Anti-calcification blood-compatible fatigue-resistant multi-silicon integrated polyurethane as well as preparation method and application thereof

Abstract

The invention provides anti-calcification blood-compatible fatigue-resistant multi-silicon integrated polyurethane as well as a preparation method and application thereof, and belongs to the field of biomedical materials. According to the polyurethane, hydroxyl-terminated polycarbonate (PCDL) and polydimethylsiloxane (PMDS) are jointly used as a soft segment and polymerized with diisocyanate to prepare a prepolymer, 1, 3-bis (3-aminopropyl)-1, 1, 3, 3-tetramethyldisiloxane is selected for primary chain extension, a silane structure is introduced into the soft segment of the polyurethane, then 3, 9-bis (1, 1-dimethyl-2-hydroxyethyl)-2, 4, 8, 9-tetramethyl-1, 3, 3-tetramethyldisiloxane is added into the soft segment of the polyurethane, and then the polyurethane is prepared. And carrying out secondary chain extension on 1, 10-oxo-helix, and adding beta-cyclodextrin to seal the end, thereby preparing the polyurethane elastomer. The polyurethane elastomer prepared by the method is excellent in biocompatibility, blood compatibility and calcification resistance. The mechanical property is adjustable, and the fatigue resistance, the creep resistance and the shearing resistance are good. The prepared polyurethane molecules are easy to compound and modify. Polyurethane has thermoplasticity and can adapt to different processing modes for constructing in-vivo implants with specific requirements.

Description

Technical Field

[0001] The present invention provides an anti-calcification, blood-compatible, fatigue-resistant multi-silicon integrated polyurethane and its preparation method and application, belonging to the field of biomedical materials. By regulating the distribution of silane in the molecular structure, the anti-calcification ability and blood compatibility of the polyurethane can be achieved, and the material has mechanical stability and biocompatibility under long-term use. Background Art

[0002] With the rapid development of medical technology, the demand for high-performance biomaterials is growing. Especially in the field of in vivo implants, higher requirements are placed on the stability of materials under long-term use. Polyurethane, as a multifunctional polymer material, is widely used in the medical field due to its excellent mechanical properties, processing convenience and good biocompatibility. However, traditional polyurethane materials may encounter problems such as mechanical property degradation, reduced biocompatibility and insufficient anti-calcification ability during long-term use, which limits its application in high-end medical implants.

[0003] Silane-based materials are generally considered to be implants with good biocompatibility, but such materials are usually difficult to withstand long-term use due to their poor mechanical properties. In addition, considering the adaptability to more stringent microenvironments, the blood compatibility and anti-calcification capabilities of the materials are more stringent. In the past, this ability was usually improved through surface modification, but under the requirements of long-term use, performance degradation, severe degenerative lesions of tissues in the body, and even the risk of secondary surgery will usually occur. How to achieve long-term in vivo implant stability by regulating the structure of polyurethane has become the key to material design.

[0004] The flexible molecular structure of polyurethane makes it possible to design structures for different environments. The introduction of silane segments into polyurethane can improve biocompatibility. However, since there is no obvious intermolecular interaction between silanes, this leads to a loss of mechanical properties of the material. In order to solve this problem, by regulating the composition of chain extenders and crosslinkers as hard segments in polyurethane, the intermolecular interaction mode can be effectively regulated to regulate the mechanical properties of polyurethane under different environments. However, in order to achieve good secondary processing capabilities of polyurethane, polyurethane needs to be designed as a thermoplastic polyurethane with no crosslinking or low crosslinking degree, which further increases the demand for polyurethane structural design.

