CN115245599A

CN115245599A - Preparation and application of anticoagulant lubrication bracket

Info

Publication number: CN115245599A
Application number: CN202210569683.7A
Authority: CN
Inventors: 不公告发明人
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: 2022-10-28
Anticipated expiration: 2042-05-24
Also published as: CN115245599B

Abstract

The invention belongs to the technical field of A61K, and particularly relates to preparation and application of an anticoagulant lubrication bracket. The preparation method of the anticoagulant lubrication stent comprises the following steps: 1) The tubular stent is manufactured by adopting a laser engraving or weaving method, and the surface passivation is finished by using a passivation solution and then the cleaning treatment is carried out; 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 solution for 0.5 to 96 hours, controlling the temperature to be between 4 and 80 ℃, and adjusting the pH value to be between 7.5 and 14; 4) Placing the stent treated in the step 3) into a polymer aqueous solution containing a phosphorylcholine group for soaking for 5min to 48h, and controlling the temperature to be 4 to 80 ℃; 5) And (4) carrying out post-treatment on the bracket treated in the step 4) to obtain the anticoagulant lubrication bracket. The anticoagulant lubricating stent prepared by the invention has hydrophilic performance, can reduce the adhesion, activation and aggregation of platelets in the subsequent use process, and avoids the formation of thrombus.

Description

Preparation and application of anticoagulant lubrication bracket

Technical Field

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

Background

Intracranial aneurysms are abnormal protrusions on the wall of cerebral arteries, the wall of the cerebral aneurysm is thin and easy to break spontaneously, and once the intracranial aneurysm breaks, the intracranial aneurysm often has disastrous results. With the innovation of nerve intervention materials and the progress of technology, researchers are gradually aware that the basis of aneurysm lesion is parent artery, and the reconstruction and repair of lesion blood vessels at the neck of a tumor is the key to the treatment of intracranial aneurysm. The intravascular stent can drain blood flow along the long axis direction of a lumen, reduce the blood flow amount flowing into and out of a tumor cavity, and reduce or even avoid relapse and rupture bleeding of an aneurysm, however, the intravascular stent is transplanted into a body as a foreign object, which easily causes adhesion, activation and aggregation of platelets, and finally causes formation of thrombus.

Mussel biomimetic adhesion is an aqueous phase coating technology developed in recent years, which almost realizes adhesion of all substrate surfaces through synergistic effects such as covalent bonds, electrostatic interaction, pi-pi conjugation and the like among key adhesion units dopamine and/or dopamine-like structures in mussels, and has broad-spectrum adhesion advantages. In addition, the dopamine and/or the dopamine-like substances have good biocompatibility, and have reactive amino, aldehyde and hydroxyl on the structure, so that the subsequent grafting modification is facilitated. Therefore, the dopamine and/or dopamine-like structure has good application prospect in the technical field of surface modification.

The Chinese invention patent CN105073070 discloses a coated medical device and a manufacturing and using method thereof, and the coating prepared on the surface of the medical device by dip coating and blade coating processes belongs to the physical coating field, the thickness of the prepared coating is usually in the micron level, and the thicker the coating is, the easier the coating is to fall off from the surface of a substrate to cause serious consequences such as vessel blockage. In addition, to avoid coating in the mesh of the medical device, the patent requires continuous coating of the stent with an air knife, which is a complicated process.

Chinese patent CN10578068.8 discloses an anticoagulant dense-mesh stent and a preparation method thereof. According to the patent, organic micromolecular acid such as citric acid is adopted to form a coating on the surface of a dense mesh stent substrate, so that the anticoagulation effect is achieved. However, organic small molecule acids such as citric acid achieve the effect of preventing thrombosis by complexing calcium ions in blood, are often used as in vitro anticoagulants, and are not widely recommended for in vivo use.

Chinese invention patent CN105744965 discloses a medical device and a method for resisting generation of thrombus. This patent utilizes a silane coupling agent to immobilize the phosphorylcholine polymer, thereby forming an antithrombotic surface. However, most silane coupling agents are water-insoluble silanes, and a large amount of organic solvent is required in the processes of grafting the silane coupling agent and removing the excess silane coupling agent, so that the production cost is increased and the potential biological toxicity is caused.

In the face of the problems appearing at present, the development of a hydrophilic anticoagulant intravascular stent has great clinical significance.

