A high molecular weight polysiloxane polyether type polyurethane urea and its preparation method

Abstract

The present invention relates to a high molecular weight polysiloxane polyether type polyurethane urea and a preparation method thereof, belonging to the field of development and application of biomedical materials. The high molecular weight polysiloxane polyether type polyurethane urea polymer is composed of a soft segment and a hard segment, and the content of the hard segment is 25 wt.% - 45 wt.%; the soft segment includes polydimethylsiloxane and polyether, and the hard segment includes diisocyanate and a small molecule chain extender. It is prepared by a polymerization method combining bulk and solution; first, polyether diol, polydimethylsiloxane and diisocyanate are used for prepolymerization reaction in a bulk form; after the prepolymerization is completed, a secondary chain extender is added, and then a solvent is added to dissolve the reaction system into a solution, and a main chain extender is added to react until the reaction ends. This method is simple and reliable, and the prepared material has excellent biocompatibility, biological stability and good mechanical properties. The prepared polyurethane urea material is a polymer heart valve material with great application prospects.

Description

Technical Field

[0001] The present invention relates to a high molecular weight polysiloxane polyether type polyurethane urea and a preparation method thereof, and particularly relates to a preparation method of a high molecular weight polysiloxane polyether type polyurethane urea which is applied to a polymer heart valve and can be directly applied to a dip coating process, belonging to the field of development and application of biomedical materials. Background Art

[0002] Compared with biological valves, polymer valves are not only more durable, but also thinner and more bend-resistant, which will make them shine in the field of minimally invasive heart valves, expanding the variety of heart valve surgeries and greatly reducing the pain of surgical patients and the postoperative recovery time. In addition, compared with mechanical valves, their excellent biocompatibility can eliminate the use of anticoagulant drugs after surgery, greatly improving the quality of life of patients and reducing the risk of sequelae. At the same time, the relatively low material cost and processing cost make the price of polymer valves and the surgical cost lower, reducing the economic burden on patients in underdeveloped countries and regions. With the development of materials and the progress of technology, it is believed that in the near future, artificial heart valves will enter the polymer era.

[0003] The polymer for developing a polymer valve meeting the usage requirements should meet the following requirements: (1) having a relatively high molecular weight and a narrow dispersity; (2) having soft segments and hard segments in the polymer structure and having a certain degree of phase separation; (3) having sufficient (physical or chemical) crosslinking between polymer segments to increase resilience and avoid excessive creep effects; (4) good biological stability; (5) low non-specific protein adhesion; (6) excellent blood compatibility; (7) simple processing methods, such as solution processing (casting, dip coating, electrospinning), melt processing, 3D printing, etc.; (8) cheap price and low cost.

[0004] In order to develop new and durable polymer heart valves, researchers at home and abroad are working hard to find the perfect polymer materials and processing methods for artificial heart valves. Researchers at the University of Cambridge prepared an artificial heart valve with a leaflet thickness of 0.4 mm using styrene-ethylene-butylene-styrene copolymer (SEBS) and injection molding. It has excellent biocompatibility and the highest reported fatigue life of 1.2 billion cycles (Joanna R. Stasiak et al., Biomater. Sci., 2020, 8, 4467). They first used SEBS29 (PS content of 29%) to prepare the scaffold. Then the scaffold was placed in a mold, and molten SEBS20 (PS content of 20%) was injected into the mold (each leaflet) through a small hole in the middle of the leaflet, and molded onto the previously made scaffold. The area above the injection point mainly shows the circumferential direction of the cylinder, similar to the direction of collagen fibers in natural heart valve tissue. Below the injection point, a bimodal orientation was formed, with some materials aligned along the flow direction and some perpendicular to the flow direction. This is most similar to the fiber structure of natural biological valves. After injection, the mold was slowly cooled (annealed) for 10 minutes. Annealing helps the orientation of polymer molecules and enhances the order of its cylindrical configuration. Taurus Apex, developed by the domestic high-tech heart valve enterprise, Shanghai MicroPort Valve Medical Co., Ltd., is the first domestic polymer interventional valve to publish laboratory and animal experiment data in China. This artificial heart valve adopts a multi-layer bionic composite structure - having the characteristics of anisotropy similar to that of autologous valves, and can also meet the requirements of biocompatibility, physical properties and fatigue properties.

[0005] Whether it is SEBS or multi-layer bionic composite structure materials, their processing and synthesis methods are relatively cumbersome. Moreover, for SEBS, its biocompatibility and mechanical properties still need to be investigated. These points are particularly important for polymer heart valves. Recently developed silicone polyurethanes and silicone polyurethane ureas are materials that combine biocompatibility and mechanical properties. Moreover, the addition of polysiloxane greatly improves their biological stability, making them a class of artificial heart valve materials with great development prospects. Biostable poly(1,6-hexanediol)-polydimethylsiloxane-based polyurethane (urea) is such a synthetic polymer material that combines excellent mechanical properties and biocompatibility (P. A. Gunatillake et al., Polym Rev, 2019, 59(3): 391-417; L. S. Dandeniyage et al., J Biomed Mater Res Part B, 2018:106B: 1712–1720). Foldax Company has developed an artificial heart valve with this material and carried out clinical experimental research. In addition, SAT Company in South Africa and DSM Company have cooperated, and the polymer interventional valve Carbosil 2080A TSiPCU produced by DSM Company has also completed animal experiments and is about to enter the clinical experimental research stage. The above two polymer valves both use organosilicon-modified polyurethanes and polyurethane ureas, showing excellent biological stability, mechanical properties and biocompatibility, and both adopt the solution processing method of dip coating. This processing method greatly retains the original properties of the material, and the processing method is simple and convenient.

