CN113842495A - Adhesive nanofiber hydrogel dressing capable of being peeled off as required and preparation method thereof - Google Patents

Abstract

Translated fromChinese

本发明涉及一种可按需剥离的粘性纳米纤维水凝胶敷料及其制备方法，所述辅料以含天然高分子材料、儿茶酚化合物、胱胺二盐酸盐、偶联剂的原料，通过静电纺，后处理获得。本发明的方法赋予纳米纤维水凝胶优异的力学强度和粘附性能，且在更换或移除敷料时，在紧密贴合在皮肤上的粘性敷料上滴加水就可以使敷料轻松无痛剥离，不会对伤口造成二次损伤。去除后的敷料放置在空气中蒸发一定的水分，当敷料的含水量为150％左右时仍具有粘性，从而做到反复粘附，延长了敷料的使用寿命。

The invention relates to a viscous nanofiber hydrogel dressing that can be peeled off on demand and a preparation method thereof. Obtained by electrospinning and post-processing. The method of the present invention endows the nanofiber hydrogel with excellent mechanical strength and adhesion properties, and when the dressing is replaced or removed, the dressing can be easily and painlessly peeled off by dripping water on the adhesive dressing that is closely attached to the skin. Will not cause secondary damage to the wound. The removed dressing is placed in the air to evaporate a certain amount of water, and when the water content of the dressing is about 150%, it is still sticky, so as to achieve repeated adhesion and prolong the service life of the dressing.

Description

Adhesive nanofiber hydrogel dressing capable of being peeled off as required and preparation method thereof

Technical Field

The invention belongs to the field of auxiliary materials and preparation thereof, and particularly relates to an adhesive nanofiber hydrogel dressing capable of being peeled off as required and a preparation method thereof.

Background

Statistically, about hundreds of millions of people worldwide suffer skin wounds due to natural disasters, accidents or operations every year, and ineffective treatment of skin injuries can lead to disability and even death. The skin dressing is one of the most common medical consumables in clinic, and has the effects of protecting a wound surface, diminishing inflammation, stopping bleeding and the like. In order to realize effective nursing to wounds, the skin dressing also needs to have good biocompatibility, certain mechanical property, adhesion to skin, biodegradability and the like. The nanofiber prepared by the electrostatic spinning technology has the excellent characteristics of large specific surface area, porosity and the like, so the nanofiber draws continuous attention of researchers in the field of biomedicine and is well applied to aspects of controlled drug release, wound repair, biological tissue engineering and the like. The hydrogel has a wide application prospect in the field of biomedicine, can absorb and retain a large amount of moisture in a network, maintains the moist environment of a wound area, can be tightly adhered to an uneven wound surface, reduces the opportunity of bacterial breeding, and prevents wound infection of the wound surface. The electrostatic spinning hydrogel nanofiber has the advantages of hydrogel, can simulate a natural extracellular matrix structure, and is a skin dressing material with great potential.

Aiming at the problems that the strength and the toughness of common hydrogel are poor, the hydrogel is difficult to be made into nanofibers, and the nanofibers are difficult to be crosslinked, the high-strength high-toughness hydrogel nanofibers are designed and prepared by the domestic patent CN 201510631809.9. Firstly, sodium alginate, a polymeric monomer, a chemical cross-linking agent, an initiator and a macromolecule for assisting spinning are dissolved in water to prepare spinning solution, and the nanofiber is obtained by a high-voltage electrostatic spinning technology. Putting the spinning formed nano-fiber into an incubator with certain humidity and temperature for fumigation, enabling the nano-fiber to absorb water properly and wet, then sealing and introducing nitrogen to remove oxygen, and initiating polymerization by irradiation. And finally, soaking the polymerized hydrogel nanofiber in an ionic crosslinking agent solution for crosslinking to obtain the high-strength high-toughness hydrogel nanofiber. The preparation method is simple, the cost is low, no organic solvent is used, and the obtained high-strength high-toughness hydrogel nanofiber has good application prospects in the fields of skin dressings and the like. However, the dressing does not have strong adhesion, and cannot meet the requirement that the dressing can be stably attached to skin wound tissues in the process of limb movement, secondary fixation is needed, and the practical application range is limited. Natural mussel-like substances contain catechol molecules, have been confirmed to exhibit strong adhesion to skin tissues, have been widely used in bioadhesive materials, and exhibit strong adhesion. The domestic patent CN202011373707.9 provides an adhesive chitosan-alginate hydrogel and a preparation method and an application method thereof, and the hydrogel has good adhesion performance, so that the hydrogel has good application in the field of medical wound dressings. The viscous chitosan-alginate hydrogel of the embodiment comprises the following components in percentage by mass: 1 to 5 percent of chitosan, 1 to 5 percent of alginic acid, 88 to 97 percent of monovalent metal salt solution, a natural cross-linking agent of chitosan, an ionic cross-linking agent of alginate and a tackifier; the tackifier is one or more of clay, dopamine or carrageenan; the mass of the tackifier is 0.5-10% of the total mass of the hydrogel. The patent can be well applied to the field of medical wound dressings. However, the dressing may stick to the wound when removed, causing skin damage.

