WO2023169028A1 - 一种止血海绵及其制备方法 - Google Patents

一种止血海绵及其制备方法 Download PDF

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WO2023169028A1
WO2023169028A1 PCT/CN2022/138355 CN2022138355W WO2023169028A1 WO 2023169028 A1 WO2023169028 A1 WO 2023169028A1 CN 2022138355 W CN2022138355 W CN 2022138355W WO 2023169028 A1 WO2023169028 A1 WO 2023169028A1
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sponge
preparation
aqueous solution
chitosan
precursor liquid
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English (en)
French (fr)
Inventor
吴德成
潘正
张冲
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Southern University of Science and Technology
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Southern University of Science and Technology
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Priority to US18/843,396 priority Critical patent/US20250195716A1/en
Priority to EP22930650.1A priority patent/EP4480506A4/en
Publication of WO2023169028A1 publication Critical patent/WO2023169028A1/zh
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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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—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
    • 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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • 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
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • C08F2/50—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light with sensitising agents
    • 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
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • 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 medical field, and in particular to a hemostatic sponge and a preparation method thereof.
  • Hemostatic bandages cannot adapt to irregular-shaped wounds and cannot block the bleeding of deep-seated wounds; when hemostatic powders and hemostatic gels are used to deal with large bleeding wounds, they are difficult to adhere to the wound surface due to the erosion of blood flow, which limits their application.
  • the expandable hemostatic sponge because it can quickly expand and seal the wound, has become an excellent choice for dealing with bleeding from deep wounds in emergencies. Infection can seriously affect wound healing.
  • a hemostatic sponge is provided.
  • the components used to prepare the hemostatic sponge include: 3 to 30 parts of compounds containing double bonds, 1 to 10 parts of chitosan. , 0.1 to 15 parts of photoinitiator.
  • a method for preparing the hemostatic sponge described in the first aspect including:
  • the precursor liquid preparation step includes mixing each component according to the formula amount and dissolving it in a solvent to prepare the precursor liquid;
  • the step of depressurizing the precursor liquid includes depressurizing the precursor liquid to obtain an expanded precursor liquid;
  • the illumination step includes illuminating the expanded precursor liquid to obtain a shaped sponge
  • the soaking step includes soaking the formed sponge in a salt solution to obtain a soaked sponge;
  • the freeze-drying step includes freeze-drying the soaked sponge to prepare the hemostatic sponge.
  • the hemostatic sponge of the present invention has simple raw materials, and all raw materials have high biocompatibility.
  • the hemostatic sponge of the present invention has higher water absorption rate and water absorption rate than existing products, and can expand rapidly after absorbing water. When applied to wounds to stop bleeding, it can quickly seal the wound and stop bleeding.
  • the chitosan in the hemostatic sponge of the present invention can adsorb red blood cells, trigger endogenous coagulation, and reduce the time for wound hemostasis.
  • the hemostatic sponge of the present invention has high strength and meets the requirements for hemostasis by pressing.
  • Figure 1 is a schematic diagram of the water absorption expansion of the sponge prepared in Example 1 after compression.
  • Figure 2 is a stress-strain diagram of the sponge prepared in Example 1 subjected to 10 times of 80% strain cyclic compression.
  • Figure 3 is a diagram showing the hemostatic effect of the sponge prepared in Example 1 on rat femoral artery.
  • Figure 4 is an outline view of the sponge prepared in Example 2.
  • Figure 5 is an SEM image of the sponge prepared in Example 2 adsorbing red blood cells.
  • connection and “connection” mentioned in this application include direct and indirect connections (connections) unless otherwise specified.
  • a hemostatic sponge is provided.
  • the components used to prepare the hemostatic sponge include: 3 to 30 parts of compounds containing double bonds, 1 to 10 parts of chitosan. , 0.1 to 15 parts of photoinitiator.
  • the mass parts of the compound containing double bonds include but are not limited to 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts , 14 copies, 15 copies, 16 copies, 17 copies, 18 copies, 19 copies, 20 copies, 21 copies, 22 copies, 23 copies, 24 copies, 25 copies, 26 copies, 27 copies, 28 copies, 29 copies, 30 copies portions and so on.
  • the mass parts of chitosan include but are not limited to 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, etc.
  • the mass parts of the photoinitiator include but are not limited to 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, 1 part, 2 part, 3 part servings, 4 servings, 5 servings, 6 servings, 7 servings, 8 servings, 9 servings, 10 servings, 11 servings, 12 servings, 13 servings, 14 servings, 15 servings and so on.
  • the components used to prepare the hemostatic sponge include: 3 to 20 parts of a compound containing double bonds, 1 to 10 parts of chitosan, and 0.7 to 15 parts of a photoinitiator.
  • the compound containing double bonds includes a compound represented by the following general formula I:
  • R 1 is hydrogen (-H) or methyl (-CH 3 );
  • R 2 is oxygen (-O-) or imino (-NH-);
  • R 2 is connected to Represents the main chain.
  • the main chain is the chain with the largest number of links among polymer chains with branched (side chain) structures.
  • the compound containing double bonds includes at least one of the compounds represented by the following general formula II to general formula IX:
  • R 1 is hydrogen (-H) or methyl (-CH 3 ), R 2 is oxygen (-O-) or imino (-NH-);
  • Formula II is acrylic acid or methacrylic acid containing double bonds
  • Formula III is polyethylene glycol (PEG-AA) containing double bonds, where m represents the number of arms of polyethylene glycol, specifically an integer from 2 to 8; " ⁇ " represents multi-arm polyethylene glycol acrylate or The carbon atom in the middle of the multi-arm polyethylene glycol methacrylate is used to connect multiple identical polyethylene glycol acrylate or polyethylene glycol methacrylate segments; n represents the number of repeating units of polyethylene glycol. , specifically it can be an integer from 28 to 112, and the corresponding molecular weight of formula III is 2 to 40kDa;
  • Formula IV is hyaluronic acid containing double bonds, where n represents the number of repeating units of hyaluronic acid, which can be an integer from 25 to 2500, and the corresponding molecular weight of Formula IV is 10 to 1000kDa;
  • Formula V is gelatin containing double bonds (Gel-MA);
  • Formula VI is chitosan containing double bonds, where x, y, and z represent the number of each repeating unit of chitosan, which can be an integer from 62 to 6200, and the corresponding molecular weight of Formula VI is 10 to 1000kDa;
  • Formula VII is a double bond compound with a carboxyl group at the end.
  • R 3 represents a side chain group, which can be any group, such as hydrogen (-H) shown in formula VIII and -CH 2 -COOH shown in formula IX, where If R 2 is imino (-NH-), formula VII can be a double-bond functionalized amino acid;
  • formula VIII is N-(meth)acryloylglycine; if R 2 in formula IX is an imino group, then formula IX is (meth)acryloyl glutamic acid.
  • R 3 includes but is not limited to hydrogen, -CH 3 , -OH, -CH 2 -COOH, -CH 2 CH 3 , -CH 2 -CH(CH 3 ) 2 , -CH 2 -C 6 H 5 , -CH 2 -C 6 H 4 -OH, -CH 2 -SH.
  • the chitosan is water-soluble chitosan. Chitosan that is soluble in water is suitable for use in the present invention.
  • the molecular weight of the chitosan is about 5 to 20 kDa (kilodaltons), including but not limited to 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, 15 kDa , 16kDa, 17kDa, 18kDa, 19kDa, 20kDa.
  • the photoinitiator includes but is not limited to 651 photoinitiator (also known as benzyl bismethyl ether, a, a-dimethoxy-a-phenyl acetophenone, DMPA for short, CAS No.: 24650-42-8), 1173 photoinitiator (2-hydroxy-2-methyl-1-phenyl-1-propanone, referred to as HMPP, CAS No.: 7473-98-5), 2959 photoinitiator ( 2-Hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, CAS number: 106797-53-9), TPO (2,4,6-trimethyl benzoyl-diphenylphosphine oxide, CAS number: 75980-60-8), ⁇ -ketoglutaric acid (2-oxoglutaric acid, CAS number: 328-50-7), LAP (phenyl -At least one of -2,4,6-trimethylbenzoyl,
  • the components used to prepare the hemostatic sponge further comprise salt.
