CN109280129B - Injectable hydrogel polymer based on salt response under physiological conditions and preparation method thereof - Google Patents
Injectable hydrogel polymer based on salt response under physiological conditions and preparation method thereof Download PDFInfo
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- CN109280129B CN109280129B CN201811070100.6A CN201811070100A CN109280129B CN 109280129 B CN109280129 B CN 109280129B CN 201811070100 A CN201811070100 A CN 201811070100A CN 109280129 B CN109280129 B CN 109280129B
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- 229920000642 polymer Polymers 0.000 title claims abstract description 63
- 150000003839 salts Chemical class 0.000 title claims abstract description 33
- 239000000017 hydrogel Substances 0.000 title claims abstract description 24
- 230000004044 response Effects 0.000 title claims abstract description 22
- 230000004962 physiological condition Effects 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229920001577 copolymer Polymers 0.000 claims abstract description 14
- 239000011159 matrix material Substances 0.000 claims abstract description 14
- 229920002521 macromolecule Polymers 0.000 claims abstract description 10
- 230000004043 responsiveness Effects 0.000 claims abstract description 9
- 229920001661 Chitosan Polymers 0.000 claims description 25
- 239000000178 monomer Substances 0.000 claims description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- -1 N-alkyl acrylamide Chemical compound 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 229920000578 graft copolymer Polymers 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- 239000003999 initiator Substances 0.000 claims description 10
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 10
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 10
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 claims description 8
- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 claims description 8
- 229940047670 sodium acrylate Drugs 0.000 claims description 8
- AGBXYHCHUYARJY-UHFFFAOYSA-N 2-phenylethenesulfonic acid Chemical compound OS(=O)(=O)C=CC1=CC=CC=C1 AGBXYHCHUYARJY-UHFFFAOYSA-N 0.000 claims description 7
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 7
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052786 argon Inorganic materials 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 230000000977 initiatory effect Effects 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 238000007334 copolymerization reaction Methods 0.000 claims description 5
- 229920002488 Hemicellulose Polymers 0.000 claims description 4
- SCFQUKBBGYTJNC-UHFFFAOYSA-N heptyl prop-2-enoate Chemical compound CCCCCCCOC(=O)C=C SCFQUKBBGYTJNC-UHFFFAOYSA-N 0.000 claims description 4
- AWGZKFQMWZYCHF-UHFFFAOYSA-N n-octylprop-2-enamide Chemical compound CCCCCCCCNC(=O)C=C AWGZKFQMWZYCHF-UHFFFAOYSA-N 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- XKXSONBEEJNXFM-UHFFFAOYSA-N C(CCCCCCCCC)S(=O)(=O)O.C(C=C)(=O)N Chemical compound C(CCCCCCCCC)S(=O)(=O)O.C(C=C)(=O)N XKXSONBEEJNXFM-UHFFFAOYSA-N 0.000 claims description 3
- GIOFFWIPRYLRBQ-UHFFFAOYSA-N C(CCCCCCCCCCC)S(=O)(=O)O.C(C=C)(=O)N Chemical compound C(CCCCCCCCCCC)S(=O)(=O)O.C(C=C)(=O)N GIOFFWIPRYLRBQ-UHFFFAOYSA-N 0.000 claims description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- QIBPEYMJKPVNHE-UHFFFAOYSA-N butane-1-sulfonic acid;prop-2-enamide Chemical compound NC(=O)C=C.CCCCS(O)(=O)=O QIBPEYMJKPVNHE-UHFFFAOYSA-N 0.000 claims description 3
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 235000010980 cellulose Nutrition 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- BOYUIPMXHJCTPO-UHFFFAOYSA-N hexane-1-sulfonic acid;prop-2-enamide Chemical compound NC(=O)C=C.CCCCCCS(O)(=O)=O BOYUIPMXHJCTPO-UHFFFAOYSA-N 0.000 claims description 3
- XFHJDMUEHUHAJW-UHFFFAOYSA-N n-tert-butylprop-2-enamide Chemical compound CC(C)(C)NC(=O)C=C XFHJDMUEHUHAJW-UHFFFAOYSA-N 0.000 claims description 3
- MDYPDLBFDATSCF-UHFFFAOYSA-N nonyl prop-2-enoate Chemical compound CCCCCCCCCOC(=O)C=C MDYPDLBFDATSCF-UHFFFAOYSA-N 0.000 claims description 3
- AZDADDWDOCKMHR-UHFFFAOYSA-N octane-1-sulfonic acid;prop-2-enamide Chemical compound NC(=O)C=C.CCCCCCCCS(O)(=O)=O AZDADDWDOCKMHR-UHFFFAOYSA-N 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 230000006698 induction Effects 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 239000000499 gel Substances 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 9
- 230000009471 action Effects 0.000 abstract description 6
- 230000002209 hydrophobic effect Effects 0.000 abstract description 6
- 238000004132 cross linking Methods 0.000 abstract description 5
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- 238000001815 biotherapy Methods 0.000 abstract description 4
- 238000001879 gelation Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 2
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- 239000000243 solution Substances 0.000 description 23
- 239000008279 sol Substances 0.000 description 7