Disclosure of Invention

The invention aims to solve the technical problem of providing an adhesive nanofiber hydrogel dressing capable of being peeled off as required and a preparation method thereof, and overcomes the defects that the tissue of the nanofiber hydrogel dressing in the prior art is not adhesive enough, needs secondary fixation usually and cannot meet the requirement that the dressing is firmly adhered to the skin in the movement process of a human body. And the prior adhesive dressing usually causes secondary injury of wounds when being peeled off, can not be peeled off painlessly as required when the dressing is changed, and can not be adhered for repeated use for many times.

The nanofiber hydrogel dressing is prepared by carrying out electrostatic spinning and post-treatment on raw materials containing a natural polymer material, a catechol compound, cystamine dihydrochloride and a coupling agent.

The dressing has good adhesive property, can be tightly attached to the skin at the edge of a wound to prevent bacteria from entering the wound to cause infection, has weak viscosity at the wound part containing body fluid to maintain the moist environment of the wound area, does not need external dressing fixation, and creates a good biological environment for the healing of the skin. The dressing can be peeled off as required, when the dressing is replaced or removed, the dressing can be easily peeled off painlessly only by dripping water on the adhesive dressing closely attached to the edge of the wound, the wound cannot be pulled and adhered, pain caused by dressing replacement is reduced, and the dressing can be repeatedly adhered for many times, so that a doctor can conveniently observe the condition of the wound.

The preparation method of the nanofiber hydrogel dressing comprises the following steps:

(1) mixing a natural polymer material and a solvent, and stirring and dissolving to obtain a natural polymer solution; then adding a catechol compound, stirring in a dark place, adding cystamine dihydrochloride, stirring, adding a coupling agent, and stirring to obtain a spinning solution;

(2) standing the spinning solution, performing ultrasonic treatment to eliminate bubbles, then placing the spinning solution into an injector, and performing electrostatic spinning under the condition of keeping out of the sun to obtain a nanofiber membrane;

(3) and carrying out post-treatment on the nanofiber membrane to obtain a nanofiber hydrogel auxiliary material.

The preferred mode of the above preparation method is as follows:

the step (1) further comprises the following steps: dissolving natural polymers in a mixed solution of deionized water and organic acid, stirring for 10-30 min in a water bath at 30 ℃, heating to 40-50 ℃, continuously stirring until the natural polymers are completely dissolved to obtain a natural polymer solution, then adding a catechol compound, stirring for 1-2 h in the dark, adding cystamine dihydrochloride, stirring for 1-2 h, adding a coupling agent, stirring for 2-6 h at room temperature until the solution is uniform, and obtaining a stable spinning solution.

The natural polymer material in the step (1) is one or more of gelatin, methacrylic acid anhydrization gelatin, collagen, hyaluronic acid, chitin, chitosan, sodium alginate and protein; the catechol compound is one or more of dopamine, tannic acid and tea polyphenol; the solvent is a mixed solution of water and organic acid; the coupling agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC/N-hydroxysuccinimide NHS.

The organic acid is one or more of acetic acid, oxalic acid, glacial acetic acid, propionic acid and butyric acid; the molar ratio of EDS to NHS in the coupling agent is 3-5: 0.5 to 2.

The mass percentage concentration of the natural polymer solution in the step (1) is 10-30 wt%; the mass fraction of the catechol compound is 0.5-5 wt% of the natural polymer solution, and the mass fraction of the cystamine dihydrochloride is 1-10 wt% of the natural polymer solution (for example, 10g of spinning solution is prepared, and 3g of natural polymer is weighed to obtain a natural polymer solution with a mass concentration of 30%); if the dosage of the substances is higher than the concentration range, the needle head is easy to block in the spinning process, so that the spun fiber membrane has defects; if the concentration is less than the above range, the entanglement strength between polymer molecular chains is insufficient, and the spun fiber film is not uniform and has poor mechanical properties.

The mass fraction of the coupling agent is 0.5-1 wt% of the natural polymer solution, and if the using amount of the coupling agent is higher than the concentration range, the spinning process is not smooth; if the amount of EDC/NHS is less than this concentration range, the desired effect of crosslinking is not achieved.

The standing time in the step (2) is 10-20 min; the ultrasonic frequency is 50-80 kHz, and the time is 10-20 min.

The electrostatic spinning process parameters in the step (2) are as follows: under the dark condition, the spinning voltage is 10-30 kV, the receiving distance is 10-25 cm, the filling speed is 0.5-5 mL/h, the temperature is 10-30 ℃, and the relative humidity is 20-60%; the receiving substrate in the electrospinning process is glossy paper, aluminum foil, steel plate, or nonwoven fabric. Spinning voltage affects the stability of the jet; when the receiving distance is long, too few fibers collected by the receiving base material are collected, and when the receiving distance is short, the spinning solution cannot be volatilized in time, so that the diameter distribution of the fibers is disordered; the size of the perfusion speed is also a key factor in the spinning process, spinning liquid drop injection can be formed when the perfusion speed is too high, and the blockage condition can occur when the needle head is too small.

The post-treatment in the step (2) is to perform post-treatment for 4-24 hours by using a cross-linking liquid; the solute of the crosslinking solution is a mixed solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC and N-hydroxysuccinimide NHS; the solvent of the crosslinking liquid is a mixed liquid of ethanol and water.

The mass percentage concentration of the cross-linking liquid is 0.5-1%; the mass ratio of EDC to NHS is 3-5: 0.5 to 2; the mass ratio of ethanol to water in the mixed solution of ethanol and water is 7-9: 1 to 3.

