A biodegradable polyurethane elastomer, its preparation method and application

Abstract

The present invention relates to the technical field of biomaterials, and discloses a biodegradable polyurethane elastomer, a preparation method thereof and an application. The preparation method comprises the following steps: (1) Using polycaprolactone diol, poly-3-hydroxybutyrate, polyethylene glycol, diisocyanate and 2-hydroxyethyl methacrylate as raw materials, under a nitrogen or inert gas environment, preparing a vinyl-terminated polyurethane prepolymer; (2) Heating the product in (1), adding a diluent, mixing evenly, adding an initiator, and raising the temperature for reaction for 3 to 4 h to obtain a biodegradable polyurethane elastomer; using the prepared biodegradable polyurethane elastomer to prepare an artificial tissue engineering hard bone tissue material. The present invention uses three kinds of diols as raw materials, as a mixed soft segment for preparing the biodegradable polyurethane elastomer, exerts the synergistic effect of the three kinds of diols, and regulates the biodegradation rate of the biodegradable polyurethane elastomer by controlling the mass ratio and molecular weight of the three.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and specifically to a biodegradable polyurethane elastomer and its preparation method and application. Background Art

[0002] In recent years, polyurethane elastomers have been widely used in the biomedical field. For example, they can be used as tissue engineering materials. Materials used in tissue engineering need to have a controllable biodegradation rate, good biocompatibility, and mechanical properties matching those of tissues. Biodegradable polyurethane elastomers have been relatively successful in simulating tissue mechanics, and their mechanical properties and degradation rate can be regulated by the type and content of the soft segment and the crosslinking density. Polymers with biodegradability and biocompatibility, such as polylactic acid, polyglycolic acid, polycaprolactone, and poly-3-hydroxybutyrate (poly(3-hydroxybutyrate) diol), etc., can be widely used in the biomedical field, and they can also be used as comonomers for biodegradable polyurethane soft segments.

[0003] In the prior art, polylactic acid, polyglycolic acid, and polycaprolactone are used as comonomers for biodegradable polyurethane soft segments. These polymers belong to aliphatic polyesters and have the advantages of easy hydrolysis degradation and non-toxic degradation products. However, when such polymers are applied to tissue engineering, it is impossible to achieve good effects in both mechanical properties and biodegradation rate simultaneously. Therefore, it is necessary to prepare a biodegradable polyurethane elastomer with good effects in both mechanical properties and biodegradation rate simultaneously. Summary of the Invention

[0004] Embodiments of the present invention provide a biodegradable polyurethane elastomer and its preparation method and application, so as to solve the problem that polyester-based biodegradable polyurethane elastomers in the prior art cannot achieve good effects in both mechanical properties and biodegradation rate simultaneously.

[0005] The present invention discloses a preparation method of a biodegradable polyurethane elastomer, and the method includes the following steps:

[0006] (1) Preparation of vinyl-terminated polyurethane prepolymer:

[0007] Using polycaprolactone diol, poly-3-hydroxybutyrate 、 polyethylene glycol, diisocyanate, and 2-hydroxyethyl methacrylate as raw materials, preparing a vinyl-terminated polyurethane prepolymer under a nitrogen or inert gas environment;

[0008] The mass ratio of the polycaprolactone diol, the poly-3-hydroxybutyrate, the polyethylene glycol, the diisocyanate, and the 2-hydroxyethyl methacrylate is 108.64 g - 287.2 g: 18.36 g - 24.26 g: 13.58 g - 35.90 g: 60 g: 35.27 g - 46.52 g;

[0009] (2) Preparation of the polyurethane elastomer:

[0010] Heat the prepared vinyl-terminated polyurethane prepolymer to 30 - 35 °C, add a diluent, mix evenly, then add an initiator, raise the temperature of the system to 75 - 80 °C, and react for 3 - 4 h to obtain a biodegradable polyurethane elastomer for biomedical use.

