CN113980292A - Preparation method of novel biocompatible polyether sulfone-based hydrogel - Google Patents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/20—Polysulfones
- C08G75/23—Polyethersulfones
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2381/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing sulfur with or without nitrogen, oxygen, or carbon only; Polysulfones; Derivatives of such polymers
- C08J2381/06—Polysulfones; Polyethersulfones
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Abstract
本发明公开了一种新型生物相容性聚醚砜基水凝胶的制备方法，属于生物医用材料技术领域，该方法包括以下步骤：S1.低聚体的合成：将端羟基砜单体与端氟基砜单体溶于N，N’‑二甲基乙酰胺和甲苯的混合溶液，以无水碳酸钾为催化剂，排除空气，加热反应生成低聚体；S2.新型生物相容性聚醚砜基水凝胶的制备：将温度升高促进步骤S1所得低聚体交联结合形成水凝胶。本发明通过缩聚法制备新型生物相容性水凝胶，在水凝胶表面富集磺酸基、羧基和氨基等生物活性基团，利用生物活性基团提高水凝胶表面的血液相容性和细胞相容性。该水凝胶的制备方法简单易行，具备聚醚砜优异的物理性能和生物活性基团的生物相容性，适用于生物医学领域。
The invention discloses a preparation method of a novel biocompatible polyethersulfone-based hydrogel, which belongs to the technical field of biomedical materials. The method includes the following steps: S1. Synthesis of oligomers: combining a hydroxyl-terminated sulfone monomer with a The fluorine-terminated sulfone monomer is dissolved in a mixed solution of N,N'-dimethylacetamide and toluene, and anhydrous potassium carbonate is used as a catalyst to remove air and heat to react to generate oligomers; S2. Novel biocompatible polymer Preparation of ether sulfone-based hydrogel: increasing the temperature to promote the cross-linking of the oligomers obtained in step S1 to form a hydrogel. The invention prepares a novel biocompatible hydrogel by a polycondensation method, enriches bioactive groups such as sulfonic acid groups, carboxyl groups and amino groups on the surface of the hydrogel, and utilizes the bioactive groups to improve the blood compatibility of the hydrogel surface and cytocompatibility. The preparation method of the hydrogel is simple and feasible, has the excellent physical properties of polyethersulfone and the biocompatibility of bioactive groups, and is suitable for the field of biomedicine.
Description
Technical Field
The invention belongs to the technical field of biological high polymer materials, and particularly relates to a preparation method of a novel biocompatible polyether sulfone-based hydrogel.
Background
Polyether sulfone is a thermoplastic polymer material with excellent comprehensive performance developed by British ICI company in 1972, and is one of the few special engineering plastics. The polyethersulfone has excellent heat resistance, physical and mechanical properties, insulating property and the like, is usually processed into a film form, and is widely applied to the fields of blood contact and tissue engineering. However, the inherent hydrophobicity of polyethersulfone causes adsorption of plasma proteins, particularly fibrinogen associated with clotting functions, which results in platelet adhesion, aggregation, and subsequent initiation of clotting. Therefore, in order to improve the biocompatibility of the polyethersulfone material, researchers usually modify the polyethersulfone by blending, surface grafting or surface coating. However, these modification methods are not only inefficient and inadequate in stability, but may also result in a decrease in the physical properties of the polyethersulfone substrate. Therefore, the development of a polyethersulfone material with biocompatibility remains a bottleneck.
In recent decades, hydrogels have been widely used in biomedical applications as a three-dimensionally crosslinked hydrophilic polymer material. The three-dimensional structure of the hydrogel has more modification sites and thus exhibits better biocompatibility than a two-dimensional material. More and more natural or synthetic polymers are being made into hydrogels to modify biomaterials. Although polyethersulfone is widely used in clinical applications in the form of membrane materials, it has never been prepared in the form of a hydrogel. There are many methods currently available for preparing hydrogels, and the addition of a cross-linking agent is one of the most common methods. However, the residual crosslinking agent is often toxic and can be harmful to the body during use. Therefore, the selection of a hydrogel preparation method which does not require a cross-linking agent is of great significance for the synthesis of biomedical hydrogels.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a novel biocompatible polyether sulfone-based hydrogel. In the preparation process of the method, no cross-linking agent is used, and the prepared hydrogel not only has excellent blood compatibility and cell compatibility, but also can regulate and control the surface chemical structure of the hydrogel so as to meet different application requirements.
