CN117860952A - Adhesive material and application thereof - Google Patents
Adhesive material and application thereof Download PDFInfo
- Publication number
- CN117860952A CN117860952A CN202410274986.5A CN202410274986A CN117860952A CN 117860952 A CN117860952 A CN 117860952A CN 202410274986 A CN202410274986 A CN 202410274986A CN 117860952 A CN117860952 A CN 117860952A
- Authority
- CN
- China
- Prior art keywords
- polyethylene glycol
- adhesive material
- arm polyethylene
- acrylic acid
- glycol acrylate
- Prior art date
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- Granted
Links
- 239000000463 material Substances 0.000 title claims abstract description 68
- 230000001070 adhesive effect Effects 0.000 title claims abstract description 24
- 239000000853 adhesive Substances 0.000 title claims abstract description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 72
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 71
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims abstract description 42
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 19
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims abstract description 18
- YXMISKNUHHOXFT-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) prop-2-enoate Chemical compound C=CC(=O)ON1C(=O)CCC1=O YXMISKNUHHOXFT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 238000009472 formulation Methods 0.000 claims abstract description 3
- -1 acrylic ester Chemical class 0.000 claims description 7
- 239000012620 biological material Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000011521 glass Substances 0.000 claims description 5
- 239000005060 rubber Substances 0.000 claims description 5
- 239000012956 1-hydroxycyclohexylphenyl-ketone Substances 0.000 claims description 4
- MQDJYUACMFCOFT-UHFFFAOYSA-N bis[2-(1-hydroxycyclohexyl)phenyl]methanone Chemical compound C=1C=CC=C(C(=O)C=2C(=CC=CC=2)C2(O)CCCCC2)C=1C1(O)CCCCC1 MQDJYUACMFCOFT-UHFFFAOYSA-N 0.000 claims description 4
- KHDZXBKJADQNKK-UHFFFAOYSA-N P(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C Chemical compound P(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C KHDZXBKJADQNKK-UHFFFAOYSA-N 0.000 claims description 3
- GUCYFKSBFREPBC-UHFFFAOYSA-N [phenyl-(2,4,6-trimethylbenzoyl)phosphoryl]-(2,4,6-trimethylphenyl)methanone Chemical compound CC1=CC(C)=CC(C)=C1C(=O)P(=O)(C=1C=CC=CC=1)C(=O)C1=C(C)C=C(C)C=C1C GUCYFKSBFREPBC-UHFFFAOYSA-N 0.000 claims description 3
- KWVGIHKZDCUPEU-UHFFFAOYSA-N 2,2-dimethoxy-2-phenylacetophenone Chemical compound C=1C=CC=CC=1C(OC)(OC)C(=O)C1=CC=CC=C1 KWVGIHKZDCUPEU-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 206010052428 Wound Diseases 0.000 abstract description 7
- 208000027418 Wounds and injury Diseases 0.000 abstract description 7
- 239000003364 biologic glue Substances 0.000 abstract description 6
- 239000003106 tissue adhesive Substances 0.000 abstract description 4
- 230000002579 anti-swelling effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000003894 surgical glue Substances 0.000 abstract description 2
- 239000000227 bioadhesive Substances 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 9
- 239000000017 hydrogel Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 230000008961 swelling Effects 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical compound CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000012045 crude solution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000031737 Tissue Adhesions Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000009864 tensile test Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- QNODIIQQMGDSEF-UHFFFAOYSA-N (1-hydroxycyclohexyl)-phenylmethanone Chemical compound C=1C=CC=CC=1C(=O)C1(O)CCCCC1 QNODIIQQMGDSEF-UHFFFAOYSA-N 0.000 description 1
- 238000010146 3D printing Methods 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- TZNDMQPVWYWNFW-UHFFFAOYSA-N diphenyl (2,4,6-trimethylphenyl) phosphate Chemical compound CC1=CC(C)=CC(C)=C1OP(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 TZNDMQPVWYWNFW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J171/00—Adhesives based on polyethers obtained by reactions forming an ether link in the main chain; Adhesives based on derivatives of such polymers
- C09J171/02—Polyalkylene oxides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention belongs to the field of material medicine, and particularly relates to an adhesive material and application thereof. The specific technical scheme comprises the following steps: an adhesive material, the adhesive material formulation comprising: four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester, acrylic acid and a photoinitiator. The biological adhesive material is a high molecular material with excellent adhesiveness, biodegradability and biocompatibility, has higher toughness, strong wet tissue adhesiveness and good anti-swelling property, has the advantages of high efficiency, safety, convenience, mildness and the like, is an ideal tissue adhesive material, can be used as a surgical sealant, plays roles in adhering, fixing and closing wounds, and has great application prospects in the fields of cell engineering, tissue engineering, biomedical materials and the like.
