阅读说明：本技术 一种基于聚ε-己内酯的聚酯型生物可降解形状记忆共聚物及其制备方法 (Polyester type biodegradable shape memory copolymer based on poly epsilon-caprolactone and preparation method thereof ) 是由 邝旻翾 张秀芹 楚雪梅 王锐 张文娟 马慧玲 赵惠 于 2021-05-20 设计创作，主要内容包括：本发明提供了一种聚ε-己内酯生物可降解形状记忆共聚物及其制备方法,该聚ε-己内酯生物可降解形状记忆共聚物由聚ε-己内酯、柠檬酸和1,8-辛二酯共聚后经交联固化制得,其具有力学性能良好、形变量大、高倍拉伸下回复率高和生物可降解的优点,同时该形状记忆共聚物的制备方法简单、便于操作、制备效率高,具有广阔的应用前景。(The poly-epsilon-caprolactone biodegradable shape memory copolymer is prepared by copolymerizing poly-epsilon-caprolactone, citric acid and 1, 8-octanedioate and then crosslinking and curing, has the advantages of good mechanical property, large deformation amount, high recovery rate under high-order stretching and biodegradability, and meanwhile, has the advantages of simple preparation method, convenient operation, high preparation efficiency and wide application prospect.)

1. The poly-epsilon-caprolactone biodegradable shape memory copolymer is characterized by being prepared by copolymerizing poly-epsilon-caprolactone, citric acid and 1, 8-octanediol and then crosslinking and curing.

2. The poly-epsilon-caprolactone biodegradable shape memory copolymer of claim 1, wherein,

the relative molecular mass of the poly-epsilon-caprolactone is 5000-100000, and the poly-epsilon-caprolactone accounts for 65-95% of the mass fraction of the copolymer;

the molar ratio of the citric acid to the 1, 8-octanediol is (0.1-10): 1.

3. The poly-epsilon-caprolactone biodegradable shape memory copolymer of claim 1, wherein,

the shape recovery temperature is 20-60 ℃, the setting temperature is-20-30 ℃, the deformation recovery degree is 90-100%, and the maximum stretching rate can reach 2500%.

4. A preparation method of a poly-epsilon-caprolactone biodegradable shape memory copolymer is characterized in that the preparation method takes poly-epsilon-caprolactone, citric acid and 1, 8-octanediol as raw materials to prepare.

5. The method of manufacturing according to claim 4, comprising the steps of:

step 1, performing polymerization reaction on poly epsilon-caprolactone, citric acid and 1, 8-octanediol to obtain a copolymer prepolymer;

and 2, curing the copolymer prepolymer obtained in the step 1 to obtain the shape memory copolymer.

6. The production method according to claim 5, wherein, in step 1,

the poly-epsilon-caprolactone is selected from one or more of poly-epsilon-caprolactone diol with hydroxyl at two ends, poly-epsilon-caprolactone with hydroxyl at one end and carboxyl at the other end and poly-epsilon-caprolactone with carboxyl at two ends;

the relative molecular mass of the poly epsilon-caprolactone is 5000-100000.

7. The production method according to claim 5, wherein, in step 1,

the molar ratio of the citric acid to the 1, 8-octanediol is (0.1-10): 1, and the mass fraction of the poly-epsilon-caprolactone in the copolymer is 65-95%.

8. The production method according to claim 5, wherein, in step 1,

before the polymerization reaction, preferably heating and then stirring, heating to 120-200 ℃ and stirring for 10-60 min;

after stirring, reducing the temperature to the reaction temperature for polymerization reaction, wherein the reaction temperature is 100-180 ℃, and the reaction time is 1-7 h.

9. The production method according to claim 5, wherein, in the step 2,

the curing temperature is 100-150 ℃, and the curing time is 8-48 h.

10. Use of the poly-epsilon-caprolactone biodegradable shape memory copolymer according to one of the claims 1 to 3 or the poly-epsilon-caprolactone biodegradable shape memory copolymer prepared by the preparation method according to one of the claims 4 to 9 in the biomedical field, preferably in sutures, drug sustained release carriers, dental appliance materials, stent materials and fixation materials.

Technical Field

The invention relates to the field of intelligent polymer materials, in particular to a polyester type biodegradable shape memory copolymer based on poly epsilon-caprolactone and a preparation method thereof.