[0006] Biostable polyurethanes have been developed in response to the demand for long-term implantable medical devices such as catheters and cardiac pacing leads. The development of biostable polyurethanes has gone through the following stages: In 1967, the application of polyurethanes in biomedical materials was first reported. However, the ester bonds in the soft segments of polyester-based polyurethanes are vulnerable to attack by water molecules and undergo degradation, so they are generally not used as biostable polyurethanes. The subsequent development of polyether polyurethanes initiated the application of biostable polyurethanes. However, the ether bonds on the polyether segments are easily oxidized and degraded, limiting their further application. To improve their biostability, two methods have been proposed in the scientific community: One is to completely replace the polyether with polycarbonate with better biostability. Although the biostability of both polycarbonate-based polyurethanes and polysiloxane-polyether-based polyurethanes has been improved, degradation still occurs in polycarbonate-based polyurethanes; the other is to partially replace the polyether with polysiloxane. The development of polysiloxane-polyether-based polyurethanes can be further divided into three stages. Polysiloxane polyurethanes, but due to the non-polar macromolecular nature of polysiloxane, its compatibility with urethane and urea groups is poor, resulting in poor mechanical properties. Therefore, the synthesis and development of polysiloxane-polyether co-soft segment polyurethanes have been carried out, and two commercial products, Elast-Eon and PurSil, have been formed. In subsequent studies, it was found that both of these polyurethane materials have excellent biocompatibility and biostability, meeting the requirements for long-term implant materials. However, as artificial heart valves, the mechanical properties still cannot meet the requirements. Therefore, researchers have carried out molecular regulation and modification of polyurethanes to adjust the mechanical properties and enhance the biostability. P. A. Gunatillake et al. prepared PHMO-PMDS type polyurethane urea (P. A. Gunatillake et al., US2017119923A1) by using a mixed chain extender composed of 1,3-dihydroxybutyl-1,1,3,3-tetramethyldisilane (BHTD) and ethylenediamine (EDA) with a molar ratio of 1:1 to replace the single chain extender BDO on the basis of Elast-Eon 2A. The introduction of urea groups increases the number of intermolecular hydrogen bonds and also improves the microphase separation structure. Compared with Elast-Eon 2A and other polyurethane materials, its elasticity, tensile and tear strengths have been significantly improved. More importantly, on the stress-strain curve, no yield phenomenon appears, indicating that this PHMO-PMDS type polyurethane urea has good anti-creep ability (L. S. Dandeniyage et al., J Biomed Mater Res Part B, 2018, 106: 1712–1720). In addition, the development timeline of artificial heart valves is similar to that of biostable polyurethanes. This also shows that the development and application of new materials can promote the renewal and iteration of the industry.However, the research on bio-stable polyurethanes in China has just started. Moreover, the new generation of polymer artificial heart valves based on bio-stable polyurethanes will be the future development direction worldwide. In this context, it is urgent to carry out research on polysiloxane polyurethanes.

[0007] For polymer artificial heart valves, the choice of processing method is crucial. Currently, the processing methods are divided into solution processing and melt processing. Melt processing requires large-scale instruments and exploration of many processes. Moreover, for polyurethanes and polyurethane ureas, the melt processing method will damage the original molecular structure, causing molecular chain breakage, etc., and then affecting the mechanical properties and biocompatibility. The solution processing method has a low temperature, is easy to control, has a simple operation, and will not damage the molecular structure of polyurethane ureas. It is an advanced molding method for preparing polyurethane artificial heart valves.

[0008] Therefore, based on the above practical needs, the present invention develops a high-molecular-weight polysiloxane polyether-based polyurethane urea directly applied to the dip-coating process to meet the requirements of polymer artificial heart valves for mechanical properties, bio-stability, biocompatibility, and processing convenience. Summary of the Invention

[0009] In order to meet the requirements of polymer artificial heart valves for the molecular weight, biocompatibility, mechanical properties, bio-stability, and processing properties of polyurethane urea materials, the present invention provides a high-molecular-weight polysiloxane polyether-based polyurethane urea directly applicable to the dip-coating process and its preparation method. Among them, a semi-bulk-semi-solution synthesis method is adopted. Using polysiloxane and polyether as mixed soft segments, and small molecule diols and small molecule diamines as chain extenders, a high-molecular-weight polysiloxane polyether-based polyurethane (urea) with excellent bio-stability and good mechanical properties is synthesized. Moreover, the polyurethane urea material synthesized by this method does not add catalysts and can be used for dip-coating to prepare artificial heart valves without subsequent treatment, which is convenient, fast, and environmentally friendly.

[0010] The present invention uses polydimethylsiloxane (PDMS) with a specific ratio to partially replace polyether diol, and uses polyether diol and polydimethylsiloxane (PDMS) as mixed soft segments. Small molecule diols and diamines are used as mixed chain extenders and together with diisocyanate as hard segments. A high molecular weight polysiloxane polyether type polyurethane urea with a hard segment content of 40% - 45% and applicable directly to the dip coating process for polymer heart valves is prepared by a semi-bulk - semi-solution synthesis method. This material contains about 35% of polysiloxane components, and the surface energy of polysiloxane is relatively low. During the solution processing, it can migrate to the surface and gradually accumulate to form a polysiloxane layer to protect the material from biodegradation, thereby achieving the purpose of improving biological stability. The use of double chain extenders and double soft segments increases the number of phases to balance the degree of microphase separation and improve mechanical and biological stability. Using small molecule diamine as the main chain extender introduces urea groups that can form double hydrogen bonds, increasing the number of hydrogen bonds in the polyurethane urea to improve the biological stability, tensile strength, tear strength, and creep resistance of the polymer material. At the same time, the semi-bulk - semi-solution polymerization form not only improves the reaction rate but also reduces the use of catalysts during the reaction, making the reaction system more environmentally friendly and avoiding the introduction of heavy metal ions. The resulting polyurethane urea material has the advantage of high molecular weight, greatly improving the mechanical properties of the polyurethane urea material. In addition, the synthesized polyurethane urea solution can be used for the dip coating process to prepare polymer valves without subsequent treatment, which is convenient and fast.

[0011] To achieve the above objectives, the present invention adopts the following technical solutions:

[0012] The present invention provides a polysiloxane polyether type polyurethane urea, which is composed of hard segments and soft segments; the hard segment content is 40 wt.% - 45 wt.%, including diisocyanate and small molecule chain extenders; the soft segments include polydimethylsiloxane and polyether, and the proportion of polydimethylsiloxane in the soft segments is 55 - 65%, preferably 60%.

[0013] The polysiloxane polyether type polyurethane urea is a random copolymer, with a number average molecular weight of 140,000 - 160,000, a weight average molecular weight of 250,000 - 300,000, and a molecular weight distribution index ≤ 1.9.

[0014] The polyether is polytetrahydrofuran with a number average molecular weight of 500 - 3000; the polydimethylsiloxane is α,ω-bis(hydroxyethoxypropyl) polydimethylsiloxane with a number average molecular weight of 500 - 3000, and the diisocyanate is diphenylmethane diisocyanate. The mass ratio of the diisocyanate in the hard segments is 70 wt.% - 75 wt.%.

