A 3D printing ink for a biodegradable hepatobiliary duct stent

Abstract

The present invention discloses a 3D printing ink for a biodegradable hepatobiliary duct stent, which is characterized by consisting of acrylamide, an initiator, N-vinylpyrrolidone, F127DA, N,N-bis(acryloyl)cystamine, and a light absorbent. The present invention can achieve high-precision printing through N-vinylpyrrolidone + acrylamide. By introducing the synthesized F127 with double bonds, F127DA of diacrylic acid, and the crosslinking agent N,N-bis(acryloyl)cystamine with disulfide bonds, the biodegradable performance of the 3D printing ink is improved, thereby the present invention well solves the problem of poor manufacturing accuracy of the existing printing ink.

Description

Technical Field

[0001] The present invention relates to the technical field of 3D printing inks, and specifically refers to a 3D printing ink for a biodegradable hepatobiliary duct stent. Background Art

[0002] Currently, liver transplantation surgery is considered an effective means for treating end-stage liver diseases and is widely carried out worldwide. However, the implementation of liver transplantation still faces various problems. Therefore, establishing a stable liver transplantation animal model for relevant research has extremely important clinical significance. Clinically, biliary stricture after liver transplantation is one of the important reasons for liver failure. Studying the pathological and biological models of biliary stricture is of great clinical significance. In the relevant research using liver transplantation animal models, it is closer to human physiological indicators. Therefore, the mouse liver transplantation model is used as the main liver transplantation animal model for relevant research. Clinically, bile duct stents can be used as a means to avoid bile duct stricture and obstruction.

[0003] However, the mouse bile duct is extremely thin (about 200 microns), and it is difficult for conventional 3D printing inks to achieve a precision of less than 1 mm when printing stents, making it difficult to conduct animal research. At the same time, bile duct stents should have certain biodegradable properties. Therefore, the existing problem of poor production precision of printing inks cannot well meet the needs of relevant research using liver transplantation animal models. We need to develop a 3D printing ink that not only has biodegradable properties but also can improve printing precision, so as to meet the needs of relevant research using liver transplantation animal models. Summary of the Invention

[0004] The purpose of the present invention is to solve the above problems and provide a 3D printing ink for a biodegradable hepatobiliary duct stent that not only has biodegradable properties but also can improve printing precision, thus meeting the needs of relevant research using liver transplantation animal models.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A hollow vascular anastomosis stent based on 3D printing self-expanding hydrogel, which is composed of acrylamide, initiator, N-vinylpyrrolidone, F127DA, N,N-bis(acryloyl)cystamine, and light absorbent.

[0007] Among them, the weight parts of N-vinylpyrrolidone are 1 to 6 parts, the weight parts of F127DA are 1 to 4 parts, the weight parts of acrylamide are 1 to 4 parts, the weight parts of N,N-bis(acryloyl)cystamine are 0.01 to 0.06 parts, the weight parts of the initiator are 0.01 to 0.02 parts, and the weight parts of the light absorbent are 0.01 - 0.04 parts.

[0008] The F127DA is composed of 10 g of F127, 10 times the molar mass of triethylamine, and 10 times the molar mass of acryloyl chloride.

[0009] Further, the light absorbent is one or a mixture of several of curcumin, fast green, tartrazine, and sudan.

[0010] As a preferred embodiment of the present invention, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine is 1.2 to 1.3 (mPa·s, 25°C), and the relative density (25°C, 4°C) is 1.012 to 1.2 (25°C, 4°C).

[0011] As a preferred embodiment of the present invention, the initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), and the molecular weight of this initiator is 294.2, with a purity ≥ 99%.

[0012] As a preferred embodiment of the present invention, the density of acrylamide is 1.27 g / cm 3 ~1.38 g / cm 3 and the melting point is 85°C.

