CN110669168B - Modifying agent, preparation method and use method thereof and medical material - Google Patents
Modifying agent, preparation method and use method thereof and medical material Download PDFInfo
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- CN110669168B CN110669168B CN201910052614.7A CN201910052614A CN110669168B CN 110669168 B CN110669168 B CN 110669168B CN 201910052614 A CN201910052614 A CN 201910052614A CN 110669168 B CN110669168 B CN 110669168B
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- 239000012567 medical material Substances 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003607 modifier Substances 0.000 claims abstract description 65
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 31
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 16
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 5
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical class NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 117
- 150000001875 compounds Chemical class 0.000 claims description 58
- 239000000463 material Substances 0.000 claims description 46
- 229960003638 dopamine Drugs 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000007259 addition reaction Methods 0.000 claims description 16
- 125000005156 substituted alkylene group Chemical group 0.000 claims description 16
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 150000003254 radicals Chemical class 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 8
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 230000002862 amidating effect Effects 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 4
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
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- 238000004108 freeze drying Methods 0.000 claims description 3
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- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims description 3
- ZQMHJBXHRFJKOT-UHFFFAOYSA-N methyl 2-[(1-methoxy-2-methyl-1-oxopropan-2-yl)diazenyl]-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC ZQMHJBXHRFJKOT-UHFFFAOYSA-N 0.000 claims description 3
- 238000002407 reforming Methods 0.000 claims description 3
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- VLCLHFYFMCKBRP-UHFFFAOYSA-N tricalcium;diborate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]B([O-])[O-].[O-]B([O-])[O-] VLCLHFYFMCKBRP-UHFFFAOYSA-N 0.000 claims description 3
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 claims description 3
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 3
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical group C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 claims 1
- -1 R4 is a direct bond Chemical group 0.000 abstract description 3
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- 238000002474 experimental method Methods 0.000 description 12
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- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 4
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- 230000003385 bacteriostatic effect Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 230000009286 beneficial effect Effects 0.000 description 2
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- PSBDWGZCVUAZQS-UHFFFAOYSA-N (dimethylsulfonio)acetate Chemical group C[S+](C)CC([O-])=O PSBDWGZCVUAZQS-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
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- 241000194019 Streptococcus mutans Species 0.000 description 1
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- CDMADVZSLOHIFP-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 CDMADVZSLOHIFP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C08F220/10—Esters
- C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
- C08F220/36—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate containing oxygen in addition to the carboxy oxygen, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
-
- 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
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
-
- 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
- C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F230/02—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a modifier, which comprisesThe structural unit is shown in a formula (I), wherein R1 is a direct bond or alkylene or substituted alkylene with 1-5 carbon atoms, R2 is a direct bond or alkyl or substituted alkyl with 1-5 carbon atoms, R3 is a direct bond or alkyl or substituted alkyl with 1-5 carbon atoms, R4 is a direct bond, alkylene or substituted alkylene with 1-5 carbon atoms or acyloxy with 1-5 carbon atoms, R5 is a zwitterionic group, and the molecular weight of the modifier is 10 KDa-180 KDa. The invention also discloses a preparation method and a use method of the modifier and a medical material.
Description
Technical Field
The invention relates to the field of functional materials, in particular to a modifier, a preparation method and a use method thereof, and a medical material.
Background
Biomedical materials are materials used to diagnose, treat, repair, or replace damaged tissues, organs, or to enhance the function of an organism. It is the foundation of research artificial organs and medical instruments, has become an important branch of modern material discipline, and especially with the vigorous development and major breakthrough of biotechnology, biomedical materials have become hot spots for research and development by various scientists in competition.