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 229910001415 sodium ion Inorganic materials 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 125000003010 ionic group Chemical group 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960002901 sodium glycerophosphate Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- MNCGMVDMOKPCSQ-UHFFFAOYSA-M sodium;2-phenylethenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C=CC1=CC=CC=C1 MNCGMVDMOKPCSQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F261/00—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00
- C08F261/02—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols
- C08F261/04—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols on to polymers of vinyl alcohol
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
- Graft Or Block Polymers (AREA)
- Medicinal Preparation (AREA)
Abstract
A polymer for injectable hydrogel based on salt response under physiological conditions and a preparation method thereof are provided, wherein the polymer is prepared by grafting a functional chain segment with salt response on a matrix material with biocompatibility. The matrix material provides good water solubility and biocompatibility for the polymer, the salt response functional unit can enable the polymer to generate hydrophobic association effect under the action of electrolyte due to electrostatic shielding, and physical cross-linking points are constructed among macromolecules, so that the polymer is subjected to sol-gel conversion to form hydrogel. By reasonably designing the molecular structure of the polymer, the copolymer is sol in pure water at room temperature, has injectability, and can generate gelation transformation under the action of electrolyte after entering a living body to form hydrogel. The polymer for injectable hydrogel based on salt responsiveness under physiological conditions is used in the field of biological therapy.
Description
Technical Field
The invention relates to the technical field of polymers, in particular to an injectable gel polymer with salt response under physiological conditions and a preparation method thereof.
Background
Tissue engineering has been widely used in the field of biological therapy for decades, and is particularly useful for the treatment of defect sites. However, its clinical use is very limited because conventional tissue regeneration methods, such as the formation of hydrogel scaffolds, are subject to wound trauma, infection, and failure of the scaffold due to improper adaptation to the defect site. Therefore, it is necessary to find a new gel material which has good biocompatibility, can be injected in a minimally invasive way, can repair deep tissue injuries and does not damage blood supply of a repair area.
At present, polysaccharides and polyvinyl alcohol are the major polymers with good biocompatibility. The polysaccharide is a natural polymer, widely exists in the bodies of animals and plants, so the source is wide, and the polysaccharide also has the characteristics of biodegradability, no toxicity of metabolites, complete absorption by organisms and the like; polyvinyl alcohol is also a synthetic polymer material that has been used in biological therapy and has proven to be very safe and biocompatible. However, these two types of polymer materials are generally difficult to form hydrogel, so many scholars propose to modify them, and introduce other components into the solution or directly modify the polymer to make the polymer solution have injectability and physiological responsiveness. At present, most researches are carried out on temperature-sensitive hydrogel, such as chitosan/beta-sodium glycerophosphate injectable gel, which is aqueous solution at room temperature, and when the temperature reaches about 37 ℃, the hydrophobic effect of chitosan is enhanced through proton transfer to form gel. However, the multi-component system has the problems of long phase transition time, easy diffusion and transfer of beta-sodium glycerophosphate micromolecules, uneven concentration, certain side effect when the content is higher, insufficient gel strength and the like, so that the application of the multi-component system is limited.
In view of the above problems, the present invention provides a salt response-based water-soluble polymer, which is prepared by introducing a salt response functional structural unit into a hydrophilic macromolecule with good biocompatibility, wherein such functional segments can enhance the hydrophobic association between polymers under the electrostatic shielding effect of an electrolyte, thereby causing the polymers to be gelled. By reasonably designing the molecular structure, the polymer can be sol in pure water, has injectability, and can form hydrogel under the action of sodium ions under physiological conditions. Secondly, the molecular structure of the gel can be adjusted according to actual needs to change the size of intermolecular action, and the properties such as gel strength, gelation speed and the like can be adjusted, thereby widening the application range of the gel. In addition, compared with a general temperature sensitive system, the system does not contain small molecules and diffusion transfer, so that the concentration is more uniform, the responsiveness is more sensitive, no side effect is caused, deep tissues can be repaired, and blood supply of a repair area is not damaged.