[0013] Further, the preparation method of the F127DA is as follows:

[0014] ① Dissolve 10 g of F127 and 10 times the molar mass of triethylamine in a three-necked flask under a nitrogen atmosphere, and add 100 mL of anhydrous dichloromethane and stir to obtain a mixed solution of F127 and triethylamine.

[0015] ② Introduce 10 times the molar mass of acryloyl chloride into the mixed solution of F127 and triethylamine in the three-necked flask through a dropping funnel, inject nitrogen at 25°C into the three-necked flask, and stir for 24 h under the condition of injecting nitrogen at 25°C to obtain a mixed filtrate.

[0016] ③ Filter out the precipitate in the obtained mixed filtrate to obtain a supernatant. Add anhydrous ether to the supernatant to precipitate the filtrate, and obtain a product with F127DA, and repeatedly wash the product with anhydrous ether to remove the unreacted raw materials in the product.

[0017] ④ Dry the washed product in a vacuum environment at 30°C for 24 hours to obtain the final F127DA. Further, the preparation steps of the biodegradable 3D printing ink for the bile duct stent are as follows:

[0018] S1. Add N-vinylpyrrolidone in an amount of 1 to 6 parts by weight, acrylamide in an amount of 1 to 4 parts by weight, and F127DA in an amount of 1 to 4 parts by weight into a container, stir clockwise for 5 to 10 minutes, let stand for 2 minutes, and then stir counterclockwise for 5 to 10 minutes to obtain a clear solution.

[0019] S2. Add N,N-bis(acryloyl)cystamine in an amount of 0.06 to 1 part by weight to the obtained clear solution, stir for 5 to 10 minutes, let stand until there are no bubbles, add an initiator in an amount of 0.01 to 1 part by weight and a light absorbent in an amount of 0.01 to 0.04 part by weight, and stir again for 5 to 15 minutes to obtain a 3D printing hydrogel ink.

[0020] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0021] (1) The present invention can achieve high-precision printing through N-vinylpyrrolidone + acrylamide. By introducing the synthesized F127 with double bonds, F127DA of diacrylic acid, and the cross-linking agent N,N-bis(acryloyl)cystamine with disulfide bonds, the degradability of the 3D printing ink is improved, thus the present invention well solves the problem of poor manufacturing accuracy of the existing printing ink.

[0022] (2) By controlling the viscosity, relative density of N,N-bis(acryloyl)cystamine and the density of acrylamide, the printing accuracy and degradation rate of the 3D printing ink for biodegradable hepatobiliary duct stents can be changed. Description of the Drawings

[0023] Figure 1 It is a preparation flow chart of F127DA of the present invention. Detailed Embodiments

[0024] The following further elaborates the present invention in detail with reference to the embodiments, but the implementation manners of the present invention are not limited thereto.

[0025] Embodiment 1

[0026] A 3D printing ink for biodegradable hepatobiliary duct stents in this embodiment is composed of acrylamide, an initiator, N-vinylpyrrolidone, F127DA, N,N-bis(acryloyl)cystamine, and a light absorbent. Specifically, the viscosity (mPa·s, 25 °C) of the N,N-bis(acryloyl)cystamine is 1.2 to (mPa·s, 25 °C): 1.3, and the relative density (25 °C, 4 °C) is 1.012 to (25 °C, 4 °C): 1.2. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥ 99%. The density of the acrylamide is 1.27 g / cm3 ~1.38 g / cm 3 with a melting point of 85°C. The light absorbent is a mixture of one or more of curcumin, fast green, tartrazine, and sudan.

[0027] Among them, the weight parts of N-vinylpyrrolidone are 1 to 6 parts, the weight parts of F127DA are 1 to 4 parts, the weight parts of acrylamide are 1 to 4 parts, the weight parts of N,N-bis(acryloyl)cystamine are 0.01 to 0.06 parts, the weight parts of the initiator are 0.01 to 0.02 parts, and the weight parts of the light absorbent are 0.01 to 0.04 parts.

