Preparation method of polymer pipe and nerve scaffold
By using a frozen polymer aqueous solution or salt solution mold to freeze-dry the polyurethane solution, the problems of uneven micropores and closed pores in the prior art were solved, and open-pore microporous polyurethane tubing suitable for neural scaffolds was prepared.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-16
- Publication Date
- 2026-04-03
AI Technical Summary
In existing methods for preparing polyurethane neural scaffolds, sodium chloride is difficult to disperse, resulting in uneven micropores, some of which are closed pores. This leads to low water replacement efficiency and makes it difficult to form scaffolds with small inner diameters.
A frozen polymer aqueous solution or salt solution is used as a mold. The polyurethane solution is freeze-dried under vacuum to form a polyurethane tube. The mold material is then cleaned and removed to prepare an open-pore microporous structure.
The fabrication of polyurethane tubing with uniform micropores and open structure has been achieved, which is suitable for neural scaffolds of different specifications, especially scaffolds with low inner diameter, and simplifies the process.
Smart Images
Figure CN121777441A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of neural scaffold technology, specifically to a method for preparing a polymer tubing and a neural scaffold. Background Technology
[0002] Neural repair scaffolds, also known as neural scaffolds, are a type of tissue engineering scaffold. Polyurethane is a commonly used material for neural scaffolds, often referred to as polyurethane neural scaffolds. The inner diameter of polyurethane neural scaffolds is typically 1-10 mm, the wall thickness is approximately 0.5 mm, and the length is approximately 1-10 cm. The wall material is required to have a multi-microporous structure to facilitate the storage and delivery of drugs or nutrients. Current methods for preparing polyurethane neural scaffolds usually involve adding nano- or micro-sized sodium chloride to the polyurethane material, extruding it to obtain a tubular material, and then using water extraction to displace the sodium chloride from the polyurethane tubing, forming micropores. However, this method has the following problems: (1) Sodium chloride has a higher specific gravity than polyurethane and is not easy to disperse, resulting in uneven micropores; (2) Some micropores are closed-cell structures, and water cannot penetrate into the closed-cell micropores, thus failing to displace the sodium chloride, resulting in sodium chloride residue or fewer micropores; (3) The efficiency of water displacing sodium chloride is very low, resulting in a long process time; (4) For neural scaffolds with very fine inner diameters, such as 1-3 mm, extrusion molding is difficult to achieve.
[0003] Therefore, there is an urgent need for a better molding method for polyurethane neural scaffolds to improve pore formation efficiency and effect, and to be suitable for different size specifications. Summary of the Invention
[0004] To address the aforementioned problems in the fabrication process of neural scaffolds in the prior art, this application provides a method for preparing polymer tubing and a neural scaffold.
[0005] The technical solution adopted in this application is as follows: A method for preparing a polymer pipe involves transferring a polyurethane solution into a solid mold, freezing and vacuum drying the mold below its melting point, and cleaning it to obtain the polymer pipe. The mold is made of a polymer aqueous solution or a salt aqueous solution.
[0006] Preferably, the weight concentration of the polymer aqueous solution or salt aqueous solution is 0-15%.
[0007] Preferably, the polyurethane polymer structure used in the polyurethane solution contains at least one first block and at least one second block, the first block and the second block are arranged alternately, and adjacent first blocks and second blocks are connected by urethane bonds; The first block is formed of aliphatic polyester diol and / or alicyclic polyester diol; The second block is formed from an aliphatic polyether diol.
[0008] Preferably, the solvent used in the polyurethane solution has a melting point of -100 to 0°C.
[0009] Preferably, the concentration of the polyurethane solution is 5-80 wt%.
[0010] Preferably, the cavity of the mold is matched with the polyurethane pipe.
[0011] Preferably, the temperature of the freeze-drying is lower than the melting point of the solvent used in the polyurethane solution.
[0012] More preferably, the solvent has a melting point of -60°C to 0°C.