[0015] The small molecule chain extender includes a secondary chain extender and a primary chain extender. The secondary chain extender is a C1-C6 diol, preferably butanediol, and the primary chain extender is a C1-C6 diamine, preferably ethylenediamine. Preferably, the weight ratio of butanediol to ethylenediamine is 3:2.

[0016] The preparation method of the high molecular weight polysiloxane polyether type polyurethane urea that can be directly applied to the dip coating process in the present invention is prepared by a polymerization method combining bulk and solution; first, at a relatively high temperature, polyether diol (polyether diol), polydimethylsiloxane and diisocyanate are used for prepolymerization reaction in a bulk form; after the prepolymerization is completed, a secondary chain extender is added, and then the reaction continues for a period of time at a set temperature. Then, an appropriate amount of solvent is added to dissolve the reaction system into a solution. In the solution state, a primary chain extender is added and the reaction is carried out for a period of time at a suitable temperature until the reaction ends; the completely reacted polysiloxane polyether type polyurethane urea solution can be directly cast into a film to prepare a polymer film, the polyurethane urea solid material can be obtained after solution replacement and drying, or the solution viscosity can be adjusted by a simple operation of adding a post-solution or evaporating the solution for dip coating processing to form a polymer heart valve.

[0017] Different ways of forming hydrogen bonds between urethane groups and urea groups in the hard segment:

[0018]

[0019] The present invention further provides a preparation method of a high molecular weight polysiloxane polyether type polyurethane urea that can be directly applied to the dip coating process, including the following steps:

[0020] (1) Polymerize polyether diol and diisocyanate, and the molar ratio of polyether diol to diisocyanate is 2:1;

[0021] (2) After the reaction in step (1) is completed, add polydimethylsiloxane and diisocyanate to the system and heat for polymerization;

[0022] (3) After the reaction in step (2) is completed, add a secondary chain extender to the system for chain extension;

[0023] (4) After the reaction in step (3) is completed, add a primary chain extender to the system for chain extension.

[0024] The more specific steps are as follows:

[0025] (1) In a reaction vessel, add polyether diol, heat, and after the polyether diol is completely dissolved, add 1 / 2 equimolar amount of diisocyanate; after the sample is fully dissolved and miscible under mechanical stirring, keep the temperature at the reaction temperature, introduce dry nitrogen and maintain a nitrogen atmosphere, maintain the ventilation rate at 1-2 bubbles per second, and the reaction process is detected by infrared until at 2270 cm -1The disappearance of the characteristic absorption peak of isocyanate at this point indicates the end of the reaction;

[0026] (2) Maintain the temperature of the reaction system in step (1) at 55 - 65 °C, and add polydimethylsiloxane (PDMS) and an appropriate amount of diisocyanate thereto. The mass ratio of polyether diol to PDMS is 2:8 to 6:4. After the newly added materials are melted and mixed evenly, keep the temperature at the reaction temperature, continue to maintain the nitrogen gas flow rate at 1 - 2 bubbles per second, and carry out the reaction under strong stirring;

[0027] (3) After the prepolymerization reaction is completed, keep the temperature at 55 - 65 °C, add an appropriate amount of secondary chain extender. After it is fully dissolved and stirred evenly, adjust the temperature to the preset temperature, and keep nitrogen gas continuously introduced to carry out the reaction;

[0028] (4) Add a solvent to the reaction system after the reaction in step (3) is completed to reach the preset concentration. After it is fully dissolved, transfer the reaction system to a pre - set low - temperature bath. When the temperature is constant, add the solution dissolved with the main chain extender dropwise to the reaction system; keep the temperature unchanged, and keep nitrogen gas continuously introduced to carry out the reaction; then, transfer the reaction system to an oil bath pot at the preset temperature and continue the reaction to obtain a polyurethane urea solution (polysiloxane polyether - type polyurethane urea solution).

[0029] In step (1), the polyether diol (polyether diol) includes, but is not limited to, polytetrahydrofuran (polytetramethylene oxide glycol, PTMG), polypropylene glycol (PPG), polyhexamethylene oxide glycol, polyethylene glycol (PEG), etc., and the molecular weight range is 500 - 3,000.

[0030] The diisocyanate includes, but is not limited to, diphenylmethane diisocyanate (MDI), 4,4'-dicyclohexylmethane diisocyanate (HMDI), hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), xylene diisocyanate, and / or isophorone diisocyanate (IPDI), etc.

[0031] The temperature for heating and dissolving the polyether diol is 55 - 65 °C.

[0032] The reaction temperature range is 60 °C - 100 °C, and the preferred temperature range is 70 °C - 80 °C.

[0033] In step (2), the polydimethylsiloxane (PDMS) includes, but is not limited to, α,ω - bis(hydroxyethoxypropyl)polydimethylsiloxane, bis(hydroxybutyl)polydimethylsiloxane, bis(hydroxypropyl)polydimethylsiloxane, and / or bis(aminopropyl)polydimethylsiloxane, etc., and the molecular weight range is 500 - 4,000, and the preferred molecular weight range is 500 - 3,000.

[0034] In step (2), the appropriate amount of diisocyanate means that the overall R value is 0.98 - 1.05, preferably 0.99 - 1.02. The R value is the molar ratio of the number of moles of isocyanate groups to the sum of hydroxyl and amino groups.

[0035] The reaction temperature range is 60°C - 100°C, and the preferred temperature range is 70°C - 80°C; the reaction time range is 0 - 8 h, preferably 0.5 - 8 h.

[0036] In step (3), the secondary chain extender includes, but is not limited to, hydroquinone - bis(β - hydroxyethyl) ether, N - dihydroxy(diisopropyl) aniline, 1,4 - butanediol, 1,6 - hexanediol, 1,3 - propanediol, 1,5 - pentanediol, 1,4 - bis(2 - hydroxyethoxy) benzene, and / or N - methyldiethanolamine, etc.; the addition amount range is 0 - 100% of the total content of the chain extender, and the molar ratio range of the secondary chain extender to the polyether diol is 0 - 5.

[0037] The preset temperature range is 25°C - 100°C, preferably 50°C - 100°C; the reaction time range is 0 - 8 h, preferably 0.5 - 5 h.

