WO2020233547A1 - 外伤止血海绵及其制备方法和应用 - Google Patents

外伤止血海绵及其制备方法和应用 Download PDF

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WO2020233547A1
WO2020233547A1 PCT/CN2020/090868 CN2020090868W WO2020233547A1 WO 2020233547 A1 WO2020233547 A1 WO 2020233547A1 CN 2020090868 W CN2020090868 W CN 2020090868W WO 2020233547 A1 WO2020233547 A1 WO 2020233547A1
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zeolite
graphene
traumatic
graphene oxide
preparation
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French (fr)
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王兴
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北京化工大学
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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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the invention relates to the technical field of hemostasis, in particular to a trauma hemostatic sponge, and a preparation method and application thereof.
  • bleeding is not only the direct cause of death in accidents, but rapid control of bleeding in the early stage of bleeding is of great significance for saving lives, reducing patient pain and preventing complications.
  • Zeolite is one of the most classic hemostatic agents and has been widely used since FDA approval in 2002. Zeolite has the property of quickly absorbing water. After contact with wounds, it can quickly absorb plasma, enrich blood cells and other components to achieve rapid control of bleeding; at the same time, the inert composition of zeolite does not cause toxicity to organisms. However, the application of exposed zeolite can cause severe thermal damage and necrosis of surrounding tissues. Z-Medica has developed a pre-hydrated zeolite hemostatic material (ACS+), which can produce less exothermic reaction and reduce thermal damage, but its hemostatic performance will be reduced. Meanwhile, Naresh Ahuj et al.
  • ACS+ pre-hydrated zeolite hemostatic material
  • the object of the present invention is to provide a traumatic hemostatic sponge, which can quickly stop bleeding without causing heat damage.
  • the present invention provides a traumatic hemostatic sponge, including zeolite and graphene;
  • the graphene has a three-dimensional cross-linked structure
  • the zeolite is dispersed in the three-dimensional crosslinked structure
  • the mass ratio of the zeolite and graphene is 1:(0.2-5).
  • the present invention also provides a method for preparing the trauma hemostatic sponge described in the above technical scheme, which includes the following steps:
  • the zeolite-graphene composite aerogel is subjected to microwave expansion and high temperature treatment in sequence to obtain a traumatic hemostatic sponge.
  • the preparation method of the zeolite-graphene oxide composite hydrogel includes the following steps:
  • the graphene oxide solution, the crosslinking agent, and the zeolite are mixed to perform a crosslinking reaction to obtain a zeolite-graphene oxide composite hydrogel.
  • the concentration of the graphene oxide solution is (3-10) mg/mL;
  • the mass ratio of the crosslinking agent, zeolite, and graphene oxide in the graphene oxide solution is (1-2.0):(0.5-2):(0.3-1.2).
  • the temperature of the crosslinking reaction is 80-120°C, and the time of the crosslinking reaction is 5-7h.
  • the temperature of the freeze-drying is -30°C to -70°C, and the time of the freeze-drying is 36-60h.
  • freeze-drying after the freeze-drying is completed, it further includes sequentially washing and drying the zeolite-graphene composite aerogel obtained by freeze-drying;
  • the cleaning agent used in the cleaning is ethanol; the cleaning time is 36-60h;
  • the drying temperature is 20-40°C, and the drying time is 24-48h.
  • the power of the microwave expansion is 300-800W, and the time of the microwave expansion is 5-40s.
  • the temperature of the high-temperature treatment is 100-400°C, and the time of the high-temperature treatment is 1-6h, preferably 2-6h.
  • the present invention also provides the application of the trauma hemostatic sponge described in the above technical solution or the trauma hemostatic sponge prepared by the preparation method described in the above technical solution in trauma hemostasis.
  • the present invention provides a traumatic hemostatic sponge, comprising zeolite and graphene; the graphene has a three-dimensional cross-linked structure; the zeolite is dispersed in the three-dimensional cross-linked structure; the mass ratio of the zeolite and graphene is 1 :(0.2-5).
  • the traumatic hemostatic sponge of the present invention has a distinctive hemostatic mechanism: 1. Physical adsorption: When applied to a bleeding site, the traumatic hemostatic sponge can quickly absorb liquid components in the blood, and enrich blood cells and other components on the interface; 2. Interface stimulation: The electrical potential of zeolite can stimulate blood cells to trigger the coagulation cascade reaction; 3.
  • the traumatic hemostatic sponge of the present invention has excellent hemostatic properties. According to the records of the examples, the traumatic hemostatic sponge of the present invention has fast hemostasis, mild exothermic reaction, and high biological safety; after removing the skin above the right leg artery of SD rats with a scalpel and creating trauma, the trauma Hemostatic sponge is used for hemostasis.
  • the hemostasis time is 69 ⁇ 15s, the blood loss is 0.35 ⁇ 0.21g, the maximum temperature of the wound is 40 ⁇ 2.93°C, and the wound is not burned; compared with zeolite powder (hemostasis time is 70 ⁇ 30s, blood loss is 1.90 ⁇ 0.48 g, the maximum temperature of the wound is 73 ⁇ 3.78°C, and the wound has burns) and commercial QuikClot combat gauze (Combat Gauze) (hemostasis time is 85 ⁇ 10s, blood loss is 2.66 ⁇ 0.16g) with faster hemostasis speed and gentler Exothermic temperature. Moreover, the traumatic hemostatic sponge of the present invention does not produce hemolysis after being used in a wound.