[0028] In this example, according to the need, the weight parts of N-vinylpyrrolidone are 6 parts, the weight parts of F127DA are 2 parts, the weight parts of acrylamide are 2 parts, the weight parts of N,N-bis(acryloyl)cystamine are 0.06 parts, the weight parts of the initiator are 0.01 part, and the weight parts of the light absorbent are 0.02 part. Among them, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine is 1.2, and the relative density (25°C, 4°C) is 1.012. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥99%. The density of acrylamide is 1.27 g / cm 3 with a melting point of 85°C. The light absorbent is a mixture of curcumin, fast green, and tartrazine.

[0029] In addition, the F127DA is composed of 10 g of F127, 10 times the molar mass of triethylamine, and 10 times the molar mass of acryloyl chloride. As shown in the appendix Figure 1 The preparation method of the F127DA is as follows:

[0030] ① Dissolve 10 g of F127 and 10 times the molar mass of triethylamine in a three-necked flask under a nitrogen atmosphere, and add 100 mL of anhydrous dichloromethane and stir to obtain a mixed solution of F127 and triethylamine.

[0031] ② Introduce 10 times the molar amount of acryloyl chloride into the mixed solution of F127 and triethylamine in the three-necked flask through a dropping funnel, and inject nitrogen at 25°C into the three-necked flask. Stir for 24 h under the condition of injecting nitrogen at 25°C to obtain a mixed filtrate.

[0032] ③ Filter out the precipitate in the obtained mixed filtrate to obtain a supernatant. Add anhydrous ether to the supernatant to precipitate the filtrate to obtain a product with F127DA, and repeatedly wash the product with anhydrous ether to remove the unreacted raw materials in the product.

[0033] ④ After drying the washed product in a vacuum environment at 30 °C for 24 hours, the final F127DA is obtained. Further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary stent are as follows:

[0034] S1. Add 6 parts by weight of N-vinylpyrrolidone, 2 parts by weight of acrylamide, and 2 parts by weight of F127DA into a container, stir clockwise for 5 - 10 min, let stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clear solution.

[0035] S2. Add 0.06 parts by weight of N,N-bis(acryloyl)cystamine to the obtained clear solution, stir for 5 - 10 min, let stand until there are no bubbles, then add 0.01 parts by weight of initiator and 0.02 parts by weight of light absorbent, and stir again for 5 - 15 min to obtain the 3D printing hydrogel ink.

[0036] Specifically, in the implementation, N-vinylpyrrolidone + acrylamide can achieve high-precision printing. By introducing the synthesized F127 with double bonds, F127DA with diacrylic acid, and the cross-linking agent N,N-bis(acryloyl)cystamine with disulfide bonds, the degradable performance of the 3D printing ink is improved.

[0037] Example 2

[0038] This example is basically the same as Example 1, and the difference lies in:

[0039] In this example, according to the need, the parts by weight of N-vinylpyrrolidone is 6, the parts by weight of acrylamide is 4, the parts by weight of N,N-bis(acryloyl)cystamine is 0.06, the parts by weight of initiator is 0.01, and the parts by weight of light absorbent is 0.02. Among them, the viscosity (mPa·s, 25 °C) of N,N-bis(acryloyl)cystamine: 1.2, relative density (25 °C, 4 °C): 1.012. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥ 99%. The density of acrylamide is 1.27 g / cm 3 , the melting point is 85 °C. The light absorbent is curcumin.

[0040] In addition, further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary stent are as follows:

[0041] S1. Add 6 parts by weight of N-vinylpyrrolidone and 4 parts by weight of acrylamide into a container, stir clockwise for 5 - 10 min, let stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clear solution.

[0042] S2. Add 0.06 parts by weight of N,N-bis(acryloyl)cystamine to the obtained clarified solution. After stirring for 5 - 10 min, let it stand until there are no bubbles, then add 0.01 parts by weight of initiator and 0.02 parts by weight of light absorbent. After stirring again for 5 - 15 min, 3D printing hydrogel ink is obtained.

