WO2021077540A1 - 一种韧性可粘附湿态组织水凝胶敷料盒及其制备方法和用途 - Google Patents

一种韧性可粘附湿态组织水凝胶敷料盒及其制备方法和用途 Download PDF

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WO2021077540A1
WO2021077540A1 PCT/CN2019/121782 CN2019121782W WO2021077540A1 WO 2021077540 A1 WO2021077540 A1 WO 2021077540A1 CN 2019121782 W CN2019121782 W CN 2019121782W WO 2021077540 A1 WO2021077540 A1 WO 2021077540A1
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component
hydrogel
sodium alginate
mass
hydrogel dressing
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English (en)
French (fr)
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胡兵
邓旭
冯哲
郭竣畅
曾宪晖
叶连松
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四川大学华西医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/009—Materials resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels

Definitions

  • the invention belongs to the field of biomedical materials, and specifically relates to a tough and adherent wet tissue hydrogel dressing box, and a preparation method and application thereof.
  • Wound healing refers to the healing process after the body is subjected to external forces and internal and external tissues such as the liver and skin are severed or damaged; it is an extremely complex mechanism through the pathophysiological process of inflammation, tissue regeneration and remodeling.
  • wound dressings are often used to treat wounds to resist external microbial infections, reduce body fluid and heat loss from damaged wounds, and accelerate wound healing.
  • Traditional dressings represented by gauze, bandages, and cotton pads are the most widely used. They are inexpensive, but non-degradable, easy to adhere to the wound surface, and difficult to maintain long-term efficacy. The process of dressing change will increase the pain.
  • Se'verine Rose et al. used high-concentration (30wt%-50wt%) nano-SiO 2 particle solution through physical action to achieve low adhesion to the wetted surface, but it could not meet the surgical requirements (Rose S, Prevoteau A, Elzière P, et al. Nature, 2014, 505, 382.).
  • Some new dressings enhance the adhesion to tissues by adding adhesives to the dressing, but the adhesion between these adhesives and the dressing is poor, such as commercialized fibrin glue and polyethylene glycol adhesives It can form a covalent bond with tissues (Dastjerdi AK, Pagano M, Kaartinen MT, et al. Acta Biomaterialia, 2012, 8, 3349.), which greatly enhances adhesion, but lacks sufficient force with the dressing, and the dressing is easy to debond .
  • the existing dressings are mostly used for skin healing, and the healing effect on the surface of wet tissues in the body is poor.
  • the present invention provides a flexible and adherent wet tissue hydrogel dressing box, and a preparation method and application thereof.
  • the present invention provides a tough and adherent wet tissue hydrogel dressing box, which includes two components stored separately: component A is a hydrogel formed by cross-linking sodium alginate and acrylamide, and component A is a hydrogel formed by cross-linking sodium alginate and acrylamide.
  • B is a connecting solution prepared from a coupling agent, a linking agent, and a buffer as raw materials.
  • hydrogel is prepared from sodium alginate, acrylamide, crosslinking agent, initiator, catalyst, and deionized water as raw materials.
  • the viscosity of the sodium alginate is 75-650mPa.s; preferably, the viscosity of the sodium alginate is one or more of 75mPa.s, 250mPa.s, 450mPa.s, 650mPa.s; more preferably Ground, the viscosity of the sodium alginate is composed of 75mPa.s and 450mPa.s; wherein the mass ratio of sodium alginate with a viscosity of 75mPa.s and sodium alginate with a viscosity of 450mPa.s is 1:1;
  • the crosslinking agent is composed of an ionic crosslinking agent and a chemical crosslinking agent; preferably, the ionic crosslinking agent is calcium sulfate; the chemical crosslinking agent is N,N'-methylene bis Acrylamide; more preferably, the calcium sulfate is an aqueous calcium sulfate solution with a concentration of 0.75M, and the N,N'-methylenebisacrylamide is N,N'-methylenebispropylene with a concentration of 2wt% Amide aqueous solution;
  • the initiator is ammonium persulfate; preferably, the ammonium persulfate is an aqueous ammonium persulfate solution with a concentration of 0.27M;
  • the catalyst is tetramethylethylenediamine
  • the deionized water is secondary deionized water
  • the coupling agent is composed of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide, preferably, the 1-(3- The mass ratio of dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide is 1:1;
  • the linking agent is chitosan, polylysine, bovine serum albumin or SiO 2 nanoparticles, and the SiO 2 nanoparticles are amino modified SiO 2 nanoparticles;
  • the buffer is an MES buffer.
  • the mass ratio of the sodium alginate and acrylamide is 1:(1-10);
  • the mass-volume ratio of the sodium alginate and the ionic crosslinking agent is 1: (0.5-5) (w/v);
  • the mass-volume ratio of the sodium alginate and the chemical cross-linking agent is 1: (0.1-0.5) (w/v);
  • the mass-volume ratio of the sodium alginate and the initiator is 2:(1 ⁇ 5)(w/v);
  • the mass-volume ratio of the sodium alginate to the catalyst is 2: (0.1-0.5) (w/v);
  • the mass-volume ratio of the sodium alginate and deionized water is 1: (10-60) (w/v);
  • the mass ratio of the coupling agent and the linking agent is (1-2):1;
  • the mass-volume ratio of the linking agent and the MES buffer is 1: (10-60) (w/v);
  • the mass ratio of sodium alginate and acrylamide is 1:6;
  • the mass-volume ratio of the sodium alginate and the ionic crosslinking agent is 1:1 (w/v);
  • the mass volume ratio of the sodium alginate and the chemical crosslinking agent is 1:0.2 (w/v);
  • the mass-volume ratio of the sodium alginate and the initiator is 2:2.3 (w/v);
  • the mass-volume ratio of the sodium alginate and the catalyst is 2:0.1 (w/v);
  • the mass-volume ratio of the sodium alginate and deionized water is 1:43 (w/v);
  • the mass ratio of the coupling agent and the linking agent is 1.2:1;
  • the mass-volume ratio of the linking agent and the MES buffer is 1:50 (w/v).