  • the present invention also provides a preparation method of the traumatic hemostatic sponge.
  • the method has the characteristics of low cost, easy operation, and easy scale-up production, and the traumatic hemostatic sponge prepared by the preparation method is convenient to carry and has a long shelf life.
  • Figure 1 is a SEM image of the traumatic hemostatic sponge according to the present invention.
  • Figure 2 is a diagram of the blood compatibility of the trauma hemostatic sponge and zeolite powder described in Example 1 and Example 2 of the present invention.
  • water refers to deionized water, ultrapure water or distilled water unless otherwise specified.
  • the present invention provides a traumatic hemostatic sponge, which is characterized by comprising zeolite and graphene;
  • the graphene has a three-dimensional cross-linked structure
  • the zeolite is dispersed in the three-dimensional cross-linked structure (as shown in Figure 1).
  • the mass ratio of the zeolite and graphene is 1:(0.2-5), preferably 1:(0.43-3), more preferably 1:(0.75-2.86).
  • the traumatic hemostatic sponge uses the zeolite and graphene sponge structure to have its own hemostatic effect. Since the zeolite itself emits heat during hemostasis, it is dispersed in the graphene of the three-dimensional cross-linked structure. , The thermal conductivity of graphene can be used to reduce the temperature of the wound during hemostasis and avoid wound tissue burns; further, by controlling the mass ratio of zeolite and graphene oxide during the preparation process, the mass ratio of zeolite and graphene is above Within the range, the traumatic hemostatic sponge can control the temperature of the wound at 40 ⁇ 2.93°C during the hemostasis process, and thermal stimulation is used to further improve the hemostatic effect of trauma.
  • the present invention also provides a method for preparing the trauma hemostatic sponge described in the above technical scheme, which includes the following steps:
  • the zeolite-graphene composite aerogel is subjected to microwave expansion and high temperature treatment in sequence to obtain a traumatic hemostatic sponge.
  • the zeolite-graphene oxide hydrogel is freeze-dried to obtain the zeolite-graphene composite aerogel.
  • the preparation method of the zeolite-graphene oxide composite hydrogel includes the following steps: mixing the graphene oxide solution, the crosslinking agent, and the zeolite to perform a crosslinking reaction to obtain the zeolite-graphene oxide composite water gel.
  • the graphene oxide solution is preferably an aqueous graphene oxide solution; the concentration of the graphene oxide solution is preferably (3-10) mg/mL, more preferably (5-10) mg/mL.
  • the crosslinking agent is preferably one or more of ethylenediamine, aminoalanine, ethanedithiol and propylenedithiol; when the crosslinking agent is two of the above-mentioned specific options
  • the present invention does not have any special restrictions on the proportion of the specific substances, and the mixture can be mixed according to any proportion.
  • the crosslinking agent is added in the form of a crosslinking agent solution, preferably in the form of an aqueous solution of the crosslinking agent.
  • the concentration of the crosslinking agent solution is 0.5-1.5 g/mL, preferably 0.9-1.5 g/mL.
  • the concentration of the crosslinking agent solution is the total concentration of the crosslinking agent.
  • the zeolite is preferably zeolite powder; the particle size of the zeolite powder is preferably 100-400 mesh, more preferably 200-400 mesh.
  • the particle size of the so-called zeolite powder is determined according to the number of meshes screened.
  • the particle size of the zeolite powder obtained by passing the zeolite powder through a 200 mesh sieve is 200 mesh.
  • the mass ratio of the crosslinking agent, zeolite, and graphene oxide in the graphene oxide solution is preferably (1-2.0):(0.5-2):(0.3-1.2).
  • the present invention does not have any special restrictions on the mixing method, and it is only necessary to adopt a mixing method well known to those skilled in the art to achieve the purpose of uniform mixing.
  • the temperature of the crosslinking reaction is preferably 80-120°C, more preferably 96-110°C; the time of the crosslinking reaction is preferably 5-7h.
  • the purpose of the cross-linking reaction is to cause the functional groups on the graphene oxide surface of the sheet to undergo a cross-linking reaction under the action of a cross-linking agent.
  • a cross-linking reaction most of the oxygen-containing functional groups are consumed.
  • the graphene oxide whose microstructure is a three-dimensional cross-linked structure is generated, and a macroscopic sponge structure is formed; at the same time, when the cross-linking reaction proceeds, the zeolite is coated in the three-dimensional cross-linked structure.
  • the freeze-drying temperature is preferably -30°C to -70°C, more preferably -45°C to -70°C; the freeze-drying time is preferably 36-60h, more preferably 36-48h .
  • the freeze-drying after the freeze-drying is completed, it preferably further includes sequentially washing and drying the zeolite-graphene composite aerogel obtained after freeze-drying.
  • the cleaning agent used in the cleaning is preferably ethanol.
  • the cleaning is preferably performed in a Soxhlet extractor; the cleaning time is preferably 36-60h, more preferably 36-48h; in the present invention, the drying temperature is preferably 20-40 °C, more preferably 25-35 °C; the drying time is preferably 24-48h.
  • the present invention subjects the zeolite-graphene composite aerogel to microwave expansion and high temperature treatment to obtain a traumatic hemostatic sponge.