[0043] Example 3

[0044] This example is basically the same as Example 1, and the difference lies in:

[0045] In this example, according to requirements, the parts by weight of N-vinylpyrrolidone is 6 parts, the parts by weight of F127DA is 4 parts, the parts by weight of N,N-bis(acryloyl)cystamine is 0.06 parts, the parts by weight of initiator is 0.01 parts, and the parts by weight of light absorbent is 0.02 parts. Among them, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine: 1.2, relative density (25°C, 4°C): 1.012. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥ 99%. The density of acrylamide is 1.27 g / cm 3 , and the melting point is 85°C. The light absorbent is a mixture of curcumin and sudan.

[0046] In addition, further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary stent are as follows:

[0047] S1. Add 6 parts by weight of N-vinylpyrrolidone and 4 parts by weight of F127DA to a container and stir clockwise for 5 - 10 min, then let it stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clarified solution.

[0048] S2. Add 0.06 parts by weight of N,N-bis(acryloyl)cystamine to the obtained clarified solution. After stirring for 5 - 10 min, let it stand until there are no bubbles, then add 0.01 parts by weight of initiator and 0.02 parts by weight of light absorbent. After stirring again for 5 - 15 min, 3D printing hydrogel ink is obtained.

[0049] Example 4

[0050] This example is basically the same as Example 1, and the difference lies in:

[0051] In this embodiment, according to requirements, the weight parts of N-vinylpyrrolidone is 6 parts, acrylamide is 3 parts, F127DA is 1 part, N,N-bis(acryloyl)cystamine is 0.5 part, the initiator is 0.5 part, and the light absorbent is 0.01 part. Among them, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine: 1.25, relative density (25°C, 4°C): 1.1. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥99%. The density of acrylamide is 1.32 g / cm 3 , and the melting point is 85°C. The light absorbent is a mixture of tartrazine and sudan.

[0052] In addition, further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary duct stent are as follows:

[0053] S1. Add 6 parts by weight of N-vinylpyrrolidone, 3 parts by weight of acrylamide, and 1 part by weight of F127DA into a container, stir clockwise for 5 - 10 min, then let it stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clear solution.

[0054] S2. Add 0.5 part by weight of N,N-bis(acryloyl)cystamine to the obtained clear solution, stir for 5 - 10 min, then let it stand until there are no bubbles, add 0.5 part by weight of the initiator and 0.01 part by weight of the light absorbent, and stir again for 5 - 15 min to obtain the 3D printing hydrogel ink.

[0055] Example 5

[0056] This example is basically the same as Example 1, and the difference is:

[0057] In this embodiment, according to requirements, the weight parts of N-vinylpyrrolidone is 6 parts, acrylamide is 1 part, F127DA is 3 parts, N,N-bis(acryloyl)cystamine is 1 part, the initiator is 1 part, and the light absorbent is 0.04 part. Among them, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine: 1.27, relative density (25°C, 4°C): 1.15. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥99%. The density of acrylamide is 1.35 g / cm 3 , and the melting point is 85°C. The light absorbent is tartrazine.

[0058] In addition, further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary duct stent are as follows:

[0059] S1. Add 6 parts by weight of N-vinylpyrrolidone, 1 part by weight of acrylamide, and 3 parts by weight of F127DA into a container, stir clockwise for 5 - 10 min, let it stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clear solution.

[0060] S2. Add 1 part by weight of N,N-bis(acryloyl)cystamine to the obtained clear solution, stir for 5 - 10 min, let it stand until there are no bubbles, then add 1 part by weight of initiator and 0.04 part by weight of light absorbent, and stir again for 5 - 15 min to obtain a 3D printing hydrogel ink.

