CN115245599B

CN115245599B - Preparation and application of anticoagulation lubrication bracket

Info

Publication number: CN115245599B
Application number: CN202210569683.7A
Authority: CN
Inventors: 请求不公布姓名
Original assignee: Shanghai Weimi Medical Technology Co ltd
Current assignee: Shanghai Weimi Medical Technology Co ltd
Priority date: 2022-05-24
Filing date: 2022-05-24
Publication date: 2023-12-26
Anticipated expiration: 2042-05-24
Also published as: CN115245599A

Abstract

The invention belongs to the technical field of A61K, and particularly relates to preparation and application of an anticoagulation lubrication bracket. The preparation of the anticoagulation lubrication bracket comprises the following steps: 1) The tubular bracket is manufactured by adopting a laser engraving or braiding method, and surface passivation and cleaning treatment are completed by using passivation liquid; 2) Carrying out surface activation treatment on the bracket treated in the step 1); 3) Placing the bracket treated in the step 2) into a treatment liquid for 0.5-96 h, controlling the temperature to be 4-80 ℃ and regulating the pH to be 7.5-14; 4) Soaking the stent treated in the step 3) in a polymer water solution containing a phosphorylcholine group for 5 min-48 h, and controlling the temperature at 4-80 ℃; 5) And (3) carrying out post-treatment on the stent treated in the step (4) to obtain the anticoagulation lubrication stent. The anticoagulation lubrication stent prepared by the invention has hydrophilic performance, can reduce the adhesion, activation and aggregation of blood platelets in the subsequent use process, and avoids the formation of thrombus.

Description

Preparation and application of anticoagulation lubrication bracket

Technical Field

The invention belongs to the technical field of A61K, and particularly relates to preparation and application of an anticoagulation lubrication bracket.

Background

Intracranial aneurysms are abnormal protrusions on the wall of cerebral arteries, whose walls are thin and prone to spontaneous rupture, which often lead to catastrophic consequences once ruptured. With the innovation of neuro-interventional materials and the progress of technology, researchers are gradually aware that the basis of aneurysm lesions is an aneurysm-carrying artery, and the reconstruction and repair of the neck lesion blood vessels of the aneurysm are key to treating intracranial aneurysms. The intravascular stent can drain blood flow along the long axis direction of the lumen, reduce the blood flow flowing into and out of the tumor cavity, reduce or even avoid recurrence and rupture bleeding of the aneurysm, however, the intravascular stent is transplanted in the body as a foreign object, which is easy to cause adhesion, activation and aggregation of platelets and finally leads to thrombosis.

Mussel bionic adhesion is an aqueous phase coating technology developed in recent years, and almost realizes adhesion of all substrate surfaces through the synergistic effects of covalent bonds, electrostatic interactions, pi-pi conjugation and the like among key adhesion units dopamine and/or dopamine-like structures in the mussels, and has the advantage of broad-spectrum adhesion. Furthermore, the dopamine and/or the dopamine-like substance not only has good biocompatibility, but also has reactive amino, aldehyde and hydroxyl on the structure, thereby being beneficial to subsequent grafting modification. Therefore, the dopamine and/or dopamine-like structure has good application prospect in the technical field of surface modification.

Chinese patent No. 105073070 discloses a coated medical device and a method for manufacturing and using the same, wherein the coating prepared on the surface of the medical device by dip coating and knife coating processes belongs to the field of physical coating, the thickness of the prepared coating is generally in the micron level, and the thicker the coating, the more easily the coating falls off from the surface of the substrate, causing serious consequences such as blood vessel blockage. In addition, to avoid the coating from meshing in the mesh of the medical device, the patent requires the continuous blade coating of the stent with an air knife, which is relatively complex.

Chinese patent No. CN10578068.8 discloses an anticoagulant dense net support and its preparation. The patent achieves the anticoagulation effect by forming a coating on the surface of the substrate of the dense net bracket by adopting organic small molecular acid such as citric acid. However, small organic molecule acids such as citric acid, which have been widely used as anticoagulants for extracorporeal applications and have not been proposed for in vivo use, achieve the effect of preventing thrombosis by complexing calcium ions in blood.

Chinese patent No. CN105744965 discloses an antithrombotic medical device and method. The patent utilizes a silane coupling agent to immobilize the phosphorylcholine polymer, thereby forming an antithrombotic surface. However, most of the silane coupling agents are water-insoluble silanes, and a large amount of organic solvents are required in the process of grafting the silane coupling agent and removing the excess silane coupling agent, which not only increases the production cost but also has potential for biotoxicity.

In face of the current problems, developing a hydrophilic anticoagulation intravascular stent has great clinical significance.