Disclosure of Invention
The present invention aims to overcome the disadvantages of the prior art and to provide a polymer for injectable hydrogels based on the salt response under physiological conditions.
An injectable hydrogel polymer based on salt response under physiological conditions is prepared by grafting functional macromolecules with salt response on a biocompatible matrix material.
Wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch and polyvinyl alcohol; the monomer with the salt-responsive functional chain segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate and acrylamide alkyl sulfonate; the polymer is sol in pure water, has injectability, and can be converted into hydrogel based on salt response under physiological conditions.
The polymer at least contains one ionic functional monomer unit and at least contains one functional monomer unit with an alkyl chain.
Preferably, the number of carbon atoms in the alkyl chain in the alkyl acrylate, the N-alkyl acrylamide and the acrylamide alkyl sulfonate is 3-12 independently.
Preferably, the functional monomer is selected from one or more of acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-tert-butyl acrylamide, N-octyl acrylamide, styrene sulfonate, acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate and acrylamide dodecyl sulfonate.
Preferably, the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch, polyvinyl alcohol.
The grafting rate of the polymer is 30-300%. The calculation mode of the grafting ratio is as follows: the mass of the graft copolymer obtained by purification is m1The mass of the base material before grafting is m2(ii) a The graft ratio G [ (% m) ]1-m2)/m2]×100％。
The invention also provides a preparation method of the polymer, which comprises the following steps:
the polymer is prepared by homogeneous grafting or heterogeneous grafting copolymerization.
The preparation method of the polymer is carried out as follows: preparing a mixed system with the concentration of 0.1 wt% -5 wt% by using deionized water or 1% acetic acid for macromolecules with biocompatibility, adding a certain proportion of functional monomers, introducing argon gas for 30min at room temperature, controlling the initiation temperature to be between 40 ℃ and 70 ℃, adding an initiator, reacting for 2 h-6 h, and separating, purifying and drying the obtained copolymer from a solution to obtain the graft copolymer.
The biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch and polyvinyl alcohol;
the monomer of the functional chain segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate and acrylamide alkyl sulfonate;
the polymer at least contains one ionic functional monomer unit and at least contains one functional monomer unit with an alkyl chain;
the grafting rate of the polymer is 30-300%. The calculation mode of the grafting ratio is as follows: the mass of the graft copolymer obtained by purification is m1The mass of the base material before grafting is m2(ii) a The graft ratio G [ (% m) ]1-m2)/m2]×100％；
The initiator is an initiator well known to those skilled in the art, and is not particularly limited;
the invention also provides the use of the polymer in the field of biological therapy.
The invention has the following beneficial effects:
the invention provides a polymer for injectable hydrogel based on salt response under physiological conditions and a preparation method thereof, wherein the polymer is prepared by grafting functional structural units with salt response on a biocompatible matrix material, and the polymer has the following beneficial effects: 1. the matrix polymer has good hydrophilicity and biocompatibility; 2. the responsiveness of the salt is based on the electrostatic shielding effect of electrolyte but not the ionic crosslinking effect under physiological conditions, when the ionic groups on the functional units are shielded by the electrostatic, the hydrophilicity of the polymer is reduced, so that the hydrophobic association effect is generated, physical crosslinking points are constructed among macromolecules, the polymer is subjected to sol-gel transformation to form hydrogel, and other crosslinking agent components are not required to be introduced; 3. by reasonably designing the molecular structure, the polymer can be sol in pure water, has injectability, and can form hydrogel under the action of sodium ions under physiological conditions. In addition, the gel strength, the gelation speed and other properties can be adjusted according to actual requirements, and the application range is wide. 4. Wide raw material source, mild synthesis condition and easy industrialization.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides an injectable hydrogel polymer based on salt response under physiological conditions, which is prepared by grafting functional macromolecules with salt response on a biocompatible matrix material.
Wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch and polyvinyl alcohol; the monomer with the salt-responsive functional chain segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate and acrylamide alkyl sulfonate; the polymer is sol in pure water, has injectability, and can be converted into hydrogel based on salt response under physiological conditions.
The polymer at least contains one ionic functional monomer unit and at least contains one functional monomer unit with an alkyl chain.