[0038] In step (4), the solvent includes, but is not limited to, DMAc (N,N - dimethylacetamide), DMSO (dimethyl sulfoxide), DMF (N,N - dimethylformamide), THF (tetrahydrofuran), DCE (dichloroethane), dioxane, toluene, and / or xylene, etc.

[0039] The preset concentration range of the synthesized polymer is 10 wt.% - 30 wt.%.

[0040] The main chain extender includes, but is not limited to, diethylaminoethanol, 1,2 - ethylenediamine (EDA), 1,4 - butanediamine, 3,3'-dichloro - 4,4'-diaminodiphenylmethane, and / or 1,6 - hexanediamine, etc.; the addition amount range is 0 - 100% of the total content of the chain extender, and the molar ratio range of the main chain extender to the polyether diol is 0 - 5; the main chain extender is dissolved using the same solvent as added to the reaction system.

[0041] The low - temperature bath temperature range is 0°C - 50°C; the reaction time range is 0 - 8 h, preferably 0.5 - 8 h.

[0042] The preset temperature range of the oil bath is 25°C - 100°C, preferably 50°C - 100°C; the reaction time range is 0 - 8 h, preferably 0.5 - 8 h. The total reaction time for adding the main chain extender ranges from 0 - 12 h.

[0043] In the method of the present invention, step (5) may further be included. The fully reacted polymer solution is obtained to form a polyurethane-urea solution with a certain concentration by adding or evaporating a solvent, or without subsequent operations, and then a polymer valve is obtained by drying the polyurethane-urea solution through a simple dip-coating process; or the fully reacted polysiloxane-polyether type polyurethane-urea solution is directly cast into a film to prepare a polymer film or a polyurethane-urea solid material is obtained by solution replacement and drying.

[0044] In step (5), the concentration range of the polyurethane-urea solution is 5 wt.% - 30 wt.%, preferably 10 wt.% - 30 wt.%; the dip-coating process belongs to the scope of solution processing; the drying temperature range is 25°C - 80°C. The solution viscosity is adjusted by a simple operation of adding or evaporating the solution for dip-coating processing to form a polymer heart valve, and the adjusted solution concentration is 5 wt.% - 30 wt.%.

[0045] In the method of the present invention, by mass parts, in step (1), 2000 - 6000 parts of polyether diol and 500 - 600 parts of diisocyanate; in step (2), 4000 - 8000 parts of polydimethylsiloxane (PDMS) and 2500 - 5800 parts of diisocyanate are added; in step (3), 540 - 1846 parts of a secondary chain extender are added; in step (4), 360 - 756 parts of a main chain extender are added.

[0046] In the method of the present invention, the prepolymerization reaction is carried out in bulk, and no catalyst is added to the whole reaction system.

[0047] In the present invention, the ratio or "parts" of different substances, unless otherwise specified, are all mass ratios.

[0048] Advantages of the present invention:

[0049] (1) By regulating the content of the hard segment, the ratio of polyether and polydimethylsiloxane, controlling the molecular weight and molecular weight distribution, the mechanical properties are regulated to obtain a material with a greater final tensile strength and tear strength, and the Young's modulus E is controlled;

[0050] (2) Adopting a semi-bulk - semi-solution processing method not only improves the reaction rate, shortens the reaction time, but also can directly carry out dip-coating processing, which is green and environmentally friendly; no catalyst is used, ensuring biological safety;

[0051] (3) Adopting a chain extension method with a double chain extender improves the reaction activity, and introducing ureido groups increases the number of hydrogen bonds, improving mechanical properties such as tensile strength and tear properties.

[0052] The present invention also provides an artificial heart valve, the material of which is the polysiloxane-polyether type polyurethane-urea described in the present invention.

[0053] The invention is advanced and practical, and the material can meet the requirements of long-term implantation of polymer heart valves.

[0054] The high-molecular-weight polysiloxane polyether polyurethane urea prepared by the present invention, which can be directly applied in dip-coating processes, uses polyether diol and polydimethylsiloxane diol as soft segments, and aromatic diisocyanate and low-molecule diol / diamine as hard segments. The synthesis process uses a semi-bulk, semi-solution polymerization method in the absence of a catalyst to produce the polysiloxane polyether polyurethane urea solution.

[0055] The polyurethane urea solution can be cast into a film or dip-coated to obtain a polyurethane urea film material. The content of polydimethylsiloxane in the obtained polyurethane urea material accounts for about 35wt% of the whole, and because the surface energy of polydimethylsiloxane is relatively low, it will spontaneously migrate and enrich to the surface of the material during the solution processing, forming a polydimethylsiloxane protective layer to protect or reduce the effects of hydrolysis, enzymatic hydrolysis and oxidative degradation on the material. In addition, the polyether component and small molecule chain extender in the polyurethane urea material can act as a compatibilizer between non-polar polydimethylsiloxane and polar carbamate and urea groups through intermolecular hydrogen bonds to improve the phase separation degree of the material and enhance the overall mechanical strength and biological stability.

[0056] The polysiloxane polyether polyurethane urea solution prepared by the present invention can be directly used for dipping and casting without complicated processes such as post-processing. At the same time, the solution concentration can be adjusted by simply adding solvents at a later stage to meet the needs of different solution processing methods. The number average molecular weight of the polysiloxane polyether polyurethane urea prepared by the present invention is between 140,000 and 160,000, the weight average molecular weight is between 250,000 and 300,000, and the molecular weight distribution is ≤1.9, which can meet the requirements of polymer heart valves for the molecular weight of materials. From the tensile performance test results, it can be seen that the tensile strength of this series of polyurethane urea materials exceeds 40MPa, which far exceeds the test results of currently available biological valves, and the tear strength meets the requirements of polymer heart valves. What is particularly important is that the polyurethane urea material exhibits excellent biocompatibility and biostability.