The invention is realized by the following technical scheme:
a preparation method of a novel biocompatible polyether sulfone-based hydrogel comprises the following steps:
s1, synthesis of an oligomer: dissolving a hydroxyl-terminated sulfone monomer and a fluorine-terminated sulfone monomer in a mixed solvent of N, N' -dimethylacetamide and toluene, removing air by using anhydrous potassium carbonate as a catalyst, and heating to react to generate an oligomer;
s2, preparing the novel biocompatible polyether sulfone-based hydrogel: the temperature is increased to promote the cross-linking combination of the oligomers obtained in step S1 to form a hydrogel.
The invention further improves the scheme as follows:
the hydroxyl-terminated sulfone monomer or/and the fluorine-terminated sulfone monomer have amino groups, and the fluorine-terminated sulfone monomer contains sulfonic acid groups.
Further, the hydroxyl-terminated sulfone monomer is bis (3-amino-4-hydroxyphenyl) sulfone or bis (4-hydroxyphenyl) sulfone or a mixture of the two, and the fluorine-terminated sulfone monomer is one or more of bis (4-fluorophenyl) sulfone, bis (3-sulfonic acid group-4-fluorophenyl) sulfone sodium salt or bis (3-amino-4-fluorophenyl) sulfone.
Further, the molar ratio of the hydroxyl-terminated sulfone monomer to the fluorine-terminated sulfone monomer is 1: 1-1: 2.
Furthermore, in the mixed solvent, the volume ratio of the N, N' -dimethylacetamide to the toluene is 5:1-5: 4.
Further, in step S1, before the reaction starts, the reaction is pumped by a water pump for 5-10 min, then nitrogen is injected for 1-5 min, and the cycle is repeated for 3 times to ensure that no impurity gas exists in the solution, and the circulation protection of nitrogen is constantly maintained.
Further, in step S1, a serpentine condenser is used, and a Dean-Stark trap is used to collect the water produced by the reaction, and a certain amount of potassium hydride is added to the bottom of the trap to convert the small molecular water into hydrogen gas and discharge the hydrogen gas together with the protected nitrogen gas.
Further, in the step S1, the reaction temperature is 140-155 ℃, and the reaction time is 3-6 h.
Further, in step S2, the reaction temperature is raised to 200-300 ℃ and the reaction time is 8-12 h.
Further, after the reaction in step S2 is completed, the hydrogel is cooled to 100 ℃, and a certain amount or an excessive amount of maleic anhydride is added to continue the reaction for 12 to 18 hours, so that part or all of the amino groups on the surface of the hydrogel are converted into carboxyl groups.
Further, after the reaction in step S2 is completed, the hydrogel is washed for more than 48 hours by using a MW3500 dialysis bag.
Has the advantages that:
1. the invention provides a preparation method of a novel biocompatible polyether sulfone-based hydrogel, which improves blood compatibility and cell compatibility by introducing sulfonic acid groups, carboxyl groups and amino groups. The prepared polyether sulfone-based hydrogel combines the excellent physical properties of polyether sulfone and the improvement of the biocompatibility of active groups, and has great application potential in the field of biomedicine. In addition, the introduction of amino provides possibility for secondary modification of the polyether sulfone-based hydrogel, so that the surface chemical structure of the hydrogel can be adjusted according to different application requirements.
2. The polyether sulfone-based hydrogel is prepared by a polycondensation method, and a cross-linking agent is not used in the preparation process, so that the influence of the residual cross-linking agent on the biocompatibility of the material is avoided. According to the method, water-soluble anhydrous potassium carbonate is used as a catalyst, and after the reaction is finished, the residual anhydrous potassium carbonate can be removed through dialysis. Even with a small amount of residue, anhydrous potassium carbonate as a food additive has almost negligible toxic effects compared to conventional cross-linking agents.
3. The preparation method is simple and suitable for large-scale industrialization.
Drawings
FIG. 1 is a fluorescence image of platelet adhesion in comparative examples and examples 1 to 3 of the present invention;
FIG. 2 shows the cell activity of human vascular endothelial cells measured by MTT method at different times in comparative examples and examples 1 to 3 of the present invention.