[0005] In this context, the present invention aims to improve the biocompatibility, anti-calcification ability and blood compatibility of polyurethane materials by introducing multiple silane structures, while maintaining their mechanical stability under long-term use. In addition, the thermoplastic polyurethane elastomer developed by the present invention can be flexibly processed to meet the specific requirements of different medical applications for material properties, so as to adapt to different medical device and implant designs. Summary of the invention

[0006] The first purpose of the present invention is to provide an anti-calcification, blood-compatible, fatigue-resistant multi-silicon integrated polyurethane, in which terminal hydroxyl polycarbonate (PCDL) and polydimethylsiloxane (PMDS) are used as soft segments and polymerized with diisocyanate to prepare a prepolymer. 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane is selected for preliminary chain extension to introduce a silane structure into the soft segment of the polyurethane, and then 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix is ​​used for secondary chain extension, and finally, the polyurethane elastomer is synthesized by end-capping with β-cyclodextrin according to the requirements of mechanical properties.

[0007] Among them, polydimethylsiloxane and 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane were introduced simultaneously to uniformly integrate silane segments in polyurethane, thereby regulating the adaptability to the microenvironment. Furthermore, 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix was used as a chain extender to achieve continuous regeneration of hydrogen bonds between polyurethane molecules, so as to obtain an elastomer with good mechanical stability. Among them, β-cyclodextrin was used to enhance hydrophilicity and achieve modification through host-guest interaction. The polyurethane synthesized by this method is thermoplastic and can be used for material processing by repeated dissolution; the viscosity of the polyurethane solvent process can also be regulated by organic solvents. This polyurethane has a stable structure and will not cause mechanical property loss due to repeated processing.

[0008] The characteristics of the above polyurethane are: the polyurethane elastomer with uniform integration of silane has good biocompatibility and can adapt to different microenvironments such as blood, bile, gastric juice, urine, and tissue fluid. Polyurethane has mechanical stability, including fatigue resistance, creep resistance, shear resistance, and tear resistance, and can also be used to maintain stable hemodynamics. Polyurethane has the ability to be secondary modified through host-guest effects, and can be suitable for drug loading, structural composites, interface connections, molecular recognition, material detection, etc. Polyurethane is thermoplastic and can be processed into different shapes to meet the needs of implants in different environments, including artificial heart valves, heart patches, heart occluders, artificial blood vessels, vascular stents, vascular prostheses, balloon catheters, guidewires, spring coils and other different medical devices.

[0009] The molecular structure of the polyurethane needs to be designed before preparation, including the following steps:

[0010] (1) According to the elasticity of the target application scenario, the molecular weights of PCDL and PMDS are calculated, and the elastic modulus of polyurethane is regulated by controlling the molecular weight and degree of polymerization of the prepolymer. PCDL is used to increase the elastic modulus, while an increase in the molecular weight of PDMS will reduce the elasticity. In order to maintain biocompatibility, the molar ratio of PCDL to PDMS is controlled to (1-4):1.

[0011] (2) Calculate the amount of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane based on the blood compatibility and anti-calcification requirements of the application scenario. The more 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane, the better the anti-adhesion ability of the polyurethane. The amount of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane should always be controlled to no more than one-half of the total amount of chain extender to prevent the mechanical properties of the material from deteriorating.

[0012] (3) According to the requirements of the viscoelasticity of the material in the application scenario, the amount of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo helix is ​​adjusted. The higher the deformation frequency in the application environment of the material, the greater the amount of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo helix is ​​used, and the higher the tan δ of the polyurethane is.

[0013] (4) Based on the fatigue resistance requirements of the application environment, the remaining isocyanate is cross-linked through cyclodextrin. The degree of cross-linking is regulated according to the requirements for material toughness, but β-cyclodextrin is used to provide an average of 3 cross-linking points at most, otherwise it will affect the thermoplasticity of the polyurethane.

[0014] The second object of the present invention is to provide a method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane, comprising the following steps:

[0015] (1) PCDL and PMDS are added to a three-necked flask and heated to a molten state to obtain a mixture; the purpose of heating and melting is to remove water. The purpose of removing water is to accurately control the subsequent reaction process and eliminate the side reaction between H2O and isocyanate.

[0016] (2) The mixture obtained in (1) is cooled to 50-70° C., hexamethylene diisocyanate and dibutyltin dilaurate as catalyst are added, and the mixture is stirred for reaction for 2-6 hours under nitrogen protection to obtain a polyurethane prepolymer. During the reaction, the viscosity of the system needs to be always controlled at the same level, and dimethyl sulfoxide can be added to control the viscosity of the system to ensure a stable reaction process.