Background

Shape memory polymers are a class of polymers that sense a stimulus from a change in their environment (e.g., temperature, force, electromagnetic, solvent, etc.) and, in response to such a change, adjust their mechanical parameters (e.g., shape, position, strain, etc.) to return to their pre-set state. Such materials are also referred to as smart materials because of their good dexterity and their potential important applications in smart or smart architectures.

Biodegradable shape memory polymers differ from conventional materials in their biodegradability, i.e., the ability of the material to automatically degrade into fragments or small molecules in a physiological environment and then be excreted outside the body by digestion and metabolism of the body without leaving toxic or indigestible substances. Therefore, such materials are the most desirable materials for applications in the medical field.

Most biodegradable polymers have little or poor shape memory properties, which limits the field of application of biodegradable shape memory polymers, particularly in biomedical engineering.

At present, there are two main preparation methods for the poly epsilon-caprolactone-based biodegradable shape memory copolymer: one is to use poly epsilon-caprolactone diol as raw material to synthesize shape memory polyurethane, and the other is to copolymerize or blend poly epsilon-caprolactone with polylactic acid.

However, the general shape memory poly epsilon-caprolactone material has poor mechanical property and low recovery rate under high-power stretching, so that the application of the material is limited.

Disclosure of Invention

Based on the above technical background, the present inventors have made a keen search and, as a result, have found that: the poly-epsilon-caprolactone biodegradable shape memory copolymer prepared by copolymerizing the poly-epsilon-caprolactone, the citric acid and the 1, 8-octanedionate as raw materials and then crosslinking and curing has good mechanical property, has the advantages of large deformation amount, high recovery rate under high-magnification stretching and biodegradability, is simple in preparation method and high in preparation efficiency, and can be applied to the medical field as a degradable intelligent material.

The first aspect of the invention provides a poly-epsilon-caprolactone biodegradable shape memory copolymer, which is prepared by copolymerizing poly-epsilon-caprolactone, citric acid and 1, 8-octanediol and then crosslinking and curing.

The second aspect of the present invention is to provide a method for preparing the poly-epsilon-caprolactone biodegradable shape memory copolymer, which is prepared by using poly-epsilon-caprolactone, citric acid and 1, 8-octanediol as raw materials.

The third aspect of the present invention provides a use of the biodegradable shape memory copolymer of polyepsilon caprolactone according to the first aspect of the present invention or the biodegradable shape memory copolymer of polyepsilon caprolactone prepared by the preparation method of the second aspect of the present invention, which can be used as a degradable intelligent material in the biomedical field, preferably in sutures, drug sustained release carriers, orthodontic appliance materials, stent materials and fixation materials.

The biodegradable shape memory copolymer of poly epsilon-caprolactone and the preparation method thereof provided by the invention have the following advantages:

(1) the poly epsilon-caprolactone biodegradable shape memory copolymer has the advantages of large deformation amount, high deformation recovery rate and biodegradability;

(2) the preparation method of the poly epsilon-caprolactone biodegradable shape memory copolymer is simple and convenient to operate;

(3) the poly epsilon-caprolactone biodegradable shape memory copolymer can be used as a degradable intelligent material to be applied to sutures, drug sustained-release carriers, orthodontic appliance materials, stent materials and fixing materials.

Drawings

FIG. 1 shows the torsional deformation-recovery process of a biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared in example 1 of the present invention;

FIG. 2 shows the process of tensile deformation-recovery of a biodegradable shape memory copolymer of poly-epsilon-caprolactone produced in example 2 of the present invention;

FIG. 3 shows stress-strain curves at 50 ℃ of a biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared in example 1 of the present invention;

FIG. 4 shows the temperature rise-fall DSC curve of the biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared in example 2 of the present invention;

FIG. 5 shows the weight loss curves of the biodegradable shape memory co-polymer bodies of poly-epsilon-caprolactone prepared in example 1 of the present invention in phosphate buffered saline solutions of different pH values.

Detailed Description

The present invention will be described in detail below, and features and advantages of the present invention will become more apparent and apparent with reference to the following description.

The first aspect of the invention provides a poly-epsilon-caprolactone biodegradable shape memory copolymer, which is prepared by copolymerizing poly-epsilon-caprolactone, citric acid and 1, 8-octanediol and then crosslinking and curing.