Disclosure of Invention

In order to solve the technical problem, a first aspect of the present invention provides a preparation method of an anticoagulant lubrication stent, including the following steps:

1) The tubular bracket is manufactured by adopting a laser engraving or braiding method, and surface passivation and cleaning treatment are completed by using passivation liquid;

2) Carrying out surface activation treatment on the bracket treated in the step 1);

3) Placing the bracket treated in the step 2) into a treatment liquid for 0.5-96 h, controlling the temperature to be 4-80 ℃ and regulating the pH to be 7.5-14;

4) Soaking the stent treated in the step 3) in a polymer water solution containing a phosphorylcholine group for 5 min-48 h, and controlling the temperature at 4-80 ℃;

5) And (3) carrying out post-treatment on the stent treated in the step (4) to obtain the anticoagulation lubrication stent.

In some preferred embodiments, the passivation solution is a mixed solution of aqueous nitric acid and aqueous hydrofluoric acid. More preferably, the mass fraction of the aqueous nitric acid solution is 65%, and the mass fraction of the aqueous hydrofluoric acid solution is 35%.

In some preferred embodiments, the volume ratio of nitric acid aqueous solution to hydrofluoric acid aqueous solution is (10-90): (90-10).

More preferably, the volume ratio of the nitric acid aqueous solution to the hydrofluoric acid aqueous solution is 65:35.

in some preferred embodiments, the activation treatment described in step 2) is performed by an activation solution; the activation solution is selected from one or a combination of more of oxygen plasma solution, nitrogen plasma solution, sodium hydroxide solution, nitric acid solution, sulfuric acid solution, hydrochloric acid solution, ammonium hydroxide solution, sodium hydroxide solution, hydrogen peroxide solution, potassium permanganate solution, hydrofluoric acid solution, piranha solution, potassium dichromate solution and perchloric acid solution.

Further preferably, the activating solution is sodium hydroxide solution.

In some preferred embodiments, the activating solution has a mass concentration of 1 to 100%.

Further preferably, the mass concentration of the activation solution is 20%.

In some preferred embodiments, the activation treatment is for a period of time ranging from 5 minutes to 96 hours; the temperature of the activation treatment is 20-100 ℃.

More preferably, the sodium hydroxide solution is a sodium hydroxide aqueous solution with a mass concentration of 20%.

Through a great deal of creative experimental study of applicant, in the system, after the surface of the bracket is treated by using the sodium hydroxide aqueous solution with the mass concentration of 20%, a certain amount of charged charges can be ensured to exist on the surface of the bracket after passivation treatment, substances such as grease possibly existing on the surface of the bracket after passivation treatment can be further removed after the treatment, and the damage to the surface of the bracket after passivation treatment can be avoided when the surface of the bracket is treated by using the sodium hydroxide aqueous solution with the mass concentration of 20%, and the use effect of the bracket in the intracranial aneurysm treatment process can be further ensured by ensuring that a formed coating can be stably formed on the surface of the bracket when the subsequent functionalization treatment is performed on the surface of the bracket.

In some preferred embodiments, the treatment fluid of step 3) is an aqueous dopamine and/or dopamine-like solution.

In some preferred embodiments, the aqueous dopamine-like solution is selected from one or more of epicatechin aqueous solution, epigallocatechin aqueous solution, catechin gallate aqueous solution, tannic acid aqueous solution, protocatechuic aldehyde aqueous solution, norepinephrine aqueous solution, ferulic acid aqueous solution, and 2, 3-dihydroxybenzaldehyde.

Further preferably, the dopamine-like aqueous solution is a protocatechuic aldehyde aqueous solution.

In some preferred embodiments, the treatment fluid has a mass concentration of 0.05mg/mL to 20mg/mL.

Further preferably, the mass concentration of the treatment liquid is 2mg/mL.

Through a great deal of creative experimental researches of the applicant, the surface of the activated stent can be further modified by selecting treatment liquid and determining treatment conditions in the system, dopamine or dopamine-like modification is carried out on the surface of the stent, a basis is provided for grafting polymers in subsequent steps, the applicant finds that the surface of the stent can be further modified by a dopamine-like aqueous solution (protocatechuic aldehyde aqueous solution) after treatment for 24 hours at the temperature of 70 ℃ and the pH value of 8.5 in the system, the adhesion of the protocatechuic aldehyde aqueous solution on the surface of the stent can be ensured, mussel bionic adhesion can be carried out on the surface of the activated stent through strong intermolecular interaction, and the basis is provided for subsequent grafting modification on the surface of the stent.