  • the components for preparing the hemostatic sponge further comprise an aqueous solution containing the salt.
  • the salts include, but are not limited to, NaCl, CaCl 2 , KCl, NaH 2 PO 4 , KH 2 PO 4 , Na 2 CO 3 , Na 2 SO 4 , Na 2 HPO 4 , K 2 HPO 4 , At least one of KH 2 PO 4 , Na 3 Cit, and Na 3 PO 4 .
  • the salt solution may be a saturated aqueous solution.
  • the concentration of salt in the salt solution may range from 15wt% to 40wt%.
  • the saline solution may be PBS buffer.
  • a method for preparing the hemostatic sponge described in the first aspect including:
  • the precursor liquid preparation step includes mixing each component according to the formula amount and dissolving it in a solvent to prepare the precursor liquid;
  • the step of depressurizing the precursor liquid includes depressurizing the precursor liquid to obtain an expanded precursor liquid;
  • the illumination step includes illuminating the expanded precursor liquid to obtain a shaped sponge
  • the soaking step includes soaking the formed sponge in a salt solution to obtain a soaked sponge;
  • the freeze-drying step includes freeze-drying the soaked sponge to prepare the hemostatic sponge.
  • the solvent is water.
  • the mass of the solvent is 1 to 100 times the mass of chitosan, preferably 10 to 100 times.
  • the mass of the solvent can be 5 times or more than the mass of the compound monomer containing double bonds, so that the material can be shaped after illumination and maintain its shape after the vacuum returns to atmospheric pressure.
  • the mass of the solvent is 10 to 100 times the mass of chitosan. If the amount of solvent is too high, good bubbles will not be generated; if the amount of solvent is too low, it will As a result, chitosan cannot be dissolved. There are no specific requirements for the amount of photoinitiator.
  • the precursor liquid in the precursor liquid preparation step, is stirred until uniform bubbles are generated, and then enters the reduced pressure treatment step.
  • the vacuum degree in the container containing the precursor liquid is 20 to 100 mbar.
  • Vacuum degrees include but are not limited to 20mbar, 30mbar, 40mbar, 50mbar, 60mbar, 70mbar, 80mbar, 90mbar, 100mbar, etc.
  • the wavelength of light used during illumination is 200-450 nm.
  • Wavelengths include but are not limited to 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 310nm, 320nm, 330nm, 340nm, 350nm, 360nm, 370nm, 380nm, 39 0nm, 400nm, 410nm, 420nm , 430nm, 440nm, 450nm, etc.
  • the illumination time is 1 to 100 minutes.
  • Illumination time includes but is not limited to 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min, 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min, etc.
  • the salt solution in the soaking step, includes but is not limited to NaCl aqueous solution, CaCl 2 aqueous solution, KCl aqueous solution, NaH 2 PO 4 aqueous solution, KH 2 PO 4 aqueous solution, Na 2 CO 3 aqueous solution, Na 2 SO 4 At least one of aqueous solution, Na 2 HPO 4 aqueous solution, K 2 HPO 4 aqueous solution, Na 3 Cit (sodium citrate) aqueous solution, Na 3 PO 4 aqueous solution, and PBS buffer. Soaking in the salt solution allows the chitosan to create a physical network that improves the sponge's strength and shape recovery properties. If not soaked, the sponge will be brittle and slow to absorb water.
  • the soaking time in the salt solution is 1 to 200 minutes.
  • Soaking time includes but is not limited to 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min, 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min, 110min, 120min, 130min, 140min, 150min, 160min, 170min, 180min, 190min, 200min, etc.
  • the solution in the soaking step, after soaking in the salt solution, the solution is soaked in water, and then enters the freeze-drying step.
  • the sponge in the soaking step, after the salt soaking is completed, the sponge is taken out from the salt solution, left to stand for 1 to 100 hours, and then soaked in water. Resting time includes but is not limited to 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 20h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, etc.
  • the salt solution is drained from the sponge.
  • the water soaking time is 1 to 100 hours. Soaking time includes but is not limited to 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 20h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, etc.
  • the present invention provides a preparation method and application of a fast blood-absorbing, high-swelling hemostatic sponge system.
  • the hemostatic sponge is prepared from a compound with double bonds and chitosan.
  • the specific synthesis steps are to create a porous structure through a simple method of controlling the degree of vacuum, use light to initiate cross-linking of double-bond compounds to form a chemical network to maintain the shape of the sponge, and induce chitosan to form a physical cross-linked network by soaking in a salt solution, thus giving the sponge Excellent shape recovery ability.
  • the compressed sponge When exerting a hemostatic effect, the compressed sponge can quickly absorb a large amount of blood and expand in volume; it seals the bleeding wound after returning to its original shape, preventing itself from being washed away by the blood flow, and effectively sealing the bleeding wound.
  • the hemostatic sponge has good biocompatibility and can be made into different shapes and sizes as needed to be suitable for different wounds.
  • the present invention provides a highly swollen hemostatic sponge system with a porous structure prepared by a vacuuming method and its application.
  • the object of the present invention is to provide a highly swellable hemostatic sponge system and its application prepared by a simple method.
  • the hemostatic sponge has the characteristics of high swelling rate, rapid blood absorption, high strength, shape memory and Adjustable performance and other features.
  • the invention provides a highly swollen hemostatic sponge system, which is mainly prepared from compounds with double bonds and chitosan. After this double-bonded compound and chitosan are dissolved in water, bubbles are generated by stirring. The precursor liquid with uniform bubbles is poured into a container, and the container is evacuated. After the vacuum is stabilized, light is applied. The polymerization of double-bonded compounds is initiated by light to form the first layer of chemical network; then, the chitosan in the system is physically cross-linked by soaking in salt solution to form the second layer of network.
  • the first layer of chemical network can maintain the shape of the sponge, improve the strength of the sponge, and absorb water in the blood;
  • the chitosan physical cross-linked network can improve the shape recovery ability of the sponge, use the expansion of the sponge itself to seal the wound, and Chitosan can agglutinate red blood cells in the blood, enhance platelet adhesion, activation and aggregation, and promote hemostasis.
  • the positive charge of chitosan can inhibit bacteria and prevent wound infection.
  • the raw materials for preparing the hemostatic sponge include: 3 to 30 parts of compounds containing double bonds, 1 to 10 parts of chitosan, 0.1 to 15 parts of photoinitiator, and 100 parts of water.
  • the general structural formula of the compound with double bonds used in the present invention is I, wherein R 1 is hydrogen (-H) or methyl (-CH 3 ), and R 2 is oxygen (-O-) or Imino(-NH-).
  • Compounds with double bonds can specifically be (meth)acrylic acid, (meth)acrylamide, double bond functionalized polyethylene glycol (PEG-AA), double bond modified amino acids, double bond functionalized gelatin (Gel -MA), double bond modified chitosan, double bond modified sodium alginate and double bond modified hyaluronic acid, etc.
  • the structure of the double bond compound can be any one of formulas II to IX, wherein R 1 is hydrogen (-H) or methyl (-CH 3 ), and R 2 is oxygen (-O-) Or imino(-NH-).
  • formula II is (meth)acrylic acid
  • formula III is PEG with double bonds (PEG-AA), where m represents the number of arms of PEG, which can be 2 to 8; n represents the number of repeating units of PEG, which can be specifically 28 to 112, corresponding to a molecular weight of 2 to 40kDa
  • Formula IV is hyaluronic acid with double bonds, where n represents the number of repeating units of hyaluronic acid, specifically 25 to 2500, corresponding to a molecular weight of 10 to 1000kDa
  • Formula V is Gelatin with double bonds (Gel-MA);
  • Formula VI is chitosan containing double bonds, where x, y, z represent the number of each repeating unit of chitosan,
  • R 3 represents a side chain group, which can be any group, such as hydrogen (-H) shown in formula VIII and -CH 2 shown in formula IX -COOH, where if R 2 is imino (-NH-), formula VII can be a double bond functionalized amino acid. If R 2 in Formula VIII is an imino group, then Formula VIII is N-(meth)acryloylglycine; if R 2 in Formula IX is an imino group, then Formula IX is (meth)acryloyl glutamic acid.
