CN106957434B - Triblock copolymer, porous layered scaffold and preparation method thereof - Google Patents
Triblock copolymer, porous layered scaffold and preparation method thereof Download PDFInfo
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- 239000003054 catalyst Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
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- 239000002244 precipitate Substances 0.000 claims description 3
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- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
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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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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Abstract
The invention belongs to the technical field of preparation of medical stents, and particularly relates to a triblock copolymer, a porous layered stent and a preparation method thereof. The preparation method of the triblock copolymer comprises the following steps: 1): 1, 4-succinic acid and 1, 4-butanediol are used as reaction monomers, and a series of PBS prepolymers with hydroxyl end capping and different molecular weights are obtained by adopting esterification reaction and melt polycondensation reaction; 2) MPEG is taken as a raw material, MPEG-COOH is obtained through esterification reaction, and the MPEG-COCl is obtained through continuous acylation; 3): synthesis of triblock Polymer: HO-PBS-OH and MPEG-COCl are polymerized to obtain the triblock polymer. The synthesized triblock copolymer material has higher molecular weight, better mechanical strength, better hydrophilic-hydrophobic balance and biodegradability, and meets the common use conditions of being used as a medical stent material.
Description
Technical Field
The invention belongs to the technical field of preparation of medical stents, and particularly relates to a triblock copolymer, a porous layered stent and a preparation method thereof.
Background
The problems of high hydrophobicity, weak intermolecular force, difficulty in adjusting hydrophilic/hydrophobic balance, lack of reactive sites and the like of a polybutylene succinate (PBS) molecular skeleton greatly restrict the application of the PBS in the field of biomedical materials, particularly medical stent materials. Polyethylene glycol (PEG) is a polyether high molecular compound with wide application, and can be applied to a plurality of fields such as medicine, health, food, chemical industry and the like. PEG has excellent biocompatibility and water solubility. In the synthesis and modification of novel biomaterials, PEG as part of the material will impart new properties and functions to the material, such as hydrophilicity, flexibility, anticoagulation, anti-macrophage phagocytosis, etc.
Through copolymerization of PEG and PBS, the original good biocompatibility of PEG is kept, and the hydrophilic property of the obtained copolymer can be improved. In addition, the amphiphilic copolymer has biodegradability, PEG is very easy to metabolize by liver, and the hydrophobic chain segment of the polyester can be degraded into molecules through the action of in vivo hydrolytic enzyme and excreted to the outside of a body through normal physiological metabolic processes. Therefore, if PBS is modified and modified in the aspects of providing active reaction sites and controllable degradability, the PBS can be expanded to be applied to the fields of targeted controlled release drug carriers and intelligent tissue engineering scaffold materials.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a triblock copolymer, a porous layered scaffold and a preparation method thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method of preparing a triblock copolymer comprising the steps of:
1): preparing HO-PBS-OH, namely taking 1, 4-succinic acid and 1, 4-butanediol as reaction monomers, and obtaining a series of PBS prepolymers HO-PBS-OH with hydroxyl end capping and different molecular weights by adopting esterification reaction and melt polycondensation reaction; as shown in formula (I):
2) synthesis of end-acylated PEG: taking methoxy polyethylene glycol (MPEG) as a raw material, obtaining polyethylene glycol (MPEG-COOH) with carboxylated terminals through esterification, and acylating the MPEG-COOH to obtain MPEG-COCl; such as formula (II shows)
3): synthesis of triblock Polymer MPEG-PBS-MPEG: polymerizing the HO-PBS-OH obtained in the step 1) and the MPEG-COCl obtained in the step 2) to obtain a triblock polymer MPEG-PBS-MPEG.
Wherein, the molar ratio of the 1, 4-butanedioic acid to the 1, 4-butanediol in the step 1) is 1:1.0-1.5, and the Mn of the obtained HO-PBS-OH is 5000-15000.