The existing polyurethane polycaprolactone shape memory polymer is generally prepared by polymerizing low-molecular-weight polycaprolactone diol and isocyanate, and a hard phase formed by the isocyanate is used as a physical crosslinking point, so that the polyurethane polycaprolactone shape memory polymer is a thermoplastic polymer. But the mechanical property is poor, and the recovery rate under high-power stretching is low.

The poly epsilon-caprolactone copolymer is prepared by adopting poly epsilon-caprolactone, citric acid and 1, 8-octanediol as raw materials, and experiments show that the poly epsilon-caprolactone component in the poly epsilon-caprolactone biodegradable shape memory copolymer prepared by adopting the raw materials can be crystallized, the copolymer is in a plastic state below a melting point, the copolymer is in a rubber state above the melting point, and the recovery rate is high under high-power stretching.

According to the invention, the poly-epsilon-caprolactone is selected from one or more of poly-epsilon-caprolactone diol with hydroxyl groups at two ends, poly-epsilon-caprolactone with carboxyl groups at one end and carboxyl groups at the other end and poly-epsilon-caprolactone with carboxyl groups at two ends, preferably from one or two of poly-epsilon-caprolactone diol with hydroxyl groups at two ends and poly-epsilon-caprolactone with carboxyl groups at one end and hydroxyl groups at the other end, more preferably poly-epsilon-caprolactone diol with hydroxyl groups at two ends or poly-epsilon-caprolactone with carboxyl groups at one end and hydroxyl groups at the other end.

The poly-epsilon-caprolactone has excellent biocompatibility, memory and biodegradability, and tests show that the biodegradable shape memory copolymer prepared from the poly-epsilon-caprolactone with the structure has larger deformation and higher recovery rate.

The poly epsilon-caprolactone accounts for 65-95% of the mass of the copolymer, preferably accounts for 70-90% of the mass of the copolymer, and more preferably accounts for 75-80% of the mass of the copolymer.

The relative molecular mass of the poly-epsilon-caprolactone is 5000-100000, preferably 7000-60000 and more preferably 9000-40000.

The melting point of the poly-epsilon-caprolactone biodegradable shape memory copolymer can be regulated and controlled by changing the relative molecular mass and mass fraction of the poly-epsilon-caprolactone. The higher the relative molecular mass of the poly-epsilon-caprolactone, the higher the mass fraction of the copolymer, and the higher the melting point of the prepared poly-epsilon-caprolactone biodegradable shape memory copolymer.

The molar ratio of the citric acid to the 1, 8-octanediol is (0.1-10): 1, and the preferred molar ratio is (0.5-5): 1, and more preferably the molar ratio is (0.5 to 2): 1.

The poly epsilon-caprolactone biodegradable shape memory copolymer has the advantages of large deformation amount, high deformation recovery rate and biodegradability, the shape recovery temperature is 20-60 ℃, the setting temperature is-20-30 ℃, the deformation recovery degree is 90-100%, the maximum stretching rate can reach 2500%, the poly epsilon-caprolactone biodegradable shape memory copolymer can be degraded in acid solution, neutral solution and alkaline solution, and the degradation rate in the alkaline solution is the highest and can reach more than 90%.

In the present invention, the biodegradable shape memory copolymer of poly-e-caprolactone as described in the present invention is prepared by a method comprising the steps of:

step 1, performing polymerization reaction on poly epsilon-caprolactone, citric acid and 1, 8-octanediol to obtain a copolymer prepolymer;

and 2, curing the copolymer prepolymer obtained in the step 1 to obtain the shape memory copolymer.

The second aspect of the present invention is to provide a method for preparing the poly-epsilon-caprolactone biodegradable shape memory copolymer, which is prepared by using poly-epsilon-caprolactone, citric acid and 1, 8-octanediol as raw materials.

According to the invention, the preparation method comprises the following steps:

step 1, performing polymerization reaction on poly epsilon-caprolactone, citric acid and 1, 8-octanediol to obtain a copolymer prepolymer;

and 2, curing the copolymer prepolymer obtained in the step 1 to obtain the shape memory copolymer.

This step is specifically described and illustrated below.

Step 1, performing polymerization reaction on poly epsilon-caprolactone, citric acid and 1, 8-octanediol to obtain a copolymer prepolymer.