[0011] Preferably, in (1), add the polycaprolactone diol, poly-3-hydroxybutyrate, and polyethylene glycol to a reactor equipped with a nitrogen or inert gas device, stir at 150 - 200 rpm, heat to 55 - 60 °C, mix evenly, then add the diisocyanate. After adding, raise the temperature to 80 - 85 °C and increase the stirring speed to 250 - 300 rpm. When the molar percentage of the remaining NCO in the reaction system reaches 49.7%, lower the temperature of the reaction system to 40 - 45 °C; then add 2-hydroxyethyl methacrylate to the reactor. After adding, raise the reaction temperature to 80 - 85 °C again. Stop the reaction when all the remaining NCO in the system has reacted to obtain a vinyl-terminated polyurethane prepolymer.

[0012] Preferably, the molecular weight of the polycaprolactone diol is 1000 g / mol or 2000 g / mol, the molecular weight of the polyethylene glycol is 1000 g / mol or 2000 g / mol, and the molecular weight of the poly-3-hydroxybutyrate is 1352 g / mol.

[0013] Preferably, in (1), the diisocyanate is one of isophorone diisocyanate and 1,6-hexamethylene diisocyanate, and the diisocyanate accounts for 9.25 - 17.81% of the total mass of the vinyl-terminated polyurethane prepolymer and the diluent.

[0014] Preferably, the diluent is 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate, and the mass ratio of the 2-hydroxyethyl methacrylate to the ethylene glycol dimethacrylate is 3:1.

[0015] Preferably, in (1), the 2-hydroxyethyl methacrylate accounts for 22.2 - 22.7% of the total mass of the vinyl-terminated polyurethane prepolymer and the diluent.

[0016] Preferably, in (2), the mass ratio of the vinyl-terminated polyurethane prepolymer to the diluent is 7:3.

[0017] Preferably, the initiator described in (2) is 2,2-azobisisobutyronitrile, accounting for 0.9-1.1% of the total mass of the vinyl-terminated polyurethane prepolymer and the mixed diluent.

[0018] The second object of the present invention is to provide a biodegradable polyurethane elastomer prepared by the preparation method of the biodegradable polyurethane elastomer.

[0019] The third object of the present invention is to use the prepared biodegradable polyurethane elastomer to prepare artificial tissue engineering hard bone tissue materials.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] The present invention uses polycaprolactone diol, poly-3-hydroxybutyrate and polyethylene glycol as raw materials, as a mixed soft segment for preparing biodegradable polyurethane elastomers, giving play to the synergistic effect of the three diols, and by controlling their mass ratio and molecular weight, the mechanical properties, crystallization properties, hydrophilic-hydrophobic properties and biodegradation rate of the biodegradable polyurethane elastomer can be simultaneously achieved with good results.

[0022] Using polycaprolactone diol as a raw material is because it has good biocompatibility, good compatibility with organic polymers, and good biodegradability, and can be used as a cell growth support material. However, in the natural environment, the degradation of polycaprolactone is slow, and the degradation time is 2-3 years; compared with polycaprolactone, poly-3-hydroxybutyrate has better biodegradability and biocompatibility, and its synergistic use with polycaprolactone can regulate the biodegradability of biomaterials; using polyethylene glycol as a raw material is because it has good water solubility, good compatibility with many organic components, good cell adhesion and proliferation, and although polyethylene glycol is not easily degraded, it can be excreted from the body.