  • the chitosan used in the present invention is water-soluble chitosan.
  • the photoinitiator used in the present invention can be photoinitiator 651, 1173, 2959, TPO, ⁇ -ketoglutarate, LAP, etc.
  • the preparation method of the hemostatic sponge provided by the present invention includes: dissolving 3 to 30 parts by mass of a compound containing double bonds, 1 to 10 parts of chitosan, and 0.1 to 15 parts of a photoinitiator in 100 into water to make precursor fluid.
  • a certain amount of stirred precursor liquid is placed in a container, and the container is depressurized with a vacuum degree of 20 to 100 mbar to expand the precursor liquid. After the pressure is stabilized and the volume of the precursor liquid no longer changes, the container is irradiated with light with a wavelength of 200 to 450 nm for 1 to 100 minutes to cause the precursor liquid to gel.
  • the porosity of the hemostatic sponge prepared by the present invention is 85% to 99%, the density is 0.01 to 0.1g/cm 3 , the saturated water absorption rate is 2000% to 50000%, and the time required for saturated water absorption is 1 ⁇ 300s, the compressive strength of 80% strain is 30 ⁇ 200kPa.
  • the hemostatic sponge produced by the present invention has shape recovery properties. It can maintain its shape when compressed in a dry state, and can quickly return to the shape before compression after absorbing water.
  • the hemostatic sponge of the present invention has simple raw materials, and all raw materials have high biocompatibility.
  • the preparation method of the hemostatic sponge of the present invention is simple, the preparation cycle is short, and the performance is adjustable.
  • the hemostatic sponge of the present invention has higher water absorption rate and water absorption rate than existing products, and can expand rapidly after absorbing water. When applied to wounds to stop bleeding, it can quickly seal the wound and stop bleeding.
  • the chitosan in the hemostatic sponge of the present invention can adsorb red blood cells, trigger endogenous coagulation, and reduce the time for wound hemostasis.
  • the hemostatic sponge of the present invention has high strength and meets the requirements for hemostasis by pressing.
  • the molecular weight of chitosan without double bonds used is about 10kDa.
  • the chitosan with a mass of 0.05g is chitosan without double bonds.
  • Others The same applies to the Examples and Comparative Examples.
  • the sample was taken out from the ultrapure water, and then placed in a freeze dryer and lyophilized at -50 ⁇ -45°C and 0.05 ⁇ 0.15mbar to obtain a sponge. If there is a freeze-drying step in subsequent examples and comparative examples, the freeze-drying conditions are the same as in this example.
  • W t The final mass of the sponge that absorbs water and swells
  • W 0 The initial mass of the sponge before absorbing water.
  • the water absorption rate of the sponge measured according to the above method is 5800%.
  • Water absorption time test Take a dry sponge with a height of about 10mm, a diameter of about 13cm, and a mass of about 0.04g, and compress it to obtain a compressed sponge with a height of 2 to 3mm. Put the sponge into the water and start timing. Stop when the sponge is completely expanded. The time taken is recorded as the sponge water absorption time, as shown in Figure 1. Take 5 samples from each group for testing, and take the average value as the final water absorption time. The time it takes for the sponge to absorb water measured according to the above method is 7.2 seconds.
  • Water retention performance test Take a dry sponge with a height of about 10mm and weigh the initial mass W 0 . Immerse it in ultrapure water to fully swell it to saturation. After taking it out, centrifuge it at 500r/min for 3 minutes, and weigh its mass W 1 .
  • the formula for calculating the water retention rate of sponge is as follows:
  • W 1 The mass of the sponge after absorbing water and centrifuging
  • W 0 The initial mass of the sponge before absorbing water.
  • the water retention rate of the sponge measured according to the above method is 2200%.
  • the density calculation formula is as follows:
  • ⁇ E Density of ethanol. In each measurement, the density of all ethanol in the measurement is obtained by dividing the mass of ethanol by the volume. The value is close to 0.79g/cm 3 .
  • the porosity of the sponge measured according to the above method is 89%, and the density is 0.031g/cm 3 .
  • Rat femoral artery truncation hemostasis test expose the left and right femoral arteries of the rat, use a 6mm tissue sampler/puncher to create a 5mm deep cavity in the femoral artery and surrounding tissue, then inject the compressed sponge into it, and use absorbent cotton to Collect the outflowing blood and observe the bleeding situation.
  • the time required to observe that the blood does not flow is the hemostatic time.
  • the quality of the blood collected is the blood loss.
  • the hemostatic effect is shown in Figure 3.
  • the hemostasis time measured according to the above method was 101s, and the blood loss was 2.31g.
  • FIG. 4 is an SEM image of red blood cell adsorption by the sponge. It can be seen from the figure that the prepared sponge can adsorb a large number of red blood cells and can effectively promote the coagulation process.
  • the water absorption rate of the sponge was measured to be 50000%, the water absorption time was 9.1s, the water retention rate was 10000%, the strength was 36kPa, the porosity was 92%, the density was 0.039g/cm 3 , the hemostasis time was 79s, and the blood loss was 1.73g. .
  • the rested sample was placed in ultrapure water for 20 hours, the sample was taken out from the ultrapure water, and then freeze-dried in a freeze dryer to obtain a sponge.
  • the water absorption rate of the sponge was measured to be 25000%, the water absorption time was 8.9s, the water retention rate was 5100%, the strength was 59kPa, the porosity was 93%, the density was 0.041g/cm 3 , the hemostasis time was 186s, and the blood loss was 3.21g. .
  • the sample was placed in ultrapure water for 15 hours, the sample was taken out from the ultrapure water, and then freeze-dried in a freeze dryer to obtain a sponge.
  • the water absorption rate of the sponge was measured to be 31000%, the water absorption time was 10.2s, the water retention rate was 7100%, the strength was 67kPa, the porosity was 92%, the density was 0.029g/cm 3 , the hemostasis time was 134s, and the blood loss was 2.97g. .
  • hyaluronic acid with a molecular weight of 200kDa, 0.02g of photoinitiator TPO, and 0.075g of chitosan. Dissolve all materials in 1g of ultrapure water. Use a mixer to create even bubbles. Fill all materials into a vacuum container, evacuate to 30mbar, and irradiate with 320nm light for 10 minutes after the pressure stabilizes. After forming, take it out, soak it in 15wt% CaCl2 aqueous solution for 6 minutes, then take it out and let it stand for 5 hours.
  • the sample After standing, the sample was placed in ultrapure water for 40 hours, the sample was taken out from the ultrapure water, and then freeze-dried in a freeze dryer to obtain a sponge.
  • the water absorption rate of the sponge was measured to be 11000%, the water absorption time was 9.9s, the water retention rate was 2300%, the strength was 78kPa, the porosity was 89%, the density was 0.041g/cm 3 , the hemostasis time was 156s, and the blood loss was 2.44g. .
  • the water absorption rate of the sponge was measured to be 1800%, the water absorption time was 5.1s, the water retention rate was 700%, the strength was 88kPa, the porosity was 87%, the density was 0.055g/cm 3 , the bleeding time was 199s, and the blood loss was 2.77g. .
  • the sample After standing, the sample was placed in ultrapure water for 40 hours, the sample was taken out from the ultrapure water, and then freeze-dried in a freeze dryer to obtain a sponge.
  • the water absorption rate of the sponge was measured to be 6000%, the water absorption time was 11.7s, the water retention rate was 1500%, the strength was 59kPa, the porosity was 95%, the density was 0.027g/cm 3 , the hemostasis time was 87s, and the blood loss was 1.92g. .