  • the preparation method of the amino modified SiO 2 nanoparticles includes the following steps:
  • step A the volume ratio of the absolute ethanol, ethyl orthosilicate and ammonia is 100: (1 ⁇ 6): (10 ⁇ 15);
  • step A the centrifugal cleaning is three centrifugation with ethanol
  • step A the drying is drying in a vacuum drying oven at 80°C;
  • step B the mass ratio of the SiO 2 nanoparticles and aminopropyltriethoxysilane is 1: (1 to 5); the mass volume ratio of the SiO 2 nanoparticles and toluene is 1:(50 ⁇ 70)(w/v);
  • the centrifugal cleaning is 3 times of ethanol centrifugal cleaning, and 3 times of secondary deionized water centrifugal cleaning;
  • step B the drying is drying in a vacuum drying oven at 80°C;
  • step A the volume ratio of the absolute ethanol, ethyl orthosilicate and ammonia water is 100:6:15;
  • step B the mass ratio of the SiO 2 nanoparticles and aminopropyltriethoxysilane is 1:4; the mass-volume ratio of the SiO 2 nanoparticles and toluene is 1:60 ( w/v).
  • preparation method of the component A hydrogel includes the following steps:
  • step (1) the mixing solution is degassed; and/or, in step (2), the gelation condition is room temperature overnight.
  • preparation method of the component B connecting solution includes the following steps:
  • the water content of the component A hydrogel is 80-90%; preferably, the water content of the component A hydrogel is 86%.
  • component A hydrogel is a small drug-loaded molecule; preferably, the small drug molecule is a small water-soluble drug molecule.
  • the present invention also provides a method for preparing the aforementioned hydrogel dressing box, which includes the following steps:
  • the present invention also provides a tough and adherent wet tissue hydrogel dressing, which takes the aforementioned tough and adherent wet tissue hydrogel dressing box, and coats component B on component A, namely Got.
  • the dosage of the component B and the component A is (0.1-0.5): 100 (g: cm 2 );
  • the dosage of the component B and the component A is 0.3:100 (g:cm 2 ).
  • the present invention also provides the aforementioned flexible and adherent wet tissue hydrogel dressing box and the use of the aforementioned flexible and adherent wet tissue hydrogel dressing in preparing wound surface repair materials.
  • wound surface is the surface of the skin or the surface of the wet tissue in the body.
  • v/w is the volume-to-mass ratio, and the unit is mL/g; w/v is the mass-to-volume ratio, and the unit is g/mL.
  • room temperature is 25 ⁇ 5°C; overnight is 12 ⁇ 2h.
  • the hydrogel dressing box of the present invention is composed of a component A hydrogel and a component B connecting liquid.
  • the hydrogel dressing box significantly improves the adhesive performance of the hydrogel dressing by adding component B.
  • the hydrogel dressing has high adhesion strength to the surface of the skin and the surface of the wet tissue in the body, and is not easy to fall off. Meet clinical needs.
  • the hydrogel dressing has excellent mechanical properties and biocompatibility, the raw materials have no toxic side effects, no damage to the tissues during use, it is degradable, and does not need to be taken out after the body tissue is repaired, thereby avoiding secondary damage.
  • the water content of the hydrogel dressing is as high as 86%, and a large amount of drugs can be loaded.
  • the introduction of drugs can provide a good environment for tissue healing and promote tissue healing.
  • the hydrogel dressing box of the present invention not only overcomes the problems of poor treatment effect of traditional dressings and inability to degrade the wound surface, but also overcomes the problem of poor adhesion of the new dressing, can be applied to internal tissues, and has broad application prospects.
  • Figure 1 is a schematic diagram of the method of using the hydrogel dressing box of the present invention.
  • Figure 2 shows the adhesion effect of the dressing on the liver and pigskin.
  • Figure 3 is a scanning electron micrograph of SiO 2 nanoparticles before and after amino modification.
  • Figure 4 shows the elongation at break (A) and elastic modulus (B) of PAM/SA hydrogels prepared with different viscosities of sodium alginate.
  • Figure 5 shows the effect of pressing the dressing at different times on the adhesion of pig liver.
  • Figure 6 shows the effect of the pressure applied on the dressing on the adhesion strength of the liver during the adhesion process.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
  • Example 1 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes (shown in Figure 1), press for 5 to 30 minutes, pressing pressure ⁇ 6000Pa, that's all.
  • Figure 2 shows the adhesion effect of the dressing box of the present invention on liver and pigskin.
  • Example 2 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 3 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 4 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 5 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 6 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 7 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 8 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Example 9 A hydrogel dressing box with toughness and adherence to wet tissues of the present invention
  • the dosage of component B and component A is 0.3g: 100cm 2 , and stick it on the wound surface.