The number of carbon atoms of an alkyl chain in the alkyl acrylate, the N-alkyl acrylamide and the acrylamide alkyl sulfonate is 3-12, preferably 4-10, more preferably 6-9, and most preferably 8.
Preferably, the functional monomer is selected from one of acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-tert-butyl acrylamide, N-octyl acrylamide, styrene sulfonate, acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate and acrylamide dodecyl sulfonate.
Preferably, the biocompatible matrix material is selected from one of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch, and polyvinyl alcohol.
The graft ratio of the polymer is 30-300%, preferably 50-300%, more preferably 80-250%, and most preferably 100-200%. The calculation mode of the grafting ratio is as follows: the mass of the graft copolymer obtained by purification is m1The mass of the base material before grafting is m2(ii) a The graft ratio G [ (% m) ]1-m2)/m2]×100％。
The polymers can undergo a sol-gel transition under physiological conditions based on electrostatic shielding and hydrophobic association.
The polymer is prepared by grafting functional structural units with salt response on a biocompatible base material, so that the polymer has good hydrophilicity and biocompatibility; the responsiveness of the salt is based on the electrostatic shielding effect of electrolyte but not the ionic crosslinking effect, when the ionic groups on the functional units are shielded by the electrostatic, the hydrophilicity of the polymer is reduced, so that the hydrophobic association effect is generated, physical crosslinking points are constructed among macromolecules, the polymer is subjected to sol-gel conversion, and the hydrogel can be formed without introducing other crosslinking agents. By reasonably designing the molecular structure, the polymer can be sol in pure water, has injectability, and can form hydrogel under the action of sodium ions under physiological conditions. In addition, the gel strength, the gelation speed and other properties can be adjusted according to actual requirements, and the application range is wide. The raw materials for preparing the polymer have wide sources, the synthesis conditions are mild, and the industrialization is easy.
The invention also provides a preparation method of the polymer for injectable hydrogel based on salt response.
The polymer is prepared by homogeneous grafting or heterogeneous grafting copolymerization. The specific preparation method comprises the following steps: preparing a mixed system with the concentration of 0.1 wt% -5 wt% by using deionized water or 1% acetic acid for macromolecules with biocompatibility, adding a certain proportion of functional monomers, introducing argon gas for 30min at room temperature, controlling the initiation temperature to be between 40 ℃ and 70 ℃, adding an initiator, reacting for 2 h-6 h, and separating, purifying and drying the obtained copolymer from a solution to obtain the graft copolymer.
Wherein the raw materials and the proportion are the same as above, and are not described again. The initiator is not particularly limited as long as it is known to those skilled in the art. The graft ratio of the polymer is 30-300%, preferably 50-300%, more preferably 80-250%, and most preferably 100-200%.
The polymer for injectable hydrogel based on salt response and the preparation method thereof according to the present invention are further illustrated by the following examples.
The reagents used in the following examples are all commercially available.
Example 1
Homogeneous graft copolymerization: dissolving 2g of polyvinyl alcohol in 100g of deionized water to prepare a solution with the mass concentration of 2%, adding 2g of a functional monomer acrylamide octyl sodium sulfonate, introducing argon at room temperature for 30min, controlling the initiation temperature to be 40 ℃, adding an initiator ceric ammonium nitrate to ensure that the concentration is 0.2mol/L, reacting for 4h, separating, purifying and drying the obtained copolymer from the solution to obtain the copolymerGraft copolymer 3.6 g. Calculation of the grafting ratio: the mass of the graft copolymer obtained by purification is m1The mass of the base material before grafting is m2(ii) a The graft ratio G [ (% m) ]1-m2)/m2]× 100% the graft ratio of the copolymer was calculated to be 80% as described above.
Example 2
Heterogeneous graft copolymerization: dissolving 1g of chitosan in 100g of deionized water to prepare a mixed system with the mass concentration of 1%, adding 2g of acrylamide decyl sodium sulfonate as a functional monomer, introducing argon at room temperature for 30min, controlling the initiation temperature to be 40 ℃, adding an initiator ammonium ceric nitrate to make the concentration be 0.2mol/L, reacting for 2h, and separating, purifying and drying the obtained copolymer from the solution to obtain 1.35g of a graft copolymer. The graft ratio of the copolymer was calculated to be 35% in the same manner as in example 1.
