WO2024026668A1 - Injectable hydrogel adhesive having both fast-curing and anti-swelling properties and use - Google Patents

Injectable hydrogel adhesive having both fast-curing and anti-swelling properties and use Download PDF

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WO2024026668A1
WO2024026668A1 PCT/CN2022/109659 CN2022109659W WO2024026668A1 WO 2024026668 A1 WO2024026668 A1 WO 2024026668A1 CN 2022109659 W CN2022109659 W CN 2022109659W WO 2024026668 A1 WO2024026668 A1 WO 2024026668A1
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poloxamer
acrylate
terminal
biodegradable
injectable hydrogel
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PCT/CN2022/109659
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French (fr)
Chinese (zh)
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WO2024026668A9 (en
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赵晓丽
边少荃
潘浩波
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深圳先进技术研究院
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Priority to PCT/CN2022/109659 priority Critical patent/WO2024026668A1/en
Publication of WO2024026668A1 publication Critical patent/WO2024026668A1/en
Publication of WO2024026668A9 publication Critical patent/WO2024026668A9/en

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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
    • 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
    • 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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • 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
    • 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
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04—Acids; Metal salts or ammonium salts thereof
    • C08F220/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts 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
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
    • C08F290/06—Polymers provided for in subclass C08G
    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements

Definitions

  • the invention belongs to the technical field of biomedical materials, and specifically relates to an injectable hydrogel adhesive with both rapid solidification and swelling resistance and its application.
  • the invention aims to provide an injectable hydrogel adhesive with both fast curing and anti-swelling properties and its application.
  • the invention is an injectable hydrogel adhesive that has both rapid curing and anti-swelling properties. It is mainly composed of terminal biodegradable poloxamer, adhesion functional small molecules, photoinitiator and dissolving liquid, and is rapidly cured under light conditions. forming.
  • the present invention uses poloxamer nanomicelles with heat-sensitive shrinkage properties as gel factors and cross-linking agents to prepare hydrogels, in which the heat-sensitive shrinkage nanomicelles enhance the cohesion of the hydrogel and give it resistance to swelling in the water environment. characteristic.
  • the photo-initiated cross-linking property ensures rapid and controllable solidification of the hydrogel.
  • Adhesion functional small molecules can be integrated into the hydrogel network during the photo-cross-linking process, providing long-lasting and stable tissue through covalent bonding with the amino groups on the tissue surface. Adhesion.
  • the terminal biodegradable design of the terminal biodegradable poloxamer is used to control the degradation time by changing the chemical structure of the poloxamer and the components of the hydrogel to meet the needs of different degradation times in different usage scenarios.
  • a first aspect of the present invention provides a terminal biodegradable poloxamer, which is obtained by introducing terminal modification structures to both ends of the poloxamer;
  • the molecular weight of the terminal modification structure is less than 300, the terminal modification structure contains biodegradable ester bonds or amide bonds, and the end of the terminal modification structure is a carbon-carbon double bond;
  • the terminal biodegradable poloxamer can initiate a cross-linking reaction by illumination.
  • R is a side group, and the R side group is an amino acid side group, which is selected according to the side groups of amino acids in the prior art.
  • x and y are determined according to the type of poloxamer.
  • the terminal biodegradable poloxamer is poloxamer diacetylacrylate, poloxamer dipropionyl acrylate, poloxamer dibutyryl acrylate, and poloxamer diglycine acrylate. , poloxamer dialanine acrylate or poloxamer di-alanine acrylate;
  • the poloxamer is preferably poloxamer 407, poloxamer 188, poloxamer 237 or poloxamer 338.
  • a second aspect of the invention provides a method for synthesizing terminal biodegradable poloxamer, which includes the following steps:
  • the molar ratio of the poloxamer to chloroalkyl acid chloride, amino acid, sodium acrylate and acryloyl chloride is 1:2.
  • a third aspect of the present invention provides the use of the terminal biodegradable poloxamer in the preparation of injectable hydrogel adhesives.
  • the fourth aspect of the present invention provides an injectable hydrogel adhesive that has both rapid curing and swelling resistance.
  • the injectable hydrogel includes the following components:
  • the small adhesion functional molecules have the ability to react with amino groups and can be integrated into the hydrogel network through light-induced double bond cross-linking;
  • the terminal biodegradable poloxamer is selected from one or more of the above-mentioned terminal biodegradable poloxamer.
  • the terminal biodegradable poloxamer is selected from the group consisting of poloxamer 407 diacetylacrylate (PF127-bis-AA), poloxamer 407 dipropionyl acrylate (PF127-bis-PA), poloxamer 407 dipropionyl acrylate (PF127-bis-PA), Losamer 407 dibutyryl acrylate (PF127-bis-BA), Poloxamer 407 diglycine acrylate (PF127-bis-GA), Poloxamer 407 dialanine acrylate (PF127-bis- AlA) and one or more of poloxamer 407 bis- ⁇ -alanine acrylate (PF127-bis- ⁇ -AlA).
  • PF127-bis-AA poloxamer 407 diacetylacrylate
  • PF127-bis-PA poloxamer 407 dipropionyl acrylate
  • PF127-bis-PA poloxamer 407 dipropionyl acrylate
  • adhesion functional small molecule is selected from N-hydroxysuccinimide acrylate (AA-NHS), 3-methacryloyl dopamine (DA-MA) and 4-vinylbenzaldehyde (EBA) of one or more.
  • AA-NHS N-hydroxysuccinimide acrylate
  • DA-MA 3-methacryloyl dopamine
  • EBA 4-vinylbenzaldehyde
  • the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), 2-hydroxy-2-methyl-1-phenyl- One or more of 1-propanone (I1173) and phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP).
  • the dissolving solution is selected from commonly used medical liquids such as deionized water, physiological saline, PBS buffer or SPF simulated body fluid.
  • each component of the injectable hydrogel is cross-linked under 365-405 nm light to form the injectable hydrogel adhesive.
  • the injectable hydrogel also contains a photo-crosslinkable natural polysaccharide polymer derivative, and the mass percentage content of the photo-crosslinkable natural polysaccharide polymer derivative is 0.1%-10%.
  • the photo-crosslinkable natural polysaccharide polymer derivative is selected from double bond modified gelatin (Gel-MA), double bond modified hyaluronic acid (HA-MA), double bond modified chitosan ( CS-MA), double bond modified sodium alginate (SA-MA), double bond modified silk fibroin (SF-MA), double bond modified cellulose (MA-C) and double bond modified dextran
  • Gel-MA double bond modified gelatin
  • HA-MA double bond modified hyaluronic acid
  • CS-MA double bond modified chitosan
  • SA-MA double bond modified sodium alginate
  • SF-MA double bond modified silk fibroin
  • MA-C double bond modified cellulose
  • MA-Glu double bond modified dextran
  • the fifth aspect of the present invention provides the application of the injectable hydrogel adhesive with both rapid curing and anti-swelling properties in sealing and/or rapid hemostasis of accidental wounds or surgical wounds of the human or animal body;
  • the surgical wound includes a neurosurgical wound.
  • the sixth aspect of the present invention provides the application method of the injectable hydrogel adhesive that has both rapid curing and anti-swelling properties.
  • Each component of the injectable hydrogel adhesive is added to the dissolving solution to fully dissolve, and the injection When reaching the use site, the light source is irradiated to trigger a photo-crosslinking reaction, causing the injectable hydrogel to solidify;
  • the wavelength range of the light source is 365-405nm
  • the irradiation time of the light source is 5-20 seconds.
  • the injectable hydrogel adhesive provided by the invention has the ability of rapid light curing, good biological safety and controllable biodegradation speed, excellent tissue adhesion and mechanical properties, and anti-swelling properties in water environments.
  • the hydrogel can quickly seal wounds and stop bleeding. It can avoid compression damage to surrounding tissues or wound sealing failure due to volume changes after surgery, and can gradually degrade as the wound heals.
  • the injectable hydrogel of the present invention can achieve adhesion to moist tissue within a few seconds after ultraviolet light irradiation, and can be used for wound closure and rapid hemostasis. It is especially suitable for wound treatment in neurosurgery, such as brain or spine surgery, to avoid The risk of post-operative adhesive volume expansion and compression of nerve tissue should be ensured to ensure patient safety after surgery.
  • Figure 1 Chemical structural formulas of PF127-bis-AA, PF127-bis-PA, PF127-bis-BA, PF127-bis-GA, PF127-bis-AlA and PF127-bis- ⁇ -AlA.
  • Figure 2 shows the appearance of an injectable hydrogel adhesive that has both rapid light curing and anti-swelling properties.
  • Figure 3 shows the rapid light curing performance of the hydrogel adhesive of the present invention.
  • A Rheological test of gel time;
  • B Light solidification of hydrogel.
  • Figure 4 shows the anti-swelling properties of the hydrogel adhesive of the present invention, compared with common polyethylene glycol swollen hydrogels.
  • A The appearance of the hydrogel soaked in PBS at different time points;
  • B The swelling rate of the hydrogel soaked in PBS at different time points.
  • Figure 5 shows the pressure burst tissue adhesion of the hydrogel adhesive of the present invention.
  • A Pressure burst test experimental device; B: Pressure burst adhesion data.
  • Figure 6 shows the rapid hemostatic effect of hydrogel adhesive on emergency cardiac bleeding in rats and rabbits.
  • Figure 7 is a diagram of the effect of hydrogel adhesive sealing dural injury in rabbits. (1) Expose the dura mater; (2) Create a dural injury model; (3) Successfully seal the dura mater to avoid cerebrospinal fluid leakage.