  • the wound surface is the surface of the skin or the surface of the wet tissue in the body. Yes, press for 5 to 30 minutes, and press pressure ⁇ 6000Pa.
  • Test example 1 Mechanical properties of component A of the present invention PAM/SA hydrogel
  • the component A PAM/SA hydrogels prepared in Examples 1 to 6 were placed in a universal material testing machine to test the mechanical properties.
  • the test methods are as follows:
  • the elastic modulus is calculated as follows:
  • P is the maximum load, the unit is N; S is the cross-sectional area of the sample, the unit is mm 2 .
  • the elongation at break is calculated as follows:
  • L is the running length of the universal material testing machine in mm
  • L O is the original length of the experiment in mm.
  • FIG. 4 The mechanical properties of different component A PAM/SA hydrogels are shown in Figure 4. It can be seen from Fig. 4 that the elastic modulus and elongation at break of PAM/SA hydrogels have average values of 0.04 MPa and 1600%, respectively. Among them, the 75/450-PAM/SA hydrogel has the most reliable performance, with an elastic modulus of 0.04 MPa and a breaking elongation of 1700-1900%.
  • the method for testing the adhesion strength of the hydrogel dressing box of the present invention to biological tissues is as follows:
  • Adhesion strength is calculated by the following formula
  • F is the maximum peel force, in N, and w is the width of the adhesion interface of the gel during the peeling process, in mm.
  • the maximum peel force (adhesion strength) of the gel is detected by the 90° peeling method.
  • the pressing strength is 0, 10000 and 20000 Pa. After pressing for 1 hour, the maximum peeling force (adhesion strength) of the gel is detected by the 90° peeling method.
  • the results of the adhesive strength of the tough and adherent wet tissue hydrogel dressing box of the present invention to biological tissues are shown in Figures 5-6. It can be seen from Figure 5 that the dressing can reach the maximum adhesion strength after pressing for 5-10 minutes; it can be seen from Figure 6 that during the implementation of the dressing box, it is necessary to apply pressure on the side facing away from the biological tissue component A, and the pressure is ⁇ 6000Pa, That is, good adhesion strength can be obtained.
  • the tough and adherent wet tissue hydrogel dressing box of the present invention has short pressing time, low pressing strength, and method of use; at the same time, it has good adhesion and maximum adhesion to biological tissues. About 0.2N/mm.
