CN116421792B

CN116421792B - Preparation method of self-reinforced polymer bile duct stent and product thereof

Info

Publication number: CN116421792B
Application number: CN202310225003.4A
Authority: CN
Inventors: 严强; 任科峰; 计剑; 胡佳琪
Original assignee: Huzhou Central Hospital
Current assignee: Huzhou Central Hospital
Priority date: 2023-03-10
Filing date: 2023-03-10
Publication date: 2024-08-02
Anticipated expiration: 2043-03-10
Also published as: CN116421792A

Abstract

The invention discloses a preparation method of a self-reinforced polymer bile duct bracket, which comprises the following steps: s1: preparing zinc oxide aqueous dispersion; blending a monomer with the zinc oxide aqueous dispersion liquid, and fully reacting to obtain a zinc ion complexing monomer; the monomer is selected from acrylic monomers and/or methacrylic monomers; s2: uniformly mixing a zinc ion complexing monomer, gelatin and a photoinitiator to obtain a prepolymer solution; s3: immersing the bracket into the prepolymer solution, and taking out the bracket for ultraviolet curing after the bracket is immersed completely; repeating the dipping and ultraviolet curing processes for a plurality of times to obtain a bracket deposited with a coating; s4: immersing the stent deposited with the coating into a buffer solution, and taking out the stent to obtain the self-reinforced polymer bile duct stent. The product prepared by the invention can be self-reinforced after being soaked in bile, has better support and has excellent bending property and biocompatibility.

Description

Preparation method of self-reinforced polymer bile duct stent and product thereof

Technical Field

The invention relates to the technical field of medical appliances, in particular to a preparation method of a self-reinforced polymer bile duct bracket and a product thereof.

Background

Liver and gall diseases are one of the diseases threatening the life health of human beings at present due to the characteristics of high incidence rate, multiple complications and the like. At present, surgical treatment such as T-tube drainage after choledocholithiasis and stone removal is mainly adopted for the treatment of gall stones, although the technology is mature, the risk of gall leakage can be reduced, residual crushed stones are led out, the problems of easy infection, easy falling off, possibility of retrograde infection, inflammatory stenosis and the like are also existed, the normal life of a patient can be influenced by remaining the T-tube, the digestion function of the patient can be influenced by long-term drainage, and the problems of bile peritonitis and the like are also easy to occur when the T-tube is removed. Therefore, an alternative treatment scheme for postoperative T-tube drainage is required in clinic.

Implantation of the biliary stent is a good choice. A good-performance bracket is required to have proper mechanical properties, such as enough radial supporting force to ensure the smooth bile duct and prevent restenosis; and the bending performance is good, and twisting and breaking caused by bile duct movement are prevented.

Currently, the commonly used bile duct brackets mainly comprise a metal bile duct bracket and a plastic bile duct bracket. The metal bile duct bracket has longer service life and can provide enough supporting force, but has poorer biocompatibility and is easy to cause the problems of endothelial tissue hyperplasia and the like; although the common materials of plastic bile duct stents, such as polycaprolactone, polylactic acid and other hydrophobic materials, have better propping property, the hydrophobic materials are generally poor in biocompatibility and are not easy to bend. The hydrophilic material can well solve the problems, but the swelling property of the hydrophilic material such as the hydrogel materials with lower mechanical properties such as .PVA(Nagakawa,Y.;Fujita,S.;Yunoki,S.;Tsuchiya,T.;Suye,S.i.;Itoi,T.,Self-expandable hydrogel biliary stent design utilizing the swelling property of poly(vinyl alcohol)hydrogel.Journal of Applied Polymer Science 2019,137(28).) like the methacrylic acid gelatin (GelMA)/polyethylene glycol diacrylate stent (Liu,X.;Yan,J.;Liu,J.;Wang,Y.;Yin,J.;Fu,J.,Fabrication of a dual-layer cell-laden tubular scaffold for nerve regeneration and bileduct reconstruction.Biofabrication 2021,13(3).) can realize self-expansion, but the swelling of tubular hydrogel also prolongs the length of the tubular hydrogel, and the wall of the tubular hydrogel becomes thicker, so that the tubular hydrogel is unfavorable for application.

Disclosure of Invention

Aiming at the problems in the prior art, the invention discloses a preparation method of a polymer bile duct bracket, and the prepared product can be self-reinforced after being soaked in bile, has better support and excellent bending property and biocompatibility.