In addition, the applicant found that in the present system, the treatment temperature through step 3) has a great influence on the bionic adhesion of mussels, when the treatment temperature is lower than 4 ℃, the adhesion effect of protocatechuic aldehyde aqueous solution on the surface of the bracket is reduced, but when the treatment temperature is higher than 80 ℃, the frequency of the intermolecular movement is accelerated, so that the collision frequency between active groups is greatly increased, further, the adhesion coating is too thick, the polymer grafted later is easy to fall off from the surface of the bracket when the grafting modification is performed, and the application of the bracket is limited.

In some preferred embodiments, the polymer comprising phosphorylcholine groups of step 4) has the formulaWherein R is ₁ And R is ₂ Is H, CH ₃ ，C ₂ H ₅ One of the following; a is O or N; b is 2-5-CH ₂ -carbon chain units; m and n are the number of monomers, m: n=1: 99 to 99:1.

in some preferred embodiments, the weight average molecular weight of the phosphorylcholine group-containing polymer is in the range of 2000 to 2000000; the mass concentration of the polymer aqueous solution containing the phosphorylcholine group is 0.05-50%.

The source of the polymer containing phosphorylcholine groups is not particularly required, and the polymer can be self-made or purchased.

The preparation method of the polymer containing the phosphorylcholine group is as follows if the polymer is self-made:

(1) Dissolving a phospholipid-containing group and an acrylic monomer in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent in proportion to obtain an initiator solution; (3) Mixing the two mixed solutions according to a proportion, adjusting the pH value of the acid solution to 3.5, removing water and deoxidizing, controlling the temperature to react for 24 hours under the protection of inert gas, and purifying to obtain the product.

The acrylic monomer is 2-aminoethyl methacrylate hydrochloride; the phospholipid-containing group is 2-methacryloyloxyethyl phosphorylcholine.

The reaction solvent is methanol; the initiator is benzoyl peroxide; the acid solution is a methanol solution of phosphoric acid.

The polymer containing phosphorylcholine groups can be purchased from daily oil company if purchased.

More preferably, the mass concentration of the polymer aqueous solution containing the phosphorylcholine group is 1-20%.

More preferably, the mass concentration of the aqueous polymer solution containing phosphorylcholine groups is 5%.

In some preferred embodiments, the post-treatment of step 5) comprises a dry control and a sterilization.

Further preferably, the control temperature of the drying operation is 20-180 ℃ and the time is 5min-96h.

Further preferably, the sterilization is not limited to ethylene oxide sterilization, co-60 radiation sterilization, and X-ray sterilization.

In addition, it should be noted that, in the process of specifically preparing the anticoagulation lubrication stent, the stent treated by the treatment solution in step 3) needs to be rinsed to remove the excessive treatment solution.

The second aspect of the invention provides an application of the anticoagulant lubrication stent in preparation of medical instrument materials.

The beneficial effects are that: compared with the prior art, the preparation of the anticoagulation lubrication bracket provided by the invention has the following advantages:

1. the anticoagulation lubrication stent prepared by the invention has hydrophilic performance, can reduce the adhesion, activation and coagulant of platelets in the subsequent use process, and avoids the formation of thrombus;

2. after the anticoagulation lubrication stent prepared by the method is subjected to strict passivation treatment, activation treatment, dopamine or dopamine-like treatment and polymer treatment containing phosphorylcholine groups, a stable coating can be formed on the surface of the stent, and due to the contained phosphorylcholine structure, hydroxyl and other active functional groups, covalent-noncovalent interaction is further established, so that excellent hydrophilicity and biocompatibility of the anticoagulation lubrication stent in the use in blood vessels are ensured, namely, modification of non-organic components is realized, and the stability of the coating on the surface of the stent is also ensured.

3. In the preparation process of the anticoagulation lubrication stent prepared by the invention, a great deal of attempts are made on the activation condition and the dopamine or dopamine-like treatment condition, and researches show that when the temperature is 70 ℃ and the pH is 8.5, after 24 hours of treatment, the surface of the stent can be further modified by the dopamine-like aqueous solution protocatechuic aldehyde aqueous solution, the protocatechuic aldehyde aqueous solution can be ensured to adhere to the surface of the stent, and mussel bionic adhesion can be generated on the surface of the activated stent through intermolecular strong interaction, so that a foundation is provided for subsequent grafting modification on the surface of the stent.