  • Step 1 First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 230mg chloroacetyl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichloroacetate (PF127-bis-CA).
  • Step 2 First dissolve 12.6g PF127-bis-CA and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain Losamer 407 diacetoacrylate (PF127-bis-AA).
  • Step 1 First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 250mg chloropropionyl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichloropropionate (PF127-bis-CP).
  • Step 2 First dissolve 12.6g PF127-bis-CP and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dipropionyl acrylate (PF127-bis-PA).
  • Step 1 First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 280mg chlorobutyryl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichlorobutyrate (PF127-bis-CB).
  • Step 2 First dissolve 12.6g PF127-bis-CB and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dibutyryl acrylate (PF127-bis-BA).
  • Step 1 First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 150mg glycine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 diglycine (PF127-bis-Gly).
  • Step 2 First dissolve 12.6g PF127-bis-Gly in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 diglycine acrylate (PF127-bis-GA).
  • Step 1 First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 180mg alanine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dialanine (PF127-bis-Ala).
  • Step 2 First dissolve 12.6g PF127-bis-Ala in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dialanine acrylate (PF127-bis-AlA).
  • Step 1 First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 180mg ⁇ -alanine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 bis- ⁇ -glycine (PF127-bis- ⁇ -Ala).
  • Step 2 First dissolve 12.6g PF127-bis-Ala in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 bis- ⁇ -alanine acrylate (PF127-bis- ⁇ -AlA).
  • Preparation of injectable hydrogel with both rapid light curing and anti-swelling First, add 100 mg PF127-bis-AA, 1 mg AA-NHS, and 2.5 mg LAP into 900 ⁇ l PBS buffer, and vortex until fully dissolved; Then, the solution was added to the mold and irradiated with 365nm UV light for 5 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both fast light curing and anti-swelling First, add 100 mg PF127-bis-AA, 1 mg AA-NHS, 10 mg Gel-MA, 2.5 mg LAP into 890 ⁇ l PBS buffer, vortex Shake until fully dissolved; then, add the solution into the mold and irradiate it with 365nm light source for 5 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogels with both rapid light curing and anti-swelling First, add 50 mg PF127-bis-AA, 50 mg PF127-bis-PA, 1 mg DA-MA, and 2.5 mg LAP into 900 ⁇ l PBS buffer , vortex until fully dissolved; then, add the solution into the mold, irradiate it with 365nm light source for 10 seconds, and solidify to form a hydrogel.
  • Preparation of injectable hydrogels with both rapid light curing and anti-swelling First, add 50 mg PF127-bis-AA, 50 mg PF127-bis-PA, 1 mg DA-MA, 10 mg HA-MA, and 2.5 mg LAP into 890 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold, irradiate it with 405nm light source for 10 seconds, and solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both rapid light curing and anti-swelling First, add 30 mg PF127-bis-AA, 30 mg PF127-bis-PA, 40 mg PF127-bis-BA, 1 mg EBA, and 2.5 mg LAP into 900 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold and irradiate it with 405nm light source for 20 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both fast light curing and anti-swelling First, 30mg PF127-bis-AA, 30mg PF127-bis-PA, 40mg PF127-bis-BA, 1mg EBA, 10mg CS-MA, 2.5 mg LAP was added to 890 microliters of PBS buffer and vortexed until fully dissolved; then, the solution was added to the mold and irradiated with 365nm light source for 10 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both rapid light curing and anti-swelling First, add 100 mg PF127-bis-GA, 1 mg AA-NHS, and 2.5 mg LAP into 900 ⁇ l PBS buffer, and vortex until fully dissolved; Then, the solution was added to the mold and irradiated with 365nm UV light for 5 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both fast light curing and anti-swelling First, add 100 mg PF127-bis-GA, 1 mg AA-NHS, 10 mg Gel-MA, 2.5 mg LAP into 890 ⁇ l PBS buffer, vortex Shake until fully dissolved; then, add the solution into the mold and irradiate it with 365nm light source for 5 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogels with both fast light curing and anti-swelling First, add 50 mg PF127-bis-GA, 50 mg PF127-bis-AlA, 1 mg DA-MA, and 2.5 mg LAP into 900 ⁇ l PBS buffer , vortex until fully dissolved; then, add the solution into the mold, irradiate it with 365nm light source for 10 seconds, and solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both rapid light curing and anti-swelling First, add 50 mg PF127-bis-GA, 50 mg PF127-bis-AlA, 1 mg DA-MA, 10 mg HA-MA, and 2.5 mg LAP into 890 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold, irradiate it with 405nm light source for 10 seconds, and solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both fast light curing and anti-swelling First, add 30mg PF127-bis-GA, 30mg PF127-bis-AlA, 40mg PF127-bis- ⁇ -AlA, 1mg EBA, 2.5mg LAP into 900 microliters of PBS buffer, vortex until fully dissolved; then, add the solution to the mold and irradiate it with 405nm light source for 20 seconds to solidify to form a hydrogel.
  • Preparation of injectable hydrogel with both fast light curing and anti-swelling First, 30mg PF127-bis-GA, 30mg PF127-bis-AlA, 40mg PF127-bis- ⁇ -AlA, 1mg EBA, 10mg CS-MA , 2.5mg LAP was added to 890 microliters of PBS buffer, and vortexed until fully dissolved; then, the solution was added to the mold and irradiated with 365nm light source for 10 seconds to solidify to form a hydrogel.
  • the appearance of the hydrogel is a colorless, highly transparent elastic solid, as shown in Figure 2.
  • the left side of the figure is the hydrogel of Example 2, and the right side of the figure is the hydrogel of Example 3.
  • the wound condition can be easily observed and the treatment plan can be improved in a timely manner.
  • test temperature is 25°C
  • test platform 40mm diameter flat plate, 1mm gap
  • deformation is 1%
  • frequency is 1Hz
  • light source 365nm, 100mW cm-2
  • the starting irradiation time is set to 0 seconds
  • the storage modulus (G′) and loss modulus (G′′) values of the hydrogel change with time.
  • the time point of the intersection of the two is collected. That is the photocuring time of the hydrogel.
  • Figure 3A The results are shown in Figure 3A.
  • the pressure burst experiment was used to test the tissue adhesion of the hydrogel.
  • the experimental device is shown in Figure 5.
  • a hole-shaped wound with a diameter of 2 mm is made on the surface of round pig skin, then the hydrogel precursor solution is dripped on the wound surface, and it is cured by UV irradiation for 5 seconds.
  • the injection is pushed to observe the barometer reading when the hydrogel ruptures. That is, the adhesion strength of the hydrogel.
  • the results are shown in Figure 5.
  • the results show that the burst strength of the hydrogel can reach 200mm Hg, which is much stronger than human blood pressure of 120mm Hg. It is suitable for rapid hemostasis of emergency bleeding, and the strength does not decrease and remains stable in a water environment.
  • Polyethylene glycol diacrylate of the same molecular weight was used to replace PF127-bis-AA, and other components were the same to prepare a control polyethylene glycol hydrogel.
  • the adhesive strength of polyethylene glycol hydrogels significantly decreased in aqueous environments.

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Abstract

Disclosed in the present invention are an injectable hydrogel adhesive having both fast-curing and anti-swelling properties and a use. The injectable hydrogel adhesive comprises the following components in percentage by mass: 5%-20% of terminal-biodegradable poloxamer, 0.1%-5% of small adhesion molecules, 0.1%-0.5% of photoinitiator, and a dissolving amount of solving liquid, wherein the terminal-biodegradable poloxamer is obtained by introducing a terminal modification structure to two terminals of poloxamer, the terminal modification structure has a molecular weight of less than 300 and contains a biodegradable ester bond or amide bond, and a carbon-carbon double bond is at the endmost position of the terminal modification structure. The injectable hydrogel adhesive has both fast adhesion and anti-swelling properties, can achieve adhesion of wet tissue within several seconds after ultraviolet irradiation, can be used for wound closure and rapid hemostasis, and is particularly suitable for wound treatment in neurosurgery, thereby avoiding the risk of compression of nervous tissue due to volume expansion of adhesives after surgery, and guaranteeing the postoperative safety of patients.

Description

一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用An injectable hydrogel adhesive with both fast curing and anti-swelling properties and its application 技术领域Technical field
本发明属于生物医用材料技术领域，具体涉及一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用。The invention belongs to the technical field of biomedical materials, and specifically relates to an injectable hydrogel adhesive with both rapid solidification and swelling resistance and its application.
背景技术Background technique
在处理意外创伤或外科手术造成的损伤时，伤口闭合和快速止血是必须的，常用的方法包括缝合线、吻合钉或绷带。但是，这些技术不适合封闭易碎组织或伴随有液体或气体泄漏的伤口，原因在于会造成组织的二次损伤，以及不理想的气体或液体密封性。近些年来，随着生物材料科学的发展，研究人员开发出了一系列可注射水凝胶粘合剂，用于伤口封闭和创面止血，比如纤维蛋白胶和高分子水凝胶等，它们易于使用，对柔软的组织损伤小，具有良好的水密性和气密性，受到临床治疗的广泛关注。When dealing with injuries caused by accidental trauma or surgery, wound closure and rapid hemostasis are necessary, and common methods include sutures, staples, or bandages. However, these techniques are not suitable for sealing fragile tissues or wounds with fluid or gas leakage due to secondary damage to the tissue and suboptimal gas or liquid sealing. In recent years, with the development of biomaterial science, researchers have developed a series of injectable hydrogel adhesives for wound closure and wound hemostasis, such as fibrin glue and polymer hydrogel, which are easy to When used, it causes little damage to soft tissues, has good water tightness and air tightness, and has received widespread attention in clinical treatment.