The nanofiber hydrogel dressing disclosed by the invention can be applied to wounded skin dressings.

The invention prepares the nanofiber membrane through electrostatic spinning, and obtains the nanofiber hydrogel through subsequent crosslinking treatment. The original fibrous membrane obtained before crosslinking is composed of smooth fibers which are three-dimensionally stacked and randomly oriented, a natural polymer matrix after crosslinking is subjected to chemical crosslinking reaction with a catechol compound and cystamine dihydrochloride, and then the crosslinked natural polymer matrix absorbs water to swell, the swollen state can keep a large volume of water but not dissolve, the diameter of the fibers is obviously thickened, entanglement is generated among the fibers, and the original porous structure is still kept. The nanofiber hydrogel dressing can simulate the natural extracellular matrix of a human body, and provides ideal conditions for supporting the wound healing process.

According to the invention, the nanofiber membrane is subjected to post-treatment to initiate a chemical crosslinking reaction between a natural polymer matrix, a catechol compound and cystamine dihydrochloride, molecular chains penetrate through each other, and the molecular chains of every two polymers are crosslinked in an amido bond mode to form a multiple hybrid interpenetrating network structure. The resulting nanofiber hydrogel dressing reacts with skin containing amine or thiol groups through schiff base or michael addition, and thus can be firmly adhered to the skin. In addition, under the condition that tissue fluid exists in a wound, a hydration layer is formed between the dressing and the wound, a weak boundary layer can inhibit interface reaction between the hydrogel material and the skin, so that the adhesive strength of the hydrogel material is reduced, and the dressing can be firmly attached to the edge of the wound to create a good biological environment for healing of the skin. When the dressing is replaced, the dressing can be easily peeled off only by dripping water at the bonding part, the adhesion to the wound can not be caused, the healing process of the wound is accelerated, and the moisture on the dressing is still viscous after being evaporated in the air, so that the repeated adhesion is realized, and the service life of the dressing is prolonged.

Firstly, sequentially adding a catechol compound, cystamine dihydrochloride and EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) into a natural polymer base material, and reacting step by step in an acidic solution (Ph is approximately equal to 4) to obtain a spinning precursor solution. In the process, carboxyl on the natural polymer, a catechol compound and amino on cystamine dihydrochloride are subjected to amidation reaction under the action of a coupling agent EDC/NHS, amino and carboxyl in the molecular chain of the natural polymer also undergo condensation reaction, and disulfide bonds in the cystamine dihydrochloride are introduced into a system during crosslinking reaction. EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), as a carboxyl activator, does not itself form part of the actual crosslinking, and EDC is used in combination with NHS to increase the efficiency of the coupling reaction. Then, a uniform nanofiber membrane is prepared by an electrostatic spinning method, and catechol groups are remained in a non-oxidized form and are uniformly distributed in an acidic environment. Subsequently, the nanofiber membrane prepared is immersed in a cross-linking agent under weakly basic conditions, the weakly basic conditions being determined by controlling the ratio of ethanol to water, wherein the cross-linking agent stabilizes the fiber structure and insolubilizes the fiber, and catechol undergoes complex chemical and physical interactions, enhancing the single fiber strength and fiber-to-fiber bonding. The catechol has strong hydrogen bond interaction, and can form stable covalent crosslinking with abundant primary amine groups on the tissue surface, so that the viscosity of the nanofiber hydrogel is improved. Cystamine dihydrochloride is highly hygroscopic, can remove interfacial water from wet tissue surfaces, forms transient physical crosslinks with tissue surfaces, and the disulfide bonds therein also have the effect of enhancing the structure and adhesion within the nanofiber hydrogel.

The core of the strong adhesion of the nanofiber hydrogel is the action of covalent bonds and non-covalent bonds, wherein the covalent bond action is through Schiff base or Michael addition reaction, namely the reaction of phenolic hydroxyl and skin containing amino, carboxyl or thiol groups; non-covalent interactions include hydrogen bonding, pi-pi stacking, cationic interactions, etc., thereby forming an adhesive layer between the material and the skin. In addition, phenolic hydroxyl in the catechol compound can be oxidized into semiquinone free radicals and o-benzoquinone (dopaquinone), and a series of chemical reactions are carried out with active groups on natural macromolecules, so that the overall mechanical property of the material is improved, and the mechanical property of the material is also improved due to the interaction between bonds.

In addition, the water content of the nanofiber hydrogel influences the viscosity of the nanofiber hydrogel, a hydration layer can be formed between the dressing and the skin due to excessive water content, a weak boundary layer can inhibit interfacial reaction between the hydrogel material and the skin, and accordingly the bonding strength of the hydrogel material is reduced, so that when the dressing is replaced, the dressing can be easily peeled off only by dripping water at the bonding position, and secondary damage caused by tearing of a wound is avoided. After the removed dressing is placed for a period of time, the moisture of the dressing is evaporated in the air, and the dressing still has viscosity when the moisture content of the dressing is about 150%, so that repeated adhesion is realized, and the service life of the dressing is prolonged.

Advantageous effects

(1) The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required is simple and easy to implement and low in cost;

(2) according to the adhesive nanofiber hydrogel dressing capable of being peeled as required, multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds) are generated between natural polymers and catechol compounds and cystamine dihydrochloride with good biocompatibility, so that the nanofiber hydrogel is endowed with excellent mechanical strength and adhesive property.