Detailed Description
The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The invention discloses a novel biocompatible polyether sulfone-based hydrogel, which comprises the following steps:
(1) and (3) synthesis of oligomers: dissolving a hydroxyl-terminated sulfone monomer and a fluorine-terminated sulfone monomer in a mixed solution of N, N' -dimethylacetamide and toluene in a certain ratio, and taking anhydrous potassium carbonate as a catalyst, wherein the hydroxyl-terminated sulfone monomer or/and the fluorine-terminated sulfone monomer has an amino group or a sulfonic group, and the molar ratio of the hydroxyl-terminated sulfone monomer to the fluorine-terminated sulfone monomer is 1: 1-1: 2. Before the reaction begins, a water pump is used for vacuumizing for 5-10 min, then nitrogen is injected for 1-5 min, and the circulation is repeated for 3 times to ensure that no impurity gas exists in the solution. The reaction temperature ranges from 140 ℃ to 155 ℃, the reaction time is 3-6 h, and the oligomer is prepared.
(2) Preparing novel biocompatible polyether sulfone-based hydrogel with different surface chemical structures: and (3) raising the temperature to more than 200 ℃, and reacting for 8-12 h to enable the oligomers to be combined in a crosslinking manner to form the hydrogel. And after the reaction is finished, cooling to 100 ℃, adding a certain amount or excessive maleic anhydride, and continuing to react for 12-18 h to convert part or all of amino groups on the surface of the hydrogel into carboxyl groups. After the reaction is finished, the hydrogel is cleaned for more than 48 hours by using a MW3500 dialysis bag.
The invention uses a polycondensation method to prepare the polyether sulfone-based hydrogel, selects monomers with different groups, and can regulate and control the chemical structure of the surface of the polyether sulfone-based hydrogel. The catalyst anhydrous potassium carbonate is a common food additive, has low toxicity, is soluble in water and is easy to wash away. The polyether sulfone-based hydrogel prepared by the polycondensation method can improve the biocompatibility, and can accurately regulate and control the chemical structure of the surface of the hydrogel according to the application field of the hydrogel.
The following 3 examples and a comparative example were made for the above preparation:
example 1
4 mM of bis (3-amino-4-hydroxyphenyl) sulfone and 6 mM of bis (3-amino-4-fluorophenyl) were added to a mixed solvent of 50 mL of N, N' -dimethylacetamide and 40 mL of toluene, and 10 mM of anhydrous potassium carbonate was added. Defoaming for 5 min by using a water pump, then filling nitrogen for 1 min, and repeating for 3 times. The reaction was carried out in an oil bath at 155 ℃ for 5.5 h under nitrogen flow protection. The whole reaction was then heated to 220 ℃ and the reaction was continued for 12 h. The water produced in the reaction was removed from the reaction system by azeotropic distillation with toluene, collected by a Dean-Stark trap and reacted with potassium hydride. And washing the product with a MW3500 dialysis bag in DI water for 96 h to obtain the novel biocompatible polyethersulfone-based hydrogel.
Example 2
4 mM of bis (3-amino-4-hydroxyphenyl) sulfone and 6 mM of bis (3-sulfonic acid-4-fluorophenyl) sulfone sodium salt were added to a mixed solvent of 50 mL of N, N' -dimethylacetamide and 40 mL of toluene, and 10 mM of anhydrous potassium carbonate was added. Defoaming for 5 min by using a water pump, then filling nitrogen for 1 min, and repeating for 3 times. The reaction was carried out in an oil bath at 155 ℃ for 5.5 h under nitrogen flow protection. The whole reaction was then heated to 220 ℃ and the reaction was continued for 12 h. The water produced in the reaction was removed from the reaction system by azeotropic distillation with toluene, collected by a Dean-Stark trap and reacted with potassium hydride. And washing the product with a MW3500 dialysis bag in DI water for 96 h to obtain the novel biocompatible polyethersulfone-based hydrogel.
Example 3
4 mM of bis (3-amino-4-hydroxyphenyl) sulfone and 6 mM of bis (3-sulfonic acid-4-fluorophenyl) sulfone sodium salt were added to a mixed solvent of 50 mL of N, N' -dimethylacetamide and 40 mL of toluene, and 10 mM of anhydrous potassium carbonate was added. Defoaming for 5 min by using a water pump, then filling nitrogen for 1 min, and repeating for 3 times. The reaction was carried out in an oil bath at 155 ℃ for 5.5 h under nitrogen flow protection. The whole reaction was then heated to 240 ℃ and the reaction was continued for 12 h. The water produced in the reaction was removed from the reaction system by azeotropic distillation with toluene, collected by a Dean-Stark trap and reacted with potassium hydride. After the reaction is finished, the temperature is cooled to 100 ℃, excessive maleic anhydride and 50 mL of N, N' -dimethylacetamide are added, and the reaction is continued for 12 hours. And washing the product with a MW3500 dialysis bag in DI water for 96 h to obtain the novel biocompatible polyethersulfone-based hydrogel.