Specifically, the specific steps of the step 1) are as follows:
adding 1, 4-succinic acid, 1, 4-butanediol and a catalyst into a reactor flask, heating the reactor, introducing nitrogen for a period of time, slowly raising the reaction temperature to 170 ℃, and reacting for about 2 hours at the temperature until water drops are not generated any more; then the temperature is increased to 240 ℃, the pressure is gradually reduced to below 60Pa, and the stirring is accelerated for about 3 hours. After the reaction is finished, the product is dissolved by chloroform and then is precipitated by methanol to obtain milky flocculent solid. The sample was oven dried in a vacuum oven at 50 ℃ for 24h for use.
Specifically, the step 2) comprises the following specific steps:
adding methoxypolyethylene glycol and toluene into a reactor, mixing, heating, refluxing for 30min, heating for azeotropy to remove water in MPEG, adding 1.5-2 times of succinic anhydride with the molar weight of the MPEG, controlling the temperature at 80 ℃, reacting for 6 hours, then heating to 100 ℃, carrying out vacuum filtration, and finishing the reaction after 2 hours; distilling with water pump under reduced pressure until a small amount of toluene remains, washing the precipitate with a large amount of diethyl ether, removing excessive succinic anhydride and toluene to obtain MPEG-COOH, and placing in a vacuum drying oven for use;
dissolving the obtained MPEG-COOH with carboxylated terminals into toluene, adding thionyl chloride of 4-8 molar times of the MPEG-COOH, introducing nitrogen for protection, and absorbing gas generated in the reaction by alkali liquor. Sealing the reaction device, controlling the temperature at 50 ℃ and reacting for about 16 hours to finish the experiment; after most of toluene was distilled off under reduced pressure, 60mL of toluene was added and the excess thionyl chloride was distilled off continuously to obtain terminally acylchlorinated polyethylene glycol MPEG-COCl.
Specifically, the specific steps of step 3) are as follows:
in an ice-water bath, 1 molar equivalent of HO-PBS-OH and 1.5-2 molar equivalents of MPEG-COCl are added into a reactor, chloroform is used as a solvent, and a catalytic amount of pyridine is added. Absorbing the gas generated by the reaction with alkali liquor, magnetically stirring under the protection of nitrogen, and sealing the reaction device. After the reaction is carried out for one hour, the reaction is continued for 4 hours at room temperature, the temperature is adjusted to 60 ℃ for reaction for 3 hours, and the experiment is finished; and then adding the product into excessive cold ether, precipitating and separating out, and performing vacuum filtration under reduced pressure and vacuum drying for 24 hours to obtain the triblock copolymer.
The invention also comprises a triblock copolymer obtained by the preparation method.
The preparation method of a porous layered scaffold adopts 8-10 parts by mass of triblock copolymer and 1 part by mass of polyethylene oxide (PEO) as raw materials, fully mixes the raw materials in a drum mixer, puts the mixture into a hopper of an injection molding machine, and regulates and controls the injection molding pressure; performing injection molding and cooling shaping to obtain a dumbbell-shaped injection molding sample strip; and immediately soaking the molded sample bar in water at 37 ℃, gradually leaching out the water-soluble PEO in the blend, and keeping the weight constant to finally obtain the porous layered structure scaffold.
The invention also comprises a porous layer stent prepared by the preparation method.
Compared with the prior art, the invention has the beneficial effects that:
the synthesized triblock aliphatic copolymer material has higher molecular weight, better mechanical strength, better hydrophilic-hydrophobic balance and biodegradability, and meets the general use conditions of being used as a medical stent material; compared with the traditional porous stent prepared by adopting polylactic acid (PLA) material, the MPEG-PBS-MPEG porous layer stent prepared by the injection molding method has a laminated structure, higher porosity, evenly distributed aperture size, mutually communicated open void structure and good hydrophilicity. The copolymer scaffold porosity is greater than 92.5%; the size range of the macropores is 100-300 mu m; the radial strength of the copolymer stent reaches 7.8 kPa; the expansion rate of the copolymer stent is about 4-6 percent, and the longitudinal shortening rate of the stent is less than 9 percent; the water contact angle of the copolymer support is below 25 degrees.