  • the power of the microwave expansion is preferably 300-800W; the time of the microwave expansion is preferably 5-40s.
  • the microwave expansion treatment process can completely reduce the remaining oxidized functional groups on the graphene surface to obtain graphene; at the same time, microwave expansion can also make the sponge pores larger and the specific surface area increased, thereby improving the structure of the graphene sponge. Adsorption capacity.
  • the temperature of the high-temperature treatment is preferably 100-400°C; the time of the high-temperature treatment is 1-6h, preferably 2-6h.
  • the graphene oxide solution, the cross-linking agent and the zeolite are mixed for cross-linking reaction to obtain a hydrogel; in the cross-linking reaction, most of the oxygen-containing functional groups Is consumed to generate graphene oxide whose microstructure is a three-dimensional cross-linked structure, and form a macroscopic sponge structure; at the same time, when the cross-linking reaction proceeds, the zeolite is coated in the three-dimensional cross-linked structure; thus, the present invention will
  • the hydrogel obtained by mixing graphene oxide solution, crosslinking agent and zeolite for crosslinking reaction is called "zeolite-graphene oxide composite hydrogel".
  • the hydrogel obtained by mixing the graphene oxide solution, crosslinking agent and zeolite for crosslinking reaction is freeze-dried to obtain an aerogel; the freeze-drying process is a physical dehydration process;
  • the aerogel obtained by lyophilizing the hydrogel obtained by mixing graphene oxide solution, crosslinking agent and zeolite for crosslinking reaction is called “zeolite-graphene composite aerogel” or “zeolite-graphene gas Gel", the two can be used interchangeably.
  • the aerogel obtained in the above process is subjected to microwave expansion and high temperature treatment in sequence to obtain a sponge; the microwave expansion treatment process can completely reduce the remaining oxidized functional groups on the graphene surface to obtain graphene; at the same time, microwave expansion also The pores of the sponge can be enlarged, the specific surface area is increased, and the adsorption capacity of the graphene sponge structure can be improved.
  • the zeolite since the zeolite has been hydrated before the high temperature treatment, that is, water molecules occupy the pores of the zeolite molecular sieve and no longer have the function of traumatic hemostasis.
  • the above-mentioned high-temperature treatment can remove the water molecules in the hydrated zeolite, thereby restoring the traumatic hemostatic function.
  • the temperature of the high-temperature treatment can control the exothermic ability of the zeolite in the traumatic hemostatic sponge during hemostasis, so as to ensure that the traumatic hemostatic sponge keeps the wound temperature below 43°C during the hemostatic process and above the human body temperature. Effectiveness of thermal stimulation.
  • the sponge obtained by successively subjecting the aerogel obtained by the above process to microwave expansion and high temperature treatment is called “traumatic hemostatic sponge” or “zeolite-graphene hemostatic sponge”, and the two can be used interchangeably.
  • the present invention also provides the application of the trauma hemostatic sponge described in the above technical solution or the trauma hemostatic sponge prepared by the preparation method described in the above technical solution in trauma hemostasis.
  • the trauma hemostatic sponge provided by the present invention and its preparation method and application are described in detail below in conjunction with examples, but they cannot be understood as limiting the scope of protection of the present invention.
  • the experimental methods described below, unless otherwise specified, are routine laboratory methods.
  • the experimental materials, raw materials or components described below, unless otherwise specified, can be obtained from commercial channels or conventional methods.
  • the zeolite powder used in the following examples and comparative examples needs to be passed through a 200-mesh sieve before use.
  • SD rats (Sprague-Dawly rats) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The animals weigh about 250g when they are purchased, and they are kept in groups, 6 per cage. Keep constant temperature and humidity in the animal room (temperature 20-25°C, humidity 60% ⁇ 10%). Before the start of the experiment, the animals were adaptively reared in the animal room for 3 days, with free drinking and eating. During the experiment, all the experimental operations the rats received met the requirements of experimental animal ethics, abided by the regulations promulgated by the National and Beijing University of Chemical Technology Biomedical Ethics Committee and the China-Japan Friendship Hospital Laboratory Animal Welfare Ethics Committee. Approved by the Medical Ethics Committee and the Experimental Animal Welfare Ethics Committee of China-Japan Friendship Hospital.
  • the zeolite-graphene composite hydrogel was freeze-dried at -45°C for 48h, and the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol (washing 48h), and dried at 25°C for 48h to obtain zeolite- Graphene aerogel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 10s and treated at 100°C for 1 hour to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 7:20), which can be directly used for traumatic hemostasis;
  • FIG. 1 Figure 1
  • Figure B is a 100-fold magnification of Figure A. It can be seen that the graphene in the traumatic hemostatic sponge of the present invention has a three-dimensional cross-linked structure, that is, a large number of graphene sheets criss-cross form a loose porous structure of the sponge, and zeolite particles are embedded in the graphene sheets.
  • the zeolite-graphene composite hydrogel was freeze-dried at -45°C for 48h, and the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol (washing 48h), and dried at 25°C for 48h to obtain zeolite- Graphene aerogel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 20s and treated at 100°C for 2 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 7:3), which can be directly used for traumatic hemostasis.
  • the SEM test result of the trauma hemostatic sponge is similar to that of Example 1.