[0057] In summary, the present invention provides a simple and reliable method for preparing a polymer heart valve material, polysiloxane polyether polyurethane. The resulting material exhibits excellent biocompatibility, biostability, and mechanical properties. This polyurethaneurea material is a promising polymer heart valve material. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 1 is the infrared spectrum of polysiloxane polyether polyurethane urea with different hard segment contents prepared by the present invention;

[0059] Figure 2Gel permeation chromatogram of polysiloxane polyether type polyurethane ureas with different hard segment contents prepared by the present invention in DMF;

[0060] Figure 3 Among them, Figure 3 (a) Stress-strain curves of polysiloxane polyether type polyurethane ureas with different hard segment contents prepared by the present invention in the dry state; Figure 3 (b) Stress-strain curves in the wet state; Figure 3 (c) Tensile moduli of polysiloxane polyether type polyurethane ureas with different hard segment contents in dry and wet environments;

[0061] Figure 4 Biocompatibility tests (four coagulation items, cytotoxicity) of the present invention at a hard segment content of 40 wt.%;

[0062] Figure 5 Biostability tests (in vivo, in vitro) of the present invention at a hard segment content of 40 wt.%. Detailed implementation manners

[0063] Preparation method of high molecular weight polysiloxane polyether type polyurethane ureas that can be directly applied to dip coating process of the present invention, comprising the following steps:

[0064] (1) In a reaction vessel, add 40 parts by mass of polyether diol (such as PTMG), heat up to 60 °C, and after the polyether diol is completely dissolved, add 1 / 2 molar amount of diisocyanate (such as MDI); after the samples are fully dissolved and miscible under mechanical stirring, raise the reaction temperature to a preset temperature, and introduce dry nitrogen and maintain a nitrogen atmosphere, maintain the ventilation rate at 1-2 bubbles per second, and use infrared detection during the reaction process until the characteristic absorption peak of isocyanate at 2270 cm -1 disappears, which is the end point of the reaction; polyether diols include but are not limited to PEG, PTMG, PTMO, PHMO, PPG, etc.; diisocyanates include but are not limited to diphenylmethane diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, toluene diisocyanate, xylene diisocyanate; the preset temperature range is 25 °C - 100 °C.

[0065] (2) Lower the temperature of the reaction system in step (1) to 60°C, and add 60 parts by mass of polydimethylsiloxane (PDMS) and an appropriate amount of diisocyanate thereto. After the newly added materials are melted and mixed evenly, raise the temperature to an appropriate temperature, and continue to maintain the nitrogen gas flow rate at 1 - 2 bubbles per second. React for a period of time under strong stirring; polydimethylsiloxane (PDMS) includes, but is not limited to, α,ω-bis(hydroxyethoxypropyl)polydimethylsiloxane, bis(hydroxybutyl)polydimethylsiloxane, bis(hydroxypropyl)polydimethylsiloxane, bis(aminopropyl)polydimethylsiloxane, etc., with a molecular weight range of 500 - 4,000; the appropriate temperature range is 25°C - 100°C; the reaction time range is 0 - 8 h.

[0066] (3) After the prepolymerization reaction is completed, lower the temperature to 60°C, add an appropriate amount of secondary chain extender, and after it is fully dissolved and stirred evenly, adjust the temperature to the preset temperature, and continue to introduce nitrogen gas. React for a period of time; secondary chain extenders include, but are not limited to, hydroquinone - bis(β - hydroxyethyl) ether, N - dihydroxy(diisopropyl)aniline, 1,4 - butanediol, 1,6 - hexanediol, 1,3 - propanediol, 1,5 - pentanediol, etc.; the preset temperature range is 25°C - 100°C; the reaction time range is 0 - 8 h.

[0067] (4) Add a solvent to the reaction system after the reaction in step (3) is completed to the preset concentration. After it is fully dissolved, transfer the reaction system to a pre - set low - temperature bath. When the temperature is constant, add a solution of an appropriate amount of main chain extender dropwise to the reaction system. Keep the temperature unchanged, and continue to introduce nitrogen gas. React for a period of time; the low - temperature bath temperature range is 0°C - 50°C; main chain extenders include, but are not limited to, diethylaminoethanol, 1,2 - ethylenediamine (EDA), 1,4 - butanediamine, 3,3'-dichloro - 4,4'-diaminodiphenylmethane, 1,6 - hexanediamine, etc.; solvents include, but are not limited to, DMAc, DMSO, DMF, THF, DCE, dioxane, toluene, xylene, etc.; the reaction time range is 0 - 8 h; the preset concentration range is 10% - 30%.

[0068] (5) After the main chain extender is added dropwise and the reaction is carried out for a period of time under the low - temperature bath, transfer the reaction system to an oil bath pot at the preset temperature and continue to react for a period of time; the temperature range is 25°C - 100°C; the reaction time range is 0 - 8 h.

[0069] (6) After the reaction is completed, the fully reacted polymer solution can obtain a polyurethane urea solution with a fixed concentration by adding / evaporating the solvent or without subsequent operations. Using this polyurethane urea solution, a polymer valve can be obtained through a simple dip - coating process and drying. The fixed concentration range is 10% - 30%; the dip - coating process belongs to the solution processing range; the drying temperature range is 25°C - 80°C.

[0070] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0071] In the embodiments, unless otherwise specified, the feed ratio is in parts by mass.

[0072] Example 1 (Si28)

[0073] Take 4000 parts of polytetrahydrofuran (M n = 1000) and place it in a reaction vessel. Heat it to 60 °C. After the polytetrahydrofuran is completely melted, take 500 parts of MDI (diphenylmethane diisocyanate) and add it thereto. After it is dissolved in PTMG (polytetrahydrofuran), raise the temperature to 80 °C, and introduce dry nitrogen and maintain a nitrogen atmosphere. Maintain the gas flow rate at 1 - 2 bubbles per second. The reaction process is detected by infrared until the characteristic absorption peak of isocyanate at 2270 cm -1 disappears, which is the end point of the reaction. Lower the temperature of the reaction system to 60 °C, and add 6000 parts of α,ω-bis(hydroxyethoxypropyl)polydimethylsiloxane (Mn = 1000) and 2500 parts of MDI thereto. After the newly added materials are melted and mixed evenly, raise the temperature to 80 °C, continue to maintain the nitrogen gas flow rate at 1 - 2 bubbles per second, and react under strong stirring for 3 hours. After the prepolymerization reaction is completed, lower the temperature to 60 °C, add 540 parts of 1,4-butanediol. After it is fully dissolved and stirred evenly, adjust the temperature to 80 °C, and continuously introduce nitrogen gas, and react for 3 h. Then add N,N-dimethylacetamide (DMAc) to the reaction system after the reaction is completed until the concentration is 25 wt%. After it is fully dissolved, transfer the reaction system to a pre-set low-temperature bath at 0 °C. When the temperature is constant, add a solution (3 ml of DMAc) dissolving 360 parts of ethylenediamine to the reaction system by dropping. Maintain the temperature unchanged, and continuously introduce nitrogen gas, and react for 1 h. Then transfer the reaction system to an oil bath at 80 °C and continue to react for 4 h until the reaction ends. The viscosity of the fully reacted polymer solution is 2542 mPa / s.