[0013] Preferably, after the freeze-drying and before the cleaning, the process further includes heating at 50-100°C for 1-12 hours.
[0014] A neural scaffold is prepared by the method for preparing polymer tubing as described in any of the above embodiments.
[0015] In summary, this application has the following beneficial effects: 1. This application proposes a method that is significantly different from the existing methods for preparing polyurethane neural scaffolds. A frozen solid aqueous polymer solution is used as the molding mold for the polyurethane tube. The polyurethane solution is added to the mold and freeze-dried under vacuum at a temperature below the mold's melting point. The solvent in the polyurethane solution has a high evaporation rate, while the evaporation rate of water in the frozen aqueous polymer solution is much lower than that of the solvent in the polyurethane solution. The polyurethane solution is first desolvated to form the polyurethane tube. Afterward, vacuum can be continued until the water in the mold evaporates, or the mold can be heated to room temperature, during which it gradually melts. Alternatively, the polyurethane tube can be directly removed from the mold.
[0016] 2. In this application, a polymer aqueous solution or a salt aqueous solution is used as the mold material. Under vacuum freeze-drying conditions, firstly, the evaporation rate of water in the frozen state is much lower than the evaporation rate of organic solvents in the polyurethane solution; secondly, after the polyurethane pipe is formed, the polymer material or salt can be directly removed by washing with clean water. The preparation process is very convenient and is also suitable for polyurethane pipes with a low inner diameter (e.g., 1-3 mm).
[0017] 3. When the temperature of freeze-drying is lower than the melting point of the solvent in the polyurethane solution, the solvent sublimates directly from the frozen state, which can directly form a large number of open micropores in the polyurethane pipe, thus making it very easy to obtain microporous polyurethane pipe. Attached Figure Description
[0018] Appendix Figure 1 This is a SEM image of the cross-section of the polyurethane pipe in Example 3; Appendix Figure 2 This is a SEM image of the cross-section of the polyurethane pipe in Comparative Example 1. Detailed Implementation
[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below.
[0020] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.
[0021] This application proposes a method for preparing polymer tubing, which involves transferring a polyurethane solution into a solid mold, freezing and vacuum drying the solution below the melting point of the mold, and cleaning the solution to obtain the polymer tubing. The mold material described above is a polymer aqueous solution or a salt aqueous solution. The weight concentration of the polymer aqueous solution or salt aqueous solution can be 0-15%. When the weight concentration of the polymer aqueous solution or salt aqueous solution is 0%, it is ice made of pure water. In this application, there are no particular restrictions on the polymer used in the polymer aqueous solution, as long as it is water-soluble. It can be a natural polymer material or a synthetic polymer material, such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, sodium alginate, carboxymethyl cellulose, hydroxypropyl cellulose seaweed, gelatin, starch, etc. In this application, the salt aqueous solution refers to an aqueous solution of inorganic or organic salts, such as sodium chloride aqueous solution, calcium chloride aqueous solution, sodium sulfate aqueous solution, magnesium sulfate aqueous solution, potassium chloride aqueous solution, ammonium carbonate aqueous solution, sodium acetate, sodium malate, etc.