  • the zeolite-graphene composite hydrogel was freeze-dried at -45°C for 48h, and the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol (washing 48h), and dried at 25°C for 48h to obtain zeolite- Graphene aerogel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 10s and treated at 100°C for 2 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 7:20), which can be directly used for traumatic hemostasis.
  • the SEM test result of the trauma hemostatic sponge is similar to that of Example 1.
  • the zeolite-graphene composite hydrogel was freeze-dried at -30°C for 36h, and the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol (cleaning 36h), and dried at 20°C for 24h to obtain zeolite- Graphene aerogel;
  • the zeolite-graphene aerogel was expanded with a 300W microwave for 40s, and treated at 100°C for 6 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 4:3), which can be directly used for traumatic hemostasis.
  • the SEM test result of the trauma hemostatic sponge is similar to that of Example 1.
  • the zeolite-graphene composite hydrogel was freeze-dried at -70°C for 60h, and the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol (washing 60h), and dried at 40°C for 48h to obtain zeolite- Graphene aerogel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 5 seconds and treated at 400° C. for 2 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 1:5), which can be directly used for traumatic hemostasis.
  • the SEM test result of the trauma hemostatic sponge is similar to that of Example 1.
  • the zeolite-graphene composite hydrogel was freeze-dried at -45°C for 48h, the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol for 48h, and dried at 25°C for 48h to obtain zeolite-graphene gas gel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 30s and treated at 150°C for 3 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 1:50), which can be directly used for traumatic hemostasis.
  • the zeolite-graphene composite hydrogel was freeze-dried at -45°C for 48h, the product obtained after the freeze-drying was washed in a Soxhlet extractor with ethanol for 48h, and dried at 25°C for 48h to obtain zeolite-graphene gas gel;
  • the zeolite-graphene aerogel was expanded with 800W microwave for 10s and treated at 150°C for 3 hours to obtain a traumatic hemostatic sponge (the mass ratio of zeolite powder and graphene is 1:46), which can be directly used for traumatic hemostasis.
  • a scalpel was used to remove the skin above the right leg artery of SD rats and create wounds.
  • the trauma hemostatic sponge, zeolite powder and commercial QuikClot Combat Gauze described in Examples 1-5 and Comparative Example 1-2 were taken to stop bleeding.
  • the hemostatic effect is shown in Table 1:
  • the hemocompatibility test was performed on the traumatic hemostatic sponge and zeolite powder described in Example 1, and the specific process was: obtaining anticoagulated blood from the heart of SD rats by taking blood from the heart. Dilute with phosphate buffered saline (PBS) and centrifuge to obtain blood cells (RBCs). Add the 10-fold diluted RBCs to the PBS solution of the sample (the traumatic hemostatic sponge or zeolite powder described in Example 1 and Example 2) (see Figure 2 for sample concentration), and use PBS and deionized water as negative and positive For comparison, put the final solution in a shaking shaker for 3 hours. After centrifugation, the absorbance of the solution was measured at 540nm with an ultraviolet spectrophotometer (MAPADA UV-1100, Shanghai Meipu Da Co., Ltd., China). And through formula (I):
  • Hemolysis rate (%) [(absorption value sample -absorption value negative )/(absorption value positive -absorption value negative )] ⁇ 100% (I)
  • the traumatic hemostatic sponge of the present invention has a distinctive hemostatic mechanism and has excellent hemostatic properties. It can be seen from the above examples that the traumatic hemostatic sponge provided by the present invention has a fast hemostasis speed, a mild exothermic reaction, and high biological safety.

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Abstract

一种外伤止血海绵及其制备方法，外伤止血海绵包括沸石和石墨烯，石墨烯为三维交联结构，沸石分散在三维交联结构中，沸石和石墨烯的质量比为1:（0.2-5）。外伤止血海绵具有优异的止血性能，止血速度快，放热反应温和，生物安全性高。

Description

外伤止血海绵及其制备方法和应用
本申请要求享有2019年05月20交的名称为“一种外伤止血海绵及其制备方法和应用”的中国专利申请CN201910417710.7的优先权，其全部内容通过引用并入本文中。
技术领域
本发明涉及止血技术领域，尤其涉及一种外伤止血海绵及其制备方法和应用。
背景技术
众所周知，出血不止是事故中导致死亡的直接原因，在出血前期进行迅速的控制出血，对于挽救生命、降低病患痛楚及防治产生并发症都有重大意义。
沸石是最经典的止血剂之一，自2002年FDA批准以来被广泛使用。沸石具有迅速吸收水分的特性，其接触伤口后能够迅速吸收血浆、富集血细胞及其他成分进而达到快速控制出血的目的；同时，沸石的惰性组成不会对生物体造成毒性。但是，应用裸露的沸石会导致严重的热损伤和周围组织坏死。Z-Medica公司开发了一种预水合沸石止血材料(ACS+)，可产生较少的放热反应，减少热损伤，但它的止血性能会降低。同时，Naresh Ahuj等人(Ahuja,N.；Ostomel,T.A.；Rhee,P.；Stucky,G.D.；Conran,R.；Chen,Z.；Al-Mubarak,G.A.；Velmahos,G.；Demoya,M.；Alam,H.B.Testing of Modified Zeolite Hemostatic Dressings in A Large Animal Model of Lethal Groin Injury.J.Trauma 2006,61,1312–1320)尝试用其他带正电荷的离子取代沸石中的钙离子，以减少放热反应并消除热损伤，结果表明伤口组织仍然会升温至50℃。
因此，如何在保持沸石的止血性能的同时实现沸石热释放的有效调控仍然是一个挑战。
发明内容
本发明的目的在于提供一种外伤止血海绵，所述外伤止血海绵止血迅速，且不产生热损伤。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种外伤止血海绵，包括沸石和石墨烯；
所述石墨烯为三维交联结构；
所述沸石分散在所述三维交联结构中；
所述沸石和石墨烯的质量比为1:(0.2-5)。
本发明还提供了上述技术方案所述的外伤止血海绵的制备方法，包括以下步骤：
将沸石-氧化石墨烯复合水凝胶进行冻干，得到沸石-石墨烯复合气凝胶；
将所述沸石-石墨烯复合气凝胶依次进行微波膨化和高温处理，得到外伤止血海绵。
优选的，所述沸石-氧化石墨烯复合水凝胶的制备方法，包括以下步骤：
将氧化石墨烯溶液、交联剂和沸石混合，进行交联反应，得到沸石-氧化石墨烯复合水凝胶。
优选的，所述氧化石墨烯溶液的浓度为(3-10)mg/mL；
所述交联剂、沸石和氧化石墨烯溶液中的氧化石墨烯的质量比为(1-2.0):(0.5-2):(0.3-1.2)。
优选的，所述交联反应的温度为80-120℃，所述交联反应的时间为5-7h。
优选的，所述冻干的温度为-30℃至-70℃，所述冻干的时间为36-60h。
优选的，所述冻干完成后，还包括对冻干得到的沸石-石墨烯复合气凝胶依次进行清洗和干燥；
