WO2020181642A1

WO2020181642A1 - Preparation method for ionic bond-covalent bond synergy-based surface heparinized anticoagulant medical device

Info

Publication number: WO2020181642A1
Application number: PCT/CN2019/085965
Authority: WO
Inventors: 王维宁; 张晓红; 陈大竞; 魏晨杰; 黄赋
Original assignee: 江苏赛腾医疗科技有限公司
Priority date: 2019-03-14
Filing date: 2019-05-08
Publication date: 2020-09-17
Also published as: CN110028692A; CN110028692B

Abstract

A preparation method for an ionic bond-covalent bond synergy-based surface heparinized anticoagulant medical device. In said method, firstly, a hydrophilic polymer of which the side chain is modified by a low molecular weight hyperbranched polyethyleneimine is used to fix heparin on the surface of a medical device by means of ionic bonding, and further, a stable heparin coating is grafted by means of covalent bonding, so as to obtain an anticoagulant biomedical device having high anticoagulant activity and high anticoagulant stability.

Description

Preparation method of medical device based on ionic bond-covalent bond coordination surface heparinized anticoagulant

Technical field:

The present invention relates to the field of medical devices, in particular to a method for preparing a medical device based on ionic bond-covalent bond coordination with surface heparinized anticoagulation.

Background technique:

Biological materials are materials that are applied to living organisms (mainly the human body) and need to be in contact with human blood, organs, and tissues when used. When blood comes into contact with the surface of the material, plasma proteins (including some coagulation factors and anticoagulation factors) are easily adsorbed on the surface of the material to denature or activate the platelet coagulation reaction, leading to the action of insoluble fibrin and platelets to form thrombus. Therefore, biomedical polymer materials must have good physical and mechanical properties, chemical stability, non-toxicity, and easy processing and moldability. In order to inhibit the formation of thrombus and avoid blood clotting on the surface of the material, it must also have good biological properties. Compatibility mainly includes two aspects: blood compatibility and histocompatibility. Among them, blood compatibility is the most important performance index of biological materials.

In order to improve the blood compatibility of anticoagulant materials, people use a variety of methods to modify the surface of the material, such as physical blending into a new type of anticoagulant material or directly surface modification of existing materials. Heparin has excellent anticoagulant properties, and can prevent the occurrence of coagulation by inhibiting the activation of various thrombins, delaying and preventing the formation of fibrin networks. Although physical blending of heparin can achieve excellent anticoagulant effects, the release time of heparin is still relatively short. With the continuous release of heparin, the content of heparin in the material will become less and less, so the anticoagulation property will gradually decrease. Therefore, the heparinized material prepared by the physical blending method can only have a short-term anticoagulant effect, and the application and development of this method has certain limitations. In contrast, surface anticoagulation modification of existing materials is a fast and effective way, which can not only maintain the excellent physical and mechanical properties of the material itself, but also endow the material with good anticoagulation performance.

Among the many surface modification methods for preparing anticoagulant biomaterials, heparin is mainly fixed by ionic bonding or covalent bonding. Patent CN105233348 discloses a method for modifying the surface of medical devices for anticoagulation by ionic bonding with heparin through alternate adsorption between positively and negatively charged polyelectrolytes. The modified device has a better anticoagulant effect in a short period of time, but the layer-by-layer adsorption method requires alternating positive and negative charge media to ensure that the fixed amount of heparin achieves the anticoagulant effect, and the process is more complicated; patent CN101879335A discloses An oxidized low-molecular-weight heparin-antithrombin complex was prepared and fixed on the surface of the extracorporeal circulation pipeline through the polyethyleneimine (PEI)-glutaraldehyde combination technology. The study found that the complex has an effect on plasma protein and The adsorption of endothelial cells is significantly less than that of heparin, and the complex can also inhibit the activity of fibrin-bound thrombin and make the fibrin thrombus bound with thrombin have anticoagulant activity. The preparation method of the complex mainly involves the non-enzymatic glycosylation of the ε-amino group of the antithrombin lysine residue and the heparin molecule with the common end of the antithrombin binding specific pentasaccharide and aldose and the butyl- Agarose fast-flow hydrophobic chromatography and diethylaminoethyl-agarose fast-flow anion exchange chromatography. However, since the proportion of heparin molecules with this special terminal in the natural heparin molecules is only about 0.4%, and the complex will be consumed during the two-step chromatography purification process, the final synthesis rate of the complex obtained by this method is about 50% . Patent CN1563157A discloses a method of covalently grafting heparin on the surface of polymer films (PE, PP, etc.). First, the film is activated by ammonium sulfate aqueous solution to form oxidizing groups, and the carboxyl and amino groups in the heparin structure are further condensed by condensation reaction. Heparin is fixed on the surface of the film by covalent bonds. Covalently bound heparin is relatively stable, but it also has certain defects. The main reason is that heparin is easily bound to the surface of the material at multiple points, making it difficult to change its conformation and affecting its anticoagulant effect.