[0017] (3) Add 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane as a chain extender to the polyurethane prepolymer obtained in (2) and react for 1-3 hours. The chain extender needs to be added dropwise while increasing the stirring speed to 200 r / min to prevent the phenomenon of violent polymerization caused by excessively fast and uneven reaction.

[0018] (4) Add 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix to the product obtained in (3) to continue chain extension and react for 1-2 hours; 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix needs to be dissolved in DMSO in advance and then the solution is added dropwise to the system.

[0019] (5) Add β-cyclodextrin as a crosslinking agent to the product obtained in (4) and react for 1-4 hours; β-cyclodextrin needs to be dried in advance and stored in a desiccator. The solid crosslinking agent needs to be dissolved in DMSO in advance, and then the solution is added dropwise to the system.

[0020] (6) collecting the product obtained in (5), drying and removing the solvent to obtain the final product;

[0021] (7) The product obtained in (6) is immersed in deionized water to remove small molecules, and then dried again to obtain a medical polyurethane elastomer.

[0022] Preferably, in step (1), the molar ratio of PCDL to PDMS is (1-4):1.

[0023] Preferably, in step (2), the molar ratio of hexamethylene diisocyanate to (PCDL+PDMS) is 1:(2-2.5), (PCDL+PDMS) is the total amount of macromolecules added in step (1). The molar ratio of dibutyltin dilaurate catalyst to hexamethylene diisocyanate is 0.01:1. The stirring speed is 60-100 r / min.

[0024] Preferably, in step (3), the molar ratio of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane to (PCDL+PDMS) is 0.4:1.

[0025] Preferably, in step (4), the molar ratio of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxospiro to (PCDL+PDMS) is 0.4:1.

[0026] Preferably, in step (5), the molar ratio of β-cyclodextrin to (PCDL+PDMS) is 0.2:1.

[0027] Preferably, in step (6), the drying is carried out in a forced air drying oven at 80°C.

[0028] Preferably, in step (7), the product obtained in (6) is immersed in deionized water for 5-10 days, and the water is changed once a day to ensure that all small molecules in the material are released. Then, the product is dried again.

[0029] Furthermore, the PCDL and PDMS in step (1) can also be replaced by other macromolecular diols. As long as the product has good biocompatibility, good reactivity and good stability, one or more macromolecular diols can be used at the same time, including but not limited to terminal hydroxyl polycarbonate, terminal hydroxyl polycaprolactone, polyethylene terephthalic anhydride-ethylene glycol, 1,4-cyclohexane polyester diol, polytetrahydrofuran, polyisosorbide diol, polyethylene glycol, etc.

[0030] Furthermore, the hexamethylene diisocyanate in step (2) can also be replaced by other diisocyanates. As long as the diisocyanate used has good biocompatibility, no biotoxicity, good reactivity, and good stability, one or more diisocyanates can be used at the same time, including but not limited to hexamethylene diisocyanate, lysine diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, and isophorone diisocyanate.

[0031] Furthermore, the 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane in step (3) can also be replaced by other chain extenders. As long as the chain extender used has good biocompatibility, no biotoxicity, good reactivity, and good stability, other small molecules can be introduced, including but not limited to 1,4-butanediol, 1,6-hexanediol, diethylene glycol, 1,4-cyclohexanediol, hexamethylenediamine, L-cystine, arginine, diisopropylbenzene peroxide, and dimethylsilanediol.

[0032] Furthermore, the β-cyclodextrin in step (5) can also be replaced by other crosslinking agents. The crosslinking agent selected for synthesizing polyurethane can be used simultaneously as long as the product has good biocompatibility, no biological toxicity, good reactivity, and good stability. One or more macrocyclic polyhydroxy compounds and their derivatives can be used, including but not limited to hydroxypropyl β-cyclodextrin and calixarene.