  • the sample was taken out of the ultrapure water and then freeze-dried in a freeze dryer to obtain an inelastic and incompressible sample, which is essentially a freeze-dried hydrogel.
  • the measured water absorption rate of the sample was 880%, the water absorption time was 3 hours, the water retention rate was 720%, and the strength was 840kPa. Because it is a freeze-dried hard hydrogel, the porosity and density cannot be measured, and it cannot be used to stop bleeding.
  • the water absorption rate of the sponge was measured to be 1100%, the time taken to absorb water was 3 hours, the water retention rate was 970%, and the strength was 790kPa. Because it is a freeze-dried hard hydrogel, the porosity and density cannot be measured, and it cannot be used to stop bleeding.
  • the water absorption rate of the sponge was measured to be 900%, the water absorption time was 67s, the water retention rate was 600%, the strength was 112kPa, the porosity was 81%, and the density was 0.075g/cm 3 . Because it is hard and slow to expand, it cannot be used to stop bleeding.
  • the water absorption rate of the sponge was measured to be 7000%, the water absorption time was 8.2s, the water retention rate was 700%, the strength was 6kPa, the porosity was 98%, and the density was 0.021g/cm 3 . It is not strong enough to stop bleeding.

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Abstract

本发明涉及医学领域，具体提供一种止血海绵及其制备方法，按质量计，用于制备所述止血海绵的组分包含：3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂。本发明的止血海绵较现有商品具有更高的吸水率和吸水速率，且吸水后可快速膨胀。应用于伤口止血时可以迅速封堵伤口止血。

Description

一种止血海绵及其制备方法 技术领域
本发明涉及医学领域，具体涉及一种止血海绵及其制备方法。
背景技术
在战场和意外事故中会发生人体组织的破损和大出血，及时的现场紧急救治会大大提高患者的存活率。目前常见的止血材料包括止血绷带、止血粉、止血凝胶、可膨胀的止血海绵等。对于止血绷带，不能适应不规则形状的伤口，不能封堵深层次伤口的止血；止血粉和止血凝胶在应对大出血伤口时，因为血流的冲刷难以附着在伤口表面，这限制了其应用。而可膨胀型止血海绵，因为可以迅速膨胀并封堵伤口，成为了处置突发状况下深伤口出血的极佳选择。感染可严重影响伤口的愈合。因此研发一种既可快速止血又抗菌的可膨胀止血海绵在现场紧急救治中具有重要的意义。但目前的止血海绵膨胀性差，压缩强度低，且制备方法复杂，受制于成孔机理，可选择的材料有限。
发明内容
根据第一方面，在一实施例中，提供一种止血海绵，按质量计，用于制备所述止血海绵的组分包含：3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂。
根据第二方面，在一实施例中，提供第一方面所述止血海绵的制备方法，包括：
前体液制备步骤，包括按配方量将各组分混合，溶于溶剂中，制得前体液；
减压处理步骤，包括对所述前体液进行减压处理，得到膨胀的前体液；
光照步骤，包括对所述膨胀的前体液进行光照，得到成型的海绵；
浸泡步骤，包括将所述成型的海绵浸泡于盐溶液中，得到浸泡后的海绵；
冻干步骤，包括对所述浸泡后的海绵进行冻干，制得所述止血海绵。
依据上述实施例的一种止血海绵及其制备方法，本发明的止血海绵原料简单，且所有原料都具有很高的生物相容性。
在一实施例中，本发明的止血海绵较现有商品具有更高的吸水率和吸水速率，且吸水后可快速膨胀。应用于伤口止血时可以迅速封堵伤口止血。
在一实施例中，本发明的止血海绵中的壳聚糖可以吸附红细胞，引发内源性凝血，减少伤口止血时间。
在一实施例中，本发明的止血海绵具有较高的强度，满足按压止血的要求。
附图说明
图1为实施例1所制备海绵压缩后的吸水膨胀示意图。
图2为对实施例1所制备海绵进行10次80％应变循环压缩的应力-应变图。
图3为实施例1所制备海绵的大鼠股动脉止血效果图。
图4为实施例2所制备海绵的外形图。
图5为实施例2所制备海绵吸附红细胞的SEM图。
具体实施方式
下面通过具体实施方式结合附图对本发明作进一步详细说明。其中不同实施方式中类似元件采用了相关联的类似的元件标号。在以下的实施方式中，很多细节描述是为了使得本申请能被更好的理解。然而，本领域技术人员可以毫不费力的认识到，其中部分特征在不同情况下是可以省略的，或者可以由其他元件、材料、方法所替代。在某些情况下，本申请相关的一些操作并没有在说明书中显示或者描述，这是为了避免本申请的核心部分被过多的描述所淹没，而对于本领域技术人员而言，详细描述这些相关操作并不是必要的，他们根据说明书中的描述以及本领域的一般技术知识即可完整了解相关操作。
另外，说明书中所描述的特点、操作或者特征可以以任意适当的方式结合形成各种实施方式。同时，方法描述中的各步骤或者动作也可以按照本领域技术人员所能显而易见的方式进行顺序调换或调整。因此，说明书和附图中的各种顺序只是为了清楚描述某一个实施例，并不意味着是必须的顺序，除非另有说明其中某个顺序是必须遵循的。
本文中为部件所编序号本身，例如“第一”、“第二”等，仅用于区分所描述的对象，不具有任何顺序或技术含义。而本申请所说“连接”、“联接”，如无特别说明，均包括直接和间接连接(联接)。
本文中，“PEG”与“聚乙二醇”可互换使用。
根据第一方面，在一实施例中，提供一种止血海绵，按质量计，用于制备所述止血海绵的组分包含：3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂。
含有双键的化合物在光照后交联形成化学网络，维持海绵的形状，使海绵在真空度恢复为大气压后仍然可以维持完整的多孔结构。壳聚糖浸泡盐溶液生成物理网 络。光引发剂用于引发具有双键的化合物交联，形成化学网络，维持海绵形状。
在一实施例中，含有双键的化合物的质量份包括但不限于3份、4份、5份、6份、7份、8份、9份、10份、11份、12份、13份、14份、15份、16份、17份、18份、19份、20份、21份、22份、23份、24份、25份、26份、27份、28份、29份、30份等等。
在一实施例中，壳聚糖的质量份包括但不限于1份、2份、3份、4份、5份、6份、7份、8份、9份、10份等等。
在一实施例中，光引发剂的质量份包括但不限于0.1份、0.2份、0.3份、0.4份、0.5份、0.6份、0.7份、0.8份、0.9份、1份、2份、3份、4份、5份、6份、7份、8份、9份、10份、11份、12份、13份、14份、15份等等。