The invention has universal applicability to various medical device structures, realized by a simple solution circulation flow device, and uses the synergistic effect of ionic bonds and covalent bonds to construct a stable heparin coating on the surface of the medical device. First, use low molecular weight hyperbranched PEI to modify the hydrophilic long-chain polymer to improve the water solubility, biocompatibility and reduce the toxicity of PEI. Using the hydrophilic polymer modified with PEI as the side chain as a bridge, heparin is fixed to the surface of the medical device through ionic bond bonding. The hydrophilic polymer can act as a bridge to improve the binding of PEI molecules on the surface to heparin. Stability; at the same time, the hydrophilic polymer modified with PEI on the side chain can increase the length of the fixed segment on the surface, thereby prolonging the contact path between plasma and the surface of the material, reducing the adsorption of plasma on the surface of medical devices; on this basis, through The valence bond further fixes heparin to the surface of the medical device, and the graft density of heparin increases with the increase of the density of low molecular weight PEI molecules on the hydrophilic backbone, which significantly improves the anticoagulant property of the medical device. This method has simple preparation process, controllable process, no solvent toxicity, is environmentally friendly and is suitable for industrialized production. The prepared medical device has good anticoagulant performance during use. This solution can improve the blood compatibility of biological materials. Sex has important reference significance.

Summary of the invention:

The technical problem to be solved by the present invention is to provide a method for preparing a heparinized anticoagulant medical device based on ionic bond-covalent bond coordination. The method has simple preparation process, low material price and no toxic reagents involved in the experimental process, which is suitable for In industrial production, the prepared biomedical device has good anticoagulant performance during use. This solution is an important way to improve the blood compatibility of biomaterials.

In order to achieve the above objective, the present invention adopts the following technical solutions:

A medical device based on ionic bond-covalent bond coordination surface heparinized anticoagulant, which is characterized in that: firstly, the side chain is a hydrophilic polymer modified with low molecular weight hyperbranched PEI and heparin is fixed to the material by ionic bond bonding. On the surface, heparin is further fixed on the surface through covalent bonds. This method avoids the traditional ionic bond bond is not strong, and the covalent bond bond unreactive group defects.

The preparation method of the medical device based on ionic bond-covalent bond synergistic surface heparinized anticoagulant includes the following steps:

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, prepare a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain: 2-10g hydrophilic monomer and 0.5-5.0g allyl group are hydrated Glyceryl ether through anionic ring-opening copolymerization to obtain a hydrophilic polymer with a large number of double bonds in the side chain; add 0.5-10.0g mercaptoethanol and 1-5g azobisisobutyronitrile (AIBN), add at 50-100℃ The formation reaction is 24-48h, so that all the double bonds of the side chain are converted into hydroxyl groups; 0.2-5.0g of p-nitrophenyl chloroformate (4-NC) is used to activate the hydroxyl groups in the hydrophilic polymer to obtain the hydrophilic side chain of NC Water polymer; Finally, 1-10g of low molecular weight PEI is added, and the amino group on the PEI reacts with NC to obtain the final product; the excess PEI is removed by deionized water dialysis and freeze-dried to obtain a side chain modified with low molecular weight PEI. Water polymer.