目前的可注射水凝胶组织粘合剂存在固化速度慢的问题，注射后还未形成凝胶的前体溶液易被血液或体液冲走，产生渗漏和流失，无法实现伤口封闭和快速止血，不宜于封闭有持续液体流出的伤口或者止血。另外，这类可注射水凝胶组织粘合剂大多数在水环境中吸水会发生体积溶胀，有造成周围组织压迫损伤的风险，尤其是神经组织(脑和脊髓)。此外，体积溶胀还会导致水凝胶组织粘合剂力学性能和组织粘附性减弱，造成伤口二次开裂或再次出血，危及患者生命健康。因此，开发一种兼具快速固化和抗溶胀双重性能的可注射水凝胶具有重要意义。Current injectable hydrogel tissue adhesives have the problem of slow curing speed. The precursor solution that has not yet formed a gel after injection is easily washed away by blood or body fluids, causing leakage and loss, making it impossible to achieve wound closure and rapid hemostasis. , not suitable for closing wounds with continuous fluid leakage or stopping bleeding. In addition, most of these injectable hydrogel tissue adhesives will swell in volume when absorbing water in an aqueous environment, which may cause compression damage to surrounding tissues, especially neural tissue (brain and spinal cord). In addition, volume swelling will also weaken the mechanical properties and tissue adhesion of the hydrogel tissue adhesive, causing secondary wound cracking or re-bleeding, endangering the patient's life and health. Therefore, it is of great significance to develop an injectable hydrogel with dual properties of rapid solidification and anti-swelling.
发明内容Contents of the invention
为了解决现有可注射水凝胶粘合剂固化过程不可控且速度较慢以及大多数水凝胶粘合剂在体内水环境中会吸水体积膨胀导致粘附性能下降而脱落的技术问题，本发明旨在提供一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用。In order to solve the technical problems that the curing process of existing injectable hydrogel adhesives is uncontrollable and slow, and that most hydrogel adhesives absorb water and expand in volume in the body's aqueous environment, resulting in reduced adhesion performance and falling off. The invention aims to provide an injectable hydrogel adhesive with both fast curing and anti-swelling properties and its application.
本发明兼具快速固化和抗溶胀的可注射水凝胶粘合剂，主要由末端生物降解的泊洛沙姆、粘附功能小分子、光引发剂和溶解液组成，在光照条件下快速固化成型。本发明利用具有热敏收缩性能的泊洛沙姆纳米胶束作为凝胶因子和交联剂制备水凝胶，其中热敏收缩纳米胶束增强了水凝胶的内聚力并赋予其水环境抗溶胀特性。光引发交联特性保证水凝胶的快速可控 固化，粘附功能小分子可以在光交联过程中整合到水凝胶网络中，通过与组织表面氨基发生共价键连接提供持久稳定的组织粘附性。此外，利用末端生物降解泊洛沙姆的末端可降解设计，通过改变泊洛沙姆的化学结构以及水凝胶的组份调控降解时间，满足不同使用场景对不同降解时间的需求。The invention is an injectable hydrogel adhesive that has both rapid curing and anti-swelling properties. It is mainly composed of terminal biodegradable poloxamer, adhesion functional small molecules, photoinitiator and dissolving liquid, and is rapidly cured under light conditions. forming. The present invention uses poloxamer nanomicelles with heat-sensitive shrinkage properties as gel factors and cross-linking agents to prepare hydrogels, in which the heat-sensitive shrinkage nanomicelles enhance the cohesion of the hydrogel and give it resistance to swelling in the water environment. characteristic. The photo-initiated cross-linking property ensures rapid and controllable solidification of the hydrogel. Adhesion functional small molecules can be integrated into the hydrogel network during the photo-cross-linking process, providing long-lasting and stable tissue through covalent bonding with the amino groups on the tissue surface. Adhesion. In addition, the terminal biodegradable design of the terminal biodegradable poloxamer is used to control the degradation time by changing the chemical structure of the poloxamer and the components of the hydrogel to meet the needs of different degradation times in different usage scenarios.
本发明的技术方案具体如下：The technical solutions of the present invention are as follows:
本发明第一方面提供一种末端生物降解泊洛沙姆，所述末端生物降解泊洛沙姆通过将末端修饰结构引入到泊洛沙姆的两个末端得到；A first aspect of the present invention provides a terminal biodegradable poloxamer, which is obtained by introducing terminal modification structures to both ends of the poloxamer;
所述末端修饰结构的分子量小于300，末端修饰结构中含有可生物降解的酯键或酰胺键，且末端修饰结构的最末端为碳碳双键；The molecular weight of the terminal modification structure is less than 300, the terminal modification structure contains biodegradable ester bonds or amide bonds, and the end of the terminal modification structure is a carbon-carbon double bond;
所述末端生物降解泊洛沙姆可通过光照引发交联反应。The terminal biodegradable poloxamer can initiate a cross-linking reaction by illumination.
进一步地，所述末端生物降解泊洛沙姆的化学结构式如下式I或式II所示；Further, the chemical structural formula of the terminal biodegradable poloxamer is as shown in the following formula I or formula II;
式I：
Figure PCTCN2022109659-appb-000001
n≤10， Formula I:
Figure PCTCN2022109659-appb-000001
n≤10,
式II：
Figure PCTCN2022109659-appb-000002
R为侧基，R侧基为氨基酸侧基，根据现有技术中氨基酸的侧基进行选择。 Formula II:
Figure PCTCN2022109659-appb-000002
R is a side group, and the R side group is an amino acid side group, which is selected according to the side groups of amino acids in the prior art.
式I和式II中x和y根据泊洛沙姆的型号进行确定。In Formula I and Formula II, x and y are determined according to the type of poloxamer.
进一步地，所述末端生物降解泊洛沙姆为泊洛沙姆二乙酰丙烯酸酯、泊洛沙姆二丙酰丙烯酸酯、泊洛沙姆二丁酰丙烯酸酯、泊洛沙姆二甘氨酸丙烯酸酯、泊洛沙姆二丙氨酸丙烯酸酯或泊洛沙姆二β-丙氨酸丙烯酸酯；Further, the terminal biodegradable poloxamer is poloxamer diacetylacrylate, poloxamer dipropionyl acrylate, poloxamer dibutyryl acrylate, and poloxamer diglycine acrylate. , poloxamer dialanine acrylate or poloxamer di-alanine acrylate;
所述泊洛沙姆二乙酰丙烯酸酯的化学结构式如下式1所示；The chemical structural formula of the poloxamer diacetylacrylate is shown in the following formula 1;
所述泊洛沙姆二丙酰丙烯酸酯的化学结构式如下式2所示；The chemical structural formula of the poloxamer dipropionyl acrylate is shown in the following formula 2;
所述泊洛沙姆二丁酰丙烯酸酯的化学结构式如下式3所示；The chemical structural formula of the poloxamer dibutyryl acrylate is shown in the following formula 3;
所述泊洛沙姆二甘氨酸丙烯酸酯的化学结构式如下式4所示；The chemical structural formula of the poloxamer diglycine acrylate is shown in Formula 4 below;
所述泊洛沙姆二丙氨酸丙烯酸酯的化学结构式如下式5所示；The chemical structural formula of the poloxamer dialanine acrylate is shown in the following formula 5;
所述泊洛沙姆二β-丙氨酸丙烯酸酯的化学结构式如下式6所示；The chemical structural formula of the poloxamer di-β-alanine acrylate is shown in the following formula 6;
Figure PCTCN2022109659-appb-000003
Figure PCTCN2022109659-appb-000003
进一步地，上述末端生物降解泊洛沙姆中，所述泊洛沙姆优选为泊洛沙姆407、泊洛沙姆188、泊洛沙姆237或泊洛沙姆338。Furthermore, among the above terminal biodegradable poloxamer, the poloxamer is preferably poloxamer 407, poloxamer 188, poloxamer 237 or poloxamer 338.