  • the inventor of the present invention used the component A PAM/SA hydrogel prepared in Example 5 (not coated with the component B connecting solution) as a dressing, applied to the wound tissue, and pressed for 5-30 minutes, and the pressing pressure was ⁇ 6000Pa. However, the viscosity force between component A and the tissue is too small to detect the adhesion strength.
  • the hydrogel dressing box of the present invention is composed of component A hydrogel and component B connecting liquid.
  • the hydrogel dressing box significantly improves the adhesive performance of the hydrogel dressing by adding component B.
  • the hydrogel dressing has high adhesion strength to the surface of the skin and the surface of the wet tissue in the body, and is not easy to fall off. Meet clinical needs.
  • the hydrogel dressing has excellent mechanical properties and biocompatibility, the raw materials have no toxic side effects, no damage to the tissues during use, it is degradable, and does not need to be taken out after the body tissue is repaired, thereby avoiding secondary damage.
  • the water content of the hydrogel dressing is as high as 86%, and a large amount of drugs can be loaded.
  • the introduction of drugs can provide a good environment for tissue healing and promote tissue healing.
  • the hydrogel dressing box of the present invention not only overcomes the problems of poor treatment effect of traditional dressings and inability to degrade the wound surface, but also overcomes the problem of poor adhesion of the new dressing, can be applied to internal tissues, and has broad application prospects.

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Abstract

一种韧性可粘附湿态组织水凝胶敷料盒，它包括分开存放的两个组分：组分A为由海藻酸钠和丙烯酰胺交联形成的水凝胶，组分B为由偶联剂、链接剂、缓冲液作为原料制备而成的连接液。该水凝胶敷料盒使用方便，通过增加组分B，显著提高了该水凝胶敷料的粘附性能，对皮肤表面和体内湿润组织表面均具有很高的粘附强度，不易脱落，满足临床需求。同时，其具有优异的机械性能和生物相容性，可降解。该水凝胶敷料中含水量高达86％，可负载大量药物，可为组织愈复提供良好的环境，促进组织愈合。该水凝胶敷料盒既克服了传统敷料创面治疗效果差、不能降解等问题；又克服了新型敷料粘附性能差的问题，还能应用于体内组织，具有广阔的应用前景。

Description

一种韧性可粘附湿态组织水凝胶敷料盒及其制备方法和用途 技术领域
本发明属于生物医用材料领域，具体涉及一种韧性可粘附湿态组织水凝胶敷料盒及其制备方法和用途。
背景技术
创伤愈合是指机体受到外力作用，肝脏、皮肤等内外组织出现离断或缺损后的愈复过程；经过炎症反应，组织再生和重塑的病理生理过程，是一种极其复杂的机制。目前，多采用创面敷料来治疗创面，以抵御外界微生物感染，减少受损创面的体液以及热量流失，加速创面的愈合。以纱布、绷带、棉垫为代表的传统敷料应用最广，其价格低廉，但不可降解，易与创面粘连，难以维持长时间药效，换药过程会增加痛感。基于伤口修复理论以及组织工程学研发的新型敷料，包括薄膜型、水凝胶型、喷雾型以及海绵型敷料，在清创、保湿、药物控制释放等方面都有较大突破。
这些新型敷料虽然修复效果得到了提高，但其黏附性能往往较差，甚至无法满足临床需求。如，Se′verine Rose等人选用高浓度(30wt％-50wt％)的纳米SiO 2颗粒溶液通过物理作用可以实现对润湿表面的低黏附，但不能满足外科要求(Rose S,Prevoteau A,Elzière P,et al.Nature,2014,505,382.)。有些新型敷料通过在敷料上增加粘合剂来增强与组织间的黏附作用，但是这些粘合剂与敷料间的黏附力差，如，商用化的纤维蛋白胶以及聚乙烯二元醇粘合剂能够与组织形成共价键(Dastjerdi A K,Pagano M,Kaartinen M T,et al.Acta Biomaterialia,2012,8,3349.)，极大增强黏附力，但与敷料缺乏足够的作用力，敷料易脱粘。同时，现有的敷料多用于皮肤的敷愈，针对于体内湿润组织表面的敷愈效果较差。
因此，研究一种粘附性能优异，能够满足临床需求，又能够用于体内湿润组织的敷料有重要意义。
发明内容
为了解决上述问题，本发明提供了一种韧性可粘附湿态组织水凝胶敷料盒及其制备方法和用途。
本发明提供了一种韧性可粘附湿态组织水凝胶敷料盒，它包括分开存放的两个组分：组分A为由海藻酸钠和丙烯酰胺交联形成的水凝胶，组分B为由偶联剂、链接剂、缓冲液作为原料制备而成的连接液。