[0023] The present invention does not add any organic solvents and catalysts during the whole process of preparing polyurethane elastomers, overcoming the disadvantage that residual organic solvents or catalysts in traditional polyurethane elastomer products may cause side effects. Without adding organic solvents, the viscosity of the vinyl-terminated polyurethane prepolymer prepared is relatively high, and insufficient crosslinking degree will affect the mechanical properties of the final elastomer. Therefore, the present invention uses two different functional acrylic monomers as crosslinking reaction diluents, which can reduce the viscosity of the reaction system while controlling the mass ratio of the monofunctional diluent to the bifunctional diluent and the crosslinking degree of the polyurethane elastomer, so that the mechanical properties, hydrophilic-hydrophobic properties and biodegradation rate of the final product can be simultaneously achieved with good results. Description of the Drawings

[0024] Figure 1This is a graph showing the mass loss data of the biomedical biodegradable polyurethane elastomer in pancreatin after 2, 4, 6, and 8 months of degradation. Detailed implementation mode

[0025] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work belong to the protection scope of the present invention.

[0026] In each embodiment of the present invention, the experimental methods are all conventional methods unless otherwise specified. The materials, reagents, etc. used can be obtained from commercial channels unless otherwise specified.

[0027] Example 1: A preparation method of a biodegradable polyurethane elastomer, with the following usage conditions of raw materials:

[0028] Isophorone diisocyanate, mass 60g; polycaprolactone diol with a molecular weight of 1000g / mol, mass 108.64g; poly-3-hydroxybutyrate, molecular weight 1352g / mol, mass 18.36g; polyethylene glycol, molecular weight 1000g / mol, mass 13.58g; 2-hydroxyethyl methacrylate, mass 111.07g; ethylene glycol dimethacrylate, 25.27g; 2,2'-azobisisobutyronitrile, 3.36g.

[0029] Among them, 2-hydroxyethyl methacrylate used for preparing vinyl-terminated polyurethane prepolymer has a mass of 35.27g; 2-hydroxyethyl methacrylate in the diluent, 75.80g.

[0030] The preparation steps and conditions are as follows:

[0031] Preparation of vinyl-terminated polyurethane prepolymer

[0032] (1) Preparation of vinyl-terminated polyurethane prepolymer: Add polycaprolactone diol, poly-3-hydroxybutyrate, and polyethylene glycol to a reactor equipped with a nitrogen or inert gas device, stir at 150 rpm, heat to 55 °C, mix evenly, then dropwise add diisocyanate. After the addition is complete, raise the temperature to 80 °C and increase the stirring speed to 250 rpm. When the molar percentage of remaining NCO in the reaction system reaches 49.7%, lower the reaction system temperature to 40 °C; then dropwise add 2-hydroxyethyl methacrylate to the reactor, complete the addition in 30 minutes, and then raise the reaction temperature to 80 °C. Stop the reaction when all the remaining NCO in the system has reacted to obtain a vinyl-terminated polyurethane prepolymer;

[0033] The remaining NCO content in the reaction system was determined by infrared spectroscopy. The specific test method was as follows: Take 0.2 g of the sample during the polyurethane prepolymerization reaction, apply it on a 3-mm KBr tablet with a glass rod, dry it by infrared baking, and then perform a scanning test to obtain an infrared spectrum. According to the infrared spectrum, the absorbance of the corresponding peak was obtained. Based on the -CH 2 - absorption peak with unchanged concentration during the reaction process was selected as the internal standard peak, and R 0 =(A 2275cm-1 / A 2980cm-1 ) 0 and R t =(A 2275cm-1 / A 2980cm-1 ) t respectively represented the absorbance ratios at the initial stage of the reaction and at the reaction time of t. The conversion rate of NCO during the reaction process could be obtained. The calculation formula for the conversion rate α of NCO was as follows:

[0034]

[0035] where A was the absorbance, A 2275cm-1 was the absorbance of the -NCO group at 2275 cm -1 , and A 2980cm-1 was the absorbance of the -CH 2 - group at 2980 cm -1 .

[0036] (2) Preparation of the polyurethane elastomer: Take 235.85 g of the prepared vinyl-terminated polyurethane prepolymer, heat it to 30 °C, add 101.07 g of the diluent, mix evenly, then add 3.36 g of the initiator 2,2-azobisisobutyronitrile, raise the temperature of the system to 75 °C, and react for 3 h to obtain a biomedical biodegradable polyurethane elastomer.