The specific technical scheme is as follows:

a method for preparing a self-reinforced polymer bile duct stent, comprising the following steps:

S1: preparing zinc oxide aqueous dispersion; blending a monomer with the zinc oxide aqueous dispersion liquid, and fully reacting to obtain a zinc ion complexing monomer;

The monomer is selected from acrylic monomers and/or methacrylic monomers;

s2: uniformly mixing the zinc ion complexing monomer, gelatin and a photoinitiator to obtain a prepolymer solution;

s3: immersing the bracket into the prepolymer solution, and taking out the bracket for ultraviolet curing after the bracket is completely immersed; and repeating the dipping and ultraviolet curing processes for a plurality of times to obtain the bracket deposited with the coating.

S4: immersing the stent deposited with the coating into a buffer solution, and taking out the stent to obtain the self-reinforced polymer bile duct stent.

The inventor of the invention surprisingly found that the self-supporting polymer scaffold prepared by adopting zinc ion complexed acrylic acid monomer and/or zinc ion complexed methacrylic acid monomer as raw materials and gelatin after photo-curing has self-reinforcing effect in bile, thus not only maintaining the original toughness and biocompatibility of the material, but also obviously increasing the radial supporting force of the material, effectively preventing restenosis in the use process, being difficult to generate blockage and prolonging the service life of the material.

In step S1:

The acrylic monomer is selected from one or more of acrylic acid, methyl acrylate, ethyl acrylate and n-butyl acrylate;

the methacrylic monomer is selected from one or more of methacrylic acid, methyl methacrylate and n-butyl methacrylate.

Preferably:

The monomer is selected from acrylic acid and/or methacrylic acid; or at least one of acrylic acid and methacrylic acid is combined with one or more of methyl acrylate, ethyl acrylate, n-butyl acrylate, methyl methacrylate and n-butyl methacrylate;

I.e. at least one of acrylic acid and methacrylic acid is necessary for reaction with zinc oxide to form a complex. Or adding one or two of other third monomers such as methyl acrylate, ethyl acrylate, n-butyl acrylate methyl, methyl acrylate and n-butyl methacrylate.

Further preferably, the monomer is selected from acrylic acid and/or methacrylic acid.

Preferably, the concentration of the zinc oxide aqueous dispersion is 5-50wt%; further preferably 10 to 30wt%, more preferably 20wt%.

Preferably, the molar ratio of the monomer to the zinc oxide is 1.8-2.5: 1.

Experiments show that the first key point in the preparation method of the invention is to control the mole ratio of the monomer to the zinc oxide, and experiments show that if the mole ratio is too large, the mole ratio is 4:1, the prepared polymer bile duct stent has no self-enhancement effect in bile, but rather has obvious swelling, so that the radial force is reduced.

Further preferably, the molar ratio of the monomer to zinc oxide is 1.8 to 2.0:1. the test shows that the radial force of the polymer bile duct stent prepared at the molar ratio is higher before and after bile soaking, but when the molar ratio of the monomer to the zinc oxide is 1.8:1, the prepared polymer bile duct stent has obvious cracking after soaking, so that the molar ratio of the monomer to the zinc oxide is more preferably 2.0:1.

In step S1, if only centrifugation is performed after the reaction, the obtained supernatant is an aqueous solution of a monomer complexed with zinc ions, and in step S2, the reaction may be performed directly using the aqueous solution as a raw material.

Preferably, the centrifugal treatment is carried out at a rotational speed of 8000-10000 rad/s for 2-10 min.

In step S2:

preferably, the gelatin has a gel strength of 100-260 g bloom;

Experiments show that the difference of the adhesive strength of the adopted gelatin can also significantly influence the reinforcing effect of the prepared polymer bile duct stent in bile.

Further preferably, the gelatin has a gel strength of 260g bloom. Experiments show that the polymer bile duct stent prepared by adopting the adhesive strength has the best enhancement effect in bile.

Preferably, the mass ratio of the zinc ion complexing monomer to the gelatin is 3-5: 1.

Experiments show that the mass ratio of the two also determines the enhancement effect of the prepared polymer bile duct stent in bile. When the mass ratio of the two is too low, such as 1:1, although a self-supporting polymer bile duct stent can be prepared, the self-supporting polymer bile duct stent has no supporting force basically; even if increased to 2:1, although a self-supporting polymeric bile duct scaffold can be prepared, which also has supporting force, significant swelling occurs after 22h of treatment in bile.