在一实施例中，按质量计，用于制备所述止血海绵的组分包含：3～20份含有双键的化合物、1～10份壳聚糖、0.7～15份光引发剂。
在一实施例中，所述含有双键的化合物包含如下通式I所示化合物：
Figure PCTCN2022138355-appb-000001
R 1为氢(-H)或甲基(-CH 3)；
R 2为氧(-O-)或亚氨基(-NH-)；
R 2所连接的
Figure PCTCN2022138355-appb-000002
表示主链。主链是有支链(侧链)结构的高分子链中链节数最多的链。
在一实施例中，所述含有双键的化合物包含如下通式II～通式IX所示化合物中的至少一种：
Figure PCTCN2022138355-appb-000003
通式II～通式IX中，R 1为氢(-H)或甲基(-CH 3)，R 2为氧(-O-)或亚氨基(-NH-)；
式II为含有双键的丙烯酸或甲基丙烯酸；
式III为含有双键的聚乙二醇(PEG-AA)，其中m表示聚乙二醇的臂数，具体可为2～8的整数；“●”表示多臂聚乙二醇丙烯酸酯或多臂聚乙二醇甲基丙烯酸酯中间的碳原子，用于连接多条同样的聚乙二醇丙烯酸酯或聚乙二醇甲基丙烯酸酯链段；n表示聚乙二醇的重复单元数，具体可为28～112的整数，对应的式III分子量为2～40kDa；
式IV为含有双键的透明质酸，其中n表示透明质酸的重复单元数，具体可为25～2500的整数，对应的式IV分子量为10～1000kDa；
式V为含有双键的明胶(Gel-MA)；
式VI为含有双键的壳聚糖，其中x、y、z表示壳聚糖每个重复单元的数目，具体可为62～6200的整数，对应的式VI分子量为10～1000kDa；
式VII为端基带有羧基的双键化合物，R 3表示侧链基团，可以是任意基团，如 式VIII所示的氢(-H)和式IX所示的-CH 2-COOH，其中若R 2为亚氨基(-NH-)，则式VII可以为双键功能化的氨基酸；
若式VIII中R 2若为亚氨基，则式VIII为N-(甲基)丙烯酰基甘氨酸；若式IX中R 2为亚氨基，则式IX为(甲基)丙烯酰基谷氨酸。
在一实施例中，式III所示含有双键的聚乙二醇(PEG)包括但不限于聚乙二醇双丙烯酸酯(式Ⅲ，m＝2)、八臂聚乙二醇丙烯酸酯(式Ⅲ，m＝8)、四臂聚乙二醇丙烯酸酯(式Ⅲ，m＝4)中的至少一种。
在一实施例中，式VII中，R 3包括但不限于氢、-CH 3、-OH、-CH 2-COOH、-CH 2CH 3、-CH 2-CH(CH 3) 2、-CH 2-C 6H 5、-CH 2-C 6H 4-OH、-CH 2-SH。
在一实施例中，所述壳聚糖为水溶性壳聚糖。可溶于水的壳聚糖均适用于本发明。
在一实施例中，所述壳聚糖的分子量约为5～20kDa(千道尔顿)，包括但不限于5kDa、6kDa、7kDa、8kDa、9kDa、10kDa、11kDa、12kDa、13kDa、14kDa、15kDa、16kDa、17kDa、18kDa、19kDa、20kDa。
在一实施例中，所述光引发剂包括但不限于651光引发剂(又名苯偶酰双甲醚、a，a-二甲氧基-a-苯基苯乙酮，简称DMPA，CAS号：24650-42-8)、1173光引发剂(2-羟基-2-甲基-1-苯基-1-丙酮，简称HMPP，CAS号：7473-98-5)、2959光引发剂(2-羟基-2-甲基-1-[4-(2-羟基乙氧基)苯基]-1-丙酮，CAS号：106797-53-9)、TPO(2,4,6-三甲基苯甲酰基-二苯基氧化膦，CAS号：75980-60-8)、α-酮戊二酸(2-氧代戊二酸，CAS号：328-50-7)、LAP(苯基-2,4,6-三甲基苯甲酰基亚磷酸锂，CAS号：85073-19-4)等等中的至少一种。
在一实施例中，用于制备所述止血海绵的组分还包含盐。
在一实施例中，用于制备所述止血海绵的组分还包含含有所述盐的水溶液。
在一实施例中，所述盐包括但不限于NaCl、CaCl 2、KCl、NaH 2PO 4、KH 2PO 4、Na 2CO 3、Na 2SO 4、Na 2HPO 4、K 2HPO 4、KH 2PO 4、Na 3Cit、Na 3PO 4中的至少一种。
在一实施例中，所述盐溶液可以为饱和的水溶液。
在一实施例中，所述盐溶液中盐的浓度可以为15wt％～40wt％。
在一实施例中，所述盐溶液可以为PBS缓冲液。
根据第二方面，在一实施例中，提供第一方面所述止血海绵的制备方法，包括：
前体液制备步骤，包括按配方量将各组分混合，溶于溶剂中，制得前体液；
减压处理步骤，包括对所述前体液进行减压处理，得到膨胀的前体液；
光照步骤，包括对所述膨胀的前体液进行光照，得到成型的海绵；
浸泡步骤，包括将所述成型的海绵浸泡于盐溶液中，得到浸泡后的海绵；
冻干步骤，包括对所述浸泡后的海绵进行冻干，制得所述止血海绵。
在一实施例中，前体液制备步骤中，所述溶剂为水。
在一实施例中，前体液制备步骤中，溶剂的质量为壳聚糖质量的1～100倍，优选为10～100倍。
在一实施例中，溶剂质量可以是含有双键的化合物单体质量的5倍及以上，使得光照后物料可以定型并在真空度恢复大气压后维持形状。
在一实施例中，前体液制备步骤中，溶剂的质量为壳聚糖质量的10～100倍，如果溶剂的用量太高，则无法产生较好的气泡；如果溶剂的用量太低，则会造成壳聚糖无法溶解。光引发剂用量没有具体要求。
在一实施例中，前体液制备步骤中，将所述前体液搅拌至产生均匀的气泡，然后进入减压处理步骤。
在一实施例中，减压处理步骤中，装有所述前体液的容器中的真空度为20～100mbar。真空度包括但不限于20mbar、30mbar、40mbar、50mbar、60mbar、70mbar、80mbar、90mbar、100mbar等等。
在一实施例中，光照步骤中，光照时使用的光的波长为200～450nm。波长包括但不限于200nm、210nm、220nm、230nm、240nm、250nm、260nm、270nm、280nm、290nm、300nm、310nm、320nm、330nm、340nm、350nm、360nm、370nm、380nm、390nm、400nm、410nm、420nm、430nm、440nm、450nm等等。
在一实施例中，光照步骤中，光照时间为1～100min。光照时间包括但不限于1min、2min、3min、4min、5min、6min、7min、8min、9min、10min、20min、30min、40min、50min、60min、70min、80min、90min、100min等等。
在一实施例中，浸泡步骤中，所述盐溶液包括但不限于NaCl水溶液、CaCl 2水溶液、KCl水溶液、NaH 2PO 4水溶液、KH 2PO 4水溶液、Na 2CO 3水溶液、Na 2SO 4水溶液、Na 2HPO 4水溶液、K 2HPO 4水溶液、Na 3Cit(柠檬酸钠)水溶液、Na 3PO 4水溶液、PBS缓冲液中的至少一种。浸泡盐溶液让壳聚糖生成物理网络，提高海绵的强度和形状恢复性能。如果不浸泡，海绵易碎，吸水慢。
在一实施例中，浸泡步骤中，盐溶液浸泡时间为1～200min。浸泡时间包括但不 限于1min、2min、3min、4min、5min、6min、7min、8min、9min、10min、20min、30min、40min、50min、60min、70min、80min、90min、100min、110min、120min、130min、140min、150min、160min、170min、180min、190min、200min等等。
在一实施例中，浸泡步骤中，盐溶液浸泡结束后，使用水浸泡，然后进入冻干步骤。
在一实施例中，浸泡步骤中，在盐浸泡结束后，从盐溶液中取出海绵，静置1～100h，然后使用水浸泡。静置时间包括但不限于1h、2h、3h、4h、5h、6h、7h、8h、9h、10h、20h、30h、40h、50h、60h、70h、80h、90h、100h等等。静置过程中，海绵上的盐溶液被沥干。
在一实施例中，浸泡步骤中，水浸泡的时间为1～100h。浸泡时间包括但不限于1h、2h、3h、4h、5h、6h、7h、8h、9h、10h、20h、30h、40h、50h、60h、70h、80h、90h、100h等等。