所述清洗采用的清洗剂为乙醇；所述清洗的时间为36-60h；
所述干燥的温度为20-40℃，所述干燥的时间为24-48h。
优选的，所述微波膨化的功率为300-800W，所述微波膨化的时间为5-40s。
优选的，所述高温处理的温度为100-400℃，所述高温处理的时间为1-6h，优选为2-6h。
本发明还提供了上述技术方案所述的外伤止血海绵或由上述技术方案所述的制备方法制备得到的外伤止血海绵在外伤止血中的应用。
本发明提供了一种外伤止血海绵，包括沸石和石墨烯；所述石墨烯为三维交联结构；所述沸石分散在所述三维交联结构中；所述沸石和石墨烯的质量比为1:(0.2-5)。本发明所述的外伤止血海绵具有与众不同的止血机制：1.物理吸附作用：外伤止血海绵应用于出血部位时能快速吸附血液中的液体成分，并在界面上富集血细胞及其他成分；2.界面刺激：沸石所带有的电势能够刺激血细胞从而触发凝血级联反应；3.热刺激：石墨烯能够迅速分散沸石产生的热量来防止热损伤的产生，同时这些热量能够增强血小板功能。因此，本发明所述的 外伤止血海绵具有优异的止血性能。根据实施例的记载，本发明所述的外伤止血海绵的止血速度快，放热反应温和，生物安全性高；用手术刀去除SD大鼠右腿动脉上方皮肤并制造创伤后，将所述外伤止血海绵进行止血，止血时间为69±15s，失血量为0.35±0.21g，伤口最高温度为40±2.93℃，伤口没有灼伤；较沸石粉(止血时间为70±30s，失血量为1.90±0.48g，伤口最高温度为73±3.78℃，伤口有灼伤)和商用QuikClot战斗纱布(Combat Gauze)(止血时间为85±10s，失血量为2.66±0.16g)具有更快的止血速度，更温和的放热温度。且本发明所述的外伤止血海绵用于伤口后不产生溶血现象。
本发明还提供了所述外伤止血海绵的制备方法，所述方法具有成本低廉，操作容易，易放大生产的特点，且利用所述的制备方法制备得到的外伤止血海绵具有携带方便，保质期长，生物相容性高，黑色不晕血等优点。
附图说明
下面结合附图来对本发明作进一步详细说明：
图1为本发明所述的外伤止血海绵的SEM图；
图2为本发明实施例1和实施例2所述的外伤止血海绵和沸石粉的血液相容性图。
具体实施方式
为使本发明容易理解，下面将详细说明本发明。但在详细描述本发明前，应当理解本发明不限于描述的具体实施方式。还应当理解，本文中使用的术语仅为了描述具体实施方式，而并不表示限制性的。
在提供了数值范围的情况下，应当理解所述范围的上限和下限和所述规定范围中的任何其他规定或居间数值之间的每个居间数值均涵盖在本发明内。这些较小范围的上限和下限可以独立包括在较小的范围中，并且也涵盖在本发明内，服从规定范围中任何明确排除的限度。在规定的范围包含一个或两个限度的情况下，排除那些包括的限度之任一或两者的范围也包含在本发明中。
除非另有定义，本文中使用的所有术语与本发明所属领域的普通技术人员的通常理解具有相同的意义。虽然与本文中描述的方法和材料类似或等同的任何方法和材料也可以在本发明的实施或测试中使用，但是现在描述了优选的方法和材料。
I.术语
本发明中所用“水”一词，在没有特别指定的情况下，是指去离子水、超纯水或蒸馏水。
在解释或说明本发明要素时，冠词“一”，“一个”，“该”和“所述”旨在表示存在一个或多个要素。用语“包括”，“含有”，“包含”和“具有”是指包括性的，意味着可以存在除所列出的元素之外的附加元素。
II.实施方案
本发明提供了一种外伤止血海绵，其特征在于，包括沸石和石墨烯；
所述石墨烯为三维交联结构；
所述沸石分散在所述三维交联结构中(如图1所示)。
所述沸石和石墨烯的质量比为1:(0.2-5)，优选为1:(0.43-3)，更优选为1:(0.75-2.86)。
在本发明中，所述外伤止血海绵在利用沸石和石墨烯海绵结构的本身的止血作用以外，由于沸石本身在止血过程中会放热，而将其分散在三维交联结构的石墨烯中后，可以利用石墨烯的导热性能降低止血过程中伤口处的温度，避免伤口组织灼伤；进一步的，通过在制备过程中控制沸石和氧化石墨烯的质量比，使沸石和石墨烯的质量比在上述范围内，使所述外伤止血海绵在止血过程中能够将伤口处的温度控制在40±2.93℃，利用热刺激来进一步改善外伤止血效果。
本发明还提供了上述技术方案所述的外伤止血海绵的制备方法，包括以下步骤：
将沸石-氧化石墨烯复合水凝胶进行冻干，得到沸石-石墨烯复合气凝胶；
将所述沸石-石墨烯复合气凝胶依次进行微波膨化和高温处理，得到外伤止血海绵。
在本发明中，若无特殊说明，所有原料组分均为本领域技术人员熟知的市售产品。
本发明将沸石-氧化石墨烯水凝胶进行冻干，得到沸石-石墨烯复合气凝胶。
在本发明中，所述沸石-氧化石墨烯复合水凝胶的制备方法，包括以下步骤：将氧化石墨烯溶液、交联剂和沸石混合，进行交联反应，得到沸石-氧化石墨烯复合水凝胶。
在本发明中，所述氧化石墨烯溶液优选为氧化石墨烯水溶液；所述氧化石墨烯溶液的浓度优选为(3-10)mg/mL，更优选为(5-10)mg/mL。
在本发明中，所述交联剂优选为乙二胺、氨基丙氨酸、乙二硫醇和丙二硫 醇中的一种或几种；当所述交联剂为上述具体选择中的两种以上时，本发明对所述具体物质的配比没有任何特殊的限定，按任意配比进行混合即可。
在本发明中，所述交联剂以交联剂溶液的形式加入，优选以交联剂水溶液的形式加入。
优选地，所述交联剂溶液的浓度为0.5-1.5g/mL，优选为0.9-1.5g/mL。
本领域技术人员应该了解的是，当采用两种以上的交联剂时，所述交联剂溶液的浓度为交联剂的总浓度。
在本发明中，所述沸石优选为沸石粉末；所述沸石粉末的粒径优选为100-400目，更优选为200-400目。
本领域技术人员应该了解的是，所谓沸石粉末的粒径根据所过筛的目数来确定，例如，将沸石粉末过200目筛所获得的沸石粉末的粒径为200目。
在本发明中，所述交联剂、沸石和氧化石墨烯溶液中的氧化石墨烯的质量比优选为(1-2.0):(0.5-2):(0.3-1.2)。
本发明对所述混合的方式没有任何特殊的限定，采用本领域技术人员熟知的混合方式进行并达到混合均匀的目的即可。
在本发明中，所述交联反应的温度优选为80-120℃，更优选为96-110℃；所述交联反应的时间优选为5-7h。
在本发明中，所述交联反应的目的是使片层的氧化石墨烯表面的官能团在交联剂的作用下发生交联反应，在交联反应中，大部分含氧官能团被消耗掉，生成微观结构为三维交联结构的氧化石墨烯，并形成宏观的海绵结构；同时在交联反应进行时，沸石被包覆在三维交联结构中。