进一步地，所述水凝胶由海藻酸钠、丙烯酰胺、交联剂、引发剂、催化 剂、去离子水为原料制备而成。
进一步地，
所述海藻酸钠的粘度为75～650mPa.s；优选地，所述海藻酸钠的粘度为75mPa.s、250mPa.s、450mPa.s、650mPa.s的其中一种或多种；更优选地，所述海藻酸钠的粘度由75mPa.s和450mPa.s组成；其中，粘度为75mPa.s的海藻酸钠和粘度为450mPa.s的海藻酸钠的质量比为1:1；
和/或，所述交联剂由离子交联剂和化学交联剂组成；优选地，所述离子交联剂为硫酸钙；所述化学交联剂为N,N’-亚甲基双丙烯酰胺；更优选地，所述硫酸钙为浓度为0.75M的硫酸钙水溶液，所述N,N’-亚甲基双丙烯酰胺为浓度为2wt％的N,N’-亚甲基双丙烯酰胺水溶液；
和/或，所述引发剂为过硫酸氨；优选地，所述过硫酸氨为浓度为0.27M的过硫酸氨水溶液；
和/或，所述催化剂为四甲基乙二胺；
和/或，所述去离子水为二次去离子水；
和/或，所述偶联剂由1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺组成，优选地，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺的质量比为1:1；
和/或，所述链接剂为壳聚糖、聚赖氨酸、牛血清白蛋白或SiO 2纳米颗粒，所述SiO 2纳米颗粒为氨基改型SiO 2纳米颗粒；
和/或，所述缓冲液为MES缓冲液。
进一步地，
所述海藻酸钠和丙烯酰胺的质量比为1:(1～10)；
和/或，所述海藻酸钠和离子交联剂的质量体积比为1:(0.5～5)(w/v)；
和/或，所述海藻酸钠和化学交联剂的质量体积比为1:(0.1～0.5)(w/v)；
和/或，所述海藻酸钠和引发剂的质量体积比为2:(1～5)(w/v)；
和/或，所述海藻酸钠和催化剂的质量体积比为2:(0.1～0.5)(w/v)；
和/或，所述海藻酸钠和去离子水的质量体积比为1:(10～60)(w/v)；
和/或，所述偶联剂和链接剂的质量比为(1～2):1；
和/或，所述链接剂和MES缓冲液的质量体积比为1:(10～60)(w/v)；
优选地，
所述海藻酸钠和丙烯酰胺的质量比为1:6；
和/或，所述海藻酸钠和离子交联剂的质量体积比为1:1(w/v)；
和/或，所述海藻酸钠和化学交联剂的质量体积比为1:0.2(w/v)；
和/或，所述海藻酸钠和引发剂的质量体积比为2:2.3(w/v)；
和/或，所述海藻酸钠和催化剂的质量体积比为2:0.1(w/v)；
和/或，所述海藻酸钠和去离子水的质量体积比为1:43(w/v)；
和/或，所述偶联剂和链接剂的质量比为1.2:1；
和/或，所述链接剂和MES缓冲液的质量体积比为1:50(w/v)。
进一步地，
所述氨基改型SiO 2纳米颗粒的制备方法包括如下步骤：
A.无水乙醇中加入正硅酸乙酯，搅拌，水浴加热至60℃，保持30min，加入浓度为28％的氨水，60℃反应6h，离心清洗，干燥，得SiO 2纳米颗粒；
B在SiO 2纳米颗粒中加入甲苯和氨丙基三乙氧基硅烷，室温反应48h，离心清洗，干燥，即得。
进一步地，
步骤A中，所述的无水乙醇、正硅酸乙酯和氨水的体积比为100:(1～6):(10～15)；
和/或，步骤A中，所述的离心清洗为用乙醇离心三次；
和/或，步骤A中，所述的干燥为80℃真空干燥箱内烘干；
和/或，步骤B中，所述的SiO 2纳米颗粒和氨丙基三乙氧基硅烷的质量比为1:(1～5)；所述的SiO 2纳米颗粒和甲苯的质量体积比为1:(50～70)(w/v)；
和/或，步骤B中，所述的离心清洗为乙醇离心清洗3次，二次去离子水离心清洗3次；
和/或，步骤B中，所述的干燥为80℃真空干燥箱内烘干；
优选地，
步骤A中，所述的无水乙醇、正硅酸乙酯和氨水的体积比为100:6:15；
和/或，步骤B中，所述的SiO 2纳米颗粒和氨丙基三乙氧基硅烷的质量比为1:4；所述的SiO 2纳米颗粒和甲苯的质量体积比为1:60(w/v)。
进一步地，所述组分A水凝胶的制备方法包括如下步骤：
(1)丙烯酰胺和海藻酸钠溶于去离子水，得混匀液；
(2)在步骤(1)制备的混匀液中加入交联剂、引发剂和催化剂后，混合均匀，凝胶化即得；
优选地，步骤(1)中，所述的混匀液要进行除气；和/或，步骤(2)中，所述的凝胶化的条件为室温过夜。
进一步地，所述组分B连接液的制备方法包括如下步骤：
将偶联剂和链接剂溶于缓冲液，即得。
进一步地，所述的组分A水凝胶含水量为80～90％；优选地，组分A水凝胶含水量为86％。
进一步地，所述的组分A水凝胶为载药物小分子；优选地，所述药物小分子为水溶性药物小分子。
本发明还提供了一种制备前述的水凝胶敷料盒的方法，它包括如下步骤：
I、组分A水凝胶的制备
(1)丙烯酰胺和海藻酸钠溶于去离子水，得混匀液；
(2)在步骤(1)制备的混匀液中加入交联剂、引发剂和催化剂后，混合均匀，凝胶化即得；
II、组分B连接液的制备
将偶联剂和链接剂溶于缓冲液，即得。
本发明还提供了一种韧性可粘附湿态组织水凝胶敷料，它是取前述的韧性可粘附湿态组织水凝胶敷料盒，将组分B涂覆与组分A上，即得。
进一步地，所述组分B与组分A用量为(0.1～0.5)：100(g：cm 2)；
优选地，所述组分B与组分A用量为0.3：100(g：cm 2)。
本发明还提供了前述的韧性可粘附湿态组织水凝胶敷料盒以及前述的韧性可粘附湿态组织水凝胶敷料在制备创面修复材料中的用途。
进一步地，所述创面为皮肤表面或体内湿润组织表面。
本发明中，v/w为体积质量比，单位为mL/g；w/v为质量体积比，单位为g/mL。
本发明中，室温为25±5℃；过夜为12±2h。
本发明水凝胶敷料盒由组分A水凝胶和组分B连接液组成。该水凝胶敷料盒使用时按压时间短、按压强度小，使用方便。该水凝胶敷料盒通过增加组分B，显著提高了该水凝胶敷料的粘附性能，该水凝胶敷料对皮肤表面和体内湿润组织表面均具有很高的粘附强度，不易脱落，满足临床需求。同时，该水凝胶敷料具有优异的机械性能和生物相容性，原料无毒副作用，使用时对组织无损害，可降解，体内组织修复后无需取出，避免二次伤害。此外，该水凝胶敷料中含水量高达86％，可负载大量药物，药物的引入可为组织愈复提供良好的环境，促进组织愈合。本发明水凝胶敷料盒既克服了传统敷料创面治疗效果差、不能降解等问题；又克服了新型敷料粘附性能差的问题，还能应用于体内组织，具有广阔的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明水凝胶敷料盒使用方法方法示意图。