In the invention, the poly epsilon-caprolactone, the citric acid and the 1, 8-octanediol can be simultaneously placed in the reaction vessel for polymerization reaction, or the citric acid and the 1, 8-octanediol can be placed in the reaction vessel for reaction for a certain time and then the poly epsilon-caprolactone can be added for polymerization reaction.

The poly-epsilon-caprolactone is one or more selected from poly-epsilon-caprolactone diol with hydroxyl at two ends, poly-epsilon-caprolactone with hydroxyl at one end and carboxyl at the other end and poly-epsilon-caprolactone with both carboxyl at two ends, preferably one or two selected from poly-epsilon-caprolactone diol with hydroxyl at two ends and poly-epsilon-caprolactone with carboxyl at one end and hydroxyl at the other end, more preferably poly-epsilon-caprolactone diol with hydroxyl at two ends or poly-epsilon-caprolactone with carboxyl at one end and hydroxyl at the other end.

The molar ratio of the citric acid to the 1, 8-octanediol is (0.1-10): 1, and the preferable molar ratio is (0.5-5): 1, and more preferably the molar ratio is (0.5 to 2): 1.

The poly-epsilon-caprolactone accounts for 65-95% of the mass of the copolymer, the poly-epsilon-caprolactone accounts for 70-90% of the mass of the copolymer, and the poly-epsilon-caprolactone accounts for 75-80% of the mass of the copolymer.

The relative molecular mass of the poly-epsilon-caprolactone is 5000-100000, preferably 7000-60000 and more preferably 9000-40000.

Tests show that the higher the relative molecular mass of poly-epsilon-caprolactone, the higher the melting point of the copolymer produced.

The polymerization reaction is preferably carried out in a reaction kettle, and the polymerization reaction is carried out in a protective atmosphere, wherein the protective atmosphere is argon or nitrogen, and preferably nitrogen.

If the polymerization reaction is carried out by the first method, according to the present invention, it is preferable to heat and stir the mixture before the polymerization reaction, and the stirring after the heating can mix the reactants in a fully molten state, and the mixture is more uniform, and the temperature is raised to 120 to 200 ℃, preferably 140 to 180 ℃, and more preferably 150 to 165 ℃.

The stirring time is 10-60 min, preferably 20-40 min, and more preferably 30 min.

After stirring, cooling to the reaction temperature for polymerization, and experiments show that the reaction temperature is 100-180 ℃ which is more favorable for controlling the reaction rate and the molecular structure of the prepared copolymer, the prepared copolymer has higher deformation recovery rate and better degradation performance, the reaction temperature is preferably 120-160 ℃, and the reaction temperature is more preferably 130-150 ℃.

The reaction time is 1-7 h, preferably 2-5 h, and more preferably 3-4 h.

If the polymerization reaction is carried out by adopting the second mode, the citric acid and the 1, 8-octanediol are added firstly for reaction for 1-3 hours, and then the poly-epsilon-caprolactone is added for continuous polymerization reaction for 1-4 hours.

And 2, curing the copolymer prepolymer obtained in the step 1 to obtain the shape memory copolymer.

In the invention, the curing is carried out in a mold, and the curing temperature is 100-150 ℃, preferably 110-140 ℃, and more preferably 120-130 ℃.

If the curing temperature is too high, such as above 150 ℃, the cured product is easy to generate internal stress to affect the mechanical properties of the material, so that the mechanical properties of the prepared product are poor, and the deformation recovery rate is low.

The curing time is 8-48 h, preferably 15-40 h, and more preferably 20-30 h.

Too short curing time leads to poor mechanical properties of the cured product, and too long curing time is also not favorable for improving the mechanical properties of the cured product, and also reduces the deformation recovery rate.

The third aspect of the present invention provides a use of the biodegradable shape memory copolymer of polyepsilon caprolactone according to the first aspect of the present invention or the biodegradable shape memory copolymer of polyepsilon caprolactone prepared by the preparation method of the second aspect of the present invention, which can be used as a degradable intelligent material in the biomedical field, preferably in sutures, drug sustained release carriers, orthodontic appliance materials, stent materials and fixation materials.

The invention has the following beneficial effects:

(1) the synthesis process of the shape memory copolymer is simple and convenient to operate;

(2) the melting point of the poly-epsilon-caprolactone biodegradable shape memory copolymer is 20-60 ℃, the shape recovery temperature is 20-60 ℃, the setting temperature is-20-30 ℃, the recovery degree is 90-100%, and the maximum stretching rate can reach 2500%;

(3) the poly epsilon-caprolactone biodegradable shape memory copolymer has good degradation performance, can be degraded in alkaline solution, neutral solution and acidic solution, and has the highest degradation rate in alkaline solution which can reach more than 90%.