When a biological body is treated with a biomedical material, the biomedical material is required to have a special property, for example, lubricity, antibacterial property, or the like, because the biomedical material is brought into close contact with blood or tissue of the biological body. Therefore, it is necessary to modify the surface of the biomedical material. Conventional substrate surface modification methods include surface grafting and physical immobilization. The surface grafting method is characterized in that a polymer is connected with a group on the surface of a base material through a chemical bond, but the requirement on the base material is high, the surface of the base material needs to be activated and modified, the reaction conditions need to be strictly controlled, the process is complicated, and the preparation period is long. The physical fixing method is to fix the polymer on the surface of the base material by van der waals force, hydrogen bond action or charge action in a physical noncovalent bond way, is simpler and quicker than the surface grafting method, but needs to modify the polymer and the base material in advance by charge or active groups, so that the application range of the base material is limited, the binding force between the polymer and the base material is weak, the polymer is easy to fall off from the base material, and the long-term use is not facilitated.
Disclosure of Invention
Therefore, a modifier which is strong in binding force, high in stability and simple and rapid in modification process, a preparation method and a use method thereof and a medical material are needed to be provided.
A modifying agent comprising a structural unit represented by the general formula (I):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, R2 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R3 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R4 is a direct bond, an alkylene or substituted alkylene group having 1 to 5 carbon atoms or an acyloxy group having 1 to 5 carbon atoms, R5 is a zwitterionic group, the molecular weight of the modifier is 10KDa to 180KDa, preferably, x is an integer of 1 to 5, and y is an integer of 1 to 5.
In one embodiment, the zwitterionic group includes at least one of a phosphocholine group, a carboxylic acid betaine group, and a sulfonic acid betaine group; and/or, the substituted alkyl and substituted alkylene are alkyl or the hydrogen on the alkylene is substituted by halogen element.
In one embodiment, the modifying agent has a structural unit represented by the general formula (v):
a method of preparing a modifying agent comprising:
the dopamine derivative modified with active alkenyl and the zwitterionic compound with active alkenyl or the zwitterionic derivative modified with active alkenyl are subjected to free radical initiated carbon-carbon addition reaction under the action of an initiator, and preferably, the mass ratio of the dopamine derivative to the zwitterionic compound is 1 (1-5).
In one embodiment, the preparation of the dopamine derivative comprises:
providing dopamine and a first compound, wherein the first compound has an active alkenyl group and an acyl group, preferably, the first compound comprises a methacrylic acid derivative, preferably, the methacrylic acid derivative comprises at least one of methacrylic anhydride, methacrylic acid chloride and glycidyl methacrylate; and
amidating the amino group of said dopamine and said acyl group of said first compound to form-C (O) NH-, to form said dopamine derivative.
In one embodiment, the preparation of the dopamine derivative comprises:
providing dopamine, a first compound having an active alkenyl and acyl group, and a second compound capable of generating BO2 -Preferably, the first compound comprises a methacrylic acid derivative, preferably, the second compound comprises at least one of sodium borate, calcium borate and magnesium borate, preferably, the pH value of the acidic environment is less than or equal to 2;
the BO generated by the second compound in an alkaline environment2 -Reacting ions with the phenolic hydroxyl group of the dopamine to cause the phenolic hydroxyl group to be borated to form modified dopamine;
amidating the amino group of said modified dopamine and said acyl group of said first compound to form-c (o) NH-, to form a dopamine derivative precursor; and
reforming the borated phenolic hydroxyl group of the dopamine derivative precursor into the phenolic hydroxyl group under an acidic environment to obtain the dopamine derivative,
the modified dopamine is represented by the general formula (VI):
preferably, the preparation of the dopamine derivative further comprises:
a step of purifying the obtained dopamine derivative by organic solvent extraction and recrystallization.
In one embodiment, the dopamine derivative is represented by general formula (vii):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, and R2 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms.
In one embodiment, the zwitterionic compound includes at least one of 2-methacryloyloxyethyl phosphorylcholine, 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate, and 3- [ N, N-dimethyl- [2- (2-methylprop-2-enoyloxy) ethyl ] ammonium ] propane-1-sulfonic acid inner salt; and/or the presence of a gas in the gas,
the initiator comprises one or more of azobisisobutyronitrile, azobisisoheptonitrile and dimethyl azobisisobutyrate.
In one embodiment, the temperature of the free radical initiated carbon-carbon addition reaction is 50 ℃ to 70 ℃ for 20 hours to 30 hours, and preferably, the free radical initiated carbon-carbon addition reaction is carried out in an inert gas.