图2为敷料对肝脏和猪皮的粘附效果展示。
图3为SiO 2纳米颗粒在氨基改性前后的扫描电镜图。
图4为不同粘度海藻酸钠制备的PAM/SA水凝胶的断裂伸长率(A)及弹性模量(B)。
图5为按压敷料不同时间对猪肝黏附的影响。
图6为粘附过程中，施加在敷料上压力的大小对肝脏的粘附强度的影响。
具体实施方式
本发明具体实施方式中使用的原料、设备除非另有说明，均为已知产品，通过购买市售产品获得。
实施例1、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
称取粘度为75mPa.s的海藻酸钠2g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL0.27M过硫酸氨，混合均匀，室温过夜凝胶化，即得PAM/SA水凝胶(75-PAM/SA)。
(2)组分B：连接液的制备
称取60mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、60mg N-羟基琥珀酰亚胺(NHS)和0.1g壳聚糖，置于小烧杯中，向其中加入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可(图1所示)，按压5～30min，按压力≥6000Pa，即可。图2为本发明敷料盒对肝脏和猪皮的粘附效果展示。
实施例2、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
称取粘度为250mPa.s的海藻酸钠2g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL 2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL0.27M过硫酸氨，混合均匀，室温过夜凝胶化，即得PAM/SA水凝胶 (250-PAM/SA)。
(2)组分B：连接液的制备
称取60mg EDC、60mg NHS和0.1g壳聚糖，置于小烧杯中，向其中加入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例3、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
称取粘度为450mPa.s的海藻酸钠2g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL 2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL0.27M过硫酸氨，混合均匀，室温过夜凝胶化，即得PAM/SA水凝胶(450-PAM/SA)。
(2)组分B：连接液的制备
称取60mg EDC、60mg NHS和0.1g壳聚糖，置于小烧杯中，向其中加入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例4、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
称取粘度为650mPa.s的海藻酸钠2g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL 2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL 0.27M过硫酸氨，混合均匀，室温过夜凝胶化，即得PAM/SA水凝胶(650-PAM/SA)。
(2)组分B：连接液的制备
称取60mg EDC、60mg NHS和0.1g壳聚糖，置于小烧杯中，向其中加 入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例5、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
分别称取粘度为75mPa.s和450mPa.s的海藻酸钠各1g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL 2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL 0.27M过硫酸氨，混合均匀，室温过夜凝胶化，即得PAM/SA水凝胶(75/450-PAM/SA)。
(2)组分B：连接液的制备
称取60mg EDC、60mg NHS和0.1g壳聚糖，置于小烧杯中，向其中加入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例6、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
分别称取粘度为75mPa.s和650mPa.s的海藻酸钠各1g，放入烧杯中，向其中加入86mL的二次去离子水，持续搅拌24h混匀后，向其中加入12g丙烯酰胺，搅拌10min，除气，取上述混匀液10mL，加入10μL四甲基乙二胺(TEMED)，40μL 2wt％N,N’-亚甲基双丙烯酰胺(MBAA)，200μL0.75M硫酸钙以及230μL 0.27M过硫酸氨，混合均匀，过夜凝胶化，即得PAM/SA水凝胶(75/450-PAM/SA)。
(2)组分B：连接液的制备
称取60mg EDC、60mg NHS和0.1g壳聚糖，置于小烧杯中，向其中加入5mL MES缓冲液，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用 量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例7、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
同实施例5中组分A PAM/SA水凝胶的制备方法。
(2)组分B：连接液的制备
称取0.1g聚赖氨酸，放入小烧杯中，加入5mL MES缓冲液，用3M NaOH调节PH至6，室温搅拌过夜，然后向其中加入60mg EDC和60mg NHS，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例8、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