[0074] The hard segment content of this material is 28 wt.%; the mass ratio of polydimethylsiloxane in the soft segment is 60 wt.%; the mass ratio of diisocyanate in the hard segment is 73.5 wt.%. The Fourier infrared spectrum is as shown in Figure 1 Si28 in, and the GPC elution curve is as shown in Figure 2 Si28 in. It can be intuitively shown by the infrared spectrum that this polymer material is a polysiloxane polyether type polyurethane urea polymer.

[0075] Example 2 (Si32)

[0076] 4000 parts of polytetrahydrofuran (Mn = 1000) were placed in a reaction vessel and heated to 60 °C. After the polytetrahydrofuran was completely melted, 500 parts of MDI were added thereto. After it was dissolved in PTMG, the temperature was raised to 80 °C, and dry nitrogen was introduced and the nitrogen atmosphere was maintained. The ventilation rate was maintained at 1-2 bubbles per second. The reaction process was detected by infrared until the characteristic absorption peak of isocyanate at 2270 cm -1 disappeared, which was the end point of the reaction. The temperature of the reaction system was lowered to 60 °C, and 6000 parts of α,ω-bis(hydroxyethoxypropyl) polydimethylsiloxane (Mn = 1000) and 3120 parts of MDI were added thereto. After the newly added materials were melted and mixed evenly, the temperature was raised to 80 °C, and the nitrogen ventilation rate was still maintained at 1-2 bubbles per second. The reaction was carried out for 3 hours under strong stirring. After the prepolymerization reaction was completed, the temperature was lowered to 60 °C, 650 parts of 1,4-butanediol were added. After it was fully dissolved and stirred evenly, the temperature was adjusted to 80 °C, and nitrogen was continuously introduced, and the reaction was carried out for 3 h. Then DMAc was added to the reaction system after the reaction was completed to a concentration of 25 wt%, and after it was fully dissolved, the reaction system was transferred to a pre-set low-temperature bath at 0 °C. When the temperature was constant, a solution (3 ml of DMAc) dissolving 435 parts of ethylenediamine was added to the reaction system by dropwise addition. The temperature was kept constant, and nitrogen was continuously introduced, and the reaction was carried out for 1 h. Then the reaction system was transferred to an oil bath at 80 °C again, and the reaction was continued for 4 h, and the reaction ended. The viscosity of the fully reacted polymer solution was 2800 mPa / s.

[0077] The hard segment content of this material was 32 wt.%; the mass ratio of polydimethylsiloxane in the soft segment was 60 wt.%; the mass ratio of diisocyanate in the hard segment was 74.2 wt.%. The Fourier infrared spectrum was as shown in Figure 1 Si32, and the GPC elution curve was as shown in Figure 2 Si32.

[0078] Example 3 (Si36)

[0079] 4000 parts of polytetrahydrofuran (Mn = 1000) were placed in a reaction vessel and heated to 60 °C. After the polytetrahydrofuran was completely melted, 500 parts of MDI were added thereto. After it was dissolved in PTMG, the temperature was raised to 80 °C, and dry nitrogen was introduced and the nitrogen atmosphere was maintained. The ventilation rate was maintained at 1-2 bubbles per second. The reaction process was detected by infrared until the characteristic absorption peak of isocyanate at 2270 cm -1The disappearance of the isocyanate characteristic absorption peak at [location] indicates the end of the reaction. The temperature of the reaction system was lowered to 60 °C, and 6000 parts by mass of α,ω-bis(hydroxyethoxypropyl)polydimethylsiloxane (Mn = 1000) and 3827 parts of MDI were added thereto. After the newly added materials were melted and mixed evenly, the temperature was raised to 80 °C, and the nitrogen gas flow rate was maintained at 1 - 2 bubbles per second. The reaction was carried out under strong stirring for 3 hours. After the prepolymerization reaction was completed, the temperature was lowered to 60 °C, 780 parts of 1,4-butanediol was added, and after it was fully dissolved and stirred evenly, the temperature was adjusted to 80 °C, and nitrogen gas was continuously introduced, and the reaction was carried out for 3 h. Then DMAc was added to the reaction system after the reaction was completed to a concentration of 25 wt%, and after it was fully dissolved, the reaction system was transferred to a pre-set low-temperature bath at 0 °C. When the temperature was constant, a solution (3 ml of DMAc) containing 520 parts of ethylenediamine was added to the reaction system by dropwise addition. The temperature was maintained constant, and nitrogen gas was continuously introduced, and the reaction was carried out for 1 h. Then the reaction system was transferred to an oil bath at 80 °C and the reaction was continued for 4 h until the reaction ended. The viscosity of the fully reacted polymer solution was 3410 mPa·s.

[0080] The hard segment content of this material is 36 wt.%; the mass ratio of polydimethylsiloxane in the soft segment is 60 wt.%; the mass ratio of diisocyanate in the hard segment is 74.6 wt.%. The Fourier infrared spectrum is as shown in Figure 1 Si36 in [reference], and the GPC elution curve is as shown in Figure 2 Si36 in [reference].