In one embodiment, the method further comprises the following steps: a step of dialyzing a product of the radical-initiated carbon-carbon addition reaction and lyophilizing the dialyzed product.
The use method of the modifier or the modifier obtained by the preparation method comprises the following steps:
applying a solution of the modifying agent to the surface of the substrate,
preferably, the solvent in the solution of the modifying agent is water or an aqueous solution, and the pH value of the water or the aqueous solution is 8-10;
preferably, the applying is soaking the substrate in a solution of the modifying agent.
A medical material comprising:
a substrate; and
the modifier or the modifier obtained by the preparation method is loaded on the surface of the substrate, and preferably, the substrate comprises one or more of metal, ceramic and inorganic carbon materials.
The modification agent is formed by copolymerizing dopamine derivatives and zwitterionic compounds, so that the modification agent has the properties of both dopamine and zwitterionic compounds. The zwitterion compound can generate cation and anion groups simultaneously, can combine with free water molecules to form a hydration layer, has a lubricating effect, can inhibit bacteria, proteins and the like from being adhered to the surface of the base material, and avoids the pollution of the base material. Meanwhile, the modifier is mild in property, has good cell compatibility and can be applied to organisms. The dopamine can be bonded on the surface of the base material by self-oxidation and self-polymerization, and the structure of the base material cannot be damaged. The dopamine derivative and the zwitterionic compound are copolymerized to form the modifier, the modifier is dispersed to form a solution during application, the solution is applied to the surface of the base material to be modified, modification can be achieved, and the modification process is simple, mild and fast. The method utilizes the property of dopamine group in the modifier to firmly combine the zwitterion group on the base material, improves the convenience of modifying the base material by the modifier compared with a grafting method which directly carries out chemical reaction on the surface of the base material, and simultaneously avoids damaging the property of the base material due to the chemical reaction and avoiding forming unnecessary impurities on the surface of the base material to influence the use of the base material. The modifier has better dispersibility in the solution within the molecular weight range, and is more favorable for modifying the base material.
Drawings
FIG. 1A is a photograph of a bacteriostasis experiment of a medical material according to an embodiment of the present invention, wherein the cultivation time is 15 hours;
FIG. 1B is a photograph of a comparative experiment showing bacteriostasis of a substrate without modifying agent, wherein the incubation time is 12 hours;
FIG. 2 is a graph of experimental data for lubricity of examples of the present invention and comparative examples;
FIG. 3A is a photograph of a comparative cytocompatibility experiment of the present invention, wherein the modifying agent concentration is 0;
FIG. 3B is a photograph of a cytocompatibility experiment according to an embodiment of the present invention, wherein the modifying agent concentration is 0.125 mg/mL;
FIG. 3C is a photograph of a cytocompatibility experiment according to another embodiment of the present invention, wherein the modifying agent concentration is 0.25 mg/mL;
FIG. 3D is a photograph of a cytocompatibility experiment according to another embodiment of the present invention, wherein the modifying agent concentration is 0.5 mg/mL;
FIG. 3E is a photograph of a cytocompatibility experiment according to another embodiment of the present invention, wherein the modifying agent concentration is 1 mg/mL;
FIG. 3F is a photograph of a cytocompatibility experiment according to another embodiment of the present invention, wherein the modifying agent concentration is 2 mg/mL.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the modifying agent, the preparation method thereof, the using method thereof and the medical material of the present invention are further described in detail by the following embodiments with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a modifier, which comprises a structural unit shown in a general formula (I):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, R2 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R3 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R4 is a direct bond, an alkylene or substituted alkylene group having 1 to 5 carbon atoms or an acyloxy group having 1 to 5 carbon atoms, R5 is a zwitterionic group, and the molecular weight of the modifier is 10KDa to 180 KDa. Preferably, the substituted alkyl and substituted alkylene are alkyl or the hydrogen on the alkylene is substituted by a halogen, more preferably by fluorine, chlorine, bromine or iodine.