本发明第二方面提供一种末端生物降解泊洛沙姆的合成方法，包括如下步骤：A second aspect of the invention provides a method for synthesizing terminal biodegradable poloxamer, which includes the following steps:
将泊洛沙姆溶于二氯甲烷中，加入三乙胺和氯烷基酰氯进行反应，反应完成后，用***沉淀，离心收集后真空干燥得到泊洛沙姆二氯烷基酸酯；将泊洛沙姆二氯乙酸酯溶于DMF中，加入丙烯酸钠进行反应，反应完成后滴加到***沉淀，离心收集后真空干燥得到泊洛沙姆二烷基酰丙烯酸酯；Dissolve poloxamer in dichloromethane, add triethylamine and chloroalkyl acid chloride to react, after the reaction is completed, precipitate with ether, collect by centrifugation and dry under vacuum to obtain poloxamer dichloroalkyl acid ester; Poloxamer dichloroacetate is dissolved in DMF, sodium acrylate is added to react, and after the reaction is completed, it is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer dialkyl acrylate;
所述氯烷基酰氯的化学结构式如下式a所示，n≤10；The chemical structural formula of the chloroalkyl acid chloride is as shown in the following formula a, n≤10;
式a：
Figure PCTCN2022109659-appb-000004
Formula a:
Figure PCTCN2022109659-appb-000004
所述泊洛沙姆二氯烷基酸酯的化学结构式如下式b所示，n≤10；The chemical structural formula of the poloxamer dichloroalkylate is shown in the following formula b, n≤10;
式b：
Figure PCTCN2022109659-appb-000005
Formula b:
Figure PCTCN2022109659-appb-000005
所述泊洛沙姆二烷基酰丙烯酸酯的化学结构式如下式c所示，n≤10；The chemical structural formula of the poloxamer dialkyl acrylate is shown in the following formula c, n≤10;
式c：
Figure PCTCN2022109659-appb-000006
Formula c:
Figure PCTCN2022109659-appb-000006
或，将泊洛沙姆溶于甲苯中，加入对甲苯磺酸和氨基酸进行反应，反应完成后，用***沉淀，离心收集后真空干燥得到泊洛沙姆二氨基酸；将泊洛沙姆二甘氨酸溶于二氯甲烷中，加入三乙胺和丙烯酰氯进行反应，反应完成后滴加到***沉淀，离心收集后真空干燥得到泊洛沙姆二氨基酸丙烯酸酯；Or, dissolve poloxamer in toluene, add p-toluenesulfonic acid and amino acid to react, after the reaction is completed, precipitate with ether, collect by centrifugation and dry under vacuum to obtain poloxamer diamino acid; convert poloxamer diglycine Dissolve in dichloromethane, add triethylamine and acryloyl chloride to react, add dropwise to diethyl ether to precipitate after the reaction is completed, collect by centrifugation and dry under vacuum to obtain poloxamer diamino acid acrylate;
所述氨基酸的化学结构式如下式d所示，R为侧基；The chemical structural formula of the amino acid is shown in the following formula d, R is a side group;
式d：
Figure PCTCN2022109659-appb-000007
Formula d:
Figure PCTCN2022109659-appb-000007
所述泊洛沙姆二氨基酸的化学结构式如下式e所示，R为侧基；The chemical structural formula of the poloxamer diamino acid is shown in the following formula e, R is a side group;
式e：
Figure PCTCN2022109659-appb-000008
Formula e:
Figure PCTCN2022109659-appb-000008
所述泊洛沙姆二氨基酸丙烯酸酯的化学结构式如下式f所示，R为侧基；The chemical structural formula of the poloxamer diamino acid acrylate is shown in the following formula f, R is a side group;
式f：
Figure PCTCN2022109659-appb-000009
Formula f:
Figure PCTCN2022109659-appb-000009
进一步地，所述泊洛沙姆在反应过程中，与氯烷基酰氯、氨基酸、丙烯酸钠和丙烯酰氯摩尔比为均为1:2。Further, during the reaction process, the molar ratio of the poloxamer to chloroalkyl acid chloride, amino acid, sodium acrylate and acryloyl chloride is 1:2.
本发明第三方面提供所述末端生物降解泊洛沙姆在制备可注射水凝胶粘合剂中的应用。A third aspect of the present invention provides the use of the terminal biodegradable poloxamer in the preparation of injectable hydrogel adhesives.
本发明第四方面提供一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂，以质量百分数计，所述可注射水凝胶包含如下组分：The fourth aspect of the present invention provides an injectable hydrogel adhesive that has both rapid curing and swelling resistance. In terms of mass percentage, the injectable hydrogel includes the following components:
Figure PCTCN2022109659-appb-000010
Figure PCTCN2022109659-appb-000010
所述粘附功能小分子具备与氨基反应能力并且可以通过光引发双键交联整合到水凝胶网络中；The small adhesion functional molecules have the ability to react with amino groups and can be integrated into the hydrogel network through light-induced double bond cross-linking;
所述末端生物降解泊洛沙姆选自任一项上述末端生物降解泊洛沙姆中的一种或几种。The terminal biodegradable poloxamer is selected from one or more of the above-mentioned terminal biodegradable poloxamer.
进一步地，所述末端生物降解泊洛沙姆选自泊洛沙姆407二乙酰丙烯酸酯(PF127-bis-AA)、泊洛沙姆407二丙酰丙烯酸酯(PF127-bis-PA)、泊洛沙姆407二丁酰丙烯酸酯(PF127-bis-BA)、泊洛沙姆407二甘氨酸丙烯酸酯(PF127-bis-GA)、泊洛沙姆407二丙氨酸丙烯酸酯(PF127-bis-AlA)和泊洛沙姆407二β-丙氨酸丙烯酸酯(PF127-bis-β-AlA)中的一种或几种。Further, the terminal biodegradable poloxamer is selected from the group consisting of poloxamer 407 diacetylacrylate (PF127-bis-AA), poloxamer 407 dipropionyl acrylate (PF127-bis-PA), poloxamer 407 dipropionyl acrylate (PF127-bis-PA), Losamer 407 dibutyryl acrylate (PF127-bis-BA), Poloxamer 407 diglycine acrylate (PF127-bis-GA), Poloxamer 407 dialanine acrylate (PF127-bis- AlA) and one or more of poloxamer 407 bis-β-alanine acrylate (PF127-bis-β-AlA).
进一步地，所述粘附功能小分子选自N-羟基琥珀酰亚胺丙烯酸酯(AA-NHS)、3-甲基丙烯酰多巴胺(DA-MA)和4-乙烯基苯甲醛(EBA)中的一种或多种。Further, the adhesion functional small molecule is selected from N-hydroxysuccinimide acrylate (AA-NHS), 3-methacryloyl dopamine (DA-MA) and 4-vinylbenzaldehyde (EBA) of one or more.
进一步地，所述光引发剂选自2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮(I2959)、2-羟基-2-甲基-1-苯基-1-丙酮(I1173)和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂(LAP)中的一种或多种。Further, the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), 2-hydroxy-2-methyl-1-phenyl- One or more of 1-propanone (I1173) and phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP).
进一步地，所述溶解液选自去离子水、生理盐水、PBS缓冲液或SPF模拟体液等常用的医用液体。Further, the dissolving solution is selected from commonly used medical liquids such as deionized water, physiological saline, PBS buffer or SPF simulated body fluid.
进一步地，可注射水凝胶的各组分在365-405nm光照下交联形成所述可注射水凝胶粘合剂。Further, each component of the injectable hydrogel is cross-linked under 365-405 nm light to form the injectable hydrogel adhesive.
进一步地，所述可注射水凝胶还包含可光交联的天然多糖高分子衍生物，所述可光交联的天然多糖高分子衍生物的质量百分数含量为0.1％-10％。Further, the injectable hydrogel also contains a photo-crosslinkable natural polysaccharide polymer derivative, and the mass percentage content of the photo-crosslinkable natural polysaccharide polymer derivative is 0.1%-10%.
优选地，所述可光交联的天然多糖高分子衍生物选自双键改性明胶(Gel-MA)、双键改性透明质酸(HA-MA)、双键改性壳聚糖(CS-MA)、双键改性海藻酸钠(SA-MA)、双键改性丝素蛋白(SF-MA)、双键改性纤维素(MA-C)和双键改性葡聚糖(MA-Glu)中的一种或多种，可以提供所需的生物学功能。Preferably, the photo-crosslinkable natural polysaccharide polymer derivative is selected from double bond modified gelatin (Gel-MA), double bond modified hyaluronic acid (HA-MA), double bond modified chitosan ( CS-MA), double bond modified sodium alginate (SA-MA), double bond modified silk fibroin (SF-MA), double bond modified cellulose (MA-C) and double bond modified dextran One or more of (MA-Glu) can provide the desired biological function.
本发明第五方面提供所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂在人体或动物体意外创伤或手术伤口的封闭和/或快速止血中的应用；The fifth aspect of the present invention provides the application of the injectable hydrogel adhesive with both rapid curing and anti-swelling properties in sealing and/or rapid hemostasis of accidental wounds or surgical wounds of the human or animal body;
优选地，所述手术伤口包括神经外科手术伤口。Preferably, the surgical wound includes a neurosurgical wound.
本发明第六方面提供所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂的应用方法，将可注射水凝胶粘合剂各组分加入到溶解液中充分溶解，注射到使用部位，光源照射后引发光交联反应，使所述可注射水凝胶发生固化；The sixth aspect of the present invention provides the application method of the injectable hydrogel adhesive that has both rapid curing and anti-swelling properties. Each component of the injectable hydrogel adhesive is added to the dissolving solution to fully dissolve, and the injection When reaching the use site, the light source is irradiated to trigger a photo-crosslinking reaction, causing the injectable hydrogel to solidify;
优选地，所述光源波长范围是365-405nm；Preferably, the wavelength range of the light source is 365-405nm;
优选地，所述光源照射的时间为5-20s。Preferably, the irradiation time of the light source is 5-20 seconds.
本发明的有益效果为：The beneficial effects of the present invention are:
本发明提供的可注射水凝胶粘合剂具有快速光固化的能力，良好的生物安全性和可控的生物降解速度，优秀的组织粘附性和力学性能，以及水环境抗溶胀特性。临床使用该水凝胶时，可快速封闭伤口和止血，术后可避免因体积变化导致的压迫损伤周围组织或伤口封闭失效，并且可以随着伤口的愈合逐渐降解。本发明可注射水凝胶在紫外光照射后的数秒内可实现针对潮湿组织的粘附，可用于伤口封闭和快速止血，特别适用于神经外科手术的伤口处理，比如脑颅或脊柱手术，避免术后粘合剂体积膨胀压迫神经组织的风险，保证患者术后的安全性。The injectable hydrogel adhesive provided by the invention has the ability of rapid light curing, good biological safety and controllable biodegradation speed, excellent tissue adhesion and mechanical properties, and anti-swelling properties in water environments. When used clinically, the hydrogel can quickly seal wounds and stop bleeding. It can avoid compression damage to surrounding tissues or wound sealing failure due to volume changes after surgery, and can gradually degrade as the wound heals. The injectable hydrogel of the present invention can achieve adhesion to moist tissue within a few seconds after ultraviolet light irradiation, and can be used for wound closure and rapid hemostasis. It is especially suitable for wound treatment in neurosurgery, such as brain or spine surgery, to avoid The risk of post-operative adhesive volume expansion and compression of nerve tissue should be ensured to ensure patient safety after surgery.