在一实施例中，本发明提供了一种快速吸血、高膨胀的止血海绵体系的制备方法及其应用。该止血海绵由一种具有双键的化合物和壳聚糖制备而成。具体合成步骤是通过控制真空度的简单方法制造多孔结构，采用光引发双键化合物交联生成化学网络维持海绵形状，通过在盐溶液中浸泡，诱导壳聚糖形成物理交联网络，从而赋予海绵优异的形状恢复能力。在发挥止血作用时，压缩后的海绵能够迅速吸收大量血液，并发生体积膨胀；在恢复原始形状后封堵住出血伤口，避免自身被血流冲走，实现对出血伤口的有效封堵。该止血海绵具有很好的生物相容性，可以根据需要制作成不同形状和尺寸以适用于不同的伤口。
在一实施例中，本发明提供一种采用抽真空的方法制备的具有多孔结构的高溶胀止血海绵体系及其应用。
在一实施例中，本发明的目的是提供一种由简单的方法制得的具有高溶胀性的止血海绵体系及其应用，该止血海绵具有溶胀率高、吸血迅速、强度高、形状记忆和性能可调节等特点。
本发明提供的一种高溶胀的止血海绵体系，主要由具有双键的化合物和壳聚糖制备而成。这种具有双键的的化合物和壳聚糖在水中溶解后，通过搅拌产生气泡，具有均匀气泡的前体液倒入容器内，并对该容器抽真空，在真空度稳定后施以光照。通过光照引发双键化合物聚合，形成第一层化学网络；之后，体系中的壳聚糖通过浸泡盐溶液发生物理交联，形成第二层网络。第一层化学网络可以维持海绵的形状， 提高海绵的强度，在血液中可以吸收水分；壳聚糖物理交联网络可提高海绵的形状恢复能力，利用海绵自身的膨胀对伤口进行封堵，并且壳聚糖在血液中可以凝集红细胞，增强血小板的粘附、活化和聚集，促进止血。另外，壳聚糖的正电荷可抑菌，防止伤口感染。
在一实施例中，按质量计，制备止血海绵的原料包括：3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂、100份水。
在一实施例中，本发明所用的具有双键的化合物的结构通式为I，其中R 1为氢(-H)或甲基(-CH 3)，R 2为氧(-O-)或亚氨基(-NH-)。带有双键的化合物具体可为(甲基)丙烯酸、(甲基)丙烯酰胺、双键功能化聚乙二醇(PEG-AA)、双键修饰的氨基酸、双键功能化的明胶(Gel-MA)、双键修饰的壳聚糖、双键修饰的海藻酸钠和双键修饰的透明质酸等。
Figure PCTCN2022138355-appb-000004
在一些实施例中，双键化合物的结构可以为式II～IX中的任意一种，其中R 1为氢(-H)或甲基(-CH 3)，R 2为氧(-O-)或亚氨基(-NH-)。如式Ⅱ为(甲基)丙烯酸；式III为具有双键的PEG(PEG-AA)，其中m表示PEG的臂数，具体可为2～8；n表示PEG的重复单元数，具体可为28～112，对应分子量为2～40kDa；式IV为具有双键的透明质酸，其中n表示透明质酸的重复单元数，具体可为25～2500，对应分子量为10-1000kDa；式V为具有双键的明胶(Gel-MA)；式VI为含有双键的壳聚糖，其中x、y、z表示壳聚糖每个重复单元的数目，具体可为62-6200，对应分子量为10-1000kDa；式VII为同时端基带有羧基的双键化合物，R 3表示侧链基团，可以是任意基团，如式Ⅷ所示的氢(-H)和式Ⅸ所示的-CH 2-COOH，其中若R 2为亚氨基(-NH-)，则式Ⅶ可以为双键功能化的氨基酸。其中式Ⅷ中R 2若为亚氨基，则式Ⅷ为N-(甲基)丙烯酰基甘氨酸；若式Ⅸ中R 2为亚氨基，则式Ⅸ为(甲基)丙烯酰基谷氨酸。
Figure PCTCN2022138355-appb-000005
在一些实施例中，本发明所用的壳聚糖为水溶性壳聚糖。
在一些实施例中，本发明所用的光引发剂可以为光引发剂651、1173、2959、TPO、α-酮戊二酸、LAP等。
在一些实施例中，本发明提供的止血海绵的制备方法包括：按质量计，将3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂溶于100份水中，制成前体液。用搅拌器在前体液中搅拌出均匀且细腻的气泡。取一定量搅拌后的前体液置于容器内，对该容器进行真空度为20～100mbar的减压处理，使前体液膨胀。待压力稳定且前体液的体积不再变化后，对该容器施以波长为200～450nm时长为1～100min的光照，使前体液成胶。取出样品，将其置于NaCl水溶液、CaCl 2水溶液、KCl水溶液、NaH 2PO 4水溶液、KH 2PO 4水溶液、Na 2CO 3水溶液、Na 2SO 4水溶液、Na 2HPO 4水溶液、K 2HPO 4水溶液、Na 3Cit水溶液、Na 3PO 4水溶液、PBS缓冲液等等至少一种溶液中浸泡1～200min后取出沥干水分并静置1～100h。将静置后的样品放入纯水中浸泡1～100h后冻干得到海绵。
在一实施例中，本发明制得的止血海绵的孔隙率为85％～99％，密度为0.01～0. 1g/cm 3，饱和吸水率为2000％～50000％，饱和吸水所需时间为1～300s，80％应变的压缩强度为30～200kPa。
在一实施例中，本发明制得的止血海绵具有形状恢复性能，干燥状态下压缩可维持形状，吸水后可迅速恢复为压缩前的形状。
在一实施例中，本发明的止血海绵原料简单，且所有原料都具有很高的生物相容性。
在一实施例中，本发明的止血海绵的制备方法简单，制备周期短，且性能可调。
在一实施例中，本发明的止血海绵较现有商品具有更高的吸水率和吸水速率，且吸水后可快速膨胀。应用于伤口止血时可以迅速封堵伤口止血。
在一实施例中，本发明止血海绵中的壳聚糖可以吸附红细胞，引发内源性凝血，减少伤口止血时间。
在一实施例中，本发明止血海绵具有较高的强度，满足按压止血的要求。
以下实施例、对比例中，使用的不含双键的壳聚糖的分子量约为10kDa，例如，实施例1中，质量为0.05g的壳聚糖为不含双键的壳聚糖，其他实施例、对比例同理。
实施例1
称取0.15g分子量为10kDa的聚乙二醇双丙烯酸酯(式Ⅲ，m＝2)，称取0.01g光引发剂2959，称取0.05g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到50mbar，压力稳定后用350nm光照射30min。成型后取出，浸泡在饱和的Na 2SO 4水溶液中20min，随后取出静置12h。静置后的样品置于超纯水中12h，从超纯水中取出样品，随后放入冷冻干燥机中，在-50～-45℃、0.05～0.15mbar环境下冻干得到海绵。后续实施例、对比例如果存在冻干步骤，则冻干条件同本实施例。
吸水性能测试：取高约10mm、直径约为13cm、质量约0.04g的干燥海绵，称取初始质量W 0。将其浸没在超纯水中。每隔一小时取出海绵，擦拭干净表面残存的水后对海绵进行称重，称重5次取平均值记为本次称重质量。称重后的海绵浸没在纯水中再次溶胀。连续三次称重，质量不再变化则记为最终质量W t。海绵吸水性能计算公式如下：
Figure PCTCN2022138355-appb-000006
SR：海绵的吸水率；
W t：海绵吸水膨胀的最终质量；
W 0：海绵吸水前的初始质量。
每组取5个样品进行测试，取平均值记为最终吸水率。按照上述方法测得的海绵吸水率为5800％。
吸水时间测试：取高约10mm、直径约为13cm、质量约0.04g的干燥海绵，将其压缩得到高度为2～3mm的压缩海绵。将海绵放入水中并开始计时，待海绵完全膨胀后停止，所用时间记为海绵吸水时间，如图1所示。每组取5个样品进行测试，取平均值记为最终的吸水时间。按照上述方法测得的海绵吸水所用时间为7.2s。
保水性能测试：取高约10mm的干燥海绵，称取初始质量W 0。将其浸没在超纯水中充分溶胀至饱和。取出后以500r/min离心3min，称取其质量W 1。海绵的保水率计算公式如下：
Figure PCTCN2022138355-appb-000007
WRV：海绵的保水率；
W 1：海绵吸水、离心后的质量；
W 0：海绵吸水前的初始质量。
每组取5个样品进行测试，取平均值记为最终保水率。按照上述方法测得的海绵保水率为2200％。
力学性能测试：取吸水、离心后的海绵，裁剪出直径与高度比值为1：(0.33～0.67)的样品，用万能试验机以5mm/min的速度对其进行80％循环压缩，记录得到的最高压缩强度δ。
海绵裁剪后得到压缩样，每次做5组取平均值，在直径与高度比值为1：(0.33～0.67)比值区间内的压缩样品数值可用。
每组取5个样品进行测试，取平均值记为最终强度。按照上述方法测得的海绵强度为67kPa。图2为10次循环的应力-应变曲线，可见，损耗较小，表明海绵有很好的强度和形状恢复性能。
孔隙率和密度测量：