在本发明中，所述冻干的温度优选为-30℃至-70℃，更优选为-45℃至-70℃；所述冻干的时间优选为36-60h，更优选为36-48h。
在本发明中，所述冻干完成后，优选还包括对冻干后得到的沸石-石墨烯复合气凝胶依次进行清洗和干燥。在本发明中，所述清洗采用的清洗剂优选为乙醇。在本发明中，所述清洗优选在索氏提取器中进行；所述清洗的时间优选为36-60h，更优选为36-48h；在本发明中，所述干燥的温度优选为20-40℃，更优选为25-35℃；所述干燥的时间优选为24-48h。
得到沸石-石墨烯复合气凝胶后，本发明将所述沸石-石墨烯复合气凝胶进行微波膨化和高温处理，得到外伤止血海绵。在本发明中，所述微波膨化的功率优选为300-800W；所述微波膨化的时间优选为5-40s。
在本发明中，所述微波膨化处理过程能够将石墨烯表面剩余的氧化官能团完全还原，得到石墨烯；同时，微波膨化还可以使海绵孔隙变大，比表面积增 加，进而提高石墨烯海绵结构的吸附能力。
在本发明中，所述高温处理的温度优选为100-400℃；所述高温处理的时间为1-6h，优选为2-6h。
根据本发明方法，在制备外伤止血海绵的过程中，首先，将氧化石墨烯溶液、交联剂和沸石混合进行交联反应得到一种水凝胶；在交联反应中，大部分含氧官能团被消耗掉，生成微观结构为三维交联结构的氧化石墨烯，并形成宏观的海绵结构；同时在交联反应进行时，沸石被包覆在三维交联结构中；由此，本发明中将氧化石墨烯溶液、交联剂和沸石混合进行交联反应得到的水凝胶称为“沸石-氧化石墨烯复合水凝胶”。
其次，将由氧化石墨烯溶液、交联剂和沸石混合进行交联反应得到的水凝胶冻干，得到一种气凝胶；该冻干过程是一种物理的脱水的过程；由此，本发明中将氧化石墨烯溶液、交联剂和沸石混合进行交联反应得到的水凝胶经冻干获得的气凝胶称为“沸石-石墨烯复合气凝胶”或“沸石-石墨烯气凝胶”，二者可以互换使用。
最后，将上述过程得到的气凝胶依次进行微波膨化和高温处理，得到一种海绵；所述微波膨化处理过程能够将石墨烯表面剩余的氧化官能团完全还原，得到石墨烯；同时，微波膨化还可以使海绵孔隙变大，比表面积增加，进而提高石墨烯海绵结构的吸附能力。
同时在本发明中，由于沸石在高温处理以前，已经被水化，即水分子占据了沸石分子筛的孔隙而不再能起到外伤止血功能。上述高温处理可以去除掉水化沸石中的水分子，进而恢复外伤止血功能。同时，所述高温处理的温度可以调控所述外伤止血海绵中的沸石在止血时的放热能力，来保证外伤止血海绵在止血过程中使伤口的温度在43℃以下，在人体温度以上，保证热刺激的有效性。
由此，本发明中将上述过程得到的气凝胶依次进行微波膨化和高温处理得到的海绵称为“外伤止血海绵”或“沸石-石墨烯外伤止血海绵”，二者可以互换使用。
本发明还提供了上述技术方案所述的外伤止血海绵或由上述技术方案所述的制备方法制备得到的外伤止血海绵在外伤止血中的应用。
III.实施例
下面结合实施例对本发明提供的外伤止血海绵及其制备方法和应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。下文所述实验方法，如无特殊说明，均为实验室常规方法。下文所述实验材料，原料或组分， 如无特别说明，均可由商业途径或常规方法获得。
以下实施例和对比例中所用沸石粉使用前需要先过200目筛。
SD大鼠(Sprague-Dawly大鼠)，购自北京维通利华实验动物技术有限公司。动物购入时体重约为250g，群居饲养，6只/笼。动物房内保持恒温、恒湿条件(温度20-25℃，湿度60％±10％)。实验开始前，动物在动物房适应性饲养3天，自由饮水进食。在实验过程中，大鼠接受的所有实验操作均符合实验动物伦理学要求，遵守国家和北京化工大学生物医学伦理委员会和中日友好医院实验动物福利伦理委员会颁布的条例，并获得北京化工大学生物医学伦理委员会和中日友好医院实验动物福利伦理委员会的批准。
实施例1：
将100mg沸石粉、20mL氧化石墨烯溶液(5mg/mL)和0.2mL乙二胺(0.90g/mL)混匀后，在96℃的条件下反应6h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-45℃下冻干48h，用乙醇在索氏提取器中清洗冻干后得到的产品(清洗48h)，在25℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化10s，在100℃下处理1h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为7:20)，可直接用于外伤止血；
采用扫描电镜(Hitachi S-4700，日立基团，日本)将所述的外伤止血海绵进行SEM测试，测试结果如图1所示(图B是图A的放大100倍的图)，由图1可知，本发明所述的外伤止血海绵中石墨烯为三维交联结构，即大量石墨烯片层纵横交错构成海绵的疏松多孔结构，沸石颗粒包埋在石墨烯片层之中。
实施例2：
将200mg沸石粉、20mL氧化石墨烯溶液(5mg/mL)和0.2mL乙二胺(0.90g/mL)混匀后，在96℃的条件下反应6h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-45℃下冻干48h，用乙醇在索氏提取器中清洗冻干后得到的产品(清洗48h)，在25℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化20s，在100℃下处理2h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为7:3)可直接用于外伤止血。
对所述外伤止血海绵的SEM测试结果与实施例1类似。
实施例3：
将100mg沸石粉、20mL氧化石墨烯溶液(5mg/mL)和0.2mL乙二胺(0.90g/mL)混匀后，在96℃的条件下反应6h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-45℃下冻干48h，用乙醇在索氏提取器中清洗冻干后得到的产品(清洗48h)，在25℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化10s，在100℃下处理2h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为7:20)，可直接用于外伤止血。
对所述外伤止血海绵的SEM测试结果与实施例1类似。
实施例4：