附图说明Description of the drawings
图1PF127-bis-AA、PF127-bis-PA、PF127-bis-BA、PF127-bis-GA、PF127-bis-AlA和PF127-bis-β-AlA的化学结构式。Figure 1 Chemical structural formulas of PF127-bis-AA, PF127-bis-PA, PF127-bis-BA, PF127-bis-GA, PF127-bis-AlA and PF127-bis-β-AlA.
图2为兼具快速光照固化和抗溶胀的可注射水凝胶粘合剂的外观图。Figure 2 shows the appearance of an injectable hydrogel adhesive that has both rapid light curing and anti-swelling properties.
图3为本发明水凝胶粘合剂的快速光照固化性能。A：凝胶时间的流变学测试；B：水凝胶的光固。Figure 3 shows the rapid light curing performance of the hydrogel adhesive of the present invention. A: Rheological test of gel time; B: Light solidification of hydrogel.
图4为本发明水凝胶粘合剂的抗溶胀特性，与常见的聚乙二醇溶胀水凝胶进行对比。A：水凝胶浸泡在PBS中不同时间点的外观图；B：水凝胶浸泡在PBS中不同时间点的溶胀率。Figure 4 shows the anti-swelling properties of the hydrogel adhesive of the present invention, compared with common polyethylene glycol swollen hydrogels. A: The appearance of the hydrogel soaked in PBS at different time points; B: The swelling rate of the hydrogel soaked in PBS at different time points.
图5为本发明水凝胶粘合剂的压力***组织粘附性。A：压力***测试实验装置；B：压力***粘附性数据。Figure 5 shows the pressure burst tissue adhesion of the hydrogel adhesive of the present invention. A: Pressure burst test experimental device; B: Pressure burst adhesion data.
图6为水凝胶粘合剂进行大鼠和兔子心脏紧急出血的快速止血效果图。(a)暴露大鼠心脏并制造穿透出血模型；(b)出血行为展示；(c)注射水凝胶粘合剂并进行光照固化，封闭伤口止血；(d)干净纱布擦拭出血部位；(e)纱布上没有血迹，说明止血成功。(a)暴露兔心脏并制造穿透出血模型；(b)出血行为展示；(c)注射水凝胶粘合剂并进行光照固化，封闭伤口止血；(d)干净纱布擦拭出血部位；(e)纱布上没有血迹，说明止血成功。Figure 6 shows the rapid hemostatic effect of hydrogel adhesive on emergency cardiac bleeding in rats and rabbits. (a) Exposing the rat heart and creating a penetrating bleeding model; (b) Demonstrating bleeding behavior; (c) Injecting hydrogel adhesive and curing it with light to seal the wound to stop bleeding; (d) Clean gauze to wipe the bleeding site; (c) e) There is no blood stain on the gauze, indicating that the bleeding has been stopped successfully. (a) Exposing the rabbit heart and creating a penetrating bleeding model; (b) Demonstrating bleeding behavior; (c) Injecting hydrogel adhesive and curing it with light to seal the wound to stop bleeding; (d) Wipe the bleeding site with clean gauze; (e) ) There is no blood on the gauze, indicating that the bleeding has been stopped successfully.
图7为水凝胶粘合剂进行大兔子硬脊膜损伤封闭的效果图。(1)暴露硬脊膜；(2)制造硬脊膜损伤模型；(3)成功封闭硬脊膜，避免脑脊液漏。Figure 7 is a diagram of the effect of hydrogel adhesive sealing dural injury in rabbits. (1) Expose the dura mater; (2) Create a dural injury model; (3) Successfully seal the dura mater to avoid cerebrospinal fluid leakage.
具体实施方式Detailed ways
为了更清楚地理解本发明，现参照下列实施例及附图进一步描述本发明。实施例仅用于 解释而不以任何方式限制本发明。实施例中，各原始试剂材料均可商购获得，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。In order to understand the present invention more clearly, the present invention will be further described with reference to the following examples and accompanying drawings. The examples are for explanation only and do not limit the invention in any way. In the examples, each original reagent material is commercially available, and the experimental methods without specifying specific conditions are conventional methods and conditions well known in the art, or according to the conditions recommended by the instrument manufacturer.
实施例1Example 1
PF127-bis-AA、PF127-bis-PA、PF127-bis-BA、PF127-bis-GA、PF127-bis-AlA和PF127-bis-β-AlA的合成：Synthesis of PF127-bis-AA, PF127-bis-PA, PF127-bis-BA, PF127-bis-GA, PF127-bis-AlA and PF127-bis-β-AlA:
1)末端生物降解的光交联PF127高分子(PF127-bis-AA)的合成：1) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-AA):
第一步：首先将12.6g PF127溶于100mL二氯甲烷中，然后加入1mL三乙胺和230mg氯乙酰氯。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二氯乙酸酯(PF127-bis-CA)。Step 1: First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 230mg chloroacetyl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichloroacetate (PF127-bis-CA).
第二步：首先将12.6g PF127-bis-CA和190mg丙烯酸钠溶于50mL DMF中。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到洛沙姆407二乙酰丙烯酸酯(PF127-bis-AA)。Step 2: First dissolve 12.6g PF127-bis-CA and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain Losamer 407 diacetoacrylate (PF127-bis-AA).
2)末端生物降解的光交联PF127高分子(PF127-bis-PA)的合成：2) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-PA):
第一步：首先将12.6g PF127溶于100mL二氯甲烷中，然后加入1mL三乙胺和250mg氯丙酰氯。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二氯丙酸酯(PF127-bis-CP)。Step 1: First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 250mg chloropropionyl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichloropropionate (PF127-bis-CP).
第二步：首先将12.6g PF127-bis-CP和190mg丙烯酸钠溶于50mL DMF中。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到泊洛沙姆407二丙酰丙烯酸酯(PF127-bis-PA)。Step 2: First dissolve 12.6g PF127-bis-CP and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dipropionyl acrylate (PF127-bis-PA).
3)末端生物降解的光交联PF127高分子(PF127-bis-BA)的合成：3) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-BA):
第一步：首先将12.6g PF127溶于100mL二氯甲烷中，然后加入1mL三乙胺和280mg氯丁酰氯。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二氯丁酸酯(PF127-bis-CB)。Step 1: First dissolve 12.6g PF127 in 100mL methylene chloride, then add 1mL triethylamine and 280mg chlorobutyryl chloride. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dichlorobutyrate (PF127-bis-CB).
第二步：首先将12.6g PF127-bis-CB和190mg丙烯酸钠溶于50mL DMF中。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到泊洛沙姆407二丁酰丙烯酸酯(PF127-bis-BA)。Step 2: First dissolve 12.6g PF127-bis-CB and 190mg sodium acrylate in 50mL DMF. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dibutyryl acrylate (PF127-bis-BA).
4)末端生物降解的光交联PF127高分子(PF127-bis-GA)的合成：4) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-GA):
第一步：首先将12.6g PF127溶于100mL甲苯中，然后加入345mg对甲苯磺酸和150mg甘氨酸。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二甘氨酸(PF127-bis-Gly)。Step 1: First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 150mg glycine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 diglycine (PF127-bis-Gly).
第二步：首先将12.6g PF127-bis-Gly溶于100mL二氯甲烷中，然后加入1mL三乙胺和181mg丙烯酰氯。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到泊洛沙姆407二甘氨酸丙烯酸酯(PF127-bis-GA)。Step 2: First dissolve 12.6g PF127-bis-Gly in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 diglycine acrylate (PF127-bis-GA).
5)末端生物降解的光交联PF127高分子(PF127-bis-AlA)的合成：5) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-AlA):
第一步：首先将12.6g PF127溶于100mL甲苯中，然后加入345mg对甲苯磺酸和180mg丙氨酸。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二丙氨酸(PF127-bis-Ala)。Step 1: First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 180mg alanine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dialanine (PF127-bis-Ala).
第二步：首先将12.6g PF127-bis-Ala溶于100mL二氯甲烷中，然后加入1mL三乙胺和181mg丙烯酰氯。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到泊洛沙姆407二丙氨酸丙烯酸酯(PF127-bis-AlA)。Step 2: First dissolve 12.6g PF127-bis-Ala in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 dialanine acrylate (PF127-bis-AlA).
6)末端生物降解的光交联PF127高分子(PF127-bis-β-AlA)的合成：6) Synthesis of terminally biodegradable photo-crosslinked PF127 polymer (PF127-bis-β-AlA):
第一步：首先将12.6g PF127溶于100mL甲苯中，然后加入345mg对甲苯磺酸和180mgβ-丙氨酸。反应完成后，反应液***中沉淀，离心收集后真空干燥得到泊洛沙姆407二β-甘氨酸(PF127-bis-β-Ala)。Step 1: First dissolve 12.6g PF127 in 100mL toluene, then add 345mg p-toluenesulfonic acid and 180mg β-alanine. After the reaction is completed, the reaction solution is precipitated in diethyl ether, collected by centrifugation and dried under vacuum to obtain poloxamer 407 bis-β-glycine (PF127-bis-β-Ala).