Further preferably, the mass ratio of the zinc ion complexing monomer to the gelatin is 3-3.9: 1, a step of; experiments show that the polymer bile duct stent prepared in the range has a good self-enhancement effect in bile. More preferably 3.9:1.

The photoinitiator is selected from one or more of dibenzoyl peroxide, amine persulfate, potassium persulfate, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, benzoin derivatives, diphenyl ketone, benzophenone derivatives, alkylaryl ketone derivatives, benzil derivatives, 2-dimethoxy-2-phenylacetophenone, acetophenone derivatives, aqueous thioxanthone and methyl vinyl ketone;

if the photoinitiator used is insoluble in water, it may be first dissolved in an organic solvent and then blended with other materials.

The organic solvent is selected from the conventional species in the art, such as ethanol and the like.

The mass of the photoinitiator is 0.5-3.0 percent based on 100 percent of the total mass of the zinc ion complexing monomer, gelatin and the photoinitiator.

In order to prevent the gelatin from solidifying, it is preferable to uniformly mix at a constant temperature of 30 to 37℃to obtain a prepolymer solution.

In step S3:

The bracket is tubular, has an average pipe diameter of 1-10 mm and a length of 20-40 mm, and is made of one or more of silica gel, TPU, polytetrafluoroethylene and glass.

The scaffold is a scaffold subjected to hydrophilic pretreatment, namely, the hydrophilicity of the scaffold is improved through pretreatment, the pretreatment means is not limited, and the scaffold is selected from conventional means capable of improving the hydrophilicity in the field. For example, plasma treatment, etc., a plasma treatment of 30 to 300W for 120 to 180 seconds is preferable.

Preferably, the ultraviolet light is solidified, the intensity of the ultraviolet light is 100-10000 mu W/cm ², and the irradiation time is 30-120 s.

Further preferably, the number of times of repeating the dipping and ultraviolet curing processes in the step S3 is 1-4, and at this time, the thickness of the self-reinforced polymer bile duct stent finally prepared after the treatment in the step S4 is 150-400 μm, and the polymer bile duct stent with the preferred thickness range not only has enough radial force, but also avoids the influence of excessive thickness on the flow of bile in the stent.

In step S4:

the buffer solution is selected from one or more of triethanolamine buffer saline solution, water and phosphate buffer saline solution.

The invention also discloses a self-reinforced polymer bile duct stent prepared by the method, and the polymer bile duct stent can be self-reinforced after being soaked in bile, has better support and excellent bending performance and biocompatibility through tests. Also, this self-enhancing technical effect occurs only in bile, and is not present in blood.

Compared with the prior art, the invention has the following beneficial effects:

the invention discloses a self-supporting polymer stent prepared from specific raw materials, which has the special self-reinforcing effect after being soaked in bile, has excellent bending property, biocompatibility and better supporting property, can effectively prevent restenosis of the bile duct stent in the actual use process, is not easy to be blocked, and prolongs the service life of the bile duct stent.

Drawings

FIG. 1 is a graph showing the change in time of soaking in bile and radial force of the polymer bile duct stent prepared in example 1;

fig. 2 is a graph showing the change in radial force before and after soaking the polymer bile duct stents prepared in examples 1 to 3 and comparative examples 1 to 3, respectively, in bile.

Detailed Description

The performance parameters of the products prepared in the following examples and comparative examples were measured as follows.

1. Radial force test:

and (3) using a universal testing machine to test the compressive radial force of the bracket with the length of 3cm, wherein the sensor is 100N, unloading is performed after the sensor is compressed to be 50% of strain, the loading speed is 2mm/min, the unloading speed is 2mm/min, and the maximum force value is taken as the radial force.

2. Bile soaking test:

Bile was obtained from human bile, and individual scaffolds were immersed in 4mL of bile and treated at constant temperature of 37 ℃ for a fixed period of time.

The bile adopted in the invention is the bile of human body, but because of individual difference, the composition of bile provided by different human bodies is different, so that a certain difference exists in the enhancement effect after soaking, but when the influence of factors such as gelatin glue strength, molar ratio of acrylic acid and zinc oxide and the like on the enhancement effect is judged, the bile from the same source is adopted.

3. Blood soaking test:

Blood was taken from rabbit atrial blood, and individual stents were immersed in 4mL of blood and incubated at 37 ℃ for a fixed period of time.