Examples

The invention is further illustrated by the following specific examples, which are intended to be illustrative only and not limiting to the scope of the invention.

Example 1

Adding citric acid and 1, 8-octanediol with a molar ratio of 1:1, and 75% of carboxyl group-at-end poly-epsilon-caprolactone with one hydroxyl group and one carboxyl group at one end, which accounts for 10000 of the total mass, into a reaction kettle, introducing nitrogen for protection, heating to 160 ℃, stirring for 30 minutes, cooling to 140 ℃, and reacting for 3 hours to obtain a copolymer prepolymer. Pouring the prepolymer into a mold, and curing for 24 hours at 120 ℃ to obtain the biodegradable shape memory copolymer product. As shown in figure 1, heating the product to 60 ℃, stretching the coiled shape, and cooling to 20 ℃ for fixing deformation; heating to 45 deg.C, and recovering the product to original shape.

Example 2

Adding citric acid, 1, 8-octanediol and poly-epsilon-caprolactone with one hydroxyl end and one carboxyl end, wherein the molar ratio of the citric acid to the 1:1 to the 1, 8-octanediol to the total mass is 75 percent, and the poly-epsilon-caprolactone with one hydroxyl end and one carboxyl end has the molecular weight of 2 ten thousand to a reaction kettle, introducing nitrogen for protection, heating to 150 ℃, stirring for 30 minutes, cooling to 140 ℃, and reacting for 3 hours to obtain the copolymer prepolymer. Pouring the prepolymer into a mold, and curing at 120 ℃ for 21 hours to obtain the biodegradable shape memory copolymer product. As shown in fig. 2, the article was stretched to 600% at room temperature, heated to 45 ℃, and the article returned to its original shape.

Examples of the experiments

Experimental example 1 stress-Strain test

The biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared in example 1 was subjected to mechanical property test in the following procedure: preparing a sample into a total length of 24.70mm and a width of an end part of 7.6mm by a Ray-Ran dumbbell-shaped sample preparation machine; the middle parallel part is a dumbbell-shaped sample strip with the length of 4mm and the width of 2.7mm, the sample strip is fixed by a clamp of a material testing machine, and the actual measurement distance is 4 mm. The experiment was carried out at a temperature of 50 ℃ and was stretched to 1500% at a stretching rate of 6mm/min and then returned to the original position at a rate of 6 mm/min. The stress-strain curve is shown in fig. 3.

As can be seen from fig. 3, the stress of the copolymer gradually increases as the strain increases. After stretching to a strain of 1500%, the recovery was 96%.

Experimental example 2 thermal Property test

A DSC tester is used for carrying out thermal performance test on the biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared in example 2, the test temperature range is-75-120 ℃, the test temperature range is nitrogen atmosphere, the temperature rising speed is 5 ℃/min, the temperature reducing speed is 5 ℃/min, and the test result is shown in figure 4.

As can be seen from FIG. 4, the temperature was raised at a rate of 5 ℃/min, and a melting absorption peak appeared at 36.8 ℃, corresponding to the melting point of the copolymer; the temperature is reduced at a rate of 5 ℃/min, and a crystallization exothermic peak appears at minus 9.8 ℃, corresponding to the crystallization temperature of the copolymer.

Experimental example 3 degradation Performance test

The biodegradable shape memory copolymer of poly-e-caprolactone prepared in example 1 was subjected to a degradation performance test in phosphate buffered saline at pH 5, pH 7 and pH 9, respectively, at room temperature, and the test results are shown in fig. 5.

As can be seen from FIG. 5, the biodegradable shape memory copolymer of poly-epsilon-caprolactone prepared can be degraded to reach equilibrium basically in about 100 days. The degradation rate is the fastest in alkaline phosphate buffered saline solution with the pH value of 9, the degradation rate is the highest and can reach more than 90%, the degradation performance is good, the degradation rate is the second of the degradation rates in neutral solution with the pH value of 7, the degradation rate is the slowest in acidic solution with the pH value of 5, and the degradation rate is the lowest. The biodegradable shape memory copolymer of poly epsilon-caprolactone has good degradation performance.

The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.