第二步：首先将12.6g PF127-bis-Ala溶于100mL二氯甲烷中，然后加入1mL三乙胺和181mg丙烯酰氯。反应完成后，反应液滴加到***中沉淀，离心收集后真空干燥得到泊洛沙姆407二β-丙氨酸丙烯酸酯(PF127-bis-β-AlA)。Step 2: First dissolve 12.6g PF127-bis-Ala in 100mL methylene chloride, then add 1mL triethylamine and 181mg acryloyl chloride. After the reaction is completed, the reaction solution is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer 407 bis-β-alanine acrylate (PF127-bis-β-AlA).
实施例2Example 2
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将100mg PF127-bis-AA，1mg AA-NHS，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm紫外光照射5秒，固化形成水凝胶。Preparation of injectable hydrogel with both rapid light curing and anti-swelling: First, add 100 mg PF127-bis-AA, 1 mg AA-NHS, and 2.5 mg LAP into 900 μl PBS buffer, and vortex until fully dissolved; Then, the solution was added to the mold and irradiated with 365nm UV light for 5 seconds to solidify to form a hydrogel.
实施例3Example 3
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将100mg PF127-bis-AA，1mg AA-NHS，10mg Gel-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射5秒，固化形成水凝胶。Preparation of injectable hydrogel with both fast light curing and anti-swelling: First, add 100 mg PF127-bis-AA, 1 mg AA-NHS, 10 mg Gel-MA, 2.5 mg LAP into 890 μl PBS buffer, vortex Shake until fully dissolved; then, add the solution into the mold and irradiate it with 365nm light source for 5 seconds to solidify to form a hydrogel.
实施例4Example 4
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将50mg PF127-bis-AA，50mg PF127-bis-PA，1mg DA-MA，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogels with both rapid light curing and anti-swelling: First, add 50 mg PF127-bis-AA, 50 mg PF127-bis-PA, 1 mg DA-MA, and 2.5 mg LAP into 900 μl PBS buffer , vortex until fully dissolved; then, add the solution into the mold, irradiate it with 365nm light source for 10 seconds, and solidify to form a hydrogel.
实施例5Example 5
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将50mg PF127-bis-AA，50mg PF127-bis-PA，1mg DA-MA，10mg HA-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用405nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogels with both rapid light curing and anti-swelling: First, add 50 mg PF127-bis-AA, 50 mg PF127-bis-PA, 1 mg DA-MA, 10 mg HA-MA, and 2.5 mg LAP into 890 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold, irradiate it with 405nm light source for 10 seconds, and solidify to form a hydrogel.
实施例6Example 6
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将30mg PF127-bis-AA，30mg PF127-bis-PA，40mg PF127-bis-BA，1mg EBA，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用405nm光源光照射20秒，固化形成水凝胶。Preparation of injectable hydrogel with both rapid light curing and anti-swelling: First, add 30 mg PF127-bis-AA, 30 mg PF127-bis-PA, 40 mg PF127-bis-BA, 1 mg EBA, and 2.5 mg LAP into 900 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold and irradiate it with 405nm light source for 20 seconds to solidify to form a hydrogel.
实施例7Example 7
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将30mg PF127-bis-AA，30mg PF127-bis-PA，40mg PF127-bis-BA，1mg EBA，10mg CS-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogel with both fast light curing and anti-swelling: First, 30mg PF127-bis-AA, 30mg PF127-bis-PA, 40mg PF127-bis-BA, 1mg EBA, 10mg CS-MA, 2.5 mg LAP was added to 890 microliters of PBS buffer and vortexed until fully dissolved; then, the solution was added to the mold and irradiated with 365nm light source for 10 seconds to solidify to form a hydrogel.
实施例8Example 8
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将100mg PF127-bis-GA，1mg AA-NHS，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm紫外光照射5秒，固化形成水凝胶。Preparation of injectable hydrogel with both rapid light curing and anti-swelling: First, add 100 mg PF127-bis-GA, 1 mg AA-NHS, and 2.5 mg LAP into 900 μl PBS buffer, and vortex until fully dissolved; Then, the solution was added to the mold and irradiated with 365nm UV light for 5 seconds to solidify to form a hydrogel.
实施例9Example 9
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将100mg PF127-bis-GA，1mg AA-NHS，10mg Gel-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射5秒，固化形成水凝胶。Preparation of injectable hydrogel with both fast light curing and anti-swelling: First, add 100 mg PF127-bis-GA, 1 mg AA-NHS, 10 mg Gel-MA, 2.5 mg LAP into 890 μl PBS buffer, vortex Shake until fully dissolved; then, add the solution into the mold and irradiate it with 365nm light source for 5 seconds to solidify to form a hydrogel.
实施例10Example 10
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将50mg PF127-bis-GA，50mg PF127-bis-AlA，1mg DA-MA，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogels with both fast light curing and anti-swelling: First, add 50 mg PF127-bis-GA, 50 mg PF127-bis-AlA, 1 mg DA-MA, and 2.5 mg LAP into 900 μl PBS buffer , vortex until fully dissolved; then, add the solution into the mold, irradiate it with 365nm light source for 10 seconds, and solidify to form a hydrogel.
实施例11Example 11
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将50mg PF127-bis-GA，50mg PF127-bis-AlA，1mg DA-MA，10mg HA-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用405nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogel with both rapid light curing and anti-swelling: First, add 50 mg PF127-bis-GA, 50 mg PF127-bis-AlA, 1 mg DA-MA, 10 mg HA-MA, and 2.5 mg LAP into 890 micron liter of PBS buffer, vortex until fully dissolved; then, add the solution to the mold, irradiate it with 405nm light source for 10 seconds, and solidify to form a hydrogel.
实施例12Example 12
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将30mg PF127-bis-GA，30mg PF127-bis-AlA，40mg PF127-bis-β-AlA，1mg EBA，2.5mg LAP加入900微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用405nm光源光照射20秒，固化形成水凝胶。Preparation of injectable hydrogel with both fast light curing and anti-swelling: First, add 30mg PF127-bis-GA, 30mg PF127-bis-AlA, 40mg PF127-bis-β-AlA, 1mg EBA, 2.5mg LAP into 900 microliters of PBS buffer, vortex until fully dissolved; then, add the solution to the mold and irradiate it with 405nm light source for 20 seconds to solidify to form a hydrogel.
实施例13Example 13
兼具快速光照固化和抗溶胀的可注射水凝胶的制备：首先，将30mg PF127-bis-GA，30mg PF127-bis-AlA，40mg PF127-bis-β-AlA，1mg EBA，10mg CS-MA，2.5mg LAP加入890微升PBS缓冲液中，旋涡震荡至充分溶解；然后，将溶液加入模具中，用365nm光源光照射10秒，固化形成水凝胶。Preparation of injectable hydrogel with both fast light curing and anti-swelling: First, 30mg PF127-bis-GA, 30mg PF127-bis-AlA, 40mg PF127-bis-β-AlA, 1mg EBA, 10mg CS-MA , 2.5mg LAP was added to 890 microliters of PBS buffer, and vortexed until fully dissolved; then, the solution was added to the mold and irradiated with 365nm light source for 10 seconds to solidify to form a hydrogel.
使用实施例3水凝胶进行下列测试The following tests were performed using the Example 3 hydrogel
1.水凝胶的外观1. Appearance of hydrogel
水凝胶外观为无色高透明弹性固体，见附图2，图左为实施例2水凝胶，图右为实施例3水凝胶。在处理伤口或止血过程中，可以方便观察创伤的情况，及时进行治疗方案的改进。The appearance of the hydrogel is a colorless, highly transparent elastic solid, as shown in Figure 2. The left side of the figure is the hydrogel of Example 2, and the right side of the figure is the hydrogel of Example 3. During the process of wound treatment or hemostasis, the wound condition can be easily observed and the treatment plan can be improved in a timely manner.
2.凝胶的固化速度2. Gel solidification speed
利用流变学测试检测水凝胶的光固化时间：测试温度25℃，将水凝剂前体溶液填充测试平台(直径40mm平板，间隙1mm)，形变量为1％，频率为1Hz，光源(365nm,100mW cm-2)开始照射时间设定为0秒，收集水凝胶的储能模量(G′)和损耗模量(G″)数值随时间的变化曲线。二者交叉的时间点即为水凝胶的光固化时间。结果见附图3A。Use rheology test to detect the photocuring time of hydrogel: test temperature is 25℃, fill the test platform (40mm diameter flat plate, 1mm gap) with hydrocoagulant precursor solution, deformation is 1%, frequency is 1Hz, light source ( 365nm, 100mW cm-2) The starting irradiation time is set to 0 seconds, and the storage modulus (G′) and loss modulus (G″) values of the hydrogel change with time. The time point of the intersection of the two is collected. That is the photocuring time of the hydrogel. The results are shown in Figure 3A.
利用称重法检测水凝胶的光固化效率：将接受不同光照时间的水凝胶冷冻干燥后称取质量Wp，根据水凝胶中组份含量可计算出初始组份质量Wo。二者比例即为水凝胶的光固化效率：光固化效率％＝(Wp/Wo)×100。结果见附图3B。结果表明，水凝胶的凝胶时间小于2秒，完全光固化时间小于5秒。Use the weighing method to detect the photocuring efficiency of hydrogel: freeze-dry the hydrogel that has been exposed to different illumination times and weigh the mass Wp. The initial component mass Wo can be calculated based on the component content in the hydrogel. The ratio between the two is the photocuring efficiency of the hydrogel: photocuring efficiency % = (Wp/Wo) × 100. The results are shown in Figure 3B. The results showed that the gelation time of the hydrogel was less than 2 seconds and the complete light-curing time was less than 5 seconds.