The embodiment of the invention forms the modifier by copolymerizing the dopamine derivative and the zwitterionic compound, so that the modifier has the properties of both dopamine and the zwitterionic compound. The zwitterion compound can generate cation and anion groups simultaneously, can combine with free water molecules to form a hydration layer, has a lubricating effect, can inhibit bacteria, proteins and the like from being adhered to the surface of the base material, and avoids the pollution of the base material. Meanwhile, the modifier is mild in property, has good cell compatibility and can be applied to organisms. The dopaminergic in the modifier can be bonded to the surface of the base material by self-polymerization through self-oxidation, and the structure of the base material can not be damaged. In the embodiment of the invention, the dopamine derivative and the zwitterionic compound are copolymerized to form the modifier, and the zwitterionic group is firmly combined on the base material by utilizing the property of the dopamine group in the modifier, so that compared with a grafting method for directly carrying out chemical reaction on the surface of the base material, the simplicity of modifying the base material by the modifier is improved, and meanwhile, the situation that the property of the base material is damaged due to the chemical reaction and the influence of unnecessary impurities on the surface of the base material on the use of the base material are avoided. The modifier has small molecular weight and can be uniformly dispersed in a solution. The modifier has better dispersibility in the solution within the molecular weight range of 10KDa to 180KDa, and is more beneficial to modifying the base material.
The modifier can be represented by the general structure- [ A ]x-By]n-represents, wherein a is a first repeat unit and B is a second repeat unit, said first and second repeat units may have a variety of arrangements. The first repeating unit and the second repeating unit may be alternately connected or connected to themselves. A contains a dopamine derivative group and B contains a zwitterionic group. X can be an integer of 1-5, y can be an integer of 1-5, and in the range, the dispersivity of the dopamine derivative group and the zwitterionic group in the modifier is ensuredAnd (3) cloth.
The zwitterion group is a group with positive charges and negative charges on a molecular chain, and the anion and cation groups enable the zwitterion group to be combined with a large number of free water molecules to form a hydration layer. Due to the formation of the hydration layer, the modifier with the zwitterionic group has better lubricity, and meanwhile, the hydration layer can isolate the adhesion of bacteria and protein, so that the modifier has a bacteriostatic action. In one embodiment, the zwitterionic group can include, but is not limited to, at least one of a phosphocholine group, a carboxylic acid betaine group, and a sulfonic acid betaine group.
In one embodiment, the phosphorylcholine group may be represented by general formula (ii):
the carboxylic acid betaine group may be represented by general formula (iii):
r6 may be a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms. The substituted alkylene group may be one in which the hydrogen on the alkylene group is substituted with a halogen element, more preferably fluorine, chlorine, bromine or iodine.
The sulfobetaine group may be represented by general formula (iv):
r7 may be a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms. The substituted alkylene group may be one in which the hydrogen on the alkylene group is substituted with a halogen element, more preferably fluorine, chlorine, bromine or iodine
In one embodiment, R5 can be the phosphorylcholine group, and the modifying agent can have a structural unit represented by formula (v):
the embodiment of the invention also provides a preparation method of the modifier, which comprises the following steps:
the dopamine derivative modified with active alkenyl and the zwitterion compound with active alkenyl or the zwitterion derivative compound modified with active alkenyl are subjected to free radical initiated carbon-carbon addition reaction under the action of an initiator.
The modifying agent of the embodiment of the invention is formed by polymerizing the dopamine derivative modified with the active alkenyl and the zwitterionic compound through the free radical polymerization reaction of carbon-carbon double bonds. The zwitterionic compound may itself carry an active alkenyl group, or the alkenyl group may be modified by additional steps. The modifier has short synthetic path and mild conditions, does not damage the functional groups of dopamine and zwitterionic compounds, reduces the generation of byproducts, and is beneficial to improving the synthetic purity of the modifier.
In one embodiment, the preparation of the dopamine derivative may comprise:
providing dopamine and a first compound having an active alkenyl group and an acyl group; and
amidating the amino group of said dopamine and said acyl group of said first compound to form-C (O) NH-, to form said dopamine derivative.
In one embodiment, the temperature of the amidation reaction may be 20 to 30 ℃ and the time may be 20 to 30 hours. The amidation reaction is preferably carried out in an inert gas, such as nitrogen. The step of amidation reaction may include stirring, and the dopamine and the first compound are brought into sufficient contact by stirring.