Description
Technical Field
The invention belongs to the field of material medicine, and particularly relates to an adhesive material and application thereof.
Background
Suturing and stapling are currently commonly employed to effect wound closure. However, this type of method causes stress concentration at the wound site, tissue damage and leakage, and secondary damage may occur during subsequent removal. Therefore, there is a need in the biomedical field to develop an adhesive material that is efficient and does not damage tissues. However, the physiological environment is typically moist, which affects the adhesive properties of the adhesive material and may also cause swelling of the adhesive material.
Therefore, if a portable, ready-to-use tissue adhesive material could be developed that is highly biosafety, and that can maintain a strong interfacial adhesion in a wet environment, while having good anti-swelling properties, would have significant practical application value in modern clinics.
Disclosure of Invention
The invention aims to provide an adhesive material and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme: a four-arm polyethylene glycol acrylate having the structural formula:
，
n is a natural number of 1 to 50.
Correspondingly, the preparation method of the four-arm polyethylene glycol acrylate utilizes the acryloyl chloride modified polyethylene glycol to prepare the four-arm polyethylene glycol acrylate.
Preferably, the preparation method comprises the following steps: under the protection of inert gas, four-arm polyethylene glycol and acrylic chloride are used as raw materials, triethylamine is used as an acid binding agent, and DMF is used as a solvent to react under the ice bath condition; according to the mole ratio, four-arm polyethylene glycol: acryloyl chloride = 1: and 8-10, after the reaction is finished, removing impurities by suction filtration, crystallizing and suction-filtering to obtain a filter cake which is the four-arm polyethylene glycol acrylate.
Correspondingly, the preparation method of the four-arm polyethylene glycol acrylate utilizes acrylic acid modified polyethylene glycol to prepare the four-arm polyethylene glycol acrylate.
Preferably, the preparation method comprises the following steps: the four-arm polyethylene glycol and acrylic acid are used as raw materials, dicyclohexylcarbodiimide is used as a condensing agent and a dehydrating agent, 4-dimethylaminopyridine is used as a catalyst, and CH is used 2 Cl 2 As solvent, and reacting at room temperature; and after the reaction is finished, removing impurities, crystallizing and filtering to obtain a filter cake which is the four-arm polyethylene glycol acrylate.
Correspondingly, the adhesive material is prepared from the four-arm polyethylene glycol acrylate or the four-arm polyethylene glycol acrylate prepared by the preparation method.
Preferably, the adhesive material formulation comprises: the four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester, acrylic acid and photoinitiator.
Preferably, the content of the four-arm polyethylene glycol acrylate is 5-30% by mass percent; and/or; the content of the acrylic acid is 30-50%; and/or; the content of the acrylic acid N-hydroxysuccinimide ester is 1 to 10 percent; and/or; the content of the photoinitiator is 0.1-1%.
Preferably, the photoinitiator is any one of phenyl-2,4,6-trimethylbenzoyl lithium phosphite, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, phenyl bis (2, 4, 6-trimethylbenzoyl) phosphine oxide, 1-hydroxycyclohexyl phenyl ketone, 2-dimethoxy-phenylacetophenone, or a combination thereof.
Correspondingly, the four-arm polyethylene glycol acrylate or the four-arm polyethylene glycol acrylate prepared by the preparation method or the application of the bonding material in bonding biological materials, rubber, metal and glass can bond any materials in the biological materials, rubber, metal and glass after any combination, for example, the biological materials can bond with rubber/metal and the like, and the biological materials can bond with the biological materials and the like.