3.水凝胶的溶胀行为3. Swelling behavior of hydrogels
将水凝胶浸泡在PBS缓冲液中，保持37℃。在1、3、5天进行湿重的测量(Ws)，并与初始的水凝胶(Wi)进行对比，计算溶胀率，评价其溶胀形变能力：溶胀率％＝((Ws-Wi)/Wi)×100。 利用相同分子量的聚乙二醇二丙烯酸酯替代PF127-bis-AA，其他组份相同，制备对照组聚乙二醇水凝胶。结果见附图4。结果表明，水凝胶在5天内表现出优秀的抗溶胀行为。Soak the hydrogel in PBS buffer and keep at 37°C. Wet weight (Ws) was measured on days 1, 3, and 5, and compared with the initial hydrogel (Wi), the swelling rate was calculated, and its swelling deformation ability was evaluated: Swelling rate % = ((Ws-Wi)/ Wi)×100. Polyethylene glycol diacrylate of the same molecular weight was used to replace PF127-bis-AA, and other components were the same to prepare a control polyethylene glycol hydrogel. The results are shown in Figure 4. The results showed that the hydrogel exhibited excellent anti-swelling behavior within 5 days.
4.水凝胶的组织粘附性4. Tissue adhesion of hydrogels
利用压力***实验测试水凝胶的组织粘附性，实验装置见附图5。首先，在圆形猪皮表面制造一个直径为2mm的孔状伤口，然后在伤口表面滴加水凝胶前体溶液，紫外照射5秒固化，最后推动注射观察水凝胶破裂时气压计的读数，即水凝胶的粘附强度，结果见附图5。结果表明，水凝胶的***强度可以达到200mm Hg，远强于人体血压的120mm Hg，适用于紧急出血的快速止血，并且水环境中强度不下降，保持稳定。利用相同分子量的聚乙二醇二丙烯酸酯替代PF127-bis-AA，其他组份相同，制备对照组聚乙二醇水凝胶。相比之下，聚乙二醇水凝胶的粘附强度在水环境中明显下降。The pressure burst experiment was used to test the tissue adhesion of the hydrogel. The experimental device is shown in Figure 5. First, a hole-shaped wound with a diameter of 2 mm is made on the surface of round pig skin, then the hydrogel precursor solution is dripped on the wound surface, and it is cured by UV irradiation for 5 seconds. Finally, the injection is pushed to observe the barometer reading when the hydrogel ruptures. That is, the adhesion strength of the hydrogel. The results are shown in Figure 5. The results show that the burst strength of the hydrogel can reach 200mm Hg, which is much stronger than human blood pressure of 120mm Hg. It is suitable for rapid hemostasis of emergency bleeding, and the strength does not decrease and remains stable in a water environment. Polyethylene glycol diacrylate of the same molecular weight was used to replace PF127-bis-AA, and other components were the same to prepare a control polyethylene glycol hydrogel. In contrast, the adhesive strength of polyethylene glycol hydrogels significantly decreased in aqueous environments.
5.水凝胶的快速止血效果5. Rapid hemostatic effect of hydrogel
以大鼠和兔子为模型动物，用注射器针头在心脏部位制造穿刺伤害，模拟紧急出血。利用水凝胶粘合剂进行止血，效果见附图6。结果表明，只需将可注射水凝胶粘合剂注射到出血部位并进行紫外照射，就可以有效止血，具备针对急性出血快速止血的功能。Using rats and rabbits as model animals, a syringe needle was used to create puncture injuries in the heart to simulate emergency bleeding. Use hydrogel adhesive to stop bleeding. The effect is shown in Figure 6. The results show that by simply injecting the injectable hydrogel adhesive into the bleeding site and irradiating it with ultraviolet light, it can effectively stop bleeding and has the function of quickly stopping acute bleeding.
6.水凝胶在神经外科手术中的应用6. Application of hydrogels in neurosurgery
以兔子为模型动物，进行脊柱手术制造硬脊膜损伤模型。利用水凝胶粘合剂封闭硬脊膜损伤避免脑脊液漏，效果见附图7。结果表明，只需将可注射水凝胶粘合剂注射到硬脊膜损伤部位并进行紫外照射，就可以有效封闭硬脊膜伤口，使用于神经外科手术中的紧急伤口处理。Using rabbits as model animals, spinal surgery was performed to create a dural injury model. Use hydrogel adhesive to seal the dural injury to avoid cerebrospinal fluid leakage. The effect is shown in Figure 7. The results show that by simply injecting the injectable hydrogel adhesive into the dural injury site and subjecting it to ultraviolet irradiation, the dural wound can be effectively sealed and used for emergency wound treatment in neurosurgery.
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。Obviously, the above-mentioned embodiments are only examples for clear explanation and are not intended to limit the implementation. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. An exhaustive list of all implementations is neither necessary nor possible. The obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims (19)

  1. 一种末端生物降解泊洛沙姆，其特征在于，所述末端生物降解泊洛沙姆通过将末端修饰结构引入到泊洛沙姆的两个末端得到；A terminal biodegradable poloxamer, characterized in that the terminal biodegradable poloxamer is obtained by introducing terminal modification structures to both ends of the poloxamer;
    所述末端修饰结构的分子量小于300，末端修饰结构中含有可生物降解的酯键或酰胺键，且末端修饰结构的最末端为碳碳双键；The molecular weight of the terminal modification structure is less than 300, the terminal modification structure contains biodegradable ester bonds or amide bonds, and the end of the terminal modification structure is a carbon-carbon double bond;
    所述末端生物降解泊洛沙姆可通过光照引发交联反应。The terminal biodegradable poloxamer can initiate a cross-linking reaction by illumination.
  2. 根据权利要求1所述的末端生物降解泊洛沙姆，其特征在于，所述末端生物降解泊洛沙姆的化学结构式如下式I或式II所示；The terminal biodegradable poloxamer according to claim 1, characterized in that the chemical structural formula of the terminal biodegradable poloxamer is as shown in the following formula I or formula II;
    Figure PCTCN2022109659-appb-100001
    n≤10，
    Figure PCTCN2022109659-appb-100001
    n≤10,
    Figure PCTCN2022109659-appb-100002
    R为侧基。
    Figure PCTCN2022109659-appb-100002
    R is a side group.
  3. 根据权利要求1所述的末端生物降解泊洛沙姆，其特征在于，所述末端生物降解泊洛沙姆为泊洛沙姆二乙酰丙烯酸酯、泊洛沙姆二丙酰丙烯酸酯、泊洛沙姆二丁酰丙烯酸酯、泊洛沙姆二甘氨酸丙烯酸酯、泊洛沙姆二丙氨酸丙烯酸酯或泊洛沙姆二β-丙氨酸丙烯酸酯；The terminal biodegradable poloxamer according to claim 1, characterized in that the terminal biodegradable poloxamer is poloxamer diacetoacrylate, poloxamer dipropionyl acrylate, poloxamer poloxamer dibutyryl acrylate, poloxamer diglycine acrylate, poloxamer dialanine acrylate or poloxamer diβ-alanine acrylate;
    所述泊洛沙姆二乙酰丙烯酸酯的化学结构式如下式1所示；The chemical structural formula of the poloxamer diacetylacrylate is shown in the following formula 1;
    所述泊洛沙姆二丙酰丙烯酸酯的化学结构式如下式2所示；The chemical structural formula of the poloxamer dipropionyl acrylate is shown in the following formula 2;
    所述泊洛沙姆二丁酰丙烯酸酯的化学结构式如下式3所示；The chemical structural formula of the poloxamer dibutyryl acrylate is shown in the following formula 3;
    所述泊洛沙姆二甘氨酸丙烯酸酯的化学结构式如下式4所示；The chemical structural formula of the poloxamer diglycine acrylate is shown in Formula 4 below;
    所述泊洛沙姆二丙氨酸丙烯酸酯的化学结构式如下式5所示；The chemical structural formula of the poloxamer dialanine acrylate is shown in the following formula 5;
    所述泊洛沙姆二β-丙氨酸丙烯酸酯的化学结构式如下式6所示；The chemical structural formula of the poloxamer di-β-alanine acrylate is shown in the following formula 6;
    Figure PCTCN2022109659-appb-100003
    Figure PCTCN2022109659-appb-100003
  4. 根据权利要求1-3任一项所述的末端生物降解泊洛沙姆，其特征在于，所述泊洛沙姆为泊洛沙姆407、泊洛沙姆188、泊洛沙姆237或泊洛沙姆338。The terminal biodegradable poloxamer according to any one of claims 1 to 3, characterized in that the poloxamer is poloxamer 407, poloxamer 188, poloxamer 237 or poloxamer. Rosham338.