Drawings
FIG. 1 is a synthesis scheme of the triblock copolymer MPEG-PBS-MPEG of the present invention.
FIG. 2 is a nuclear magnetic diagram of the triblock copolymer MPEG-PBS-MPEG of the present invention.
FIG. 3 is a scanning electron micrograph of an MPEG-PBS-MPEG porous layered scaffold of the present invention.
FIG. 4 is a schematic diagram of the preparation process of the porous layered scaffold of the present invention.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention will be further described in detail with reference to the accompanying drawings and preferred embodiments.
Example (b): FIG. 1 shows the synthesis scheme of the triblock copolymer MPEG-PBS-MPEG of the present invention.
1.1 Synthesis of HO-PBS-OH
Adding 23.6 g of 1, 4-Succinic Acid (SA), 21.6 g of 1, 4-Butanediol (BD), 0.03g of stannous chloride serving as a catalyst and 0.03g of p-toluenesulfonic acid into a four-neck flask, placing the mixture in a heating jacket, introducing nitrogen for a period of time, slowly raising the reaction temperature to 170 ℃, and reacting at the temperature for about 2 hours until no water drops are generated; then the temperature is increased to 240 ℃, the pressure is gradually reduced to below 60Pa, and the stirring is accelerated for about 3 hours. After the reaction is finished, chloroform is dissolved and then methanol is used for precipitation to obtain milky flocculent solid. Baking in a vacuum oven at 50 ℃ for 24h for later use.
1.2 Synthesis of end-carboxylated MPEG
10g of methoxypolyethylene glycol (MPEG) and 150mL of toluene are added into a four-neck flask, mixed, heated and refluxed for 30min, heated and azeotropically distilled to remove 80mL of toluene to remove water in PEG, 2g of succinic anhydride is added, the temperature is controlled at 80 ℃, after reaction for 6 hours, the temperature is raised to 100 ℃, then vacuum filtration is carried out, and the reaction is finished after 2 hours. Distilling with water pump under reduced pressure until a small amount of toluene remains, washing the precipitate with a large amount of diethyl ether, removing excessive succinic anhydride and toluene, and placing in a vacuum drying oven for use.
1.3 Synthesis of terminal acylchlorinated MPEG
10g of carboxylated MPEG-COOH is added into a four-neck flask, weighed and dissolved in 100ml of toluene, then 6 times of mol of thionyl chloride is added, nitrogen is introduced for protection, and gas generated in the reaction is absorbed by alkali liquor. And (5) sealing the reaction device. The temperature was controlled at 50 ℃ and the reaction was terminated for about 16 hours. Then most of toluene was distilled off under reduced pressure, then 60mL of toluene was added to continue the distillation to remove excess thionyl chloride, and the product was dried for further use.
1.4 Synthesis of MPEG-PBS-MPEG
HO-PBS-OH and 2 times molar amount of terminal acylchlorinated MPEG were added to a four-necked flask in an ice-water bath, chloroform as a solvent, and a catalytic amount of pyridine was added. Absorbing the gas generated by the reaction by alkali liquor. Magnetically stirring under the protection of nitrogen, and sealing the reaction device. After one hour of reaction, the reaction was allowed to proceed at room temperature for 4 hours, and then the temperature was adjusted to 60 ℃ to complete the reaction for 3 hours. Then adding the mixture into excessive cold ether, precipitating, carrying out vacuum filtration under reduced pressure, and then carrying out vacuum drying for 24 hours to obtain the MPEG-PBS-MPEG triblock copolymer.
Fig. 1 shows a nuclear magnetic spectrum of MPEG-PBS-MPEG, from which it can be seen that: peaks with chemical shifts (δ) of 1.7 and 4.1 are-CH 2-proton resonance peaks at position 1 and position 4 on the 1, 4-butanediol segment, respectively; delta is 2.6, the-CH 2-proton resonance peak at position 3 on the 1, 4-succinic acid segment; the delta of 3.6 is the proton resonance peak at position 2-CH 2-on the PEG segment, indicating that the MPEG-PBS-MPEG triblock copolymer was successfully prepared.