[0061] Example 6

[0062] This example is basically the same as Example 1, and the differences are as follows:

[0063] In this example, according to requirements, the parts by weight of N-vinylpyrrolidone is 4, the parts by weight of acrylamide is 3, the parts by weight of F127DA is 3, the parts by weight of N,N-bis(acryloyl)cystamine is 0.5, the parts by weight of initiator is 0.5, and the parts by weight of light absorbent is 0.02. Among them, the viscosity (mPa·s, 25°C) of N,N-bis(acryloyl)cystamine: 1.25, relative density (25°C, 4°C): 1.1. The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥ 99%. The density of acrylamide is 1.32 g / cm 3 , and the melting point is 85°C. The light absorbent is a mixture of fast green and lemon yellow.

[0064] In addition, further, the preparation steps of the 3D printing ink for the biodegradable hepatobiliary stent are as follows:

[0065] S1. Add 4 parts by weight of N-vinylpyrrolidone, 3 parts by weight of acrylamide, and 3 parts by weight of F127DA into a container, stir clockwise for 5 - 10 min, let it stand for 2 min, and then stir counterclockwise for 5 - 10 min to obtain a clear solution.

[0066] S2. Add 0.5 part by weight of N,N-bis(acryloyl)cystamine to the obtained clear solution, stir for 5 - 10 min, let it stand until there are no bubbles, then add 0.5 part by weight of initiator and 0.02 part by weight of light absorbent, and stir again for 5 - 15 min to obtain a 3D printing hydrogel ink.

[0067] In order to illustrate the differences between the 3D printing inks for biodegradable hepatobiliary stents prepared in Embodiments 1 to 6 of the present invention and the stents printed with existing metal printing inks in terms of the above-mentioned properties, the above-mentioned properties of the stents printed with the 3D printing inks for biodegradable hepatobiliary stents prepared in Embodiments 1 to 6 and the stents printed with existing metal printing inks were respectively tested. During the test, the length, diameter and wall thickness of the selected stents were the same, and the test data are shown in Table 1 below:

[0068] Test object Tensile strength (kPa) Printing accuracy (μm) 7-day degradation rate 28-day degradation rate Prior art 50 100 5.2±1.4％ 12.6±3.4％ Example 1 420 5 35.6±5.4％ 76.2±8.4％ Example 2 335 5 5.6±2.7％ 18.6±4.7％ Example 3 210 120 39.3±3.9％ 80.8±4.2％ Example 4 160 30 20.1±4.3％ 40.1±2.3％ Example 5 85 120 25.7±4.9％ 71.1±3.3％ Example 6 50 100 28.9±3.9％ 73.9±5.2％

[0069] Table 1

[0070] From Table 1 above, it can be well concluded that the printing accuracy, 7-day degradation rate, 28-day degradation rate and tensile strength of the 3D printing inks for biodegradable hepatobiliary stents in each embodiment of the present application are all superior to those of the existing metal printing inks. Among them, it is also concluded that the printing accuracy, 7-day degradation rate, 28-day degradation rate and tensile strength of the 3D printing ink for biodegradable hepatobiliary stents prepared in Embodiment 1 of the present invention are all superior to those of the 3D printing inks for biodegradable hepatobiliary stents prepared in other embodiments and the existing metal printing inks, which also fully shows that the components and weight parts of the 3D printing ink for biodegradable hepatobiliary stents in Embodiment 1 of the present invention are the best.

[0071] In addition, it can also be seen from the test results that by controlling the viscosity, relative density of N,N-bis(acryloyl)cystamine and the density of acrylamide, the printing accuracy, 7-day degradation rate, 28-day degradation rate and tensile strength of the 3D printing ink for biodegradable hepatobiliary stents can be changed.