(3) The adhesive nanofiber hydrogel dressing which can be peeled off as required can be peeled off painlessly as required, when the dressing needs to be replaced, the dressing can be peeled off easily and painlessly only by dripping water on the adhesive dressing which is tightly attached to the skin, the wound cannot be pulled and adhered, the pain caused by replacing the dressing is reduced, and the removed dressing still has viscosity after being placed for a period of time to enable the moisture of the removed dressing to be evaporated in the air, so that the repeated adhesion is achieved, and the service life of the dressing is prolonged.

(4) The skin dressing disclosed by the invention has good adhesion performance, can quickly close a wound and stop bleeding in emergency bleeding, prevent invasion and infection of germs, promote proliferation and repair of cells, does not need external dressing fixation, and creates a good biological environment for healing of skin. The dressing can be peeled off as required, secondary injury can not be caused when the dressing is replaced, pain caused when the dressing is replaced is reduced, and the dressing can be repeatedly adhered to facilitate a doctor to observe the wound condition.

(5) The average diameter of fibers in the nanofiber membrane prepared by the method is 200-500 nm, the average diameter of fibers in the nanofiber hydrogel dressing is 300-1200 nm, the thickness of the nanofiber hydrogel dressing is 90-200 mu m, the adhesive strength is 6-9 KPa, the tensile strength is 2-4 MPa, and the elongation at break is 50-200%.

Drawings

FIG. 1 is an SEM image of a nanofiber membrane of example 1 before crosslinking;

fig. 2 is an SEM image of the nanofiber hydrogel after crosslinking in example 1.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.

Materials: gelatin is bovine Type B, 100g, molecular weight 120000, available from Shanghai Rong En reagent, Inc. (Shanghai, China); the specification of the methacrylated gelatin is 65 percent of MA degree, 25g and 100000 of molecular weight, and the methacrylated gelatin is purchased from Aladdin reagent Co.Ltd in China; chitosan with a specification of 98% and a molecular weight of 150000, purchased from alatin reagent ltd, china; the collagen is 20mL in specification, has the molecular weight of 2000-3000D, and is derived from rat tails; sodium alginate 99%, 100g, molecular weight 216.12, available from shanghai ronn reagent ltd (shanghai, china); dopamine hydrochloride (DA) specification 99% +, 100g, molecular weight 189.64, available from Hadamard reagent, Inc.; tannic acid with a specification of 90% and a molecular weight of 1701.20, and is available from Nantong Tianxiang bioengineering Co., Ltd; the tea polyphenols are 98%, 25g, molecular weight of 281.36, and are available from Shanghai Michelin Biotechnology, Inc.; cystamine dihydrochloride, 98% in specification, 25g, molecular weight 225.19, available from Shanghai Bigdi pharmaceutical science and technology Co., Ltd; the specification of 4-arm-PEG-COOH is more than 95%, 5g, the molecular weight is 5000, and the PEG-COOH is purchased from Sigma Aldrich China Co., Ltd; 1-Ethyl-3- (3-dimethyl-aminopropyl) -1-carbodiimide hydrochloride (EDC) having a specification of 98% or more, 25g, a molecular weight of 193.72, and available from Eihh Biotechnology, Inc., Shanghai; n-hydroxysuccinimide (NHS) with a specification of 98% or more and a molecular weight of 115.08 is purchased from Aladdin Chemicals Ltd, China (Shanghai, China).

Tensile strength, elongation at break measurements: the mechanical properties of nanofiber hydrogel samples (3mm wide and 10mm high) were studied by stretching using a JQ03A tester (XQ-1C, China), with an elongation of 20-40 mm min^-1. Ten parallel samples were measured per group.

Measurement of adhesive strength: two pieces of fresh pigskin (5cm x 3cm) were selected as the bioadhesive tissue matrix, and the nanofiber hydrogel (3cm x 2cm) was placed between the fresh pigskin to ensure that the contact area of the pigskin was exactly the test area of the sample. According to the lap shear test method, by using an Instron materials testing System (Instron5565) equipped with a 100N load cell for 10-15 mm min^-1The bioadhesive properties were investigated. The laminating area and the pigskin were kept moist in time, and 5 parallel samples were measured per group. Most preferablyThe bond strength was then obtained by dividing the load by the bond area.

Example 1

The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required comprises the following specific steps:

(1) dissolving gelatin in a mixed solution of deionized water and acetic acid (mass ratio of 5: 2), wherein the mass fraction of the gelatin is 30 wt%, stirring the mixed solution in a water bath at 30 ℃ for 30min, heating to 50 ℃, and continuously stirring until the gelatin is completely dissolved.

(2) Adding Dopamine (DA) into the solution, stirring for 1h in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, continuously stirring for 1h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), and stirring for 2h at room temperature until the solution is uniform to prepare a stable precursor spinning solution. The mass fractions of dopamine and cystamine dihydrochloride are 1 wt% and 2 wt%, respectively, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) is 0.5 wt%, wherein the molar ratio of EDS to NHS is 4: 1;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 20min, treating for 10min by using ultrasonic equipment (the working frequency is 50kHz) so as to eliminate bubbles, then placing in an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving by using glossy paper to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane shown in figure 1 is 400nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: spinning voltage is 25KV, receiving distance is 15cm, perfusion speed is 1mL/h, temperature is 25 ℃, and relative humidity is 45%.