[0022] In this application, a frozen polymer aqueous solution or salt solution is used as the mold. Mold forming is convenient; the polymer aqueous solution or salt solution is injected into the corresponding molding mold, frozen or cooled to a solid state, and then demolded to obtain the frozen polymer aqueous solution or salt solution mold. Using the frozen polymer aqueous solution or salt solution as the molding mold for polyurethane pipes, a polyurethane solution pre-cooled to a certain temperature (e.g., -5℃, -6℃, below the melting point of the polymer aqueous solution) is transferred into the frozen polymer aqueous solution mold or salt solution mold. During freeze-drying, the solvent evaporation rate in the polyurethane solution is much greater than the water evaporation rate in the frozen polymer aqueous solution or salt solution. The frozen polymer aqueous solution mold or salt solution mold remains essentially intact, or the mold is damaged due to water evaporation but does not affect the polyurethane pipe forming. As the solvent in the polyurethane solution gradually evaporates and decreases, a polyurethane pipe is formed. After the polyurethane pipe is formed, it can be directly removed from the mold, or the frozen aqueous solution mold can be melted by heating to release the polyurethane pipe. Therefore, the preparation method of this application can be selected according to the specifications of the polyurethane neural scaffold, such as inner diameter, thickness and length, and different molds can be used to obtain it relatively easily. The preparation process is simple and can meet the requirements of polyurethane neural scaffolds of different specifications, especially polyurethane neural scaffolds with low inner diameter (e.g., 1-3 mm).
[0023] In this application, the frozen aqueous solution mold or salt solution mold can be formed by cooling and freezing a polymer aqueous solution or salt solution that is liquid at room temperature, or it can be a polymer aqueous solution that is frozen at room temperature. In this case, the preparation of the polymer aqueous solution needs to be carried out under heating. For example, if the polymer aqueous solution uses PVA 17-99 and the concentration of the aqueous solution is greater than 10wt%, it is in a frozen state. At this time, the preparation of the aqueous solution needs to be heated, for example, at 90-95℃. Obviously, when a polymer aqueous solution that is frozen at room temperature is used as a mold, it can also be further cooled to 0℃ or lower for use.
[0024] In a preferred embodiment of this application, the polyurethane polymer structure used in the polyurethane solution contains at least one first block and at least one second block, the first block and the second block are arranged alternately, and adjacent first blocks and second blocks are connected by urethane bonds. The first block is formed from aliphatic polyester diols and / or alicyclic polyester diols; The second block is formed from an aliphatic polyether diol.
[0025] In this application, the average molecular weight range of aliphatic polyester diols, alicyclic polyester diols, and aliphatic polyether diols can be 200-200,000, respectively. To improve the biocompatibility of the neural scaffold, aliphatic polyester diols can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), polybutylene succinate (PBS), polybutylene terephthalate (PBAT), etc., and can be one or a combination of two or more of them, such as PLA-b-PCL block copolymers. Alicyclic polyester diols can improve the mechanical strength of polyurethane neural scaffolds; alicyclic polyester diols can be, for example, polycyclohexanediol adipate diol, polycyclohexanediol succinate diol, etc. Polyether diols can be polyethylene glycol, such as PEG400 (400 represents the average molecular weight, and so on), PEG600, PEG800, PEG1000, etc.
[0026] In this application, adjacent first and second blocks are connected by urethane bonds. Therefore, a prepolymer with -NCO end groups can be prepared by reacting an aliphatic polyether diol with a diisocyanate monomer (such as IPDI, HDI, TDI, MDI, HMDI, etc.). The -NCO content in the prepolymer can be 3-10 wt%, or further, the -NCO content in the prepolymer can be 3-8 wt%. The prepolymer is then subjected to an addition reaction with an aliphatic polyester diol and / or an alicyclic polyester diol to obtain a polyurethane polymer material.
[0027] In a preferred embodiment of this application, the solvent used in the polyurethane solution has a melting point of -100 to 0°C. In this application, the solvent is not particularly limited, as long as it is a good solvent for polyurethane, or a mixed solvent capable of dissolving polyurethane. Good solvents include tetrahydrofuran, acetone, butyl acetate, ethyl acetate, butanone, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, dichloromethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, DMSO, DMF, DMAc, etc. Mixed solvents can be a combination of a good solvent and a poor solvent in a weight ratio of 9:1 to 20:1. For example, the weight ratio of a good solvent to a poor solvent can be any value from 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, etc.
[0028] In a preferred embodiment of this application, the concentration of the polyurethane solution is 5-80 wt%. For the same solvent, the lower the polyurethane concentration, the longer the required vacuum drying time. Considering the molding and processing efficiency of polyurethane pipes, a further preferred concentration is 30-80 wt%.