[0072] Therefore, it is shown that the 3D printing ink for biodegradable hepatobiliary stents of the present invention can achieve high-precision printing by setting N-vinylpyrrolidone + acrylamide, and by introducing the synthesized F127 with double bonds, F127DA of diacrylic acid and the cross-linking agent N,N-bis(acryloyl)cystamine with disulfide bonds, the degradable performance of the 3D printing ink is improved. Thus, the present invention well solves the problem of poor manufacturing accuracy of existing metal printing inks and better meets the needs of liver transplantation animal models for related research.

[0073] As described above, the present invention can be well realized.

Claims

1. A 3D printing ink for a biodegradable hepatobiliary duct stent, characterized in that, It consists of acrylamide, initiator, N-vinylpyrrolidone, F127DA, N,N-bis(acryloyl)cystamine, and light absorbent; Among them, the weight parts of N-vinylpyrrolidone are 1 to 6 parts, the weight parts of F127DA are 1 to 4 parts, the weight parts of acrylamide are 1 to 4 parts, the weight parts of N,N-bis(acryloyl)cystamine are 0.01 to 0.06 parts, the weight parts of the initiator are 0.01 to 0.02 parts, and the weight parts of the light absorbent are 0.01 - 0.04 parts; The F127DA is prepared from 10 g of F127, 10 times the molar mass of triethylamine, and 10 times the molar mass of acryloyl chloride; The light absorbent is one or a mixture of several of curcumin, fast green, lemon yellow, and sudan; 2. The bio - degradable hepatobiliary duct stent 3D printing ink according to claim 1, wherein, The viscosity of the N,N-bis(acryloyl)cystamine: 1.2 mPa·s ~ 1.3 mPa·s, relative density: 1.012~1.2; 3. The biodegradable hepatobiliary duct stent 3D printing ink according to claim 2, wherein The initiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP), the molecular weight of this initiator is 294.2, and the purity ≥ 99%; 4. The biodegradable hepatobiliary duct stent 3D printing ink according to claim 3, characterized in that, The density of the acrylamide is 1.27 g / cm 3 ~1.38 g / cm 3 , and the melting point is 85 °C.

5. The bio - degradable hepatobiliary duct stent 3D printing ink according to claim 4, wherein, The preparation method of the F127DA is as follows: ① Dissolve 10 g of F127 and 10 times the molar mass of triethylamine in a three-necked flask under a nitrogen atmosphere, and add 100 mL of anhydrous dichloromethane and stir to obtain a mixed solution of F127 and triethylamine; ② Introduce 10 times the molar amount of acryloyl chloride into the mixed solution of F127 and triethylamine in the three-necked flask through a dropping funnel, and inject nitrogen at 25 °C into the three-necked flask. Stir for 24 h under the condition of injecting nitrogen at 25 °C to obtain a mixed filtrate; ③ Filter out the precipitate in the obtained mixed filtrate to obtain a supernatant. Add anhydrous ether to the supernatant to precipitate the filtrate, and obtain a product with F127DA. Wash the product repeatedly with anhydrous ether to remove the unreacted raw materials in the product; ④ Dry the washed product in a vacuum environment at 30 °C for 24 hours to obtain the final F127DA; 6. The bio - degradable hepatobiliary duct stent 3D printing ink according to any one of claims 1 to 5, characterized in that, The preparation steps of the biodegradable bile duct stent 3D printing ink are as follows: S1. Add 1 to 6 parts by weight of N-vinylpyrrolidone, 1 to 4 parts by weight of acrylamide, and 1 to 4 parts by weight of F127DA into a container, stir clockwise for 5 to 10 min, let stand for 2 min, and then stir counterclockwise for 5 to 10 min to obtain a clear solution; S2. Add 0.06 to 1 part by weight of N,N-bis(acryloyl)cystamine to the obtained clear solution, stir for 5 to 10 min, let stand until there are no bubbles, add 0.01 to 1 part by weight of the initiator and 0.01 - 0.04 parts by weight of the light absorbent, and stir again for 5 to 15 min to obtain 3D printing hydrogel ink.

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