Example 1

S1: an aqueous dispersion of acrylic acid and 20wt% zinc oxide was prepared at a molar ratio of acrylic acid to zinc oxide of 2:1 and stirring the mixture uniformly to react for 2 hours, centrifuging the mixture at a speed of 9000rad/s for 5 minutes, and taking a supernatant to obtain 0.432g/mL of zinc acrylate aqueous solution.

S2: 9mL of the zinc acrylate aqueous solution prepared in the step S1, 1g of gelatin (260-g of bloom) and 500 mu L of ethanol solution (100 mg/mL) of photoinitiator i2959 are stirred and dissolved at a constant temperature of 30 ℃ to prepare a uniform prepolymer solution;

s3: and (2) taking a silica gel pipe with the diameter of 6mm as an inner core for preparing the bracket, treating the surface of the inner core with plasma with the power of 150W for 180S, immersing the inner core in the prepolymer solution in the step (S2), pulling the inner core out by using a dip-coating instrument at the speed of 12000 mu m/S, and then irradiating ultraviolet light with the intensity of 5000 mu W/cm ² for 40S until the free radical polymerization reaction is finished, so as to obtain an in-situ polymerized coating on the surface of the inner core. Dip coating was repeated 4 times to obtain a coating.

S4: and (3) immersing the coating obtained in the step (S3) in TBS buffer solution for 30min, and then taking off the coating from the pipe to obtain the self-supporting polymer bile duct stent.

FIG. 1 is a graph showing the change of the soaking time and radial force of the polymer bile duct stent prepared by the present embodiment in bile. From an examination of this figure, it was found that the radial force of the polymer bile duct stent had a continuously increasing tendency as the soaking time increased.

After the polymer bile duct stent prepared in the embodiment is soaked in blood for 1d, the stent is found to be obviously swelled and embrittled in blood, does not have a tubular structure any more, loses mechanical strength and cannot provide data.

Example 2

The preparation process is essentially the same as in example 1, except that the gelatin employed in step S2 is replaced by gelatin having a gel strength of 180 to g bloom.

Example 3

The preparation process is essentially the same as in example 1, except that the gelatin employed in step S2 is replaced by gelatin having a gel strength of 100 to g bloom.

Comparative example 1

The preparation process is essentially the same as in example 1, except that the molar ratio of acrylic acid to zinc oxide in step S1 is replaced by 4:1.

Comparative example 2

The preparation process is substantially the same as in comparative example 1, except that the gelatin used in step S2 is replaced with gelatin having a gel strength of 180 to g bloom.

Comparative example 3

The preparation process was substantially the same as in comparative example 1, except that the gelatin used in step S2 was replaced with gelatin having a gel strength of 100 to g bloom.

Fig. 2 is a graph showing the change in radial force after immersing the polymer bile duct stents prepared in examples 1 to 3 and comparative examples 1 to 3 respectively in bile of the same source for 3 days. From an examination of this figure, it was found that the molar ratio of monomer to zinc oxide, and the gel strength of gelatin had a significant effect on the self-reinforcing effect of the prepared polymeric bile duct scaffold.

Examples 4 to 5

The preparation process is essentially the same as in example 1, except that the molar ratio of acrylic acid to zinc oxide in step S1 is replaced by 1.8:1 and 2.5:1.

The data change in radial force after soaking the polymeric bile duct stents prepared in examples 1, 4-5 respectively in bile from the same source for 3 days is shown in table 1 below:

TABLE 1

Numbering device	Radial force/N before soaking	Radial force/N after soaking
			Example 1	0.105	0.523
Example 4	0.124	0.631
			Example 5	0.077	0.483

However, it was further observed that the three groups of soaked polymeric bile duct stents showed significant cracking during the radial force test, and the other two groups did not see cracking.

Example 6

The preparation process was substantially the same as in example 1, except that in step S2, the volume of the aqueous zinc acrylate solution was replaced with 7mL, and 2mL of ultrapure water was further added, and at this time, the mass ratio of zinc acrylate to gelatin was replaced with 3:1.

Comparative example 4

The preparation process was substantially the same as in example 1, except that the volume of the aqueous zinc acrylate solution in step (2) was replaced with 4.6mL, and 4.4mL of ultrapure water was further added, and at this time, the mass ratio of zinc acrylate to gelatin was replaced with 2:1.

Comparative example 5

The preparation process was substantially the same as in example 1, except that the volume of the aqueous zinc acrylate solution in step (2) was replaced with 2.3mL, and 6.7mL of ultrapure water was further added, and at this time, the mass ratio of zinc acrylate to gelatin was replaced with 1:1.