The invention has the following beneficial effects: the present invention provides a novel bioadhesive material. The biological adhesive material is a high molecular material with excellent adhesiveness, biodegradability and biocompatibility, has higher toughness, strong wet tissue adhesiveness and good anti-swelling property, has the advantages of high efficiency, safety, convenience, mildness and the like, is an ideal tissue adhesive material, can be used as a surgical sealant, plays roles in adhering, fixing and closing wounds, and has great application prospects in the fields of cell engineering, tissue engineering, biomedical materials and the like.
Drawings
FIG. 1 is a chemical structural formula and a nuclear magnetic resonance hydrogen spectrum of a four-arm polyethylene glycol acrylate;
FIG. 2 is a Fourier transform infrared spectrum of a four-arm polyethylene glycol acrylate;
FIG. 3 is a schematic representation of the cytotoxic effects of bioadhesive materials.
Detailed Description
The invention provides a four-arm polyethylene glycol acrylate which is prepared by modifying four-arm polyethylene glycol.
The chemical structural general formula of the four-arm polyethylene glycol is as follows:
，
n is a natural number of 1 to 50.
The preferable scheme is as follows: the number average molecular weight of the four-arm polyethylene glycol is 500-100000 Da, and a more preferable scheme is as follows: the number average molecular weight of the four-arm polyethylene glycol is 10000-50000 Da.
The preferable scheme is as follows: the molecular weight distribution coefficient of the four-arm polyethylene glycol is 1.0-2.0, and the more preferable scheme is as follows: the molecular weight distribution coefficient of the four-arm polyethylene glycol is 1.0-1.5.
The chemical structural general formula of the four-arm polyethylene glycol acrylate is as follows:
，
n is a natural number of 1 to 50.
The invention also provides a preparation method of the four-arm polyethylene glycol acrylate, which is prepared by modifying four-arm polyethylene glycol with acrylic acid or acrylic chloride. The method specifically comprises the following steps:
the method comprises the following steps: the four-arm polyethylene glycol acrylate is prepared by using the acrylic chloride modified polyethylene glycol. Under the protection of inert gas such as nitrogen, using four-arm polyethylene glycol and acryloyl chloride as raw materials, using triethylamine as an acid binding agent and using DMF (dimethylformamide) as a solvent, wherein the four-arm polyethylene glycol and the acryloyl chloride are prepared by the following steps of: the molar ratio of (8-10) is carried out under ice bath conditions. After the reaction is finished, removing impurities such as triethylamine hydrochloride and the like from the obtained crude product by suction filtration, and obtaining a filter cake by suction filtration by using methyl tertiary butyl ether with low Wen Xijing, wherein the filter cake is the required four-arm polyethylene glycol acrylate. The esterification rate is above 60% by the method.
The second method is as follows: the acrylic acid modified polyethylene glycol is used for preparing the four-arm polyethylene glycol acrylic ester. Using four-arm polyethylene glycol and acrylic acid as raw materials, DCC (dicyclohexylcarbodiimide) as condensing agent and dehydrating agent, DMAP (4-dimethylaminopyridine) as catalyst, CH 2 Cl 2 Is a solvent blend in which four-arm polyethylene glycol: acrylic acid: DCC: dmap=1: 8:0.96:1.6 (molar ratio), at room temperature. After the reaction is finished, removing impurities such as dicyclohexylurea and the like from the obtained crude product by suction filtration, and then reducing Wen Xijing by methyl tertiary butyl ether, and performing suction filtration to obtain a filter cake which is the required four-arm polyethylene glycol acrylate. The esterification rate is above 70% by the method.
The invention also provides application of the four-arm polyethylene glycol acrylate in preparation of a biological bonding material. The four-arm polyethylene glycol acrylate can keep good adhesion even in a wet complex physiological environment, and can be used for preparing biological adhesive materials.