[0037] The diluent was a mixture of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate, and the mass ratio of 2-hydroxyethyl methacrylate to the ethylene glycol dimethacrylate was 3:1.

[0038] Example 2: A method for preparing a biodegradable polyurethane elastomer, the steps and conditions were as follows:

[0039] The specific addition amounts are as follows: 1,6 - hexamethylene diisocyanate, 60 g in mass; polycaprolactone diol with a molecular weight of 1000 g / mol, 143.60 g in mass; poly - 3 - hydroxybutyrate with a molecular weight of 1352 g / mol, 24.26 g in mass; polyethylene glycol with a molecular weight of 1000 g / mol, 17.95 g in mass; 2 - hydroxyethyl methacrylate, 140.48 g in mass; ethylene glycol dimethacrylate, 31.32 g; 2,2 - azobisisobutyronitrile, 4.17 g.

[0040] Among them, 2 - hydroxyethyl methacrylate used for preparing the vinyl - terminated polyurethane prepolymer is 46.52 g in mass; 2 - hydroxyethyl methacrylate in the mixed diluent is 93.96 g.

[0041] The preparation steps and conditions are as follows:

[0042] Preparation of vinyl - terminated polyurethane prepolymer

[0043] (1) Preparation of vinyl - terminated polyurethane prepolymer: Add polycaprolactone diol, poly - 3 - hydroxybutyrate, and polyethylene glycol into a reactor equipped with a nitrogen or inert gas device, stir at 200 rpm, heat to 60 °C, after mixing evenly, add diisocyanate dropwise. After the drop - wise addition is completed, raise the temperature to 85 °C and increase the stirring speed to 300 rpm. When the molar percentage of remaining NCO in the reaction system reaches 49.7%, lower the temperature of the reaction system to 45 °C; then add 2 - hydroxyethyl methacrylate dropwise to the reactor, complete the drop - wise addition in 40 min, and then raise the reaction temperature to 85 °C. Stop the reaction when all the remaining NCO in the system has reacted to obtain the vinyl - terminated polyurethane prepolymer;

[0044] Use infrared spectroscopy to measure the content of remaining NCO in the reaction system. The specific test method is as follows: Take 0.2 g of the sample during the polyurethane prepolymer reaction, smear it on a 3 - mm KBr tablet with a glass rod, dry it by infrared baking, and then perform a scanning test to obtain an infrared spectrum. According to the infrared spectrum, obtain the absorbance of the corresponding peak. According to the absorption peak of - CH 2 - that does not change in concentration during the reaction process as the internal standard peak, use R 0 =(A 2275cm-1 / A 2980cm-1 ) 0 and use R t =(A 2275cm-1 / A 2980cm-1 ) t to represent the absorbance ratio at the initial stage of the reaction and at the reaction time t respectively, and the conversion rate of NCO in the reaction process can be obtained. The calculation formula for the conversion rate α of NCO is as follows:

[0045]

[0046] Among them, A is the absorbance, and A 2275cm-1 is the absorbance of the -NCO group at 2275 cm -1 and A 2980cm-1 is the absorbance of the -CH 2 - group at 2980 cm -1 and is the absorbance at this position.

[0047] (2) Preparation of the polyurethane elastomer: Take 292.32 g of the prepared vinyl-terminated polyurethane prepolymer, heat it to 35 °C, add 125.28 g of the diluent, mix evenly, then add 4.17 g of the initiator, raise the temperature of the system to 80 °C, and react for 4 h to obtain the biodegradable polyurethane elastomer for biomedical use.