[0029] In a preferred embodiment of this application, the mold cavity is matched with the polyurethane pipe. In this application, the matching of the mold cavity and the polyurethane pipe means that the mold cavity is a concave, hollow circular or annular shape with a circular core in the center. The dimensions of the hollow circular or annular cavity match the inner and outer diameters of the polyurethane pipe, and the diameter of the circular core matches the inner diameter of the polyurethane pipe. The height of the cavity can be greater than or equal to the length of the polyurethane pipe.
[0030] In a preferred embodiment of this application, the freeze-drying temperature is lower than the melting point of the solvent used in the polyurethane solution. At this temperature, the polyurethane solution is frozen, and under vacuum drying, the solvent directly sublimates. In the frozen polyurethane solution, the solvent occupies certain positions in the polyurethane polymer chains; that is, the solvent fills the gaps between the polyurethane polymer chains. In the frozen state, the polyurethane polymer chains are either frozen or move very slowly, causing the solvent to sublimate directly, forming micropores at these positions. Furthermore, because it is solvent sublimation, the micropores are open-pore structures, not closed-pore structures.
[0031] In a more preferred embodiment of this application, using a vacuum freeze-drying device, the solvent has a melting point of -60°C to 0°C. More preferably, the solvent's melting point can be -40°C to -10°C, and the solvent can be one or a combination of several of the following: 1,2-dichloroethane, 1,1,1-trichloro-2,2,2-trifluoroethane, 1,1,1-trichloroethane, carbon tetrachloride, 1,1,2-trichloroethane, and DMAc. The inventors have found that, from the perspective of pore formation in polyurethane tubing, it is more advantageous to select a solvent with a melting point below 0°C. If the solvent's melting point is above 0°C, for example, 1,4-dioxane, when the polyurethane solution is prepared and transferred to a frozen mold, if the temperature of the polyurethane solution is lower than the temperature of the mold, the polyurethane solution becomes frozen and cannot be transferred. Conversely, the temperature of the liquid polyurethane solution will be higher than the melting point of the frozen mold, causing the mold to melt, thus failing to achieve the purpose of this invention.
[0032] In a preferred embodiment of this application, after freeze-vacuum drying and before cleaning, the process further includes heating at 50-100°C for 1-12 hours. After freeze-vacuum drying, the polyurethane pipe is formed, but a very small amount of organic solvent may still remain. Alternatively, due to the long drying time and high cost of freeze-vacuum drying, the formed polyurethane pipe can be heated and dried. This can be done under normal or negative pressure; under negative pressure, a common vacuum oil pump or water pump can be used.
[0033] In another aspect, this application proposes a neural scaffold prepared by the method for preparing polymer tubing as described in any of the above embodiments. Preferably, the neural scaffold of this application can achieve the effects of low inner diameter, easily adjustable inner diameter, easily adjustable wall thickness, and numerous micropores, all of which are open pores.
[0034] The technical solution of this application will be described in detail below with reference to embodiments and comparative examples.
[0035] In the following examples and comparative examples, the polyurethane material was prepared as follows: PEG400 and IPDI were added to a dry container at a molar ratio of 0.7:1, nitrogen gas was purged, and 0.15% by weight of PEG400 and IPDI and dibutyltin dilaurate were added. The mixture was stirred at room temperature for 1 hour, and then heated to 70°C and reacted for another hour to obtain the prepolymer.
[0036] The prepolymer and PCL glycol with an average molecular weight of 12000 were added to a reaction vessel at a -NCO to -OH molar ratio of 0.99:1. The mixture was heated to 80°C and reacted for 5 hours. After cooling, crude polyurethane was obtained. The crude polyurethane was dissolved in acetone to prepare a 25 wt% solution, which was then added to 20 times its volume of methanol for precipitation. The precipitate was collected and dried overnight under vacuum at 50°C to obtain the polyurethane material.
