing can effectively promote wound healing, the wound can be substantially healed on the seventh day, and new skin can be substantially completely grown on the tenth day.

Example 2

15g of polycaprolactone is dissolved in 85g of 88% formic acid to form a polymer A solution with the mass fraction of 15%, 7g of zinc nitrate hexahydrate is added into the polymer A solution to form a 7 wt% mixed solution, 10g of chitosan is dissolved in 90g of 88% formic acid to be uniformly dissolved into a 10% polymer B solution, and 7g of zinc nitrate hexahydrate is added into the polymer B solution to form a 7 wt% mixed solution. Respectively transferring the A and B mixed solutions into two injectors provided with metal needles, mixing the A and B in a spinning process by adopting a T-shaped polydimethylsiloxane micro-fluidic chip with the inner diameter of 0.4mm, setting the liquid outlet speed of a micro-flow pump to be 5mL/h and 5mL/h respectively, setting the distance from the needle to a receiver to be 30cm, blowing air from a needle hole by an air pump under the pressure of 0.1MPa, and spinning for 2h to obtain a polycaprolactone/chitosan fiber support on the receiver, wherein the ambient temperature is 28 ℃ and the humidity is 60%. The fiber diameter is about 100 nm.

26g of 2-methylimidazole were dissolved in 100g of water to form a 20% strength by weight organic ligand solution, and then the fiber scaffold was put into the solution. Placing the obtained nano-fiber scaffold at normal temperature and pressure for 20h to obtain a white flexible composite nano-fiber scaffold, washing the obtained nano-fiber scaffold with ethanol for 5 times, then washing the nano-fiber scaffold with deionized water for 3 times, then drying the nano-fiber scaffold at 55 ℃ in vacuum (-0.1MPa), and removing unreacted monomers and free particles to obtain the composite medical wound dressing, wherein the diameter of the composite medical wound dressing is about 5 micrometers, the wound can be basically healed on the fifth day, and new skin basically grows completely on the eighth day.

Example 3

Dissolving 15g of polycaprolactone in 85g of 88% formic acid to form a polymer A solution with the mass fraction of 15%, and adding 7g of zinc nitrate hexahydrate to the polymer A solution to form a mixed solution with the mass fraction of 7 wt%; 12g of silk fibroin is dissolved in 88g of 88% formic acid to form a polymer B solution with the mass fraction of 12%, and 7g of zinc nitrate hexahydrate is added into the polymer B solution to form a mixed solution with the mass fraction of 7%. Respectively transferring the A and B mixed solutions into two injectors provided with metal needles, mixing the A and B in a spinning process by adopting a Y-type polydimethylsiloxane micro-fluidic chip with the inner diameter of 0.2mm, setting the liquid outlet speed of a micro-flow pump to be 3mL/h and 5mL/h respectively, setting the distance from the needle to a receiver to be 28cm, blowing air from the needle hole by an air pump under the pressure of 0.2MPa, and spinning for 4h to obtain the polycaprolactone/silk fibroin composite fiber support on the receiver. The environmental temperature is 30 ℃, the humidity is 63 percent, and the fiber diameter is about 80 nm.

32.8g of 2-methylimidazole were dissolved in 100g of water to form a 25% strength by weight organic ligand solution, and the fiber scaffold was then placed in the solution. And standing at normal temperature and pressure for 24h to obtain a white flexible composite nanofiber scaffold, washing the obtained nanofiber scaffold with ethanol for 5 times, then washing with deionized water for 5 times, then performing vacuum drying at 40 ℃ (-0.1MPa), and removing unreacted monomers and free particles to obtain the composite medical wound dressing, wherein the diameter is about 2 mu m, the wound can be basically healed on the sixth day, and new skin basically grows completely on the eighth day.

Example 4

60g of alcohol-soluble polyurethane (PU-3514, available from Wangxin chemical industry) is dissolved in 40g of absolute ethyl alcohol and uniformly dissolved to form a polymer A solution, and 4g of copper acetate is added into the polymer A solution to form a mixed solution with the weight percent of 4; 12g of polycaprolactone is dissolved in 88g of 88% formic acid to form a polymer B solution with the mass fraction of 12%, and 4g of copper acetate is added into the polymer B solution to form a mixed solution with the mass fraction of 4 wt%. Respectively transferring the A and B mixed solutions into two injectors provided with metal needles, mixing the A and B in a spinning process by adopting a T-shaped polymethyl methacrylate micro-fluidic chip with the inner diameter of 0.7mm, setting the liquid outlet speed of a micro-flow pump to be 10mL/h and 6mL/h respectively, setting the distance from the needle to a receiver to be 40cm, blowing air from the needle hole by an air pump under the pressure of 0.15MPa, and obtaining the polyurethane/polycaprolactone composite fiber support on the receiver, wherein the spinning time is 2 h. The environmental temperature is 35 ℃, the humidity is 65%, and the fiber diameter is about 180 nm.