The invention also provides a biological bonding material prepared by using the four-arm polyethylene glycol acrylate, and the formula of the biological bonding material comprises the following components: four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester, acrylic acid and a photoinitiator. Wherein, the content of the four-arm polyethylene glycol acrylic ester is 5 to 30 percent, preferably 5 to 10 percent according to the mass percent; the content of acrylic acid is 30-50%, preferably 35-45%; the content of the acrylic acid N-hydroxysuccinimide ester is 1 to 10 percent, preferably 2 to 5 percent; the content of the photoinitiator is 0.1 to 1%, preferably 0.1 to 0.3%.
The photoinitiator is any one or combination of phenyl-2,4,6-trimethylbenzoyl Lithium phosphite (Lap, lithonium phenyl-2,4, 6-trimethylphenyl phosphate), 2-Hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone (Irgacure 2959, I2959,2-Hydroxy-4' - (2-Hydroxy-phenyl) -2-methylpropionone), phenyl bis (2, 4, 6-trimethylbenzoyl) phosphine oxide (Irgacure 819, I819, diphenyl (2, 4, 6-trimethylphenyl) phosphate), 1-hydroxycyclohexyl phenyl ketone (Irgacure 184, I184,1-Hydroxycyclohexyl phenyl ketone), 2-Dimethoxy-phenyl (Irgacure 651, I, 2-dimethyl-2-methylacetophenone); preferred embodiments are Lap and/or I2959, more preferred embodiments are Lap.
The invention also provides a preparation method of the biological adhesive material, which comprises the following steps: dissolving four-arm polyethylene glycol acrylate, an acrylic acid N-hydroxysuccinimide ester monomer, an acrylic acid monomer and a photoinitiator into ultrapure water, and fully and uniformly mixing to obtain a uniform bonding solution. The bonding solution is a liquid bonding material and is suitable for scenes requiring the liquid bonding solution. The binding solution may be further irradiated to be cured to obtain a solid bio-binding material. The preferable scheme is as follows: the illumination intensity is: 1-10 mW/cm 2 The wavelength of light is 300 to 700nm, more preferably 350 to 450nm; the illumination time is preferably 5 to 60 minutes, more preferably 15 to 40 minutes.
The invention also provides a using method of the biological adhesive material, which comprises the following steps: when a liquid bonding solution is used, the bonding solution is placed (smeared) at a position to be bonded, and light curing is performed to complete bonding. When the solid adhesive material is used, the part to be adhered is cleaned up and fully exposed to the visual field, so that the visual operation is convenient. The biological binding material is sheared into proper size and shape, placed on a part to be bound, and pressed for a certain time (10-30 s) by applying a certain pressure (1-5 kPa) to the biological binding material, so that a pressed object is ensured to be dry and smooth, a metal appliance is avoided, and the pressing is stopped after the biological binding material is fully contacted and bound with the part to be bound.
The bioadhesive materials can still maintain good adhesive ability in a wet environment and are therefore particularly suitable for biological tissue adhesion, in addition to conventional object (adhesion of rubber, metal, glass, etc.) adhesion to each other, such as: adhesion of skin and mucosal wounds, wound hemostasis, soft tissue adhesion (adhesion of blood vessels, nerves, liver, spleen, kidneys, digestive tract cavity organs, bladder, ureters, uterus, bones, cartilage tissues, etc.); can also be used for preparing other medical instrument base materials such as tissue filling (face filling, breast filling, bone tissue filling and the like), vascular embolism, drug release carriers, medical patches, medical photosensitive 3D printing base materials and the like.
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated. The obtained data are all average values obtained after at least 3 repetitions, and each repetition is obtained as effective data.
Embodiment one: preparation of four-arm polyethylene glycol acrylate
1. Preparation of four-arm polyethylene glycol acrylate
The method comprises the following steps: the four-arm polyethylene glycol acrylate is prepared by using the acrylic chloride modified polyethylene glycol.
Four-arm polyethylene glycol (5 g,0.25 mmol), acryloyl chloride (0.18 g,2 mmol), triethylamine (0.5 mL), DMF (10 mL) were added to a three-necked flask under nitrogen protection and reacted for 24h. After the reaction is completed, removing triethylamine hydrochloride from the obtained crude product by suction filtration to obtain a crude solution; and (3) crystallizing at a low temperature by using methyl tertiary butyl ether with the volume of 10 times of that of the crude solution, and filtering to obtain a filter cake, namely the required four-arm polyethylene glycol acrylate which is white powder, wherein the esterification rate is 67.5%.