[0033] The third object of the present invention is to provide an application of the polyurethane, including processing and molding the polyurethane, including but not limited to casting molding, spray molding, reaction injection molding, extrusion molding, compression molding, variable fiber injection molding, etc.

[0034] Furthermore, the casting process comprises the following steps:

[0035] (1) Weigh the medical polyurethane elastomer prepared above, add it to the dimethyl sulfoxide solution, heat and stir until the elastomer is completely melted to obtain a 20-80wt% polyurethane solution, the heating temperature is 80-120°C, and the stirring speed is 50r / min; condense and reflux during the stirring process to prevent DMSO loss;

[0036] (2) Add the polyurethane solution in (1) into the injection molding machine and inject it into the mold, or directly pour it into the mold to level and form a film.

[0037] (3) The polyurethane and the mold are placed in a -20°C refrigerated storage for shaping and demolding, and then placed in a 60°C forced air drying oven to remove a large amount of organic solvents until the shape of the polyurethane is completely fixed.

[0038] (4) The polyurethane material obtained in (3) is immersed in ionized water for 7 days, and the water is changed once a day to ensure that all small molecules in the material are released, thereby obtaining the final product.

[0039] The polyurethane elastomer prepared by the above method has excellent biocompatibility, blood compatibility and anti-calcification. Its mechanical properties are adjustable, and it has good fatigue resistance, creep resistance and shear resistance. The prepared polyurethane molecules are easy to compound and modify. Polyurethane has thermoplasticity and can be adapted to different processing modes for constructing in vivo implants with specific needs.

[0040] The fatigue-resistant polyurethane material designed by the present invention has long-term blood compatibility and anti-calcification ability, and has multiple forms, adaptability to multiple occasions, simple operation, good biocompatibility, and suitable mechanical properties. It can be used for the design of long-term implants in a variety of complex in vivo environments, including artificial heart valves, heart patches, heart occluders, artificial blood vessels, vascular stents, vascular prostheses, balloon catheters, guide wires, spring coils, etc.

[0041] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0042] 1. The present invention provides a polyurethane with multiple silane structures. The polyurethane introduces polydimethylsiloxane in the soft segment to achieve good biocompatibility. The polyurethane regulates the adaptability to different tissue microenvironments through 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane. The polyurethane controls the elastic modulus by regulating the proportion and molecular weight of the soft segment, regulates the interaction between molecules through 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo helix, and achieves good fatigue resistance through local high-density hydrogen bonds.

[0043] 2. The polyurethane synthesized in the present invention has host-guest recognition and inclusion capabilities, and can be used to combine with other materials; it has thermoplasticity and meets a variety of different processing modes; it can meet the blood compatibility and anti-calcification capabilities required for in vivo implantation. It can achieve the regulation of viscoelasticity and meet the deformation requirements at different frequencies; it has good shear resistance and can achieve the surgical method of suture implantation. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0045] Figure 1 The polyurethane of Example 1 of the present invention 1 H NMR spectra;

[0046] Figure 2 is the DSC graph of the polyurethane of Example 1 of the present invention;

[0047] Figure 3 The blood compatibility test of the polyurethane of Example 2 of the present invention;

[0048] Figure 4 This is the calcium deposition of the polyurethane of Example 3 of the present invention under simulated body fluid. DETAILED DESCRIPTION

[0049] In order to make the technical problems, technical solutions and advantages to be solved by the present invention more clear, a detailed description will be given below with reference to the accompanying drawings and specific embodiments.

[0050] Example 1

[0051] In order to achieve the requirements for blood compatibility and anti-calcification ability, the molar ratio of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane to 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix is ​​1:1. However, it is not cross-linked by β-cyclodextrin, and is mainly used to make hydrophobic films, while making the films have lower toughness. The preparation and processing method of the polyurethane with multiple silane structures is as follows:

[0052] 8.0 g of hydroxy-terminated polycarbonate 2000 and 0.5 g of hydroxy-terminated polydimethylsiloxane 500 were weighed and added into a three-necked flask, and heated at 110° C. for 30 min to remove moisture; the temperature was lowered to 60° C., 1.61 mL of hexamethylene diisocyanate and 1 drop of dibutyltin dilaurate catalyst were added, and dimethyl sulfoxide was added to adjust the viscosity of the system, and the reaction was stirred for 3 h under nitrogen protection at a stirring speed of 100 r / min to obtain a polyurethane prepolymer;

[0053] 0.69 mL of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane was added to the polyurethane prepolymer and reacted for 1.5 h; then 0.76 g of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxospiro was added and reacted for 2 h; the sample was collected and placed in an 80° C. forced air drying oven to remove the solvent, thereby obtaining a medical polyurethane material;

[0054] Weigh 2.0 g of medical polyurethane material, add it to 6.0 mL of dimethyl sulfoxide solution, heat and stir at a temperature of 100°C and a stirring speed of 100 r / min; when the material is completely melted, pour the polyurethane solution into a polytetrafluoroethylene mold to level and form a film.

[0055] The film was then placed in a 60° C. forced air drying oven for 24 hours, taken out and immersed in deionized water for 7 days, with the water changed every day, to obtain a polyurethane film with good blood compatibility and anti-calcification ability.

[0056] Example 2

[0057] In order to achieve good toughness of the material, β-cyclodextrin is used to increase the crosslinking degree of polyurethane, and in order to maintain the hydrophobicity of the polyurethane material, polydimethylsiloxane 1000 with a higher molecular weight is used in the soft segment region to maintain the blood compatibility and anti-calcification ability of the material. The preparation and processing method of the polyurethane with multiple silane structures is as follows:

[0058] Weigh 5.0 g of polytetrahydrofuran 2000 and 2.5 g of terminal hydroxyl polydimethylsiloxane 1000 into a three-necked flask, heat at 110° C. for 30 min to remove moisture; cool to 60° C., add 2.58 mL of dicyclohexylmethane diisocyanate and 1 drop of dibutyltin dilaurate catalyst, add dimethyl sulfoxide to adjust the viscosity of the system, stir and react for 4 h under nitrogen protection at a stirring speed of 100 r / min to obtain a polyurethane prepolymer;

[0059] Add 0.55 mL of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane to the polyurethane prepolymer and react for 2 hours; then add 0.61 g of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxospiro and react for 3 hours; then weigh 0.76 g of β-cyclodextrin, dissolve it in 2 mL of DMSO, add it to the flask and react for 2 hours. Collect the sample and place it in an 80°C forced air drying oven to remove the solvent to obtain a medical polyurethane material;

[0060] Weigh 4.0 g of medical polyurethane material, add it to 8.0 mL of dimethyl sulfoxide solution, heat and stir at 100°C and a stirring speed of 100 r / min; wait until the material is completely melted, soak the artificial blood vessel in the polyurethane, then take out the artificial blood vessel, and cool it down to allow the polyurethane to evenly adhere to the surface of the artificial blood vessel.

[0061] The artificial blood vessel was then placed in a 60°C air drying oven for 24 hours, taken out and immersed in deionized water for 7 days, with the water changed once a day. The surface of the material was finally modified by polyurethane to improve the material's blood compatibility and anti-calcification ability.

[0062] Embodiment 3:

[0063] The hydrophilicity of the polyurethane material can also be achieved by replacing part of the polycarbonate with polyethylene glycol in the soft segment, and introducing oxalohydrazide into the chain extender to make the polyurethane have a higher elastic modulus. At the same time, 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane is still required in the chain extender to maintain the good blood compatibility of the entire polyurethane molecule. The preparation and processing method of the polyurethane with multiple silane structures is as follows:

[0064] Weigh 5.0 g of polycarbonate 2000, 3.0 g of polyethylene glycol 2000 and 0.5 g of terminal hydroxyl polydimethylsiloxane 1000 into a three-necked flask, heat at 110° C. for 30 min to remove moisture; cool to 60° C., add 2.58 mL of dicyclohexylmethane diisocyanate and 1 drop of dibutyltin dilaurate catalyst, add dimethyl sulfoxide to adjust the viscosity of the system, stir and react for 4 h under nitrogen protection at a stirring speed of 100 r / min to obtain a polyurethane prepolymer;