同实施例5中组分A PAM/SA水凝胶的制备方法。
(2)组分B：连接液的制备
称取0.1g牛血清白蛋白，放入小烧杯中，加入5mL MES缓冲液，用3M NaOH调节PH至6，室温搅拌过夜，然后向其中加入60mg EDC和60mg NHS，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
实施例9、本发明一种韧性可粘附湿态组织水凝胶敷料盒
1、制备方法
(1)组分A：PAM/SA水凝胶的制备
同实施例5中组分A PAM/SA水凝胶的制备方法。
(2)组分B：连接液的制备
A.制备SiO 2纳米颗粒
量取100mL无水乙醇，加入250mL的圆底烧瓶内，向其中加入6mL正硅酸乙酯，磁力搅拌，水浴加热至60℃，保持30min，将量取的15mL 28％氨水加入其中，60℃反应6h。将反应后溶液用乙醇离心三次，放入80℃真空干 燥箱内烘干，得SiO 2纳米颗粒，备用。通过扫描电镜观察可知SiO 2纳米颗粒粒径约200nm(图3中的SiO 2)。
B.氨基改性SiO 2颗粒
称取上述步骤A制得的SiO 2纳米颗粒1g置于250mL的圆底烧瓶内。向其中加入60mL甲苯，4g氨丙基三乙氧基硅烷，室温反应48h，乙醇离心洗三次，二次去离子水离心洗3次。放入80℃真空干燥箱内烘干，得氨基改性SiO 2纳米颗粒，备用。通过扫描电镜观察可知氨基改性SiO 2纳米颗粒表面形貌未发生明显变化(图3中的NH 2-SiO 2)。
C.组分B：连接液的制备
称取上述步骤B制得的氨基改性SiO 2纳米颗粒0.1g，放入小烧杯中，加入5mL MES缓冲液，室温搅拌过夜，然后向其中加入60mg EDC和60mg NHS，混合均匀，即得连接液。
2、使用方法
将组分B连接液涂覆于组分A PAM/SA水凝胶上，组分B与组分A用量为0.3g：100cm 2，贴敷于创面，创面为皮肤表面或体内湿润组织表面均可，按压5～30min，按压力≥6000Pa，即可。
以下通过具体的试验例证明本发明的有益效果。
试验例1、本发明组分A PAM/SA水凝胶的力学性能
1、试验方法
分别取实施例1～6制备得到的组分A PAM/SA水凝胶置于万能材料试验机测试力学性能，测试方法如下：
将制得的6mm×2mm×30mm的哑铃状PAM/SA水凝胶置于万能材料试验机进行力学拉伸测试，标距10mm，拉伸速度40mm/min，同等条件下，依次对三个样品进行测量。
弹性模量按下式计算：
Figure PCTCN2019121782-appb-000001
式中：P为最大载荷，单位为N；S为样品的截面积，单位mm 2。
断裂伸长率按下式计算：
Figure PCTCN2019121782-appb-000002
式中：L为万能材料试验机的运行长度，单位mm，L O为实验的原始长度，单位为mm。
2、试验结果
不同组分A PAM/SA水凝胶的力学性能结果如图4所示。由图4可知PAM/SA水凝胶的弹性模量和断裂伸长率，平均值分别为0.04MPa和1600％。其中75/450-PAM/SA水凝胶的性能最可靠，弹性模量为0.04MPa，断裂伸长率为1700-1900％。
试验例2、本发明水凝胶敷料盒对生物组织粘附强度
1、试验方法
本发明水凝胶敷料盒对生物组织粘附强度的测试方法如下：
取实施例5制备得到的水凝胶敷料盒，将组分B连接液均匀的涂抹于6mm×2mm×20mm的块状组分A PAM/SA水凝胶上，随后将PAM/SA水凝胶敷于固定在铁板上的猪肝表面，选用不同的按压强和按压时间后，利用90°剥离法检测凝胶的粘附强度。
粘附强度按下式计算
Figure PCTCN2019121782-appb-000003
式中：F为最大剥离力，单位为N，w为剥离过程中凝胶的粘附界面宽度，单位为mm。
(1)压强度为≥6000Pa，按压时间为5～10min、25～35min和50～60min时，利用90°剥离法检测凝胶的最大剥离力(粘附强度)。
(2)按压强度为0、10000和20000Pa，按压1h后，利用90°剥离法检测凝胶的最大剥离力(粘附强度)。
2、试验结果
本发明一种韧性可粘附湿态组织水凝胶敷料盒对生物组织粘附强度的结果如图5～6所示。由图5可知，敷料在按压5-10min后即可达到最大粘附强度；由图6可知，敷料盒在实施过程中，在背离生物组织组分A一面施加压力是需要的，压强≥6000Pa，即能获得良好的粘附强度。综上，本发明一种韧性可粘附湿态组织水凝胶敷料盒使用时按压时间短、按压强度小，使用方法；同时具有良好的粘附力，对生物组织粘附的最大粘附力约为0.2N/mm。
本发明的发明人将实施例5制备的组分A PAM/SA水凝胶上(未涂覆组分B连接液)作为敷料，贴敷于创面组织，按压5～30min，按压力≥6000Pa。但是组分A与组织间的粘度力太小，无法检测出粘附强度。
综上，本发明水凝胶敷料盒由组分A水凝胶和组分B连接液组成。该水凝胶敷料盒使用时按压时间短、按压强度小，使用方便。该水凝胶敷料盒通过增加组分B，显著提高了该水凝胶敷料的粘附性能，该水凝胶敷料对皮肤 表面和体内湿润组织表面均具有很高的粘附强度，不易脱落，满足临床需求。同时，该水凝胶敷料具有优异的机械性能和生物相容性，原料无毒副作用，使用时对组织无损害，可降解，体内组织修复后无需取出，避免二次伤害。此外，该水凝胶敷料中含水量高达86％，可负载大量药物，药物的引入可为组织愈复提供良好的环境，促进组织愈合。本发明水凝胶敷料盒既克服了传统敷料创面治疗效果差、不能降解等问题；又克服了新型敷料粘附性能差的问题，还能应用于体内组织，具有广阔的应用前景。

Claims (15)

  1. 一种韧性可粘附湿态组织水凝胶敷料盒，其特征在于：它包括分开存放的两个组分：组分A为由海藻酸钠和丙烯酰胺交联形成的水凝胶，组分B为由偶联剂、链接剂、缓冲液作为原料制备而成的连接液。
  2. 根据权利要求1所述的水凝胶敷料盒，其特征在于：所述水凝胶由海藻酸钠、丙烯酰胺、交联剂、引发剂、催化剂、去离子水为原料制备而成。
  3. 根据权利要求2所述的水凝胶敷料盒，其特征在于：