将200mg沸石粉、20mL氧化石墨烯溶液(3mg/mL)和0.08mL氨基丙氨酸(1.2719g/mL)混匀后，在80℃的条件下反应5h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-30℃下冻干36h，用乙醇在索氏提取器中清洗冻干后得到的产品(清洗36h)，在20℃的条件下干燥24h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用300W微波膨化40s，在100℃下处理6h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为4:3)，可直接用于外伤止血。
对所述外伤止血海绵的SEM测试结果与实施例1类似。
实施例5：
将85mg沸石粉、20mL氧化石墨烯溶液(10mg/mL)、0.1mL乙二硫醇(1.123g/mL)和0.2mL丙二硫醇(1.078g/mL)混匀后，在120℃的条件下反应7h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-70℃下冻干60h，用乙醇在索氏提取器中清洗冻干后得到的产品(清洗60h)，在40℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化5s，在400℃下处理2h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为1:5)，可直接用于外伤止血。
对所述外伤止血海绵的SEM测试结果与实施例1类似。
对比例1：
将5mg沸石粉、20mL氧化石墨烯溶液(5mg/mL)和0.2mL乙二胺(0.90g/mL)混匀后，在96℃的条件下反应6h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-45℃下冻干48h，用乙醇在索氏提取器中清洗冻干后得到的产品48h，在25℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化30s，在150℃下处理3h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为1:50)可直接用于外伤止血。
对比例2：
将5mg沸石粉、20mL氧化石墨烯溶液(2.5mg/mL)和0.2mL乙二胺(0.90g/mL)混匀后，在96℃的条件下反应6h，得到沸石-氧化石墨烯复合水凝胶；
将沸石-石墨烯复合水凝胶在-45℃下冻干48h，用乙醇在索氏提取器中清洗冻干后得到的产品48h，在25℃的条件下干燥48h，得到沸石-石墨烯气凝胶；
将所述沸石-石墨烯气凝胶用800W微波膨化10s，在150℃下处理3h后，得到外伤止血海绵(沸石粉和石墨烯的质量比为1:46)可直接用于外伤止血。
实施例6：
用手术刀去除SD大鼠右腿动脉上方皮肤并制造创伤，分别取实施例1-5、对比例1-2所述的外伤止血海绵、沸石粉和商用QuikClot战斗纱布(Combat Gauze)进行止血，止血效果如表1所示：
表1实施例1-5、对比例1-2所述的外伤止血海绵、沸石粉和商用QuikClot战斗纱布的止血效果
Figure PCTCN2020090868-appb-000001
对实施例1所述的外伤止血海绵和沸石粉进行血液相容性实验，具体过程为：以心脏取血方式从SD大鼠心脏获得抗凝血。使用磷酸缓冲液(PBS)稀释并离心以获得血细胞(RBCs)。将稀释10倍后的RBCs加入到样品(实施例1和实施例2所述的外伤止血海绵或沸石粉)的PBS溶液(样品浓度见图2)中，以PBS和去离子水作为阴性和阳性对照，将最终溶液放入摇动振荡器中3h。离心后用紫外分光光度计(MAPADA UV-1100，上海美谱达有限公司，中国)在540nm处测定溶液的吸光值。并通过公式(I)：
溶血率(％)＝[(吸收值 样品–吸收值 阴性)/(吸收值 阳性–吸收值 阴性)]×100％   (I)
计算溶血率。
结果如图2所示，由图2可知，实施例1-2所述的外伤止血海绵在浓度低于1000μg/mL时不产生溶血现象。
本发明所述的外伤止血海绵具有与众不同的止血机制，具有优异的止血性能。由以上实施例可知，本发明提供的外伤止血海绵的止血速度快，放热反应温和，生物安全性高。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种外伤止血海绵，其特征在于，包括沸石和石墨烯；
    所述石墨烯为三维交联结构；
    所述沸石分散在所述三维交联结构中；
    所述沸石和石墨烯的质量比为1:(0.2-5)。
  2. 权利要求1所述的外伤止血海绵的制备方法，其特征在于，包括以下步骤：
    将沸石-氧化石墨烯复合水凝胶进行冻干，得到沸石-石墨烯复合气凝胶；
    将所述沸石-石墨烯复合气凝胶依次进行微波膨化和高温处理，得到外伤止血海绵。
  3. 如权利要求2所述的制备方法，其特征在于，所述沸石-氧化石墨烯复合水凝胶的制备方法，包括以下步骤：
    将氧化石墨烯溶液、交联剂和沸石混合，进行交联反应，得到沸石-氧化石墨烯复合水凝胶。
  4. 如权利要求3所述的制备方法，其特征在于，所述氧化石墨烯溶液的浓度为(3-10)mg/mL；
    所述交联剂、沸石和氧化石墨烯溶液中的氧化石墨烯的质量比为(1-2.0):(0.5-2):(0.3-1.2)。
  5. 如权利要求3所述的制备方法，其特征在于，所述交联反应的温度为80-120℃，所述交联反应的时间为5-7h。
  6. 如权利要求2所述的制备方法，其特征在于，所述冻干的温度为-30℃至-70℃，所述冻干的时间为36-60h。
  7. 如权利要求2或6所述的制备方法，其特征在于，所述冻干完成后，还包括对冻干得到的沸石-石墨烯复合气凝胶依次进行清洗和干燥；
    所述清洗采用的清洗剂为乙醇；所述清洗的时间为36-60h；
    所述干燥的温度为20-40℃，所述干燥的时间为24-48h。
  8. 如权利要求2所述的制备方法，其特征在于，所述微波膨化的功率为300-800W，所述微波膨化的时间为5-40s。
  9. 如权利要求2或8所述的制备方法，其特征在于，所述高温处理的温度为100-400℃，所述高温处理的时间为1-6h，优选为2-6h。
  10. 权利要求1所述的外伤止血海绵或由权利要求2-9任一项所述的制备方法制备得到的外伤止血海绵在外伤止血中的应用。
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