Example 2 is the same as example 3 in preparation method of example 1 except that 1.1.HO-PBS-OH in example 2 is synthesized with 1, 4-succinic acid and 1, 4-butanediol at a molar ratio of 1:1, and 1, 4-succinic acid and 1, 4-butanediol at a molar ratio of 1:1 in example 3 is 1: 1.5. Example 4 is the same as example 5 in the preparation method of example 1 except that the molar ratio of MPEG to succinic anhydride of example 4 is 1:1.5 and the equivalent amount of dimethyl sulfoxide added in the preparation of MPEG-COCl by MPEG-COOH is 4 times by mole in the synthesis of MPEG-COCl of 1.2 to 1.3, and the molar ratio of MPEG to succinic anhydride of example 5 is 1:2 and the equivalent amount of dimethyl sulfoxide added in the preparation of MPEG-COCl by MPEG-COOH is 8 times by mole.
1.5 preparation of porous layered structure scaffold:
example 6:
as shown in FIG. 4, firstly, the MPEG-PBS-MPEG triblock copolymer obtained in example 1 and polyethylene oxide (PEO) are fully mixed in a rotary drum mixer according to a certain weight ratio (90/10), and are put into a hopper (I) of an injection molding machine, and the injection molding process conditions are regulated, wherein the injection molding process is that the maximum injection molding temperature T is regulated and controlled within the range of 140-160 ℃; the injection pressure P ranges from 40MPa to 60 MPa; performing injection molding at the mold temperature of 40 ℃; cooling for 10-20s to obtain dumbbell type injection molding sample strips; the molded bars were then immediately immersed in water at 37 ℃ for a prolonged period of time (III) until the weight remained constant, giving a porous layered structure scaffold (IV).
Example 7 was prepared in the same manner as example 8 and example 6 except that the mass ratio of the MPEG-PBS-MPEG triblock copolymer to polyethylene oxide (PEO) was different, the mass ratio of example 7 was 8:1 and the mass ratio of example 8 was 10: 1.
Wherein, the embodiment 6 is the best embodiment, fig. 3 shows the scanning electron microscope image of the porous layer stent, and the obtained porosity of the porous layer stent is more than 92.5%; the size range of the macropores is 100-300 mu m; the radial strength of the porous layer stent is more than 7.8 kPa; the expansion rate of the copolymer stent is 4-6 percent, and the longitudinal shortening rate of the stent is less than 9 percent; the water contact angle of the copolymer support is below 25 degrees.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A process for preparing a triblock copolymer comprising the steps of:
1): preparing HO-PBS-OH, namely taking 1, 4-succinic acid and 1, 4-butanediol as reaction monomers, and obtaining a series of PBS prepolymers HO-PBS-OH with hydroxyl end capping and different molecular weights by adopting esterification reaction and melt polycondensation reaction; as shown in formula (I):
2) synthesis of end-acylated PEG: taking methoxy polyethylene glycol (MPEG) as a raw material, obtaining polyethylene glycol (MPEG-COOH) with carboxylated terminals through esterification, and acylating the MPEG-COOH to obtain MPEG-COCl; as shown in formula (II):
3): synthesis of triblock Polymer MPEG-PBS-MPEG: polymerizing the HO-PBS-OH obtained in the step 1) and the MPEG-COCl obtained in the step 2) to obtain a triblock polymer MPEG-PBS-MPEG.
2. The method of claim 1, wherein the molar ratio of 1, 4-butanedioic acid to 1, 4-butanedio in step 1) is 1:1.0-1.5, and the Mn of HO-PBS-OH obtained is 5000-.