[0065] Add 0.55 mL of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane to the polyurethane prepolymer and react for 2 hours; then add 0.24 g of oxalohydrazide and react for 2 hours; then add 0.46 g of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxospiro and react for 3 hours. Collect the sample and place it in an 80°C forced air drying oven to remove the solvent to obtain a medical polyurethane material;

[0066] Weigh 4.0 g of medical polyurethane material, add it into 2.0 mL of dimethyl sulfoxide solution, heat and stir at a temperature of 100° C. and a stirring speed of 100 r / min; when the material is completely melted, inject the polyurethane into a mold through an injection molding machine to prepare an in vivo implant with a specific shape.

[0067] The mold was placed in -20℃ for 24 hours, and then the mold was opened. The polyurethane implant was then placed in a 60℃ forced air drying oven for 24 hours, taken out and immersed in deionized water for 7 days, with the water changed once a day. Finally, a polyurethane implant with good blood compatibility, anti-calcification and fatigue resistance was obtained.

[0068] The polyurethane prepared in the above example was tested for performance, and the specific results are as follows:

[0069] Figure 1 The polyurethane of Example 1 of the present invention 1 H NMR spectra. 1 The peak at 0.05ppm in H NMR comes from the methyl group in 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane, and the peak at 0.09ppm comes from polydimethylsiloxane. The triplet peak at 3.3-3.6ppm is the four methylene groups connected to the O element in 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix. The three 1:1:1 peaks at 1.14, 1.70 and 4.14ppm come from the methylene groups in three different states in polycarbonate, which verifies the presence of a large number of polycarbonate units in polyurethane.

[0070] Figure 2 This is the DSC graph of the polyurethane of Example 1 of the present invention. The polyurethane has a relatively low glass transition temperature (-27.8°C), which indicates that its molecular chain is relatively flexible. The polyurethane is highly elastic at room temperature and can exhibit good mechanical properties.

[0071] Figure 3 This is the blood compatibility test of the polyurethane of Example 2 of the present invention. After the film was used to treat fresh blood for 5 minutes, the adhesion of the material to red blood cells can be observed very intuitively, and it can be seen that there is no obvious thrombus or a large amount of blood deposition on the surface of the polyurethane film. This also verifies the good blood compatibility of the material.

[0072] Figure 4 This is the calcium deposition of the polyurethane of Example 3 of the present invention under simulated body fluid. After 28 days of SBF simulated body fluid treatment, no obvious material deposition appeared on the surface of the polyurethane film. By observing the element distribution on the surface of the material by EDS, it can be seen that no obvious concentration of Ca elements appeared. This shows that the material has good anti-calcification ability.

[0073] The preparation methods of Comparative Examples 1-4 are similar to those of Example 1, except that the molar ratio of the raw materials is different. The molar ratio of the raw materials and the performance test results of the Examples and Comparative Example 1 are listed in Table 1.

[0074] Table 1 Tensile fatigue rate, hemolysis rate and calcium deposition rate of polyurethane with different ratios after 10,000 cycles

[0075]

[0076] The long-term blood compatibility, anti-calcification and fatigue resistance of polyurethane must simultaneously meet the requirements of silane integration and intermolecular enhancement. As shown in Table 1, Comparative Example 1 showed a significantly high hemolysis rate and calcium deposition due to the lack of silane introduction; Comparative Example 2 showed poor blood compatibility due to the lack of PDMS introduction in the soft segment; Comparative Example 3 showed poor blood compatibility due to the lack of silane introduction in the hard segment through 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane, and also showed a certain amount of calcium deposition. Comparative Example 4 showed obvious fatigue in the material due to the lack of intermolecular enhancement through 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo-helix.