[0081] Example 4 (Si40)

[0082] 4000 parts of polytetrahydrofuran (Mn = 1000) was placed in a reaction vessel and heated to 60 °C. After the polytetrahydrofuran was completely melted, 500 parts of MDI was added thereto, and after it was dissolved in PTMG, the temperature was raised to 80 °C, and dry nitrogen gas was introduced and the nitrogen atmosphere was maintained. The gas flow rate was maintained at 1 - 2 bubbles per second. The reaction process was monitored by infrared detection until at 2270 cm -1The disappearance of the characteristic absorption peak of isocyanate at [location] indicates the end point of the reaction. The temperature of the reaction system was lowered to 60 °C, and 6000 parts by mass of α,ω-bis(hydroxyethoxypropyl)polydimethylsiloxane (Mn = 1000) and 4627 parts of MDI were added thereto. After the newly added materials were melted and mixed evenly, the temperature was raised to 80 °C, and the nitrogen gas flow rate was maintained at 1 - 2 bubbles per second. The reaction was carried out under strong stirring for 3 hours. After the prepolymerization reaction was completed, the temperature was lowered to 60 °C, 923 parts of 1,4-butanediol was added, and after it was fully dissolved and stirred evenly, the temperature was adjusted to 80 °C, and nitrogen gas was continuously introduced, and the reaction was carried out for 3 h. Then DMAc was added to the reaction system after the reaction was completed to a concentration of 25 wt%, and after it was fully dissolved, the reaction system was transferred to a pre-set low-temperature bath at 0 °C. When the temperature was constant, a solution (3 ml of DMAc) dissolving 616 parts of ethylenediamine was added dropwise to the reaction system. The temperature was maintained constant, and nitrogen gas was continuously introduced, and the reaction was carried out for 1 h. Then the reaction system was transferred to an oil bath at 80 °C and the reaction was continued for 4 h, and the reaction ended. The viscosity of the polymer solution after full reaction was 3387 mPa·s.

[0083] The hard segment content of this material is 40 wt.%; the mass ratio of polydimethylsiloxane in the soft segment is 60 wt.%; the mass ratio of diisocyanate in the hard segment is 75.0 wt.%. The Fourier infrared spectrum is as shown in Figure 1 Si40 in [figure], and the GPC elution curve is as shown in Figure 2 Si40 in [figure].

[0084] Example 5 (Si45)

[0085] 4000 parts of polytetrahydrofuran (Mn = 1000) was placed in a reaction vessel and heated to 60 °C. After the polytetrahydrofuran was completely melted, 500 parts of MDI was added thereto, and after it was dissolved in PTMG, the temperature was raised to 80 °C, and dry nitrogen gas was introduced and the nitrogen atmosphere was maintained. The gas flow rate was maintained at 1 - 2 bubbles per second. The reaction process was detected by infrared until at 2270 cm -1The disappearance of the characteristic absorption peak of isocyanate at [location] indicates the end of the reaction. The temperature of the reaction system was lowered to 60 °C, and 6000 parts by mass of α,ω-bis(hydroxyethoxypropyl)polydimethylsiloxane (Mn = 1000) and 5800 parts by mass of MDI were added thereto. After the newly added materials melted and were mixed evenly, the temperature was raised to 80 °C, and the nitrogen gas flow rate was maintained at 1-2 bubbles per second. The reaction was carried out under strong stirring for 3 hours. After the prepolymerization reaction was completed, the temperature was lowered to 60 °C, 1134 parts by mass of 1,4-butanediol was added, and after it was fully dissolved and stirred evenly, the temperature was adjusted to 80 °C, and nitrogen gas was continuously introduced, and the reaction was carried out for 3 h. Then DMAc was added to the reaction system after the reaction was completed to a concentration of 25 wt%, and after it was fully dissolved, the reaction system was transferred to a pre-set low-temperature bath at 0 °C. When the temperature was constant, a solution (3 ml of DMAc) dissolving 756 parts by mass of ethylenediamine was added to the reaction system by dropwise addition. The temperature was kept constant, and nitrogen gas was continuously introduced, and the reaction was carried out for 1 h. Then the reaction system was transferred to an oil bath at 80 °C and the reaction was continued for 4 h until the reaction ended. The viscosity of the fully reacted polymer solution was 3649 mPa·s.

[0086] The hard segment content of this material is 45 wt.%; the mass ratio of polydimethylsiloxane in the soft segment is 60 wt.%; the mass ratio of diisocyanate in the hard segment is 75.0 wt.%. The Fourier infrared spectrum is as shown in Figure 1 Si45 in [reference], and the GPC elution curve is as shown in Figure 2 Si45 in [reference].

[0087] Taking five samples (labeled Si28, Si32, Si36, Si40, Si45) with hard segment contents of 28 wt%, 32 wt%, 36 wt%, 40 wt%, and 45 wt% prepared in Examples 1-5 as examples, the structure and performance characterization process of the high molecular weight polysiloxane polyether type polyurethane urea that can be directly applied to the dip coating process prepared by the scheme and steps of the present invention is described.

[0088] 1) From the observation of the viscosity of the obtained polymer solution, when the solution concentration was 25%, the viscosity was 2500 mPa·s - 3000 mPa·s, and the solution was transparent without stratification, precipitation, suspension, or solid precipitation. When a solvent was added subsequently, the viscosity of the polyurethane urea solution changed, and no stratification phenomenon occurred, showing the characteristics of being directly applicable to dip coating processing.

[0089] 2) It can be seen from the infrared spectrum shown in Figure 1 that the characteristic absorption peak of isocyanate at 2270 cm -1 completely disappeared in the five samples, indicating that the polymerization system had been completely carried out. All samples had absorption peaks at 1705 cm -1 and 1541 cm -1New peaks also appeared at each position, respectively representing the carbonyl group in the urethane and C-N in the urethane. It can be seen from the infrared spectrum that as the hard segment content increases, the infrared absorption peak of the N-H bond at 3300 cm -1 gradually increases, indicating that the degree of hydrogen bonding of the polyurethane urea also shows a gradually increasing trend. In addition, the characteristic stretching vibration peak of Si-O-Si at 1030 cm -1 is also clearly visible, which can confirm the successful preparation of the polysiloxane-polyether type polyurethane urea.

[0090] 3) From Figure 2 and the GPC test results shown in Table 1, it can be seen that the number average molecular weights of the five samples synthesized in this invention are all above 120,000, and the weight average molecular weights are all in the range of 230,000 - 350,000. Especially for Si40 and Si45, the number average molecular weights are in the range of 140,000 - 160,000, and the weight average molecular weights are controlled in the range of 250,000 - 300,000. The molecular weight distribution D is below 1.9, far exceeding the molecular weight data of current commercial polyurethanes, and the molecular weight distribution is controlled to ensure the stability of the product quality.