3. The method for preparing a triblock copolymer according to claim 1, wherein the specific steps of step 1) are:
adding 1, 4-succinic acid, 1, 4-butanediol and a catalyst into a reactor flask, heating the reactor, introducing nitrogen for a period of time, slowly raising the reaction temperature to 170 ℃, and reacting for about 2 hours at the temperature until water drops are not generated any more; then heating to 240 ℃, gradually reducing the pressure to below 60Pa, and accelerating the stirring for 3 h; after the reaction is finished, dissolving the product by using chloroform, and then precipitating by using methanol to obtain a milky flocculent solid; the sample was oven dried in a vacuum oven at 50 ℃ for 24h for use.
4. The method for preparing a triblock copolymer according to claim 1, wherein the specific steps of step 2) are:
adding methoxypolyethylene glycol and toluene into a reactor, mixing, heating, refluxing for 30min, heating for azeotropy to remove water in MPEG, adding 1.5-2 times of succinic anhydride with the molar weight of the MPEG, controlling the temperature at 80 ℃, reacting for 6 hours, then heating to 100 ℃, carrying out vacuum filtration, and finishing the reaction after 2 hours; distilling with water pump under reduced pressure until a small amount of toluene remains, washing the precipitate with a large amount of diethyl ether, removing excessive succinic anhydride and toluene to obtain MPEG-COOH, and placing in a vacuum drying oven for use;
dissolving the obtained terminal carboxylated MPEG-COOH in toluene, adding thionyl chloride with the molar weight 4-8 times that of the MPEG-COOH, introducing nitrogen for protection, and absorbing gas generated in the reaction by alkali liquor. Sealing the reaction device, controlling the temperature at 50 ℃ and reacting for 16 hours to finish the experiment; after most of toluene was distilled off under reduced pressure, 60mL of toluene was added and the excess thionyl chloride was distilled off continuously to obtain terminally acylchlorinated polyethylene glycol MPEG-COCl.
5. The method for preparing a triblock copolymer according to claim 1, wherein the specific steps of step 3) are:
adding 1 molar equivalent of HO-PBS-OH and 1.5-2 molar equivalents of MPEG-COCl into a reactor in an ice water bath, using chloroform as a solvent, and adding a catalytic amount of pyridine; absorbing the gas generated by the reaction with alkali liquor, magnetically stirring under the protection of nitrogen, and sealing the reaction device; after the reaction is carried out for one hour, the reaction is continued for 4 hours at room temperature, the temperature is adjusted to 60 ℃ for reaction for 3 hours, and the experiment is finished; and then adding the product into excessive cold ether, precipitating and separating out, and performing vacuum filtration under reduced pressure and vacuum drying for 24 hours to obtain the triblock copolymer.
6. A triblock copolymer obtained by the production method according to any one of claims 1 to 5.
7. A preparation method of a porous layered scaffold is characterized in that 8-10 parts by mass of triblock copolymer and 1 part by mass of polyethylene oxide (PEO) as described in claim 6 are adopted as raw materials, fully mixed in a drum mixer, put into a hopper of an injection molding machine, and the injection molding process is regulated and controlled; performing injection molding and cooling shaping to obtain a dumbbell-shaped injection molding sample strip; and immediately soaking the injection-molded sample bar in water at 37 ℃ to obtain a blend, wherein the water-soluble PEO in the blend is gradually leached out, the weight is kept constant, and the porous layered structure scaffold is finally obtained.
8. The preparation method of the porous layered scaffold is characterized in that the injection molding process is to regulate and control the maximum injection molding temperature T range to be 140-160 ℃; the injection pressure P ranges from 40MPa to 60 MPa; the mold temperature is 40 ℃; the cooling time is 10-20 s.
9. A porous layered scaffold, which is prepared by the preparation method of claim 7 or 8; the porosity of the porous layer stent is more than 92.5%; the size range of the macropores is 100-300 mu m; the radial strength of the porous layer stent is more than 7.8 kPa; the expansion rate of the copolymer stent is 4-6 percent, and the longitudinal shortening rate of the stent is less than 9 percent; the water contact angle of the copolymer support is below 25 degrees.
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| CN105085927A (en) * | 2015-08-19 | 2015-11-25 | 河南省眼科研究所 | Tri-block copolymer, preparation method thereof and eye drop prepared from tri-block copolymer |
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