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 8 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the cross-linking liquid to the water is 9: and 1, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide), the mass concentration is 0.5%, and the mass ratio of EDC to NHS is 4: and 1, initiating a chemical crosslinking reaction between a natural polymer matrix and dopamine and cystamine dihydrochloride to prepare the viscous nanofiber hydrogel dressing.

As shown in figure 2, the average fiber diameter of the finally prepared adhesive nanofiber hydrogel dressing which can be peeled as required is 1000nm, the fiber length-diameter ratio is 100-5000, the adhesive strength is 8KPa, the tensile strength is 2.4MPa, and the elongation at break is 140%. The nanofiber hydrogel dressing is characterized in that multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds) are generated by gelatin, dopamine and cystamine dihydrochloride, so that excellent mechanical strength and adhesion performance are endowed to the nanofiber hydrogel dressing. When the dressing is replaced or removed, 1mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 3min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. The removed dressing is placed in the air for 10min to evaporate certain moisture, and the dressing still has viscosity when the moisture content is about 150%, so that repeated adhesion is achieved, and the service life of the dressing is prolonged.

Example 2

The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required comprises the following specific steps:

(1) dissolving chitosan in a mixed solution of deionized water and oxalic acid (the mass ratio is 5: 2.5), wherein the mass fraction of the chitosan is 25 wt%, stirring the mixed solution in a water bath at 30 ℃ for 1h, heating to 50 ℃, and continuously stirring until the chitosan is completely dissolved.

(2) Adding tannic acid into the solution, stirring for 1.5h in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, continuously stirring for 1.5h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), and stirring for 3h at room temperature until the solution is uniform to prepare a stable precursor spinning solution. The mass fractions of tannic acid and cystamine dihydrochloride are 0.5 wt% and 1 wt%, respectively, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) is 0.6 wt%, wherein the molar ratio of EDS to NHS is 3: 0.5;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 15min, treating for 13min by using ultrasonic equipment (the working frequency is 55kHz) so as to eliminate bubbles, then placing the precursor spinning solution into an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving through an aluminum foil to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 450nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: spinning voltage is 23KV, receiving distance is 13cm, perfusion speed is 1mL/h, temperature is 23 ℃, and relative humidity is 50%.

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 10 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the solvent to the crosslinking liquid is 7: and 3, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide), the mass concentration is 0.5%, and the mass ratio of EDC to NHS is 3: and 0.5, initiating a chemical crosslinking reaction of the natural polymer matrix, tannic acid and cystamine dihydrochloride to prepare the viscous nanofiber hydrogel dressing.

The average fiber diameter of the finally prepared adhesive nanofiber hydrogel dressing which can be peeled off as required is 950nm, the fiber length-diameter ratio is 100-5000, the adhesion strength is 7.5KPa, the tensile strength is 2.0MPa, and the elongation at break is 120%. The nanofiber hydrogel dressing is characterized in that multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds) are generated by chitosan, tannic acid and cystamine dihydrochloride, so that excellent mechanical strength and adhesion performance are endowed to the nanofiber hydrogel dressing. When the dressing is replaced or removed, 2mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 7min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. The removed dressing is placed in the air for 15min to evaporate certain moisture, and the dressing still has good viscosity when the moisture content is about 150%, so that repeated adhesion is achieved, and the service life of the dressing is prolonged.

Example 3

The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required comprises the following specific steps:

(1) dissolving methacrylic anhydrized gelatin in a mixed solution of deionized water and glacial acetic acid (the mass ratio is 5: 3), wherein the mass fraction of the methacrylic anhydrized gelatin is 20 wt%, stirring the mixed solution in a water bath at 30 ℃ for 2h, heating to 50 ℃, and continuously stirring until the methacrylic anhydrized gelatin is completely dissolved.

(2) Adding tea polyphenol into the solution, stirring for 1h in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, continuously stirring for 2h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), and stirring for 4h at room temperature until the solution is uniform to prepare a stable precursor spinning solution. The mass fractions of tea polyphenol and cystamine dihydrochloride are 1.5 wt% and 3 wt%, respectively, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) is 0.7 wt%, wherein the molar ratio of EDS to NHS is 4: 2;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 12min, treating for 15min by using ultrasonic equipment (the working frequency is 58kHz) so as to eliminate bubbles, then placing the precursor spinning solution into an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving through an aluminum foil to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 460nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: the spinning voltage is 22KV, the receiving distance is 12cm, the perfusion speed is 0.8mL/h, the temperature is 20 ℃, and the relative humidity is 40%.

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 12 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the solvent to the crosslinking liquid is 8: and 2, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide) with the mass concentration of 0.5%, wherein the mass ratio of EDC to NHS is 4:2, initiating the natural polymer matrix to perform chemical crosslinking reaction with the tea polyphenol and the cystamine dihydrochloride to prepare the adhesive nanofiber hydrogel dressing.