The amidation reaction may be represented by chemical formula (1):
in one embodiment, the first compound may include a methacrylic acid derivative. Preferably, the methacrylic acid derivative may include at least one of methacrylic anhydride, methacryloyl chloride, and glycidyl methacrylate. The molar ratio of the dopamine to the first compound can be 1 (1-3).
Preferably, the preparation method may further include: prior to the amidation reaction, a step of modifying the dopamine such that the dopamine forms a modified dopamine, the modification serving primarily to protect phenolic hydroxyl groups in the dopamine from reacting in a further amidation reaction of dopamine with the first compound.
In one embodiment, the preparation of the dopamine derivative may comprise:
dopamine, a first compound having an active alkenyl group and an acyl group, and a second compound capable of generating BO under alkaline conditions are provided2 -Ions;
the BO generated by the second compound in an alkaline environment2 -Reacting ions with the phenolic hydroxyl group of the dopamine to cause the phenolic hydroxyl group to be borated to form modified dopamine;
amidating the amino group of said modified dopamine and said acyl group of said first compound to form-c (o) NH-, to form a dopamine derivative precursor; and
reforming said borated phenolic hydroxyl group of said dopamine derivative precursor to said phenolic hydroxyl group in an acidic environment to provide said dopamine derivative.
The modified dopamine has a structural unit shown as a general formula (VI):
the reaction of the phenolic hydroxyboration may be as shown in equation (2):
in one embodiment, the second compound may include a compound capable of ionizing to produce pyroborate ions or metaborate ions. The pyroborate ions are converted to metaborate ions under alkaline conditions. The second compound may include at least one of sodium borate, calcium borate, and magnesium borate. The molar ratio of the dopamine to the second compound can be 1 (1-2). The dopamine can be dopamine hydrochloride, and compared with direct use of dopamine, the dopamine hydrochloride is lower in cost. The step of phenolic hydroxyboration may include adding an alkaline agent to cause the dopamine hydrochloride to form dopamine. The alkaline agent may include sodium hydroxide. Preferably, the step of phenolic hydroxyl boration is performed in an inert gas, such as nitrogen, to avoid the dopamine from being oxidized and losing its effect in an alkaline environment.
Preferably, the acidic environment may be a pH ≦ 2 at which the borated phenolic hydroxyl groups in the dopamine derivative precursor reform into phenolic hydroxyl groups, thereby allowing the dopamine derivative precursor to form the dopamine derivative.
In one embodiment, the dopamine derivative can be represented by general formula (vii):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, and R2 is a direct bond or an alkyl or substituted alkyl group having 1 to 5 carbon atoms. Preferably, the hydrogen substituent group in the substituted alkylene group may be an alkyl group, and the hydrogen substituent group in the substituted alkyl group may be an alkyl group.
In one embodiment, the preparation of the dopamine derivative may further include a step of purifying the obtained dopamine derivative by organic solvent extraction and recrystallization.
The step of extracting may comprise: treating the product of the amidation reaction with a first organic solvent such that the dopamine derivative remains in the first organic solvent phase. The first organic solvent may include ethyl acetate.
Between the steps of extracting and recrystallizing, may further comprise: treating the first organic solvent phase containing the dopamine derivative with a desiccant, such that the aqueous phase of the first organic solvent phase is supported on the desiccant; and filtering to remove the desiccant. The drying agent may be at least one of anhydrous magnesium sulfate or anhydrous sodium sulfate.
In one embodiment, the step of recrystallizing may comprise: treating the dried first organic solvent phase with a second organic solvent to recrystallize the dopamine derivative. The second organic solvent may include at least one of n-hexane and petroleum ether.
In one embodiment, the temperature of the free radical initiated carbon-carbon addition reaction may be between 50 ℃ and 70 ℃. The carbon-carbon addition reaction is carried out at a lower temperature, so that the reaction process is easier to control, the excessive molecular weight is avoided, the dopamine derivative and the zwitterion compound are more uniformly added, and the values of x and y in the structural unit of the general formula (I) in the modifier are smaller. The time for the free radical initiated carbon-carbon addition reaction may be 20 hours to 30 hours. The free radical initiated carbon-carbon addition reaction is preferably carried out in an inert gas, such as nitrogen. The step of free radical initiated carbon-carbon addition reaction may include stirring, by which the first intermediate and the zwitterionic compound are brought into intimate contact.