取一块干燥后的海绵，称取初始质量为W s；将海绵放入容器内并加入一定量的乙醇，使得乙醇浸没海绵(使得在海绵充分吸收乙醇后仍然能够浸没海绵)，称 取容器、乙醇、海绵的总质量W a；超声2min后取出海绵，称取容器和剩余乙醇的总质量W b；用量筒装此海绵(即前文干燥后的海绵，初始质量为W s)，称取总质量为W 1；将海绵放入量筒，使乙醇至原刻度，称取总质量W 2。海绵的孔隙率计算公式如下：
Figure PCTCN2022138355-appb-000008
密度计算公式如下：
Figure PCTCN2022138355-appb-000009
ρ E：乙醇的密度，在每次测量时，通过乙醇的质量除以体积得到该次测量所有的乙醇的密度，数值接近0.79g/cm 3。
每组取5个样品进行测试，取平均值记为最终孔隙率和密度。按照上述方法测得的海绵孔隙率为89％，密度为0.031g/cm 3。
止血时间和失血量的测量：
大鼠股动脉截断止血测试：暴露出大鼠的左右股动脉，使用6mm组织取样器/打孔器在股动脉及周围组织制造深度5mm的空腔，然后将压缩后的海绵注入其中，用脱脂棉采集流出的血液并观察流血情况，观察血液不流动所需要的时间即为止血时间，采集的血液质量即为失血量，止血效果如图3所示。
每组取5个样品进行测试，取平均值记为最终止血时间和失血量。按照上述方法测得的止血时间为101s，失血量为2.31g。
后续实施例、对比例中性能指标的测试参照本实施例进行。
实施例2
称取0.1g分子量为10kDa的含有双键的壳聚糖，称取0.008g光引发剂LAP(化学名：苯基-2,4,6-三甲基苯甲酰基亚磷酸锂，CAS号：85073-19-4)，称取0.08g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到40mbar，压力稳定后用270nm光照射5min。成型后取出，浸泡在20wt％的Na 3Cit水溶液(即柠檬酸钠水溶液)中10min，随后取出静置5h。静置后的样品置于超纯水中24h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵(图4)。测得海绵吸水率为10000％，吸水所用时间为5.8s，保水率为3300％，强度为52kPa，孔隙率为87％，密度为0.055g/cm 3，止血时间为84s，失 血量为1.92g。图5为海绵的红细胞吸附SEM图，从图中可以看出所制备的海绵可吸附大量红细胞，能够有效促进凝血进程。
实施例3
称取0.2g的N-丙烯酰基甘氨酸，称取0.02g光引发剂651，称取0.02g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到80mbar，压力稳定后用290nm光照射60min。成型后取出，浸泡在40wt％的NaCl水溶液中50min，随后取出静置3h。静置后的样品置于超纯水中30h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为50000％，吸水所用时间为9.1s，保水率为10000％，强度为36kPa，孔隙率为92％，密度为0.039g/cm 3，止血时间为79s，失血量为1.73g。
实施例4
称取0.15g分子量40kDa的含有双键的明胶，称取0.15g光引发剂α-酮戊二酸，称取0.05g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到30mbar，压力稳定后用450nm光照射6min。成型后取出，浸泡在1×PBS溶液(即PBS缓冲液)中70min，随后取出静置10h。静置后的样品置于超纯水中20h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为25000％，吸水所用时间为8.9s，保水率为5100％，强度为59kPa，孔隙率为93％，密度为0.041g/cm 3，止血时间为186s，失血量为3.21g。
实施例5
称取0.18g分子量5kDa的八臂聚乙二醇丙烯酸酯(式Ⅲ，m＝8)，称取0.007g光引发剂1173，称取0.01g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到60mbar，压力稳定后用200nm光照射70min。成型后取出，浸泡在20wt％的Na 2CO 3水溶液中2min，随后取出静置3h。静置后的样品置于超纯水中15h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为31000％，吸水所用时间为10.2s，保水率为7100％，强度为67kPa，孔隙率为92％，密度为0.029g/cm 3，止血时间为134s，失血量为2.97g。
实施例6
称取0.18g分子量200kDa的透明质酸，称取0.02g光引发剂TPO，称取0.075 g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到30mbar，压力稳定后用320nm光照射10min。成型后取出，浸泡在15wt％CaCl 2水溶液中6min，随后取出静置5h。静置后的样品置于超纯水中40h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为11000％，吸水所用时间为9.9s，保水率为2300％，强度为78kPa，孔隙率为89％，密度为0.041g/cm 3，止血时间为156s，失血量为2.44g。
实施例7
称取0.03g的甲基丙烯酰基谷氨酸，称取0.02g光引发剂1173，称取0.1g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到30mbar，压力稳定后用450nm光照射100min。成型后取出，浸泡在饱和的K 2HPO 4水溶液中200min，随后取出静置20h。静置后的样品置于超纯水中100h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为1800％，吸水所用时间为5.1s，保水率为700％，强度为88kPa，孔隙率为87％，密度为0.055g/cm 3，止血时间为199s，失血量为2.77g。
实施例8
称取0.2g的分子量20kDa的四臂聚乙二醇丙烯酸酯(式Ⅲ，m＝4)，称取0.05g光引发剂1173，称取0.08g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到45mbar，压力稳定后用340nm光照射12min。成型后取出，浸泡在饱和的NaH 2PO 4水溶液中5min，随后取出静置12h。静置后的样品置于超纯水中40h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为6000％，吸水所用时间为11.7s，保水率为1500％，强度为59kPa，孔隙率为95％，密度为0.027g/cm 3，止血时间为87s，失血量为1.92g。
对比例1
称取0.15g分子量为10kDa的聚乙二醇双丙烯酸酯(式Ⅲ，m＝2)，称取0.01g光引发剂2959，称取0.05g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。不抽真空(与实施例1不同之处在于未在容器中抽真空使海绵气泡扩大)，直接用350nm光照射30min。成型后取出，浸泡在饱和的Na 2SO 4水溶液中20min，随后取出静置12h。静置后的样品置于超纯水中12h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到没有弹性不可压缩的样品，本质为冻干后的水凝胶。 测得样品吸水率为880％，吸水所用时间3h，保水率为720％，强度为840kPa。因为是冻干的坚硬水凝胶，无法测得孔隙率和密度，且无法用于止血。
对比例2
称取0.2g的N-丙烯酰基甘氨酸，称取0.02g光引发剂651，称取0.02g壳聚糖，将所有材料溶于1g超纯水。不经搅拌(与实施例3不同之处在于未经搅拌产生均匀气泡)。将所有材料填充于真空容器之中，抽真空到80mbar，压力稳定后用290nm光照射60min。成型后取出，浸泡在40wt％的NaCl水溶液中50min，随后取出静置3h。静置后的样品置于超纯水中30h，从超纯水中取出样品，随后在冷冻干燥机中冻干得到海绵。测得海绵吸水率为1100％，吸水所用时间为3h，保水率为970％，强度为790kPa。因为是是冻干的坚硬水凝胶，无法测得孔隙率和密度，且无法用于止血。
对比例3