The average fiber diameter of the finally prepared adhesive nanofiber hydrogel dressing which can be peeled off as required is 920nm, the fiber length-diameter ratio is 100-5000, the adhesion strength is 7KPa, the tensile strength is 2.5MPa, and the elongation at break is 110%. The nanofiber hydrogel dressing is characterized in that methacrylic acid anhydrified gelatin, tea polyphenol and cystamine dihydrochloride generate multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds), so that excellent mechanical strength and adhesion performance are endowed. When the dressing is replaced or removed, 2.2mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 8min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. The removed dressing is placed in the air for 20min to evaporate certain moisture, and the dressing still has good viscosity when the moisture content is about 150%, so that repeated adhesion is achieved, and the service life of the dressing is prolonged.

Example 4

The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required comprises the following specific steps:

(1) dissolving collagen in a mixed solution of deionized water and propionic acid (the mass ratio is 5: 2.8), wherein the mass fraction of the collagen is 22 wt%, stirring the mixed solution in a water bath at 30 ℃ for 2.5h, heating to 50 ℃, and continuously stirring until the collagen is completely dissolved.

(2) Adding Dopamine (DA) into the solution, stirring for 1.2h in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, continuously stirring for 1.2h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), and stirring for 5h at room temperature until the solution is uniform to prepare a stable precursor spinning solution. The mass fractions of dopamine and cystamine dihydrochloride are respectively 2 wt% and 4 wt%, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) is 0.8 wt%, wherein the molar ratio of EDS to NHS is 3: 1;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 10min, treating for 16min by using ultrasonic equipment (the working frequency is 60kHz) so as to eliminate bubbles, then placing the precursor spinning solution into an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving through an aluminum foil to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 480nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: the spinning voltage is 20KV, the receiving distance is 10cm, the perfusion speed is 1.2mL/h, the temperature is 19 ℃, and the relative humidity is 38%; .

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 6 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the cross-linking liquid to the water is 9: and 1, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide), the mass concentration is 0.5%, and the mass ratio of EDC to NHS is 3: and 1, initiating a chemical crosslinking reaction between a natural polymer matrix and dopamine and cystamine dihydrochloride to prepare the viscous nanofiber hydrogel dressing.

The finally prepared adhesive nanofiber hydrogel dressing capable of being peeled as required has the average diameter of 980nm, the fiber length-diameter ratio of 100-5000, the adhesive strength of 6.8KPa, the tensile strength of 2.1MPa and the elongation at break of 90%. The nanofiber hydrogel dressing is characterized in that multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds) are generated by collagen, dopamine and cystamine dihydrochloride, so that excellent mechanical strength and adhesion performance are endowed to the nanofiber hydrogel dressing. When the dressing is replaced or removed, 1.2mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 5min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. The removed dressing is placed in the air for 13min to evaporate certain moisture, and the dressing still has good viscosity when the moisture content is about 150%, so that repeated adhesion is achieved, and the service life of the dressing is prolonged.

Example 5

The preparation method of the adhesive nanofiber hydrogel dressing capable of being peeled off as required comprises the following specific steps:

(1) dissolving sodium alginate in a mixed solution of deionized water and butyric acid (the mass ratio is 6: 2.2), wherein the mass fraction of the sodium alginate is 18 wt%, stirring the mixed solution in a water bath at 30 ℃ for 2.5h, heating to 50 ℃, and continuously stirring until the sodium alginate is completely dissolved.

(2) Adding tannic acid into the solution, stirring for 50min in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, continuously stirring for 2h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), stirring for 6h at room temperature until the solution is uniform, and preparing the stable precursor spinning solution. The mass fractions of tannic acid and cystamine dihydrochloride are 2 wt% and 4 wt%, respectively, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) is 0.9 wt%, wherein the molar ratio of EDS to NHS is 2: 0.5;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 18min, treating the precursor spinning solution for 18min by using ultrasonic equipment (the working frequency is 65kHz) so as to eliminate bubbles, then placing the precursor spinning solution into an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving by using an aluminum foil to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 440nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: spinning voltage is 19KV, receiving distance is 8cm, filling speed is 1.5mL/h, temperature is 30 ℃, and relative humidity is 35%; .

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 14 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the solvent to the crosslinking liquid is 7: and 3, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide), the mass concentration is 0.5%, and the mass ratio of EDC to NHS is 2: and 0.5, initiating a chemical crosslinking reaction of the natural polymer matrix, tannic acid and cystamine dihydrochloride to prepare the viscous nanofiber hydrogel dressing.

The average fiber diameter of the finally prepared adhesive nanofiber hydrogel dressing which can be peeled off as required is 900nm, the fiber length-diameter ratio is 100-5000, the adhesive strength is 7.2KPa, the tensile strength is 2.3MPa, and the elongation at break is 130%. The nanofiber hydrogel dressing is characterized in that multiple bonding effects (covalent bonds, hydrogen bonds and amido bonds) are generated by sodium alginate, tannic acid and cystamine dihydrochloride, so that excellent mechanical strength and adhesion performance are endowed to the nanofiber hydrogel dressing. When the dressing is replaced or removed, 1.5mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 6min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. The removed dressing is placed in the air for 14min to evaporate certain moisture, and the dressing still has good viscosity when the moisture content is about 150%, so that repeated adhesion is achieved, and the service life of the dressing is prolonged.

Comparative example 1

(1) Dissolving gelatin in a mixed solution of deionized water and acetic acid (mass ratio of 5: 2), wherein the mass fraction of the gelatin is 30 wt%, stirring the mixed solution in a water bath at 30 ℃ for 30min, heating to 50 ℃, and continuously stirring until the gelatin is completely dissolved.