[0048] Example 3: A preparation method of a biodegradable polyurethane elastomer, the steps and conditions are as follows:

[0049] 1,6-Hexamethylene diisocyanate, with a mass of 60 g, polycaprolactone diol with a molecular weight of 2000 g / mol, with a mass of 287.2 g; poly-3-hydroxybutyrate, with a molecular weight of 1352 g / mol, with a mass of 24.26 g; polyethylene glycol, with a molecular weight of 2000 g / mol, with a mass of 35.90 g; 2-hydroxyethyl methacrylate, with a mass of 192.41 g, ethylene glycol dimethacrylate, 48.63 g; 2,2'-azobisisobutyronitrile, 6.48 g.

[0050] Among them, 2-hydroxyethyl methacrylate used for preparing the vinyl-terminated polyurethane prepolymer, with a mass of 46.52 g; 2-hydroxyethyl methacrylate in the diluent, 145.89 g.

[0051] The preparation steps and conditions are as follows:

[0052] Preparation of the vinyl-terminated polyurethane prepolymer

[0053] (1) Preparation of the vinyl-terminated polyurethane prepolymer: Add polycaprolactone diol, poly-3-hydroxybutyrate and polyethylene glycol to a reactor equipped with a nitrogen or inert gas device, stir at 180 rpm, heat to 58 °C, mix evenly and then dropwise add diisocyanate. After the dropping is completed, raise the temperature to 85 °C and increase the stirring speed to 275 rpm. When the reaction reaches that the molar percentage of the remaining NCO in the system reaches 49.7%, lower the temperature of the reaction system to 43 °C; then dropwise add 2-hydroxyethyl methacrylate to the reactor, and complete the dropping in 35 min. Then raise the reaction temperature to 82 °C, and stop the reaction when all the remaining NCO in the system has reacted to obtain the vinyl-terminated polyurethane prepolymer;

[0054] The remaining NCO content in the reaction system was determined by infrared spectroscopy. The specific test method was as follows: Take 0.2 g of the sample during the polyurethane prepolymerization reaction, apply it on a 3-mm KBr tablet with a glass rod, dry it by infrared baking, and then perform a scanning test to obtain an infrared spectrum. According to the infrared spectrum, the absorbance of the corresponding peak was obtained. Based on the -CH 2 - absorption peak with unchanged concentration during the reaction process was selected as the internal standard peak, and R 0 =(A 2275cm-1 / A 2980cm-1 ) 0 and R t =(A 2275cm-1 / A 2980cm-1 ) t were used to represent the absorbance ratios at the initial stage of the reaction and at the reaction time of t, respectively. The conversion rate of NCO during the reaction could be obtained. The calculation formula for the conversion rate α of NCO was as follows:

[0055]

[0056] where A was the absorbance, A 2275cm-1 was the absorbance of the -NCO group at 2275 cm -1 , and A 2980cm-1 was the absorbance of the -CH 2 - group at 2980 cm -1 .

[0057] (2) Preparation of the polyurethane elastomer: Take 453.88 g of the prepared vinyl-terminated polyurethane prepolymer, heat it to 33 °C, add 194.52 g of the diluent, mix evenly, then add 6.48 g of the initiator, raise the temperature of the system to 77 °C, and react for 3.5 h to obtain a biodegradable polyurethane elastomer for biomedical use.

[0058] The properties of the biodegradable polyurethane elastomers in Examples 1 to 3 were measured.

[0059] Table 1 Tensile property data of the biodegradable polyurethane elastomer

[0060]

[0061] Table 2 Water absorption rate and water contact angle of the biodegradable polyurethane elastomer

[0062]

[0063] From Table 1, Table 2 and Figure 1It can be obtained that the products of Examples 1 to 3 all have high mechanical properties, with an elastic modulus of 86.2 to 107.8 MPa, a tensile strength of 18.5 to 22.6 MPa, and an elongation at break of 39.6 to 57.4%. The product films of Examples 1 to 3 all have good wetting properties, which are beneficial to cell adhesion. Their water contact angles are 60.7 to 66.9°, and the water absorption rate reaches 5.92 to 7.96% after 72 h. The products of Examples 1 to 3 have good biodegradability. As time increases, the mass losses of the products of the three examples all increase, and the mass losses of the three products after 8 months are 11.2 to 12.2%. Therefore, the biodegradable polyurethane elastomer can be used in the field of biomedical hard tissue engineering.