称取0.03g的甲基丙烯酰基谷氨酸，称取0.02g光引发剂1173，称取0.1g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到30mbar，压力稳定后用450nm光照射100min。成型后取出，浸泡在饱和的K 2HPO 4水溶液中200min，随后取出静置20h。直接在冷冻干燥机中冻干得到海绵(与实施例7不同之处在于浸泡盐溶液后未在水中静置，直接冻干)。测得海绵吸水率为900％，吸水所用时间为67s，保水率为600％，强度为112kPa，孔隙率为81％，密度为0.075g/cm 3。因为坚硬且膨胀慢，无法用于止血。
对比例4
称取0.2g的分子量20kDa的四臂聚乙二醇丙烯酸酯(式Ⅲ，m＝4)，称取0.05g光引发剂1173，称取0.08g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到45mbar，压力稳定后用340nm光照射12min。成型后取出，直接在冷冻干燥机中冻干得到海绵(与实施例8不同之处在于未浸泡盐溶液和水，直接冻干)。测得海绵吸水率为7000％，吸水所用时间为8.2s，保水率为700％，强度为6kPa，孔隙率为98％，密度为0.021g/cm 3。因强度不足，无法用于止血。
对比例5
称取0.2g的分子量20kDa的四臂聚乙二醇丙烯酸酯(式Ⅲ，m＝4)，称取0.05g光引发剂1173，称取0.005g壳聚糖(与实施例8不同之处在于壳聚糖含量低)， 将所有材料溶于1g超纯水。用搅拌器搅拌无法得到均匀且稳定存在的气泡，无法进行后续操作。
对比例6
称取0.01g分子量200kDa的透明质酸(与实施例6不同之处在于含有双键的化合物含量低)，称取0.02g光引发剂TPO，称取0.075g壳聚糖，将所有材料溶于1g超纯水。用搅拌器搅拌出均匀的气泡。将所有材料填充于真空容器之中，抽真空到30mbar，压力稳定后用320nm光照射10min。成型后恢复为大气压，海绵破碎无法维持原有形状，无法进行后续操作。
以上应用了具体个例对本发明进行阐述，只是用于帮助理解本发明，并不用以限制本发明。对于本发明所属技术领域的技术人员，依据本发明的思想，还可以做出若干简单推演、变形或替换。

Claims (25)

  1. 一种止血海绵，其特征在于，按质量计，用于制备所述止血海绵的组分包含：3～30份含有双键的化合物、1～10份壳聚糖、0.1～15份光引发剂；
    所述含有双键的化合物包含如下通式II～通式IX所示化合物中的至少一种：
    Figure PCTCN2022138355-appb-100001
    通式II～通式IX中，R 1为氢或甲基，R 2为氧或亚氨基；
    式II为含有双键的丙烯酸；
    式III为含有双键的聚乙二醇，其中m表示聚乙二醇的臂数，为2～8的整数；n表示聚乙二醇的重复单元数，为28～112的整数，对应的式III分子量为2～40kDa；
    式III中，“●”表示多臂聚乙二醇丙烯酸酯或多臂聚乙二醇甲基丙烯酸酯中间的碳原子，用于连接多条同样的聚乙二醇丙烯酸酯或聚乙二醇甲基丙烯酸酯链段；
    式III所示含有双键的聚乙二醇包括聚乙二醇双丙烯酸酯、八臂聚乙二醇丙烯酸酯、四臂聚乙二醇丙烯酸酯中的至少一种；
    式IV为含有双键的透明质酸，其中n表示透明质酸的重复单元数，为25～2500的整数，对应的式IV分子量为10～1000kDa；
    式V为含有双键的明胶；
    式VI为含有双键的壳聚糖，其中x、y、z表示壳聚糖每个重复单元的数目， 为62～6200的整数，对应的式VI分子量为10～1000kDa；
    式VII中，R 3选自氢、-CH 3、-OH、-CH 2-COOH、-CH 2CH 3、-CH 2-CH(CH 3) 2、-CH 2-C 6H 5、-CH 2-C 6H 4-OH或-CH 2-SH；
    用于制备所述止血海绵的组分还包含含有盐的水溶液，即盐溶液。
  2. 如权利要求1所述的止血海绵，其特征在于，按质量计，用于制备所述止血海绵的组分包含：3～20份含有双键的化合物、1～10份壳聚糖、0.7～15份光引发剂。
  3. 如权利要求1所述的止血海绵，其特征在于，所述壳聚糖为水溶性壳聚糖。
  4. 如权利要求1所述的止血海绵，其特征在于，所述壳聚糖的分子量为5～20kDa。
  5. 如权利要求1所述的止血海绵，其特征在于，所述光引发剂包括651光引发剂、1173光引发剂、2959光引发剂、TPO、α-酮戊二酸、LAP中的至少一种。
  6. 如权利要求1所述的止血海绵，其特征在于，所述盐包括NaCl、CaCl 2、KCl、NaH 2PO 4、KH 2PO 4、Na 2CO 3、Na 2SO 4、Na 2HPO 4、K 2HPO 4、Na 3Cit、Na 3PO 4中的至少一种。
  7. 如权利要求1所述的止血海绵，其特征在于，所述盐溶液为饱和的水溶液。
  8. 如权利要求1所述的止血海绵，其特征在于，所述盐溶液中盐的浓度为15wt％～40wt％。
  9. 如权利要求1所述的止血海绵，其特征在于，所述盐溶液为PBS缓冲液。
  10. 如权利要求1至9中任一项所述止血海绵的制备方法，其特征在于，包括：
    前体液制备步骤，包括按配方量将各组分混合，溶于溶剂中，制得前体液；
    搅拌步骤，包括对所述前体液进行剧烈搅拌，得到有均匀气泡的前体液；
    减压处理步骤，包括对所述前体液进行减压处理，得到膨胀的前体液；
    光照步骤，包括对所述膨胀的前体液进行光照，得到成型的海绵；
    浸泡步骤，包括将所述成型的海绵浸泡于盐溶液中，得到浸泡后的海绵；
    冻干步骤，包括对所述浸泡后的海绵进行冻干，制得所述止血海绵。
  11. 如权利要求10所述的制备方法，其特征在于，前体液制备步骤中，所述溶剂为水。
  12. 如权利要求10所述的制备方法，其特征在于，前体液制备步骤中，溶剂的质量为壳聚糖质量的1～100倍。
  13. 如权利要求12所述的制备方法，其特征在于，前体液制备步骤中，溶剂的质量为壳聚糖质量的10～100倍。
  14. 如权利要求10所述的制备方法，其特征在于，前体液制备步骤中，将所述前体液搅拌至产生均匀的气泡，然后进入减压处理步骤。
  15. 如权利要求10所述的制备方法，其特征在于，减压处理步骤中，装有所述前体液的容器中的真空度为20～100mbar。
  16. 如权利要求10所述的制备方法，其特征在于，光照步骤中，光照时使用的光的波长为200～450nm。
  17. 如权利要求10所述的制备方法，其特征在于，光照步骤中，光照时间为1～100min。
  18. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，所述盐溶液包括NaCl水溶液、CaCl 2水溶液、KCl水溶液、NaH 2PO 4水溶液、KH 2PO 4水溶液、Na 2CO 3水溶液、Na 2SO 4水溶液、Na 2HPO 4水溶液、K 2HPO 4水溶液、Na 3Cit水溶液、Na 3PO 4水溶液、PBS缓冲液中的至少一种。
  19. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，所述盐溶液为饱和的水溶液。
  20. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，所述盐溶液中盐的浓度为15wt％～40wt％。
  21. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，所述盐溶液为PBS缓冲液。
  22. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，盐溶液浸泡时间为1～200min。
  23. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，盐溶液浸泡结束后，使用水浸泡，然后进入冻干步骤。
  24. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，在盐浸泡结束后，从盐溶液中取出海绵，静置1～100h，然后使用水浸泡。
  25. 如权利要求10所述的制备方法，其特征在于，浸泡步骤中，水浸泡的时间为1～100h。
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