The radical-initiated addition reaction of the carbon-carbon double bond may be represented by chemical formula (3):
wherein R3 is a direct bond, an alkyl group or a substituted alkyl group having 1 to 5 carbon atoms, R4 is a direct bond, an alkylene group or a substituted alkylene group having 1 to 5 carbon atoms, or an acyloxy group having 1 to 5 carbon atoms, and R5 is a zwitterionic group.
In one embodiment, the zwitterionic compound may include, but is not limited to, at least one of 2-Methacryloyloxyethyl Phosphorylcholine (MPC), 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate (CBMA), and 3- [ N, N-Dimethyl- [2- (2-methylprop-2-enoyloxy) ethyl ] ammonium ] propane-1-sulfonate inner salt (3- [ Dimethyl- [2- (2-methylprop-2-enoyloxy) ethyl ] ammonium ] propane-1-Sulfonate (SPE). The initiator may include, but is not limited to, azo-type initiators, which may include one or more of azobisisobutyronitrile (2,2-Azobisisobutyronitril, AIBN), azobisisoheptonitrile, and dimethyl azobisisobutyrate. The mass ratio of the dopamine derivative to the zwitterionic compound can be 1 (1-5).
In one embodiment, the method for preparing the modifying agent may further comprise: a step of dialyzing a product of the radical-initiated carbon-carbon addition reaction and lyophilizing the dialyzed product. And (3) dialyzing to permeate impurities with small molecular weight and retain the modifier. The dialysis may be performed using a dialysis bag, and the dialysis product is a product that is not permeable through the dialysis bag. The specification of the dialysis bag can be determined according to actual conditions, for example, the cut-off molecular weight of the dialysis bag is only required to be smaller than the molecular weight of the modifier, and for example, the cut-off molecular weight of the dialysis bag can be 0.5 KD-2 KD. The dialysis time may be 20 hours to 30 hours. The freeze-drying time can be 2-4 days.
The embodiment of the invention also provides a use method of the modifier or the modifier obtained by the preparation method, which comprises the following steps: applying a solution of the modifying agent to the surface of the substrate. Preferably, the solvent in the solution of the modifying agent may be water or an aqueous solution. More preferably, the pH value of the water or the aqueous solution is 8-10, and dopamine can more easily exert an adhesion effect in a weakly alkaline environment. Preferably, the applying is soaking the substrate in a solution of the modifying agent.
The embodiment of the invention also comprises a medical material which comprises a base material and the modifier or the modifier obtained by the preparation method, wherein the modifier is loaded on the surface of the base material. The medical material can be used as an implantable medical material, and the medical material loaded with the modifier has better lubricity, cell compatibility and antibacterial property in the process of implanting into organisms and after implantation.
The modifier has a catechol structure capable of complexing with most metal atoms and performing Michael addition on the surface of a non-metal material, so that the modifier is loaded on the substrate. Compared with the method for directly grafting on the base material, the technical scheme for modifying the base material by using the modifier provided by the embodiment of the invention is simpler and milder, the modifier can be dissolved in a solvent such as water, and then the base material to be modified is treated by using the solution of the modifier, so that the loading of the modifier on the base material can be completed, and no toxic substance is introduced in the modification process of the base material, so that the modified biological material has less influence on organisms, is not easily rejected by an immune system, and is more suitable for clinical medical application.
In one embodiment, the substrate can be any material that can be implanted into a living organism. Optionally, the substrate includes, but is not limited to, one or more of a metal, a ceramic, and an inorganic carbon material.
Example 1
(1) Adding 18g of sodium pyroborate and 8g of sodium bicarbonate into 200ml of deionized water, stirring and dissolving, filtering insoluble substances, introducing nitrogen into the aqueous solution to remove water-soluble oxygen, adding 10g of dopamine hydrochloride into the aqueous solution, stirring and dissolving, properly adding 0.2mol/L NaOH solution to adjust the pH value to be more than 8, and introducing nitrogen to treat for ten minutes.