Example 3
Dissolving 5g of chitosan oligosaccharide in 100g of deionized water to prepare a solution with the mass concentration of 5%, respectively adding 0.8g of functional monomer sodium acrylate and 2g of heptyl acrylate, introducing argon at room temperature for 30min, controlling the initiation temperature to be 65 ℃, adding an initiator ammonium ceric nitrate to enable the concentration to be 0.2mol/L, reacting for 6h, and separating, purifying and drying the obtained copolymer from the solution to obtain 6.7g of a graft copolymer. The graft ratio of the copolymer was calculated in the same manner as in example 1 and found to be 34%. 1.6g of the graft copolymer was dissolved in 10g of pure water to prepare a 16% solution, which was slowly added to 10g of a 1.8% sodium chloride solution, and after stirring for 3min, the solution was placed in a 37 ℃ water bath, and the solution gradually changed from sol to gel.
Example 4
Dissolving 1g of chitosan in 100g of 1% acetic acid solution to prepare a solution with the mass concentration of 1%, respectively adding 2g of functional monomers of sodium styrene sulfonate and 2g of N-octylacrylamide, introducing argon at room temperature for 30min, controlling the initiation temperature to be 50 ℃, adding an initiator of ammonium ceric nitrate to enable the concentration to be 0.2mol/L, reacting for 4h, and separating, purifying and drying the obtained copolymer from the solution to obtain 3.2g of a graft copolymer. The graft ratio of the copolymer was calculated as in example 1 to be 220%. 1g of the graft copolymer is dissolved in 10g of pure water to prepare a solution with the mass concentration of 10%, the solution is slowly added into 10g of a sodium chloride solution with the mass concentration of 1.8%, the solution is stirred for 5min and then put into a water bath with the temperature of 37 ℃, and the solution is rapidly changed from sol to gel.
Example 5
To illustrate the importance of molecular design, polymers with different grafting ratios were synthesized using different monomers, and the state of the copolymers under room temperature pure water and physiological conditions (0.9% NaCl solution, 37 ℃) is shown in Table 1 below:
TABLE 2
Claims (7)
1. An injectable hydrogel polymer based on salt response under physiological conditions, which is prepared by grafting functional macromolecules with salt response on a biocompatible matrix material; wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch and polyvinyl alcohol; the monomer with the salt-responsive functional chain segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate and acrylamide alkyl sulfonate; the polymer is sol in pure water, has injectability and can be converted into hydrogel under physiological conditions based on salt induction energy; the polymer at least contains one ionic monomer unit with a functional chain segment with salt responsiveness, and at least contains one monomer unit with an alkyl chain with a functional chain segment with salt responsiveness.
2. The polymer according to claim 1, wherein the number of carbon atoms in the alkyl chain of the alkyl acrylate, the N-alkylacrylamide, or the acrylamide alkylsulfonate is 3 to 12, independently of each other.
3. The polymer of claim 1, wherein the monomer having a functional segment with salt responsiveness is selected from one or more of acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-t-butylacrylamide, N-octylacrylamide, styrene sulfonate, acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate, and acrylamide dodecyl sulfonate.
4. The polymer of claim 1, wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch, polyvinyl alcohol.
5. The polymer of claim 1, wherein the polymer has a grafting yield of 30% to 300%.
6. The polymer of claim 1, wherein the polymer is prepared by a homogeneous graft or heterogeneous graft copolymerization process.
7. The polymer of claim 1, wherein the polymer is prepared by the following steps: preparing a mixed system with the concentration of 0.1 wt% -5 wt% by using deionized water or 1% acetic acid for macromolecules with biocompatibility, adding a certain proportion of monomers with functional chain segments with salt responsiveness, introducing argon gas for 30min at room temperature, controlling the initiation temperature to be between 40 ℃ and 70 ℃, adding an initiator, reacting for 2 h-6 h, and separating, purifying and drying the obtained copolymer from a solution to obtain the graft copolymer.
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| CN103819613A (en) * | 2014-02-17 | 2014-05-28 | 同济大学 | Preparation method of salt-responding grafted copolymer taking chitosan as main chain |
| CN108341973A (en) * | 2018-03-22 | 2018-07-31 | 吉林大学 | A kind of preparation method of high strength ionic response lubricating hydrogel |
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| CN103819613A (en) * | 2014-02-17 | 2014-05-28 | 同济大学 | Preparation method of salt-responding grafted copolymer taking chitosan as main chain |
| CN108341973A (en) * | 2018-03-22 | 2018-07-31 | 吉林大学 | A kind of preparation method of high strength ionic response lubricating hydrogel |
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