(2) Adding Dopamine (DA) into the solution, stirring for 1h in a dark environment until the solution is uniform, then adding 4-arm-PEG-COOH, continuously stirring for 1h until the solution is uniform, finally adding a coupling agent EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide), and stirring for 2h at room temperature until the solution is uniform to prepare the stable precursor spinning solution. The mass fractions of dopamine and 4-arm-PEG-COOH were 1 wt% and 2 wt%, respectively, and the mass fraction of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)/NHS (N-hydroxysuccinimide) was 0.5 wt%, wherein the molar ratio of EDS and NHS was 4: 1;

(3) and (3) standing the precursor spinning solution prepared in the step (2) for 20min, treating for 10min by using ultrasonic equipment (the working frequency is 50kHz) so as to eliminate bubbles, then placing in an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving by using glossy paper to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 400nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: spinning voltage is 25KV, receiving distance is 15cm, perfusion speed is 1mL/h, temperature is 25 ℃, and relative humidity is 45%.

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 8 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the cross-linking liquid to the water is 9: and 1, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide), the mass concentration is 0.5%, and the mass ratio of EDC to NHS is 4: and 1, initiating a chemical crosslinking reaction of a natural polymer matrix, dopamine and 4-arm-PEG-COOH, and preparing the nanofiber hydrogel dressing.

The average fiber diameter of the finally prepared nanofiber hydrogel dressing is 998nm, the length-diameter ratio of the fibers is 100-5000, the adhesion strength is 3.7KPa, the tensile strength is 4.2MPa, and the elongation at break is 180%. The nanofiber hydrogel dressing is characterized in that multiple bonding effects (covalent bonds, hydrogen bonds and amide bonds) are generated by gelatin, dopamine and 4-arm-PEG-COOH, so that excellent mechanical strength is given to the nanofiber hydrogel dressing, and the bonding strength is relatively weak and is not enough to be firmly adhered to a wound site.

Comparative example 2

The preparation method of the nanofiber hydrogel dressing comprises the following specific steps:

(1) dissolving gelatin in a mixed solution of deionized water and acetic acid (mass ratio of 5: 2), wherein the mass fraction of the gelatin is 30 wt%, stirring the mixed solution in a water bath at 30 ℃ for 30min, heating to 50 ℃, and continuously stirring until the gelatin is completely dissolved.

(2) And adding Dopamine (DA) into the solution, stirring for 1h in a dark environment until the solution is uniform, then adding cystamine dihydrochloride, and stirring for 2h at room temperature until the solution is uniform to prepare the stable precursor spinning solution. The mass fractions of dopamine and cystamine dihydrochloride are 1 wt% and 2 wt%, respectively.

(3) And (3) standing the precursor spinning solution prepared in the step (2) for 20min, treating for 10min by using ultrasonic equipment (the working frequency is 50kHz) so as to eliminate bubbles, then placing in an injector, spinning by using an electrostatic spinning device under the condition of keeping out of the sun, and receiving by using glossy paper to prepare the nanofiber membrane, wherein the average fiber diameter of the nanofiber membrane is 400nm, and the thickness of the nanofiber membrane is 90-200 microns. Wherein the technological parameters of electrostatic spinning are as follows: spinning voltage is 25KV, receiving distance is 15cm, perfusion speed is 1mL/h, temperature is 25 ℃, and relative humidity is 45%.

(4) And (4) carrying out post-treatment on the nanofiber membrane prepared in the step (3) by using a crosslinking solution, wherein the treatment time is 8 h. The solvent of the crosslinking liquid is a mixed liquid of ethanol and water, and the mass ratio of the cross-linking liquid to the water is 9: and 1, the solute of the crosslinking liquid is a mixture of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and NHS (N-hydroxysuccinimide) with the mass concentration of 1%, wherein the mass ratio of EDC to NHS is 4: and 1, initiating a chemical crosslinking reaction between a natural polymer matrix and dopamine and cystamine dihydrochloride to prepare the viscous nanofiber hydrogel dressing.

The average fiber diameter of the finally prepared adhesive nanofiber hydrogel dressing which can be peeled off as required is 970nm, the length-diameter ratio of the fibers is 100-5000, the adhesive strength is 6KPa, the tensile strength is 1.2MPa, and the elongation at break is 60%. When the dressing is replaced or removed, 1mL of water is dripped on the adhesive dressing tightly attached to the skin, the retention time is 2min, the dressing can be easily and painlessly peeled off, and secondary damage to the wound can not be caused. As the coupling agent is not added in the spinning process, the crosslinking is insufficient, so that the obtained dressing has low tensile strength and elongation at break, and can not meet the performance requirements of the dressing.