The changes in appearance and radial force after soaking the polymer bile duct scaffolds prepared in example 1, example 6 and comparative examples 4 to 5 in bile of the same source are shown in Table 2 below.

TABLE 2

Numbering device	Example 1	Example 6	Comparative example 4	Comparative example 5
					Whether or not to prepare the bracket	Can be used for	Can be used for	Can be used for	Can be used for
With or without supporting force	Has the following components	Has the following components	Has the following components	Without any means for
					Color of	White translucency	White translucency	Colorless and transparent	Colorless and transparent
Radial force before soaking	0.092N	0.074N	0.021N	-
					Radial force after soaking for 22h	0.256N	0.312N	0.049N (swelling)	-
Radial force after 10d soaking	0.409N	0.369N	-	-

Claims

1. A method for preparing a self-reinforced polymer bile duct stent, comprising the following steps:

S1: preparing a zinc oxide aqueous dispersion; mixing a monomer with the zinc oxide aqueous dispersion to obtain a zinc ion complexing monomer after sufficient reaction;

The molar ratio of the monomer to the zinc oxide in the zinc oxide aqueous dispersion is 1.8 to 2.5:1;

The monomer is selected from acrylic monomers and/or methacrylic monomers;

S2: uniformly mixing the zinc ion complexing monomer, gelatin and photoinitiator to obtain a prepolymer solution;

The gelatin has a gel strength of 100 to 260 g bloom;

The mass ratio of zinc ion complex monomer to gelatin is 3 to 5:1;

S3: immersing the stent in the prepolymer solution, taking it out after it is completely immersed, and performing UV curing; after repeating the immersion and UV curing process several times, a stent with a coating deposited thereon is obtained;

S4: immersing the stent with the coating deposited thereon into a buffer solution, and taking out the stent to obtain the self-reinforced polymer bile duct stent.

2. The method for preparing the self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S1:

The acrylic monomer is selected from one or more of acrylic acid, methyl acrylate, ethyl acrylate, and n-butyl acrylate;

The methacrylic acid monomer is selected from one or more of methacrylic acid, methyl methacrylate, and n-butyl methacrylate;

The concentration of the zinc oxide aqueous dispersion is 5 to 50 wt %.

3. The method for preparing a self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S1, the molar ratio of the monomer to zinc oxide is 1.8 to 2.0:1.

4. The method for preparing a self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S2, the mass ratio of the zinc ion complexing monomer to gelatin is 3.0 to 3.9:1.

5. The method for preparing the self-reinforced polymer bile duct stent according to claim 1, characterized in that:

In step S1, the molar ratio of the monomer to zinc oxide is 2.0:1;

In step S2, the gelatin has a gel strength of 260 g bloom, and the mass ratio of the zinc ion complexing monomer to the gelatin is 3.9:1.

6. The method for preparing a self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S2:

The photoinitiator is selected from one or more of dibenzoyl peroxide, ammonium persulfate, potassium persulfate, 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, benzoin, benzoin derivatives, benzophenone, benzophenone derivatives, alkyl aromatic ketone derivatives, benzil derivatives, 2,2-dimethoxy-2-phenylacetophenone, acetophenone derivatives, aqueous thioxanthones, and methyl vinyl ketone;

Taking the total mass of the zinc ion complex monomer, gelatin and photoinitiator as 100%, the mass of the photoinitiator is 0.5-3.0%;

The mixture is mixed uniformly under constant temperature stirring at 30-37°C to obtain a prepolymer solution.

7. The method for preparing a self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S3:

The stent is tubular, with an average diameter of 1 to 10 mm and a length of 20 to 40 mm, and is made of one or more materials selected from silicone, TPU, polytetrafluoroethylene, and glass;

The scaffold is a scaffold that has been hydrophilically pretreated;

The ultraviolet light curing has an intensity of 100 to 10000 μW/cm ² and an irradiation time of 30 to 120 seconds.

8. The method for preparing a self-reinforced polymer bile duct stent according to claim 1, characterized in that in step S4:

The buffer solution is selected from one or more of triethanolamine buffered saline solution, water, and phosphate buffered saline solution;

The thickness of the prepared self-reinforced polymer bile duct stent is 150-400 μm.

9. A self-reinforced polymer bile duct stent prepared according to the method according to any one of claims 1 to 8.