(2) 9.4ml of methacrylic anhydride was added to 50ml of THF and stirred uniformly, followed by dropwise addition to the solution obtained in step (1), followed by maintaining a nitrogen atmosphere and stirring at room temperature overnight.
(3) Adjusting the pH of the solution obtained in the step (2) to be below 2 by using 0.2mol/L hydrochloric acid solution, and washing away oil-drop substances on the upper layer by using a small amount of ethyl acetate. The solution was extracted three times with 200ml of ethyl acetate, and the ethyl acetate phase (first organic solvent phase) was collected.
(4) And (4) drying the ethyl acetate phase obtained in the step (3) by using excessive anhydrous magnesium sulfate, and performing suction filtration to collect supernatant. Then 600ml of n-hexane was slowly added to the supernatant for recrystallization, and the solid was collected by filtration and dried in a vacuum oven.
(5) 0.2g of the product of step (4) was dissolved in 50ml of DMF, and 0.8g of MPC powder was added and stirred to dissolve it while introducing nitrogen. Then 3mg of AIBN initiator was added and the reaction was carried out at 60 ℃ for 24 hours.
(6) And (3) dialyzing the solution obtained in the step (5) for 24 hours by using a dialysis bag with the molecular weight cutoff of 1KD, and freeze-drying the solution for three days to obtain the modifier.
Dissolving the obtained modifier in Tris hydrochloric acid aqueous solution to obtain modifier solution, and soaking the titanium alloy substrate in each modifier solution for 24 hours to obtain the medical material.
Experimental example 1 bacteriostatic test
Collecting non-irritating saliva of healthy blood donor, centrifuging, collecting supernatant, and pasteurizing at 60 deg.C for 30 min. Sterile PBS was used at a 1: 1 is added into the sterilized saliva to obtain the nutrient solution. The medical material was soaked with the nutrient solution overnight at 37 ℃.
A bacteriostatic test was performed using Streptococcus mutans UA-159. The strain is firstly treated with CO at 37 DEG C2Culturing in incubator for 48 hr, inoculating single strain to BHI (brain heart leachate) culture solution, and culturing at 37 deg.C under CO2Incubated under conditions overnight. The nutrient solution-treated medical material was placed in 12-well plates, each well inoculated with 2mLBHI medium and 40. mu.L of Streptococcus mutans suspension in CO at 37 ℃2Culturing in an incubator. And (3) characterizing the morphology and the distribution of bacteria on the surface of the medical material by adopting a scanning electron microscope after culturing for 15 hours, and taking the substrate without modifying the modifier as a comparative example. The results are shown in FIGS. 1A-1B. The results show that substrates without modification of the modifier cannot be preventedThe adhesion of bacteria is improved obviously by modifying the substrate surface of the modifier.
Experimental example 2 lubrication experiment
The medical material lubrication experiment utilizes an Atomic Force Microscope (AFM) to measure the friction Coefficient (COF) of the surface of the medical material in an aqueous medium, and the comparative example is a titanium alloy substrate which is not modified by a modifier. During measurement, the lower sample is a medical material or a titanium alloy substrate, the intermediate medium is deionized water, the upper sample is a probe adhered with a polystyrene ball, and COF comparison conditions under the conditions that the lower pressure is 100, 200, 300 and 400nN and the probe moving frequency is 1, 2 and 3Hz are respectively tested. The results of the lubrication experiments are shown in FIG. 2. The result shows that the friction coefficient of the substrate surface modified by the modifier is 1-2 times lower than that of the substrate surface modified by the modifier under different loads and different frequencies, and the modification of the modifier enables the substrate to have good lubricating property.