Claims (10)

Translated fromChinese

1.一种纳米纤维水凝胶敷料，其特征在于，所述辅料以含天然高分子材料、儿茶酚化合物、胱胺二盐酸盐、偶联剂的原料，通过静电纺，后处理获得。1. a nanofiber hydrogel dressing, is characterized in that, described adjuvant is with the raw material that contains natural macromolecular material, catechol compound, cystamine dihydrochloride, coupling agent, by electrospinning, aftertreatment obtains .2.一种纳米纤维水凝胶敷料的制备方法，包括：2. a preparation method of nanofiber hydrogel dressing, comprising:(1)将天然高分子材料、溶剂混合，搅拌溶解，得到天然高分子溶液；然后加入儿茶酚化合物，避光搅拌，加入胱胺二盐酸盐，搅拌，再加入偶联剂，搅拌，得到纺丝液；(1) Mixing the natural polymer material and solvent, stirring and dissolving to obtain a natural polymer solution; then adding catechol compound, stirring in the dark, adding cystamine dihydrochloride, stirring, then adding a coupling agent, stirring, to obtain spinning solution;(2)将上述纺丝液静置，超声，静电纺丝，得到纳米纤维膜；(2) above-mentioned spinning solution is left standstill, ultrasonic, electrospinning, obtains nanofiber membrane;(3)将上述纳米纤维膜进行后处理，得到纳米纤维水凝胶辅料。(3) post-processing the above nanofiber membrane to obtain a nanofiber hydrogel auxiliary material.3.根据权利要求2所述制备方法，其特征在于，所述步骤(1)中天然高分子材料为明胶、甲基丙烯酸酐化明胶、胶原、透明质酸、甲壳素、壳聚糖、海藻酸钠、蛋白质中的一种或几种；所述儿茶酚化合物为多巴胺、单宁酸、茶多酚中的一种或几种；所述溶剂为水和有机酸的混合溶液；所述偶联剂为1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺EDC/N-羟基丁二酰亚胺NHS。3. preparation method according to claim 2 is characterized in that, in described step (1), natural macromolecular material is gelatin, methacrylic anhydride gelatin, collagen, hyaluronic acid, chitin, chitosan, seaweed One or more of sodium and protein; the catechol compound is one or more of dopamine, tannic acid, and tea polyphenols; the solvent is a mixed solution of water and organic acid; the The coupling agent was 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDC/N-hydroxysuccinimide NHS.4.根据权利要求3所述制备方法，其特征在于，所述有机酸为乙酸、乙二酸、冰醋酸、丙酸、丁酸中的一种或几种；所述偶联剂中EDS和NHS的摩尔比为3～5:0.5～2。4. preparation method according to claim 3, is characterized in that, described organic acid is one or more in acetic acid, oxalic acid, glacial acetic acid, propionic acid, butyric acid; In described coupling agent, EDS and The molar ratio of NHS is 3-5:0.5-2.5.根据权利要求2所述制备方法，其特征在于，所述步骤(1)天然高分子溶液的质量百分浓度为10～30wt％；儿茶酚化合物的质量分数为天然高分子溶液的0.5～5wt％，胱胺二盐酸盐的质量分数为天然高分子溶液的1～10wt％；偶联剂为0.5～1wt％。5 . The preparation method according to claim 2 , wherein the mass percentage concentration of the natural polymer solution in the step (1) is 10-30 wt %; the mass fraction of the catechol compound is 0.5% of the natural polymer solution. 6 . ～5wt%, the mass fraction of cystamine dihydrochloride is 1～10wt% of the natural polymer solution; the coupling agent is 0.5～1wt%.6.根据权利要求2所述制备方法，其特征在于，所述步骤(2)中静置时间为10min～20min；超声频率为50～80kHz，时间为10min～20min。The preparation method according to claim 2, characterized in that, in the step (2), the standing time is 10min-20min; the ultrasonic frequency is 50-80kHz, and the time is 10min-20min.7.根据权利要求2所述制备方法，其特征在于，所述步骤(2)中静电纺丝工艺参数为：避光条件下进行，纺丝电压10～30kV，接收距离10～25cm，灌注速度0.5～5mL/h，温度10～30℃，相对湿度20～60％；静电纺丝工艺中的接收基材为油光纸、铝箔、钢板、或非织造布。7. The preparation method according to claim 2, characterized in that, in the step (2), the electrospinning process parameters are as follows: carry out under dark conditions, spinning voltage 10～30kV, receiving distance 10～25cm, perfusion speed 0.5~5mL/h, temperature 10~30℃, relative humidity 20~60%; the receiving substrate in the electrospinning process is glossy paper, aluminum foil, steel plate, or non-woven fabric.8.根据权利要求2所述制备方法，其特征在于，所述步骤(2)中后处理为采用交联液进行后处理4～24h；所述交联液的溶质为1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺EDC和N-羟基丁二酰亚胺NHS的混合溶液；交联液的溶剂为乙醇与水的混合液。8 . The preparation method according to claim 2 , wherein the post-treatment in the step (2) is to use a cross-linking solution for post-treatment for 4 to 24 hours; the solute of the cross-linking solution is 1-(3-diol 8 . A mixed solution of methylaminopropyl)-3-ethylcarbodiimide EDC and N-hydroxysuccinimide NHS; the solvent of the cross-linking solution is a mixed solution of ethanol and water.9.根据权利要求8所述制备方法，其特征在于，所述交联液的质量百分浓度为0.5～1％；所述EDC与NHS的质量比为3～5：0.5～2；乙醇与水的混合液中乙醇和水的质量比为7～9：1～3。9 . The preparation method according to claim 8 , wherein the mass percentage concentration of the cross-linking solution is 0.5-1%; the mass ratio of the EDC to the NHS is 3-5: 0.5-2; The mass ratio of ethanol and water in the water mixture is 7-9:1-3.10.一种权利要求1所述纳米纤维水凝胶敷料的应用。10. An application of the nanofiber hydrogel dressing of claim 1.

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