[0064] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they learn the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0065] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A preparation method of a biodegradable polyurethane elastomer, characterized in that, it comprises the following steps: (1) Preparation of a vinyl-terminated polyurethane prepolymer: Using polycaprolactone diol, poly-3-hydroxybutyrate, polyethylene glycol, diisocyanate and 2-hydroxyethyl methacrylate as raw materials, in an inert gas environment, prepare a vinyl-terminated polyurethane prepolymer; The mass ratio of the polycaprolactone diol, the poly-3-hydroxybutyrate, the polyethylene glycol, the diisocyanate and the 2-hydroxyethyl methacrylate is 108.64 g - 287.2 g: 18.36 g - 24.26 g: 13.58 g - 35.90 g: 60 g: 35.27 g - 46.52 g; (2) Preparation of the polyurethane elastomer: Heat the prepared vinyl-terminated polyurethane prepolymer to 30 - 35 °C, add a diluent, mix evenly, then add an initiator, raise the temperature of the system to 75 - 80 °C, react for 3 - 4 h, to obtain a biodegradable polyurethane elastomer for biomedical use; The diluent is a mixture of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate, and the mass ratio of the 2-hydroxyethyl methacrylate to the ethylene glycol dimethacrylate is 3:1; The 2-hydroxyethyl methacrylate accounts for 22.2 - 22.7% of the total mass of the vinyl-terminated polyurethane prepolymer and the diluent.

2. The preparation method of a biodegradable polyurethane elastomer according to claim 1, characterized in that, in (1), add polycaprolactone diol, poly-3-hydroxybutyrate and polyethylene glycol to a reactor equipped with an inert gas device, stir at 150 - 200 rpm, heat to 55 - 60 °C, mix evenly and then add diisocyanate. After the addition is complete, raise the temperature to 80 - 85 °C, and raise the stirring speed to 250 - 300 rpm. When the molar percentage of the remaining NCO in the reaction system reaches 49.7%, lower the temperature of the reaction system to 40 - 45 °C; then add 2-hydroxyethyl methacrylate to the reactor. After the addition is complete, raise the reaction temperature to 80 - 85 °C again. When all the remaining NCO in the system has reacted, stop the reaction to obtain a vinyl-terminated polyurethane prepolymer.

3. The preparation method of a biodegradable polyurethane elastomer according to claim 2, characterized in that, The molecular weight of the polycaprolactone diol is 1000 g / mol or 2000 g / mol, the molecular weight of the polyethylene glycol is 1000 g / mol or 2000 g / mol, and the molecular weight of the poly-3-hydroxybutyrate is 1352 g / mol.

4. The preparation method of a biodegradable polyurethane elastomer according to claim 3, characterized in that, The diisocyanate in step (1) is one of isophorone diisocyanate and 1,6-hexamethylene diisocyanate, and the diisocyanate accounts for 9.25 - 17.81% of the total mass of the vinyl-terminated polyurethane prepolymer and the diluent.

5. The preparation method of a biodegradable polyurethane elastomer according to claim 1, characterized in that, the mass ratio of the vinyl-terminated polyurethane prepolymer to the diluent described in (2) is 7:

3.

6. The preparation method of a biodegradable polyurethane elastomer according to claim 1, characterized in that, the initiator described in (2) is 2,2-azobisisobutyronitrile, accounting for 0.9-1.1% of the total mass of the vinyl-terminated polyurethane prepolymer and the mixed diluent.

7. A biodegradable polyurethane elastomer prepared by the preparation method according to any one of claims 1-6.

8. The application of the biodegradable polyurethane elastomer according to claim 7, characterized in that, the prepared biodegradable polyurethane elastomer is used for preparing artificial tissue engineering hard bone tissue materials.

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