  5. 一种末端生物降解泊洛沙姆的合成方法，其特征在于，包括如下步骤：A method for synthesizing terminal biodegradable poloxamer, which is characterized in that it includes the following steps:
    将泊洛沙姆溶于二氯甲烷中，加入三乙胺和氯烷基酰氯进行反应，反应完成后，用***沉淀，离心收集后真空干燥得到泊洛沙姆二氯烷基酸酯；将泊洛沙姆二氯乙酸酯溶于DMF中，加入丙烯酸钠进行反应，反应完成后滴加到***沉淀，离心收集后真空干燥得到泊洛沙姆二烷基酰丙烯酸酯；Dissolve poloxamer in dichloromethane, add triethylamine and chloroalkyl acid chloride to react, after the reaction is completed, precipitate with ether, collect by centrifugation and dry under vacuum to obtain poloxamer dichloroalkyl acid ester; Poloxamer dichloroacetate is dissolved in DMF, sodium acrylate is added to react, and after the reaction is completed, it is added dropwise to diethyl ether to precipitate, collected by centrifugation and dried under vacuum to obtain poloxamer dialkyl acrylate;
    所述氯烷基酰氯的化学结构式如下式a所示，n≤10；The chemical structural formula of the chloroalkyl acid chloride is as shown in the following formula a, n≤10;
    Figure PCTCN2022109659-appb-100004
    Figure PCTCN2022109659-appb-100004
    所述泊洛沙姆二氯烷基酸酯的化学结构式如下式b所示，n≤10；The chemical structural formula of the poloxamer dichloroalkylate is shown in the following formula b, n≤10;
    Figure PCTCN2022109659-appb-100005
    Figure PCTCN2022109659-appb-100005
    所述泊洛沙姆二烷基酰丙烯酸酯的化学结构式如下式c所示，n≤10；The chemical structural formula of the poloxamer dialkyl acrylate is shown in the following formula c, n≤10;
    Figure PCTCN2022109659-appb-100006
    Figure PCTCN2022109659-appb-100006
    或，将泊洛沙姆溶于甲苯中，加入对甲苯磺酸和氨基酸进行反应，反应完成后，用***沉淀，离心收集后真空干燥得到泊洛沙姆二氨基酸；将泊洛沙姆二甘氨酸溶于二氯甲烷中，加入三乙胺和丙烯酰氯进行反应，反应完成后滴加到***沉淀，离心收集后真空干燥得到泊洛沙姆二氨基酸丙烯酸酯；Or, dissolve poloxamer in toluene, add p-toluenesulfonic acid and amino acid to react, after the reaction is completed, precipitate with ether, collect by centrifugation and dry under vacuum to obtain poloxamer diamino acid; convert poloxamer diglycine Dissolve in dichloromethane, add triethylamine and acryloyl chloride to react, add dropwise to diethyl ether to precipitate after the reaction is completed, collect by centrifugation and dry under vacuum to obtain poloxamer diamino acid acrylate;
    所述氨基酸的化学结构式如下式d所示，R为侧基；The chemical structural formula of the amino acid is shown in the following formula d, R is a side group;
    Figure PCTCN2022109659-appb-100007
    Figure PCTCN2022109659-appb-100007
    所述泊洛沙姆二氨基酸的化学结构式如下式e所示，R为侧基；The chemical structural formula of the poloxamer diamino acid is shown in the following formula e, R is a side group;
    Figure PCTCN2022109659-appb-100008
    Figure PCTCN2022109659-appb-100008
    所述泊洛沙姆二氨基酸丙烯酸酯的化学结构式如下式f所示，R为侧基；The chemical structural formula of the poloxamer diamino acid acrylate is shown in the following formula f, R is a side group;
    Figure PCTCN2022109659-appb-100009
    Figure PCTCN2022109659-appb-100009
  6. 根据权利要求5所述的合成方法，其特征在于，所述泊洛沙姆在反应过程中，与氯烷基酰氯、氨基酸、丙烯酸钠和丙烯酰氯摩尔比为均为1:2。The synthesis method according to claim 5, characterized in that during the reaction process, the molar ratio of the poloxamer to chloroalkyl acid chloride, amino acid, sodium acrylate and acryloyl chloride is 1:2.
  7. 权利要求1-4任一项所述末端生物降解泊洛沙姆在制备可注射水凝胶粘合剂中的应用。Use of the terminal biodegradable poloxamer according to any one of claims 1 to 4 in the preparation of injectable hydrogel adhesives.
  8. 一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂，其特征在于，以质量百分数计，所述可注射水凝胶包含如下组分：An injectable hydrogel adhesive with both fast curing and swelling resistance, characterized in that, in terms of mass percentage, the injectable hydrogel contains the following components:
    Figure PCTCN2022109659-appb-100010
    Figure PCTCN2022109659-appb-100010
    所述粘附功能小分子具备与氨基反应能力并且可以通过光引发双键交联整合到水凝胶网络中；The small adhesion functional molecules have the ability to react with amino groups and can be integrated into the hydrogel network through light-induced double bond cross-linking;
    所述末端生物降解泊洛沙姆选自权利要求1-4任一项所述末端生物降解泊洛沙姆中的一种或几种。The terminal biodegradable poloxamer is selected from one or more of the terminal biodegradable poloxamer described in any one of claims 1 to 4.
  9. 根据权利要求8所述的可注射水凝胶粘合剂，其特征在于，所述末端生物降解泊洛沙姆选自泊洛沙姆407二乙酰丙烯酸酯、泊洛沙姆407二丙酰丙烯酸酯、泊洛沙姆407二丁酰丙烯酸酯、泊洛沙姆407二甘氨酸丙烯酸酯、泊洛沙姆407二丙氨酸丙烯酸酯和泊洛沙姆407二β-丙氨酸丙烯酸酯中的一种或几种。The injectable hydrogel adhesive according to claim 8, wherein the terminal biodegradable poloxamer is selected from the group consisting of poloxamer 407 diacetylacrylate and poloxamer 407 dipropionyl acrylate. One of esters, Poloxamer 407 dibutyryl acrylate, Poloxamer 407 diglycine acrylate, Poloxamer 407 dialanine acrylate, and Poloxamer 407 diβ-alanine acrylate. species or several species.
  10. 根据权利要求8所述的可注射水凝胶粘合剂，其特征在于，所述粘附功能小分子选自N-羟基琥珀酰亚胺丙烯酸酯、3-甲基丙烯酰多巴胺和4-乙烯基苯甲醛中的一种或多种。The injectable hydrogel adhesive according to claim 8, wherein the adhesion functional small molecule is selected from the group consisting of N-hydroxysuccinimide acrylate, 3-methacryloyl dopamine and 4-ethylene. One or more benzaldehydes.
  11. 根据权利要求8所述的可注射水凝胶粘合剂，其特征在于，所述光引发剂选自2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮、2-羟基-2-甲基-1-苯基-1-丙酮和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂中的一种或多种。The injectable hydrogel adhesive according to claim 8, wherein the photoinitiator is selected from the group consisting of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone, One or more of 2-hydroxy-2-methyl-1-phenyl-1-propanone and phenyl-2,4,6-trimethylbenzoyl lithium phosphite.
  12. 根据权利要求8所述的可注射水凝胶粘合剂，其特征在于，所述溶解液选自去离子水、生理盐水、PBS缓冲液或SPF模拟体液。The injectable hydrogel adhesive according to claim 8, wherein the dissolving solution is selected from deionized water, physiological saline, PBS buffer or SPF simulated body fluid.
  13. 根据权利要求7所述的可注射水凝胶粘合剂，其特征在于，可注射水凝胶的各组分在365-405nm光照下交联形成所述可注射水凝胶粘合剂。The injectable hydrogel adhesive according to claim 7, wherein each component of the injectable hydrogel is cross-linked under 365-405 nm light to form the injectable hydrogel adhesive.
  14. 根据权利要求8所述的可注射水凝胶粘合剂，其特征在于，所述可注射水凝胶还包含可光交联的天然多糖高分子衍生物，所述可光交联的天然多糖高分子衍生物的质量百分数含量为0.1％-10％。The injectable hydrogel adhesive according to claim 8, wherein the injectable hydrogel further comprises a photo-crosslinkable natural polysaccharide polymer derivative, and the photo-crosslinkable natural polysaccharide The mass percentage content of polymer derivatives is 0.1%-10%.
  15. 根据权利要求14所述的可注射水凝胶粘合剂，其特征在于，所述可光交联的天然多糖高分子衍生物选自双键改性明胶、双键改性透明质酸、双键改性壳聚糖、双键改性海藻酸钠、双键改性丝素蛋白、双键改性纤维素和双键改性葡聚糖中的一种或多种。The injectable hydrogel adhesive according to claim 14, wherein the photo-crosslinkable natural polysaccharide polymer derivative is selected from the group consisting of double bond modified gelatin, double bond modified hyaluronic acid, double bond modified hyaluronic acid, One or more of bond-modified chitosan, double bond-modified sodium alginate, double bond-modified silk fibroin, double bond-modified cellulose and double bond-modified dextran.
  16. 权利要求8所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂在人体或动物体意外创伤或手术伤口的封闭和/或快速止血中的应用。The application of the injectable hydrogel adhesive with both rapid curing and anti-swelling properties as claimed in claim 8 in sealing and/or rapidly hemostasis of accidental wounds or surgical wounds of human or animal bodies.
  17. 根据权利要求16所述的应用，其特征在于，所述手术伤口包括神经外科手术伤口。The use of claim 16, wherein the surgical wound comprises a neurosurgical wound.
  18. 权利要求8所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂的应用方法，其特征在于，将可注射水凝胶粘合剂各组分加入到溶解液中充分溶解，注射到使用部位，光源照射后引发光交联反应，使所述可注射水凝胶发生固化。The application method of the injectable hydrogel adhesive with both rapid curing and swelling resistance according to claim 8, characterized in that each component of the injectable hydrogel adhesive is added to the dissolving solution to fully dissolve, After being injected into the site of use, the light source triggers a photo-crosslinking reaction, causing the injectable hydrogel to solidify.
  19. 根据权利要求18所述的应用方法，其特征在于，所述光源波长范围是365-405nm。The application method according to claim 18, characterized in that the wavelength range of the light source is 365-405nm.
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