[0091] Table 1 Molecular weights and molecular weight distributions of polysiloxane-polyether type polyurethane ureas with different hard segment contents

[0092]

[0093] 4) For the polymer materials used in polymer heart valves, the mechanical properties of the materials are crucial. Figure 3 (a) To Figure 3(c) and Table 2 show the evaluation of the tear performance and tensile performance of the above materials in dry and humid environments. It can be seen that the tensile strength and elongation at break of these five materials are respectively above 24 MPa and 500%; moreover, with the continuous increase of the hard segment content, the elastic modulus and tear resistance of the polyurethaneurea materials also increase. The tensile strengths of Si40 and Si45 both exceed 40 MPa, exceeding the existing technology materials. To further simulate the in vivo use conditions, the materials were saturated with water and their mechanical properties were evaluated under humid conditions. The results show that the tensile strength and elongation at break of the above materials are respectively above 20 MPa and 500%, far exceeding 24 MPa and 80% of the glutaraldehyde-crosslinked bovine pericardium. The tear strength of the bovine pericardium is about 58 N / mm, while regardless of the dry or wet conditions, the tear strength of the polyurethaneurea increases with the increase of the hard segment content. When the hard segment content reaches 36 wt%, that is, the tear strengths of Si36 and Si40 are comparable to that of the bovine pericardium, showing good tear resistance, and Si45 has a significant improvement. In addition, the modulus is a key parameter to ensure leaflet movement, blood flow and overall valve sealing. For polymer materials applied to heart valves, the tensile modulus should preferably be less than 50 MPa, and the above materials can basically meet the requirements. The above materials have great prospects in the application of polymer heart valve materials.

[0094] 5) For implantable / interventional materials, it is a crucial technical requirement that the materials have excellent biocompatibility. Taking the polymer material (Si40) with a hard segment content of 40 wt.% synthesized in the present invention as an example, we conducted biocompatibility tests. Figure 4 They are respectively cytotoxicity experiments and four coagulation tests. It can be seen from the cytotoxicity experiments that compared with the positive control, the relative proliferation rate of Si40 is about 100%, and it has basically no toxic effect on cells. It can be seen from the four coagulation tests that the results of the four coagulation tests are all within the normal range, and the material has no effect on the coagulation system. Combining the cytotoxicity and four coagulation analyses, the materials synthesized in the present invention show excellent biocompatibility.

[0095] 6) To comprehensively analyze the biological stability of polymer materials, such as Figure 5As shown. The present invention conducts in vivo and in vitro degradation experiments on the synthesized polymer material (Si40) with a hard segment content of 40 wt.%. The in vivo degradation experiment selects 2-week-old rats with a body weight of about 300 g for the experiment. After anesthetizing the experimental rats, sample pieces cut into 1 cm * 1 cm are implanted into the back of the rats. Each rat is implanted with 4 sample pieces, and each sample has 8 replicates. 30 days after implanting the material pieces, the rats are sacrificed by carbon dioxide and then dissected. After dissection, electron microscopy experiments are carried out to observe the surface morphology of the material. The in vitro degradation experiment method is as follows: The material to be tested is soaked in a mixed solution containing 1.63 M hydrogen peroxide and 0.05 M cobalt chloride, and oscillated at 37 °C for 30 days to simulate the in vitro oxidation situation. After washing and drying, SEM surface morphology observation is carried out. The in vivo degradation experiment and the in vitro degradation experiment show that there is no obvious degradation on the material surface, indicating excellent biostability.

[0096] Table 2 Stress-strain test results of polysiloxane-polyether type polyurethane ureas with different hard segment contents

[0097]

[0098] It is prepared by a combined bulk-solution polymerization method; first, at a relatively high temperature, polyether diol, polydimethylsiloxane, and diisocyanate are used for prepolymerization reaction in bulk form; after the prepolymerization is completed, a secondary chain extender is added, and then the reaction continues for a period of time at a set temperature. Then, an appropriate amount of solvent is added to dissolve the reaction system into a solution, and a main chain extender is added in the solution state and reacted at a suitable temperature for a period of time until the reaction ends. This method is simple and reliable, and the prepared material has excellent biocompatibility and biostability, and good mechanical properties. The prepared polyurethane urea material is a polymer heart valve material with great application prospects.

Claims

1. A polysiloxane polyether type polyurethane urea, characterized in that: The polysiloxane-polyether polyurethane urea consists of hard segments and soft segments; the content of the hard segments is 40 wt.% - 45 wt.%, including diisocyanate and a small molecule chain extender; the soft segments include polydimethylsiloxane and polyether, and the proportion of polydimethylsiloxane in the soft segments is 55 - 65%. The number average molecular weight of the polysiloxane-polyether polyurethane urea is 140,000 - 160,000, the weight average molecular weight is 250,000 - 300,000, and the molecular weight distribution index ≤ 1.

9.

2. The polysiloxane polyether type polyurethane urea according to claim 1, wherein The proportion of the polydimethylsiloxane in the soft segments is 60%.

3. The polysiloxane polyether type polyurethane urea according to claim 1, characterized in that, The polyether is polytetrahydrofuran with a number average molecular weight of 500 - 3000; the polydimethylsiloxane is α,ω-bis(hydroxyethoxypropyl) polydimethylsiloxane with a number average molecular weight of 500 - 3000, and the diisocyanate is diphenylmethane diisocyanate.

4. The polysiloxane polyether type polyurethane urea according to claim 3, characterized in that, The mass ratio of the diisocyanate in the hard segments is 70 wt.% - 75 wt.%.

5. The polysiloxane polyether type polyurethane urea according to claim 1, characterized in that, The small molecule chain extender includes a secondary chain extender and a primary chain extender. The secondary chain extender is a C1 - C6 diol, and the primary chain extender is a C1 - C6 diamine.

6. The polysiloxane polyether-based polyurethane urea according to claim 5, characterized in that, The secondary chain extender is butanediol, and the primary chain extender is ethylenediamine.

7. The polysiloxane polyether type polyurethane urea according to claim 6, characterized in that, The weight ratio of butanediol to ethylenediamine is 3:

2.

8. The preparation method of the polysiloxane polyether type polyurethane urea according to any one of claims 5-7, characterized in that, It includes the following steps: (1) Polymerize polyether diol and diisocyanate, and the molar ratio of polyether diol to diisocyanate is 2:1; (2) After the reaction in step (1) is completed, add polydimethylsiloxane and diisocyanate into the system and heat for polymerization; (3) After the reaction in step (2) is completed, add a secondary chain extender into the system for chain extension; (4) After the reaction in step (3) is completed, add a primary chain extender into the system for chain extension.

9. An artificial heart valve, the material of which is the polysiloxane-polyether polyurethane urea according to any one of claims 1 - 7.

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