[0077] By comparing the tensile fatigue rate, hemolysis rate and calcium deposition rate of different polyurethane structures, the comprehensive performance effects of silane uniform integration and 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo-helix toughening on polyurethane films can be studied. Among them, the lack of sufficient silane segments will lead to obvious blood cell damage and calcium deposition during long-term use. Only the simultaneous introduction of polydimethylsiloxane and 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane can ensure the blood compatibility and anti-calcification ability of the material. At the same time, 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxo-helix can significantly improve the fatigue resistance of polyurethane, so that the material has mechanical stability for long-term use. The samples of Examples 1-3 all showed good blood compatibility and fatigue resistance. It is conducive to long-term use in vivo.

[0078] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. An anti-calcification, blood-compatible, fatigue-resistant multi-silicon integrated polyurethane, characterized in that: The polyurethane uses terminal hydroxyl polycarbonate (PCDL) and polydimethylsiloxane (PMDS) as soft segments, polymerizes with diisocyanate to prepare a prepolymer, selects 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane for primary chain extension to introduce a silane structure into the soft segment of the polyurethane, and then uses 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix for secondary chain extension, and adds β-cyclodextrin for end-capping to prepare a polyurethane elastomer.

2. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 1, characterized in that: The following steps are involved: (1) PCDL and PMDS are added into a three-necked flask and heated to a molten state to obtain a mixture; (2) cooling the mixture obtained in (1) to 50-70° C., adding hexamethylene diisocyanate and dibutyltin dilaurate as a catalyst, and stirring the mixture under nitrogen protection for 2-6 hours to obtain a polyurethane prepolymer; (3) adding 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane as a chain extender to the polyurethane prepolymer obtained in (2) and reacting for 1-3 hours; (4) Add 3,9-di(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxohelix to the product obtained in (3) to continue chain extension and react for 1-2 hours; (5) adding β-cyclodextrin as a cross-linking agent to the product obtained in (4) and reacting for 1-4 hours; (6) collecting the product obtained in (5), drying and removing the solvent to obtain the final product; (7) The product obtained in (6) is immersed in deionized water to remove small molecules, and then dried again to obtain a medical polyurethane elastomer.

3. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: In step (1), the molar ratio of PCDL to PDMS is (1-4):

1.

4. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: In step (2), the molar ratio of hexamethylene diisocyanate to (PCDL+PDMS) is 1:(2-2.5), the molar ratio of dibutyltin dilaurate catalyst to hexamethylene diisocyanate is 0.01:1, and the stirring speed is 60-100 r / min.

5. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: In step (3), the molar ratio of 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane to (PCDL+PDMS) is 0.4:1; and / or, in step (4), the molar ratio of 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-oxospiro to (PCDL+PDMS) is 0.4:1; And / or, in step (5), the molar ratio of β-cyclodextrin to (PCDL+PDMS) is 0.2:

1.

6. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: The PCDL and PDMS in step (1) are replaced by one or more of terminal hydroxyl polycarbonate, terminal hydroxyl polycaprolactone, polyethylene terephthalic anhydride-ethylene glycol, 1,4-cyclohexane polyester diol, polytetrahydrofuran, polyisosorbide diol, and polyethylene glycol.

7. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: The hexamethylene diisocyanate in step (2) is replaced by one or more of hexamethylene diisocyanate, lysine diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, and isophorone diisocyanate.

8. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: The 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane in step (3) is replaced by one or more of 1,4-butanediol, 1,6-hexanediol, diethylene glycol, 1,4-cyclohexanediol, hexamethylenediamine, L-cystine, arginine, diisopropyl peroxide, and dimethylsilanediol.

9. The method for preparing the anti-calcification, blood-compatible, fatigue-resistant multi-silicon-integrated polyurethane according to claim 2, characterized in that: The β-cyclodextrin in step (5) is replaced by one or more of hydroxypropyl β-cyclodextrin and calixarene.

10. Use of the polyurethane according to claim 1 or the polyurethane prepared by the method according to any one of claims 2 to 9, characterized in that: The invention includes processing and molding the implant into an in vivo implant, wherein the implant is an artificial heart valve, a heart patch, a heart occluder, an artificial blood vessel, a vascular stent, a vascular prosthesis, a balloon catheter, a guide wire, and a spring coil.

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