[0037] Example 1 Pure water is injected into the molding mold beforehand, and the temperature is lowered to -10℃. The water freezes into ice, and the mold is demolded to obtain a cylindrical mold. The cavity of the cylindrical mold is a circular concave cavity with an inner diameter of 3mm, an outer diameter of 4mm, and a height of 10cm. The outer diameter of the cylindrical mold is 1.5cm.
[0038] Polyurethane material was dissolved in butyl acetate to prepare a 60 wt% solution, cooled to -20°C, and added to the cylindrical mold. The solution was then freeze-dried at -15 to -12°C under vacuum to solidify. The solidified sample was removed and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0039] Example 2 Sodium alginate was prepared with water to a concentration of 1 wt%, added to the molding mold of Example 1, cooled to -10°C, frozen, demolded, and a cylindrical mold was obtained.
[0040] Polyurethane material was dissolved in 1,1,2-trichloroethane to prepare a 50wt% solution, cooled to -20°C, and added to the cylindrical mold. The solution was then frozen to -42°C and freeze-dried under vacuum at -42 to -40°C to solidify. The solidified sample was removed, cleaned with pure water, and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0041] Example 3 PVA 17-92 was prepared with water to a concentration of 2 wt%, added to the molding mold of Example 1, cooled to -12°C, frozen, demolded, and a cylindrical mold was obtained.
[0042] Polyurethane material was dissolved in 1,1,1-trichloro-2,2,2-trifluoroethane to prepare a 45 wt% solution. The solution was cooled to -20°C and added to the cylindrical mold described above. The mold was then frozen to -42°C and freeze-dried under vacuum at -30±1°C until cured. The cured sample was removed, cleaned with pure water, and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0043] Example 4 Sodium chloride was prepared into a 10wt% aqueous solution and added to the molding mold of Example 1. The solution was cooled to 5°C and frozen. The mold was then demolded to obtain a cylindrical mold.
[0044] Polyurethane material was dissolved in 1,1,2-trichloroethane to prepare a 45wt% solution, cooled to 0°C, and added to the cylindrical mold. The solution was then frozen to -42°C and freeze-dried under vacuum at -42 to -40°C until cured. The cured sample was removed, cleaned with 60°C hot water, and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0045] Example 5 Sodium sulfate was dissolved in water to a concentration of 4 wt%, added to a molding mold, cooled to -15℃, the aqueous solution was frozen into ice, demolded, and a cylindrical mold was obtained. The cavity of the cylindrical mold was annular, with an inner diameter of 2 mm, an outer diameter of 3 mm, and a height of 10 cm. The outer diameter of the cylindrical mold was 1.2 cm.
[0046] Polyurethane material was dissolved in 1,1,1-trichloroethane to prepare a 65wt% solution, cooled to -15°C, and added to the cylindrical mold. The solution was then frozen to -35°C and freeze-dried under vacuum at -34 to -33°C to solidify. The solidified sample was removed, cleaned, and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0047] Example 6 PVP K30 was mixed with water to a concentration of 3.5 wt%, added to the molding mold of Example 5, cooled to -15°C, frozen, demolded, and a cylindrical mold was obtained.
[0048] Polyurethane material was dissolved in 1,1,2-trichloroethane to prepare a 40wt% solution, cooled to -25°C, and poured into the cylindrical mold. The solution was then frozen to -42°C and freeze-dried under vacuum at -42 to -40°C until cured. The cured sample was removed, cleaned with pure water, and then vacuum-dried overnight at 60°C to obtain the polyurethane pipe.
[0049] Example 7 The difference between Example 7 and Example 6 is that in Example 6, the PVP K30 aqueous solution was replaced with a 1.5 wt% carboxymethyl cellulose aqueous solution. The remaining steps remained unchanged.