Disclosure of Invention

In order to solve the above technical problems, a first aspect of the present invention provides a preparation method of an anticoagulation lubricating stent, comprising the following steps:

1) The tubular stent is manufactured by adopting a laser engraving or weaving method, and the surface passivation is finished by using a passivation solution and then the cleaning treatment is carried out;

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

3) Placing the bracket treated in the step 2) into the treatment fluid for 0.5 to 96 hours, controlling the temperature to be between 4 and 80 ℃, and adjusting the pH value to be between 7.5 and 14;

4) Placing the stent treated in the step 3) into a polymer aqueous solution containing a phosphorylcholine group for soaking for 5min to 48h, and controlling the temperature to be 4 to 80 ℃;

5) And (4) carrying out post-treatment on the bracket treated in the step 4) to obtain the anticoagulant lubrication bracket.

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

In some preferred embodiments, the volume ratio of the nitric acid aqueous solution to the 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 of step 2) is performed by an activation solution; the activating 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%.

More preferably, the mass concentration of the activating solution is 20%.

In some preferred embodiments, the time of the activation treatment is 5min to 96h; the temperature of the activation treatment is 20-100 ℃.

More preferably, the sodium hydroxide solution is a 20% sodium hydroxide solution.

Through a large amount of creative experimental researches of an applicant, in the system, after the surface of the stent is treated by using a 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 passivated stent, substances such as grease and the like possibly existing on the surface of the passivated stent can be further removed after the treatment, when the sodium hydroxide aqueous solution with the mass concentration of 20% is ensured, the damage to the surface of the passivated stent caused during the treatment of the surface of the stent can be avoided, and the coating formed by the coating can be ensured to be stably on the surface of the stent during the subsequent functional treatment of the surface of the stent, so that the use effect of the stent in the treatment process of intracranial aneurysm is further ensured.

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

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

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

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

More preferably, the mass concentration of the treatment solution is 2mg/mL.

Through a large amount of creative experimental researches of the applicant, the applicant discovers that the surface of the activated stent can be further modified by selecting a treatment solution and determining treatment conditions in the system, dopamine or dopamine-like modification is carried out on the surface of the stent, and a foundation is provided for grafting a polymer in a subsequent step.

In addition, the applicant finds that in the system, the treatment temperature in the step 3) has a great influence on the bionic adhesion of the mussels, when the treatment temperature is lower than 4 ℃, the adhesion effect of the protocatechuic aldehyde aqueous solution on the surface of the stent is reduced, but when the treatment temperature is higher than 80 ℃, the collision frequency between active groups is greatly increased due to the acceleration of the movement frequency among molecules, so that the adhesion coating is too thick, the grafted polymer is easy to fall off from the surface of the stent during subsequent grafting modification, and the application of the stent is limited.

In some preferred embodiments, the phosphocholine group-containing polymer of step 4) has the formula

Wherein R is ₁ And R ₂ Is H, CH ₃ ，C ₂ H ₅ One of (a) and (b); a is O or N; b is a group containing 2-5-CH ₂ -a carbon chain unit of (a); 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 polymer containing a phosphorylcholine group is from 2000 to 2000000; the mass concentration of the polymer aqueous solution containing the phosphorylcholine groups is 0.05-50%.

The sources of the polymers containing phosphorylcholine groups described in this application are not particularly critical and can be made by the house or purchased.

If the polymer containing the phosphorylcholine groups is self-made, the preparation method comprises the following steps:

(1) Dissolving a monomer containing a phospholipid group and an acrylate in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent according to a proportion to obtain an initiator solution; (3) Mixing the two mixed liquids according to a ratio, adjusting the pH value of the acid liquid to 3.5, removing water and oxygen, reacting for 24 hours under the protection of inert gas and controlling the temperature, and purifying to obtain the catalyst.

The acrylate monomer is 2-aminoethyl methacrylic acid 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 the phosphorylcholine groups can be purchased from Nichiba oil Co.

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

More preferably, the concentration by mass of the aqueous solution of the polymer having a phosphorylcholine group is 5%.

In some preferred embodiments, the post-treatment of step 5) comprises draining and sterilizing.

Further preferably, the drying control operation is carried out at the temperature of 20-180 ℃ for 5min-96h.

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

In addition, in the specific process of preparing the anticoagulant lubrication stent, the stent treated by the treatment fluid in the step 3) needs to be washed to remove the excess treatment fluid.

The second aspect of the invention provides an application of an anticoagulation lubricating bracket in preparation of medical equipment materials.