Comparative example 1
5 mM of bis (4-fluorophenyl) sulfone and 5 mM of bis (4-hydroxyphenyl) sulfone were added to a mixed solvent of 50 mL of N, N' -dimethylacetamide and 40 mL of toluene, and 10 mM of anhydrous potassium carbonate was added. Defoaming for 5 min by using a water pump, then filling nitrogen for 1 min, and repeating for 3 times. The reaction was carried out in an oil bath at 155 ℃ for 5.5 h under nitrogen flow protection. The whole reaction was then heated to 220 ℃ and the reaction was continued for 12 h. The water produced in the reaction was removed from the reaction system by azeotropic distillation with toluene, collected by a Dean-Stark trap and reacted with potassium hydride. The product was washed in DI water for 96 h using a MW3500 dialysis bag. Adding 18 g of the cleaned product into 82 mL of N, N' -dimethylacetamide, uniformly stirring to form a clear solution, defoaming for 30 min, and preparing the polyether sulfone membrane by adopting a liquid-liquid phase separation method.
For the 3 examples and comparative example 1, the platelet adhesion test and the cell activity test of human vascular endothelial cells by MTT method were performed, referring to FIG. 1, and the platelet adhesion amount of the 3 examples of the present invention was much smaller than that of the comparative example 1.
FIG. 2 shows the cell activity of human vascular endothelial cells measured by the MTT method at different times in comparative example and examples 1 to 3, and it can be seen from the figure that the absorbance of all 3 examples of the present invention is higher than that of comparative example 1.
Claims (10)
1. A preparation method of a novel biocompatible polyether sulfone-based hydrogel is characterized by comprising the following steps:
s1, synthesis of an oligomer: dissolving a hydroxyl-terminated sulfone monomer and a fluorine-terminated sulfone monomer in a mixed solvent of N, N' -dimethylacetamide and toluene, removing air by using anhydrous potassium carbonate as a catalyst, and heating to react to generate an oligomer;
s2, preparing the novel biocompatible polyether sulfone-based hydrogel: the temperature is increased to promote the cross-linking combination of the oligomers obtained in step S1 to form a hydrogel.
2. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: the hydroxyl-terminated sulfone monomer or/and the fluorine-terminated sulfone monomer contain amino, and the fluorine-terminated sulfone monomer contains sulfonic acid group.
3. The method for preparing a novel biocompatible polyethersulfone-based hydrogel according to any one of claims 1 or 2, wherein the method comprises the following steps: the hydroxyl-terminated sulfone monomer is bis (3-amino-4-hydroxyphenyl) sulfone or bis (4-hydroxyphenyl) sulfone or a mixture of the two, and the fluorine-terminated sulfone monomer is one or more than two of bis (4-fluorophenyl) sulfone, bis (3-sulfonic acid group-4-fluorophenyl) sulfone sodium salt or bis (3-amino-4-fluorophenyl) sulfone.
4. The method for preparing a novel biocompatible polyethersulfone-based hydrogel according to any one of claims 1, 2 or 3, wherein the method comprises the following steps: the molar ratio of the hydroxyl-terminated sulfone monomer to the fluorine-terminated sulfone monomer is 1: 1-1: 2.
5. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: and step S1, before the reaction starts, vacuumizing for 5-10 min by using a water pump, then injecting nitrogen for 1-5 min, and circularly reciprocating for 3 times to ensure that no impurity gas exists in the solution and constantly keep the circulation protection of the nitrogen.
6. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: in the step S1, a serpentine condenser pipe is used, a Dean-Stark water separator is used for collecting water generated by the reaction, and a certain amount of potassium hydride is added to the bottom of the water separator to convert the small molecular water into hydrogen gas which is discharged together with the protected nitrogen.
7. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: in the step S1, the reaction temperature is 140-155 ℃, and the reaction time is 3-6 h.
8. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: in step S2, the reaction temperature is raised to 200-300 ℃ and the reaction time is 8-12 h.
9. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: and S2, after the reaction is finished, cooling to 100 ℃, adding a certain amount or excessive maleic anhydride, and continuing the reaction for 12-18 hours to convert part or all of the amino groups on the surface of the hydrogel into carboxyl groups.
10. The preparation method of the novel biocompatible polyethersulfone-based hydrogel according to claim 1, characterized in that: and (5) after the reaction in the step S2 is finished, washing the hydrogel for more than 48 h by using a MW3500 dialysis bag.
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