[0050] Example 8 The difference between Example 8 and Example 6 is that in Example 6, the PVP K30 aqueous solution was replaced with a starch aqueous solution with a concentration of 1 wt%. The remaining steps remained unchanged.
[0051] Comparative Example 1 According to existing technology, 10 wt% sodium chloride particles (average particle size 0.7 μm) are added to polyurethane material, mixed evenly, and melt-extruded into tubular polyurethane tubes with an inner diameter of 6 mm and a wall thickness of 0.5 mm. These tubes are then cut to 5 cm lengths and immersed in clean water for sodium chloride replacement for 72 hours, with the water changed every 12 hours. The tubes are then removed, cleaned, and vacuum-dried overnight at 60°C to obtain the polyurethane tubing.
[0052] All the polyurethane pipes from Examples 1-8 were cut to a length of 5cm.
[0053] The density of polyurethane materials and polyurethane pipes in various embodiments and comparative examples were tested using the drainage method. The results are shown in Table 1 below.
[0054] Table 1 Density / g / cm³ 3 polyurethane materials Example 1 Example 2 Example 3 Example 4 1.155 1.104 0.651 0.647 0.644 Example 5 Example 6 Example 7 Example 8 Comparative Example 1 0.675 0.641 0.636 0.640 0.804 As can be seen from the data in Table 1, the preparation method of this application can significantly reduce the density of polyurethane pipes by forming micropores inside the polyurethane pipes.
[0055] Appendix Figure 1 Here is a SEM image of the cross-section of the polyurethane pipe in Example 3, attached. Figure 2 This is a SEM image of the cross-section of the polyurethane pipe in Comparative Example 1. (From the attached image) Figure 1 and attached Figure 2 It is known that existing polyurethane pipes prepared using sodium chloride as a pore-forming agent have uneven micropore sizes and many micropores are closed pores. The polyurethane pipes prepared by the method of this application have more uniform micropore sizes and the micropores are basically open pores.
[0056] Therefore, the preparation method of this application produces polyurethane tubing with micropores that are mostly open and have relatively uniform pore size, making it suitable for use as a neural scaffold.
[0057] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A method for preparing a polymer pipe, characterized in that, The polyurethane solution is transferred into a mold in a solid state, freeze-dried below the melting point of the mold, and then cleaned to obtain the polymer tubing. The mold is made of a polymer aqueous solution or a salt aqueous solution.
2. The method for preparing polymer tubing according to claim 1, characterized in that, The weight concentration of the polymer aqueous solution or salt aqueous solution is 0-15%.
3. The method for preparing polymer tubing according to claim 1, characterized in that, The polyurethane polymer structure used in the polyurethane solution contains at least one first block and at least one second block, the first block and the second block are arranged alternately, and adjacent first blocks and second blocks are connected by urethane bonds. The first block is formed of aliphatic polyester diol and / or alicyclic polyester diol; The second block is formed from an aliphatic polyether diol.
4. The method for preparing polymer tubing according to claim 1, characterized in that, The solvent used in the polyurethane solution has a melting point of -100~0℃.
5. The method for preparing polymer tubing according to claim 1, characterized in that, The concentration of the polyurethane solution is 5-80 wt%.
6. The method for preparing polymer tubing according to claim 1, characterized in that, The cavity of the mold is matched with the polyurethane pipe.
7. The method for preparing polymer tubing according to claim 1, characterized in that, The temperature of the freeze-drying process is lower than the melting point of the solvent used in the polyurethane solution.
8. The method for preparing polymer tubing according to claim 7, characterized in that, The solvent has a melting point of -60℃ to 0℃.
9. The method for preparing polymer tubing according to claim 1, characterized in that, After the freeze-drying process and before the cleaning process, the process further includes heating at 50-100°C for 1-12 hours.
10. A neural scaffold, characterized in that, It is prepared by the method for preparing polymer tubing according to any one of claims 1-9.