Experimental example 3 cell compatibility test
The cell compatibility test was carried out by inoculating mouse fibroblast cell line L929 into 10% fetal bovine serum solutions of the modifier of example 1 (0, 0.125, 0.25, 0.5, 1, 2mg/mL, respectively) at different concentrations and CO at 37 deg.C2Culturing in an incubator. Cell viability was monitored at 2h intervals using a high definition automated imaging system. Results of cell compatibility experiments referring to FIGS. 3A-3F, the results show that polymer solutions at various concentrations are not significantly toxic to cells, and that treatment of solutions at different concentrations may affect cell proliferation rates.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (8)
1. A medical material, comprising:
the metal base material and the modifier are loaded on the surface of the metal base material, and the metal base material is selected from titanium alloy;
the modifier comprises a structural unit shown in a general formula (I):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, R2 is hydrogen or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R3 is hydrogen or an alkyl or substituted alkyl group having 1 to 5 carbon atoms, R4 is a direct bond, an alkylene or substituted alkylene group having 1 to 5 carbon atoms or an acyloxy group having 1 to 5 carbon atoms, R5 is a zwitterionic group, the zwitterionic group is selected from a choline phosphate group, the molecular weight of the modifier is 10KDa to 180KDa, x is an integer of 1 to 5, and y is an integer of 1 to 5;
the preparation method of the modifier comprises the following steps:
the method comprises the steps of carrying out free radical initiated carbon-carbon addition reaction on a dopamine derivative modified with an active alkenyl and a zwitterionic compound with the active alkenyl or a zwitterionic derivative compound modified with the active alkenyl under the action of an initiator, dialyzing a product of the free radical initiated carbon-carbon addition reaction, and freeze-drying the dialyzed product, wherein the mass ratio of the dopamine derivative to the zwitterionic compound is 1 (1-5).
2. The medical material of claim 1 wherein the substituted alkyl and substituted alkylene groups are alkyl groups or the hydrogen on the alkylene group is substituted with a halogen element.
3. The medical material of claim 1, wherein the modifying agent has a structural unit represented by general formula (v):
4. the medical material according to claim 1, wherein the preparation of the dopamine derivative comprises:
providing dopamine and a first compound, the first compound having an active alkenyl group and an acyl group, the first compound comprising a methacrylic acid derivative, the methacrylic acid derivative comprising at least one of methacrylic anhydride, methacryloyl chloride, and glycidyl methacrylate; and
amidating the amino group of said dopamine and said acyl group of said first compound to form-C (O) NH-, to form said dopamine derivative.
5. The medical material according to claim 1, wherein the preparation of the dopamine derivative comprises:
providing dopamine, a first compound having an active alkenyl and acyl group, and a second compound capable of generating BO2 -The first compound comprises a methacrylic acid derivative, the second compound comprises at least one of sodium borate, calcium borate and magnesium borate, and the pH value of the acidic environment is less than or equal to 2;
the BO generated by the second compound in an alkaline environment2 -Reacting ions with the phenolic hydroxyl group of the dopamine to cause the phenolic hydroxyl group to be borated to form modified dopamine;
amidating the amino group of said modified dopamine and said acyl group of said first compound to form-c (o) NH-, to form a dopamine derivative precursor; and
reforming the borated phenolic hydroxyl group of the dopamine derivative precursor into the phenolic hydroxyl group under an acidic environment to obtain the dopamine derivative,
the modified dopamine is represented by the general formula (VI):
the preparation of the dopamine derivative further comprises the following steps:
a step of purifying the obtained dopamine derivative by organic solvent extraction and recrystallization.
6. The medical material according to claim 1, wherein said dopamine derivative is represented by general formula (vii):
wherein R1 is a direct bond or an alkylene or substituted alkylene group having 1 to 5 carbon atoms, and R2 is hydrogen or an alkyl or substituted alkyl group having 1 to 5 carbon atoms.
7. The medical material according to claim 1, wherein the zwitterionic compound is selected from 2-methacryloyloxyethyl phosphorylcholine; and/or the initiator comprises one or more of azobisisobutyronitrile, azobisisoheptonitrile and dimethyl azobisisobutyrate.
8. The medical material according to claim 1, wherein the temperature of the radical initiated carbon-carbon addition reaction is 50 ℃ to 70 ℃ for 20 hours to 30 hours, and the radical initiated carbon-carbon addition reaction is carried out in an inert gas.
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