42g of 2-methylimidazole were dissolved in 100g of water to form a 29% strength by weight organic ligand solution, and then the fiber scaffold was placed in the solution. Placing the composite medical wound dressing at normal temperature and normal pressure for 22h to obtain a white flexible composite nano-fiber scaffold, washing the obtained nano-fiber scaffold with deionized water for 10 times, then performing vacuum drying at 50 ℃ (-0.1MPa), and removing unreacted monomers and free particles to obtain the composite medical wound dressing, wherein the diameter is about 3 mu m, the wound can be basically healed in the seventh day, and new skin basically grows completely in the ninth day.

Example 5

10g of chitosan is dissolved in 90g of glacial acetic acid to form a polymer A solution with the mass fraction of 10%, and 3g of copper acetate is added into the polymer A solution to form a mixed solution with the mass fraction of 3 wt%; 9g of gelatin was dissolved in 91g of 8g of glacial acetic acid to give a 9% by mass polymer B solution, and 5g of zinc acetate was added to the polymer B solution to give a 5% by weight solution mixture. Respectively transferring the A and B mixed solutions into two injectors provided with metal needles, mixing the A and B in a spinning process by adopting a sleeve type polymethyl methacrylate micro-fluidic chip with the inner diameter of 0.6mm, setting the liquid outlet speed of a micro-flow pump to be 8mL/h and 6mL/h respectively, setting the distance from the needle to a receiver to be 45cm, blowing air from a needle hole by an air pump under the pressure of 0.25MPa, and obtaining a chitosan/gelatin composite fiber support on the receiver, wherein the spinning time is 6 h. The environmental temperature is 28 ℃, the humidity is 55%, and the fiber diameter is about 150 nm.

50g of 2-methylimidazole were dissolved in 100g of water to form a 33% strength by weight organic ligand solution, and then the fiber scaffold was put into the solution. Placing the obtained nano-fiber scaffold at normal temperature and pressure for 20h to obtain a white flexible composite nano-fiber scaffold, washing the obtained nano-fiber scaffold with deionized water for 10 times, then performing vacuum drying at 55 ℃ (-0.1MPa), and removing unreacted monomers and free particles to obtain the composite medical wound dressing, wherein the diameter is about 4 mu m, the wound can be basically healed on the sixth day, and new skin basically grows completely on the ninth day.

Claims

1. A method for preparing medical wound dressing by a microfluidic gas jet spinning method comprises the following specific steps:

(2) the nanofiber scaffolds were prepared using a microfluidics air jet spinning machine. Placing the injector filled with the polymer solution on a multi-stage micro-flow injection pump, and controlling parameters in the spinning process by using different micro-flow control chips to prepare a nano composite fiber bracket containing metal ions;

(3) mixing an organic ligand and water in a reactor to form a uniform solution, then placing the nanofiber scaffold in the solution, and growing the MOF nano array in situ to obtain a uniform and soft nano composite fiber scaffold;

(4) and washing and drying the obtained uniform and soft nano composite fiber scaffold to obtain the high-performance medical wound dressing.

2. The method of claim 1, wherein: the polymer in the step (1) is one or the combination of polycaprolactone, polylactic acid, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyurethane, gelatin, silk fibroin, chitosan, hyaluronic acid and tannic acid.

3. The method of claim 1, wherein: the solvent for dissolving the polymer in the step (1) is one or the combination of water, ethanol, glacial acetic acid, formic acid, N-dimethylformamide and N, N-dimethylacetamide; the mass concentration of the polymer A solution is 5-60%, and the mass concentration of the polymer B solution is 5-12%.

4. The method of claim 1, wherein: the inorganic metal salt in the step (1) is one or the combination of zinc acetate, copper acetate, manganese acetate, zinc nitrate hexahydrate or manganese sulfate-water; the mass concentration of the inorganic metal salt in the polymer solution A and the polymer solution B is 3-7 percent.

5. The method of claim 1, wherein: the material of the microfluidic chip in the step (2) is polydimethylsiloxane or polymethyl methacrylate; the inner diameter of the micro-fluidic chip is 0.2-0.8mm, and the shape of the micro-channel is one of Y-shaped, T-shaped and sleeve-type or the combination thereof.

6. The method of claim 1, wherein: the parameters of the microfluid air-jet spinning in the step (2) are as follows: the liquid inlet amount of the polymer solution A is 3-10mL/h, and the liquid inlet amount of the polymer solution B is 2-6 mL/h; the air pressure is set to be 0.1-0.3 MPa; the distance from the spinning nozzle to the receiver is 20-50 cm; the environmental temperature is 25-35 ℃; the environmental humidity is 55-65%; the spinning time is 2-6 h.

7. The method of claim 1, wherein: the organic ligand in the step (3) is 2-methylimidazole; the mass concentration of the organic ligand in the solution is 20-33%; the in situ growth time is 16-24 hours.

8. The method of claim 1, wherein: the washing solvent of the nano composite fiber scaffold in the step (4) is one or two of water or ethanol; the washing times are 8-10 times, and the drying temperature is 40-60 ℃.