Drawings

FIG. 1 is an SEM image of the platelet adhesion (a) of a blank stent (comparative example 1) and the platelet adhesion (b) of an anticoagulant lubrication stent prepared in example 1 of the present application;

FIG. 2 is an SEM image of the anti-fibrin adhesion capability (c) of a blank stent (comparative example 1) and the anti-fibrin adhesion capability (d) of an anti-coagulated lubrication stent prepared in example 1 of the present application;

Detailed Description

Examples

Example 1

The preparation of the anticoagulation lubrication bracket comprises the following steps:

1) The tubular bracket manufactured by adopting a laser engraving method is subjected to surface passivation and then cleaning treatment by using passivation liquid;

2) And (3) carrying out surface activation treatment on the bracket treated in the step (1): using a sodium hydroxide aqueous solution with the mass concentration of 20%, wherein the activation treatment time is 24; the temperature of the activation treatment is 30 ℃;

3) Placing the bracket treated in the step 2) into treatment liquid for 24 hours, controlling the temperature at 70 ℃ and regulating the pH value to 8.5;

4) Soaking the stent treated in the step 3) in a polymer water solution containing phosphorylcholine groups for 24 hours, and controlling the temperature at 30 ℃;

5) And (3) drying the stent treated in the step (4) and sterilizing, wherein the drying temperature is 80 ℃ and the time is 1h, so that the anticoagulation lubrication stent is obtained.

The passivation solution in the step 1) is a mixed solution of nitric acid aqueous solution and hydrofluoric acid aqueous solution. The mass fraction of the aqueous solution of nitric acid is 65%, the mass fraction of the aqueous solution of hydrofluoric acid is 35%, and the volume ratio of the aqueous solution of nitric acid to the aqueous solution of hydrofluoric acid is as follows: 65:35;

the treatment liquid in the step 3) is protocatechuic aldehyde water solution;

the mass concentration of the treatment fluid is 2mg/mL;

the weight average molecular weight of the polymer containing phosphorylcholine groups is as follows:

wherein R is ₁ And R is ₂ Is CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the A is N; b is a chain containing 3 carbon chain units (-CH) ₂ (-) -; m and n are the number of monomers, m: n=75: 25

The mass concentration of the polymer containing phosphorylcholine groups is 5%; purchased from daily oil company.

Comparative example 1

Comparative example 1 is an untreated tubular stent made by a laser engraving process, which is identical in its specific preparation embodiment to step 1) of example 1, with the only difference that it is not subjected to all subsequent steps.

Claims

1. The preparation method of the anticoagulation lubrication bracket is characterized by comprising the following steps of:

3) Placing the bracket treated in the step 2) into a treatment liquid for 24h, controlling the temperature at 70 ℃ and regulating the pH value to 8.5;

4) Soaking the bracket treated in the step 3) in a polymer water solution containing a phosphorylcholine group for 5 minutes to 48 hours, and controlling the temperature to be 4 ℃ to 80 ℃;

5) Carrying out post-treatment on the stent treated in the step 4) to obtain an anticoagulation lubrication stent;

the activation solution is sodium hydroxide solution, and the sodium hydroxide solution is sodium hydroxide aqueous solution with the mass concentration of 20%;

the treatment fluid in the step 3) is a dopamine aqueous solution and/or a dopamine-like aqueous solution.

2. The method for preparing an anticoagulant lubrication stent according to claim 1, wherein the time of the activation treatment is 5min-96 h; the temperature of the activation treatment is 20-100 ℃.

3. The method for preparing an anticoagulant lubrication stent according to claim 2, wherein the dopamine-like aqueous solution is one or more selected from epicatechin aqueous solution, epigallocatechin aqueous solution, catechin gallate aqueous solution, tannic acid aqueous solution, protocatechuic aldehyde aqueous solution, norepinephrine aqueous solution, ferulic acid aqueous solution, and 2, 3-dihydroxybenzaldehyde.

4. The method for preparing the anticoagulation lubrication stent according to claim 1, wherein the mass concentration of the treatment fluid is 0.05 mg/mL-20 mg/mL.

5. The method for preparing an anticoagulant lubrication stent according to claim 1, wherein the polymer containing phosphorylcholine groups in the step 4) has a structural formula ofWherein R is ₁ And R is ₂ Is H, CH ₃ ，C ₂ H ₅ One of the following; a is O or N; b is 2-5-CH ₂ -carbon chain units; m and n are the number of monomers, m: n=1: 99-99: 1.

6. the method for preparing an anticoagulant lubrication stent according to claim 1, wherein the weight average molecular weight of the polymer containing phosphorylcholine groups is 2000-2000000; the mass concentration of the polymer aqueous solution containing the phosphorylcholine group is 0.05% -50%.

7. Use of the method for the preparation of an anticoagulant lubrication stent according to any one of claims 1-6, in the preparation of a medical device material.