    所述海藻酸钠的粘度为75～650mPa.s；优选地，所述海藻酸钠的粘度为75mPa.s、250mPa.s、450mPa.s、650mPa.s的其中一种或多种；更优选地，所述海藻酸钠的粘度由75mPa.s和450mPa.s组成；其中，粘度为75mPa.s的海藻酸钠和粘度为450mPa.s的海藻酸钠的质量比为1:1；
    和/或，所述交联剂由离子交联剂和化学交联剂组成；优选地，所述离子交联剂为硫酸钙；所述化学交联剂为N,N’-亚甲基双丙烯酰胺；更优选地，所述硫酸钙为浓度为0.75M的硫酸钙水溶液，所述N,N’-亚甲基双丙烯酰胺为浓度为2wt％的N,N’-亚甲基双丙烯酰胺水溶液；
    和/或，所述引发剂为过硫酸氨；优选地，所述过硫酸氨为浓度为0.27M的过硫酸氨水溶液；
    和/或，所述催化剂为四甲基乙二胺；
    和/或，所述去离子水为二次去离子水；
    和/或，所述偶联剂由1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺组成，优选地，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺的质量比为1:1；
    和/或，所述链接剂为壳聚糖、聚赖氨酸、牛血清白蛋白或SiO 2纳米颗粒，所述SiO 2纳米颗粒为氨基改型SiO 2纳米颗粒；
    和/或，所述缓冲液为MES缓冲液。
  4. 根据权利要求3所述的水凝胶敷料盒，其特征在于：
    所述海藻酸钠和丙烯酰胺的质量比为1:(1～10)；
    和/或，所述海藻酸钠和离子交联剂的质量体积比为1:(0.5～5)(w/v)；
    和/或，所述海藻酸钠和化学交联剂的质量体积比为1:(0.1～0.5)(w/v)；
    和/或，所述海藻酸钠和引发剂的质量体积比为2:(1～5)(w/v)；
    和/或，所述海藻酸钠和催化剂的质量体积比为2:(0.1～0.5)(w/v)；
    和/或，所述海藻酸钠和去离子水的质量体积比为1:(10～60)(w/v)；
    和/或，所述偶联剂和链接剂的质量比为(1～2):1；
    和/或，所述链接剂和MES缓冲液的质量体积比为1:(10～60)(w/v)；
    优选地，
    所述海藻酸钠和丙烯酰胺的质量比为1:6；
    和/或，所述海藻酸钠和离子交联剂的质量体积比为1:1(w/v)；
    和/或，所述海藻酸钠和化学交联剂的质量体积比为1:0.2(w/v)；
    和/或，所述海藻酸钠和引发剂的质量体积比为2:2.3(w/v)；
    和/或，所述海藻酸钠和催化剂的质量体积比为2:0.1(w/v)；
    和/或，所述海藻酸钠和去离子水的质量体积比为1:43(w/v)；
    和/或，所述偶联剂和链接剂的质量比为1.2:1；
    和/或，所述链接剂和MES缓冲液的质量体积比为1:50(w/v)。
  5. 根据权利要求3所述的水凝胶敷料盒，其特征在于：所述氨基改型SiO 2纳米颗粒的制备方法包括如下步骤：
    A.无水乙醇中加入正硅酸乙酯，搅拌，水浴加热至60℃，保持30min，加入浓度为28％的氨水，60℃反应6h，离心清洗，干燥，得SiO 2纳米颗粒；
    B在SiO 2纳米颗粒中加入甲苯和氨丙基三乙氧基硅烷，室温反应48h，离心清洗，干燥，即得。
  6. 根据权利要求5所述的水凝胶敷料盒，其特征在于：
    步骤A中，所述的无水乙醇、正硅酸乙酯和氨水的体积比为100:(1～6):(10～15)；
    和/或，步骤A中，所述的离心清洗为用乙醇离心三次；
    和/或，步骤A中，所述的干燥为80℃真空干燥箱内烘干；
    和/或，步骤B中，所述的SiO 2纳米颗粒和氨丙基三乙氧基硅烷的质量比为1:(1～5)；所述的SiO 2纳米颗粒和甲苯的质量体积比为1:(50～70)(w/v)；
    和/或，步骤B中，所述的离心清洗为乙醇离心清洗3次，二次去离子水离心清洗3次；
    和/或，步骤B中，所述的干燥为80℃真空干燥箱内烘干；
    优选地，
    步骤A中，所述的无水乙醇、正硅酸乙酯和氨水的体积比为100:6:15；
    和/或，步骤B中，所述的SiO 2纳米颗粒和氨丙基三乙氧基硅烷的质量比为1:4；所述的SiO 2纳米颗粒和甲苯的质量体积比为1:60(w/v)。
  7. 根据权利要求1～6任一项所述的水凝胶敷料盒，其特征在于：所述组分A水凝胶的制备方法包括如下步骤：
    (1)丙烯酰胺和海藻酸钠溶于去离子水，得混匀液；
    (2)在步骤(1)制备的混匀液中加入交联剂、引发剂和催化剂后，混合均匀，凝胶化即得；
    优选地，步骤(1)中，所述的混匀液要进行除气；和/或，步骤(2)中，所 述的凝胶化的条件为室温过夜。
  8. 根据权利要求1～6任一项所述的水凝胶敷料盒，其特征在于：所述组分B连接液的制备方法包括如下步骤：
    将偶联剂和链接剂溶于缓冲液，即得。
  9. 根据权利要求1～6任一项所述的水凝胶敷料盒，其特征在于：所述的组分A水凝胶含水量为80～90％；优选地，组分A水凝胶含水量为86％。
  10. 根据权利要求1～6任一项所述的水凝胶敷料盒，其特征在于：所述的组分A水凝胶为载药物小分子；优选地，所述药物小分子为水溶性药物小分子。
  11. 一种制备权利要求1～10任一项所述的水凝胶敷料盒的方法，其特征在于：它包括如下步骤：
    I、组分A水凝胶的制备
    (1)丙烯酰胺和海藻酸钠溶于去离子水，得混匀液；
    (2)在步骤(1)制备的混匀液中加入交联剂、引发剂和催化剂后，混合均匀，凝胶化即得；
    II、组分B连接液的制备
    将偶联剂和链接剂溶于缓冲液，即得。
  12. 一种韧性可粘附湿态组织水凝胶敷料，其特征在于：它是取权利要求1～10任一项所述的韧性可粘附湿态组织水凝胶敷料盒，将组分B涂覆与组分A上，即得。
  13. 根据权利要求12所述的水凝胶敷料，其特征在于：所述组分B与组分A用量为(0.1～0.5)：100(g：cm 2)；
    优选地，所述组分B与组分A用量为0.3：100(g：cm 2)。
  14. 权利要求1～10任一项所述的韧性可粘附湿态组织水凝胶敷料盒以及权利要求12或13所述的韧性可粘附湿态组织水凝胶敷料在制备创面修复材料中的用途。
  15. 根据权利要求14所述的用途，其特征在于：所述创面为皮肤表面或体内湿润组织表面。
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