Has the advantages that: compared with the prior art, the preparation of the anticoagulation lubricating bracket provided by the invention has the following advantages:

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

2. the anticoagulant lubricating stent prepared by the invention can ensure that a stable coating is formed on the surface of the stent after strict passivation treatment, activation treatment, dopamine or dopamine-like treatment and polymer treatment containing phosphorylcholine groups, and covalent-non-covalent interaction is further established due to active functional groups such as phosphorylcholine structures, hydroxyl groups and the like, so that excellent hydrophilicity and biocompatibility are ensured when the anticoagulant lubricating stent is used in blood vessels, 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 anticoagulant lubrication stent prepared by the invention, a great deal of attempts are made on the activation condition and the treatment condition of dopamine or dopamine-like, and the research finds that the surface of the stent can be further modified by a protocatechuic aldehyde aqueous solution of a dopamine-like aqueous solution after 24 hours of treatment at the temperature of 70 ℃ and the pH of 8.5, the protocatechuic aldehyde aqueous solution can be ensured to be adhered to the surface of the stent, mussel bionic adhesion can be generated on the surface of the activated stent through strong intermolecular interaction, and a basis is provided for subsequent grafting modification on the surface of the activated stent.

Drawings

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

FIG. 2 is a SEM image of fibrin adhesion resistance (c) of a blank scaffold (comparative example 1) and fibrin adhesion resistance (d) of an anticoagulated lubricating scaffold prepared in example 1 of the present application;

Detailed Description

Examples

Example 1

The preparation method of the anticoagulation lubricating bracket comprises the following steps:

1) The tubular support is manufactured by adopting a laser engraving method, and cleaning treatment is carried out after surface passivation is finished by using passivation solution;

2) 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 percent, and the activation treatment time is 24; the temperature of the activation treatment is 30 ℃;

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

4) Soaking the stent treated in the step 3) in a polymer aqueous solution containing phosphorylcholine groups for 24 hours at the temperature of 30 ℃;

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

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

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

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

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

wherein R is ₁ And R ₂ Is CH ₃ (ii) a A is N; b is a unit containing 3 carbon chains (-CH) ₂ -; m and n are the number of monomers, m: n =75:25

The mass concentration of the polymer containing the phosphorylcholine groups is 5 percent; purchased from oil, inc.

Comparative example 1

Comparative example 1 is an untreated tubular stent made by a laser engraving process, and the specific manufacturing embodiment is identical to step 1) of example 1, with the only difference that treatment is not performed in all subsequent steps.

Claims

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

4) Placing the stent treated in the step 3) into a polymer aqueous solution containing phosphorylcholine groups to be soaked for 5min to 48h, and controlling the temperature to be 4 ℃ to 80 ℃;

2. The preparation of the anticoagulated lubricating stent according to claim 1, wherein the activation treatment in step 2) is performed by an activation solution; the activating solution is selected from one or a combination of more of an oxygen plasma solution, a nitrogen plasma solution, a sodium hydroxide solution, a nitric acid solution, a sulfuric acid solution, a hydrochloric acid solution, an ammonium hydroxide solution, a sodium hydroxide solution, a hydrogen peroxide solution, a potassium permanganate solution, a hydrofluoric acid solution, a piranha solution, a potassium dichromate solution and a perchloric acid solution.

3. The preparation of an anticoagulant lubrication stent according to claim 2, wherein the mass concentration of the activation solution is 1-100%.

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

5. The preparation of the anticoagulant lubricated stent according to claim 1, wherein the treatment solution in step 3) is an aqueous dopamine solution and/or an aqueous dopamine-like solution.

6. The preparation of an anticoagulant lubricated stent according to claim 5, wherein the dopamine-like aqueous 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, 2, 3-dihydroxybenzaldehyde.

7. The preparation of an anticoagulant lubrication stent according to any one of claims 1, 5 and 6, wherein the mass concentration of the treatment fluid is 0.05mg/mL to 20mg/mL.

8. The preparation of the anticoagulant lubrication stent according to claim 1, wherein the structure of the phosphocholine group-containing polymer of step 4) is

Wherein R is ₁ And R ₂ Is H, CH ₃ ，C ₂ H ₅ One of (1); a is O or N; b is a group containing 2 to 5-CH ₂ -a carbon chain unit of (a); m and n are the number of monomers, m: n =1:99 to 99:1.

9. the preparation of an anticoagulant lubricated scaffold according to claim 1 or 8, 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 groups is 0.05-50%.

10. Use of the preparation of an anticoagulant lubricated stent according to any one of claims 1 to 9 in the preparation of a medical device material.