The second method is as follows: the acrylic acid modified polyethylene glycol is used for preparing the four-arm polyethylene glycol acrylic ester.
Four-arm polyethylene glycol (5 g,0.25 mmol), acrylic acid (0.14 g,2 mmol), DCC (0.05 g,0.24 mmol), DMAP (0.04 g,0.4 mmol), CH 2 Cl 2 (10 mL) was added to a three-necked flask, and the mixture was reacted at room temperature for 24 hours. After the reaction is completed, removing dicyclohexylurea from the obtained crude product by suction filtration to obtain a crude solution; using crude solventCrystallizing methyl tertiary butyl ether with 10 times of the volume of the solution at low temperature, and obtaining a filter cake by suction filtration, namely the four-arm polyethylene glycol acrylate, wherein the esterification rate is 75.8%.
And (3) measuring the Fourier transform infrared spectrum of the product by adopting a tabletting method, and measuring the nuclear magnetic resonance hydrogen spectrum of the product by adopting deuterated dimethyl sulfoxide as a deuteration reagent, thereby determining the molecular structure of the four-arm polyethylene glycol acrylate. The four-arm polyethylene glycol acrylate products prepared by the two methods are the same, and the four-arm polyethylene glycol acrylate is successfully obtained. The chemical structural formula and nuclear magnetic resonance hydrogen spectrogram of the four-arm polyethylene glycol acrylate are shown in figure 1. Peaks at 6.5 to 5.7ppm correspond to peaks of hydrogen on double bonds a, b and c in the polymer, and chemical shifts of hydrogen on carbon-carbon double bonds of four acrylates are identical, so only one group is labeled in FIG. 1. The Fourier transform infrared spectrum of the four-arm polyethylene glycol is shown in figure 2. In fig. 2, 4-arm-PEG refers to a four-arm polyethylene glycol, 4-arm-PEGDA refers to a four-arm polyethylene glycol acrylate, and peaks marked in fig. 2 represent peaks of stretching vibration corresponding to c=o bonds and c=c double bonds of an acrylic functional group.
Embodiment two: preparation of bioadhesive materials and effect display
1. Preparation of bioadhesive materials
The biological adhesive material is prepared by initiating free radical polymerization by light under the initiation of a photoinitiator by using four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester and an acrylic acid monomer. The preparation method comprises the following steps: dissolving four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester monomer, acrylic acid monomer and photoinitiator (LAP) into ultrapure water, fully and uniformly mixing to obtain a uniform precursor solution, then injecting the precursor solution into a mould, and carrying out light irradiation curing and drying to obtain the bioadhesive material. The amount values in table 1 are mass percent, and the time in light conditions is the shortest time from light irradiation to curing of the bioadhesive material.
Table 1 comparison of preparation parameters of various bioadhesive materials
2. Biosafety effect display
The biosafety of the bioadhesive material was evaluated using the cell compatibility index by co-culturing mouse fibroblasts (L929) with each of the bioadhesive materials prepared in step 1. Preparing 1mm discs (the diameter is based on just spreading a 96-well plate) from each biosolid adhesive material prepared in the step 1, placing the discs in the 96-well plate, inoculating L929 cells on the surface of the material according to 4000 cells/well density, and culturing the materials in a carbon dioxide incubator at 37 ℃ with an RPMI-1640 culture medium. The culture medium is replaced by an Almablue reagent at 1, 3 and 7 days after inoculation, and incubation is continued for 2-4 hours, and the fluorescence intensity is measured by taking 540nm as excitation wavelength and 600nm as emission wavelength. And a blank group is arranged at the same time, no biological binding material is added, and the rest conditions are identical. The results show that: all groups of hydrogels had better cell compatibility. The gel test data prepared in blank and group 1 are shown as an example, as shown in fig. 3. The left black bar in fig. 3 represents the blank, the right gray bar represents group 1, and the difference between the data of group 1 and the blank is not significant, which proves that the bioadhesive material has no biotoxicity.
3. Demonstration of tissue adhesive Strength Effect
The adhesive properties of the bioadhesive materials were evaluated using a lap-shear tensile test using moist tissue (pigskin impregnated with PBS). The length of the single pigskin is 6cm, the width is 2.5cm, and the overlapped part is 2.5cm multiplied by 1cm; before the pigskin was glued, the pigskin was soaked with PBS to simulate a wet physiological environment in vivo, with a stretching rate of 50mm/min. Meanwhile, a positive control group is arranged, and the existing polyethylene glycol diacrylate (CN 108623729A) is used for replacing the four-arm polyethylene glycol acrylate in the bioadhesive material to prepare the bioadhesive control material. Each group was repeated 3 times and the results averaged. The results are shown in Table 2.
Table 2 comparison of the adhesive properties of the various bioadhesive materials
4. Display of swelling Performance Effect
The swelling performance can influence the adhesiveness and mechanical properties of the gel patch, a certain swelling rate is favorable for absorbing exudates on the surface of a wound, a hydration layer of a wet interface is removed, so that a strong interaction is established between the gel patch and the adhesive interface, a good and durable adhesive effect is generated, but the swelling rate is too high, the mechanical properties of the gel patch after swelling can be obviously reduced, and the adhesiveness is reduced, and therefore, the swelling rate in a wet environment is one of important performance indexes of the bioadhesive material.
Weigh 0.1g of each bioadhesive material prepared in step 1 and record as the initial weight (W 0 ) Placing in 15mL of physiological saline, respectively, taking out the swollen hydrogel from the physiological saline for a fixed period of time, gently wiping off superfluous water on the surface, and recording the mass of the gel, which is denoted as W t The hydrogel was then replaced in normal saline. The Swelling Ratio (SR) of the hydrogel can be calculated by the formula: sr= (W t -W 0 )/W 0 X 100%. The gel patch of fixed mass was placed in physiological saline solution and the mass of gel was observed and recorded for a fixed period of time. The results are shown in Table 3.
TABLE 3 comparison of swelling Properties of the various bioadhesive materials
5. Display of mechanical property effects
Hydrogel bars 10cm long and 10cm wide were prepared using a 0.5mm thick glass mold. A "dumbbell" shaped cutter was used to produce a hydrogel spline having a gauge length of 12mm, a width of 2mm, and a thickness of 0.5 mm. And (3) carrying out mechanical stretching experiments on the hydrogel sample strips on an intelligent electronic tensile testing machine, wherein the stretching speed is 100mm/min, and testing the mechanical properties of the hydrogel sample strips. The results are shown in Table 4.
Table 4 tensile strength control table for adhesive materials
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications, variations, alterations, substitutions made by those skilled in the art to the technical solution of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the spirit of the design of the present invention.
Claims (4)
1. An adhesive material, the adhesive material formulation comprising: four-arm polyethylene glycol acrylate, acrylic acid N-hydroxysuccinimide ester, acrylic acid and a photoinitiator;
the structural formula of the four-arm polyethylene glycol acrylate is as follows:
，
n is a natural number of 1 to 50.
2. The bonding material according to claim 1, wherein: according to the mass percentage, the content of the four-arm polyethylene glycol acrylic ester is 5-30%; and/or; the content of the acrylic acid is 30-50%; and/or; the content of the acrylic acid N-hydroxysuccinimide ester is 1 to 10 percent; and/or; the content of the photoinitiator is 0.1-1%.
3. The bonding material according to claim 1, wherein: the photoinitiator is any one or combination of phenyl-2,4,6-trimethylbenzoyl lithium phosphite, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, phenyl bis (2, 4, 6-trimethylbenzoyl) phosphine oxide, 1-hydroxy cyclohexyl phenyl ketone and 2, 2-dimethoxy-phenyl acetophenone.
4. Use of the adhesive material according to any one of claims 1 to 3 for bonding biological materials, rubber, metals, glass.
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