(2) At 25-80°C, use 10-60wt% acid solution to activate the medical device for 10min-2h, wash with pure water and dry.

(3) Prepare the low molecular weight PEI modified hydrophilic polymer prepared in step (1) into a solution with a concentration of 1-5 mg/ml, and circulate it over the surface of the medical device body for 10 minutes to 2 hours, and change the side chain to low molecular weight. The PEI modified hydrophilic polymer is fixed on the surface of the medical device, washed with pure water, and dried.

(4) Circulate 1-5mg/ml heparin solution over the surface of the medical device body for 10min-2h, and then use 0.1-2.0wt% crosslinking agent to circulate over the surface of the medical device body at 40-80℃ 20min-2h, fix the heparin on the surface of the medical device in an ionic bond, wash with pure water, and dry.

(5) Use a solution of activator A with a concentration of 5-15 mg/ml to activate heparin sodium for 20-50 minutes, and then add activator B to the solution containing activator A to control the mixing of the activator B The concentration in the solution is 3-6mg/ml, and the activation treatment is 2-4h. Afterwards, the solution is circulated through the surface of the modified medical device in step (4), and reacted for 24-48h. The stable heparin coating is further fixed on the surface of the medical device through covalent bonds, washed with pure water, and dried to obtain a new type of anti Blood coagulation medical device.

Preferably, the hydrophilic monomer in step (1) is selected from at least one of ethylene glycol, ethylene oxide, α,ω-aminopropyl-ethylene glycol, and vinyl alcohol.

Preferably, the acid solution in step (2) is selected from at least one of sulfuric acid, hydrochloric acid, acetic acid, nitric acid, and perchloric acid.

Preferably, the medical device in step (2) is a device that is suitable for living organisms (mainly human bodies) and can come into contact with blood.

Preferably, the crosslinking agent in step (4) is selected from at least one of formaldehyde, glutaraldehyde, and periodic acid.

Preferably, the activator A in the step (5) is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl) or N,N'- At least one of dicyclohexyl carboimide (DCC).

Preferably, in the solution of activator A in step (5), the solvent is a buffer solution of 2-morpholineethanesulfonic acid with a mass concentration of 8-10 g/L.

Preferably, the activator B in the step (5) is at least one of 4-dimethylaminopyridine (DMAP) or N-hydroxysuccinimide (NHS).

More preferably, the activator A is EDC·HCl; the activator B is NHS.

Benefits:

1. Grafting low-molecular-weight hyperbranched PEI onto a hydrophilic main chain of appropriate length can significantly improve the water solubility, biocompatibility and biotoxicity of PEI. The grafting density of PEI on the polymer chain is clearly controllable. , Suitable for application in biomedical field.

2. The present invention provides a method for preparing anticoagulant medical devices based on the method of ionic bond-covalent bond cooperating with heparin immobilization. The surface modification of existing medical devices is selected to give the material good anticoagulant performance. It overcomes the problems of low binding strength and easy dissociation of ionic bonds in the traditional scheme, as well as non-reactive sites on the surface of the material when covalent bonding, low grafting amount of heparin, and heparin is easily bound to the surface of the material by multiple points. Defects such as low anticoagulant activity.

3. The hydrophilic polymer with the side chain of low molecular weight hyperbranched PEI can play a bridging role and improve the grafting amount and graft stability of heparin molecules; at the same time, it can increase the segment length of PEI molecules on the surface of the material. Thereby, the contact path between plasma and the material surface is extended, and the adsorption behavior of plasma and the material surface is reduced.

4. Graft a large amount of low molecular weight PEI onto the main chain of the hydrophilic polymer, and the density of PEl molecules on the entire molecular segment will increase accordingly. The increase of the density of PEI molecules is conducive to the fixation of heparin and can improve the fixation of heparin. In order to improve the anticoagulant properties of biological materials.

5. Due to the large molecular weight of heparin molecules, the size of the molecules is huge, so that there is a certain steric hindrance between the heparin molecules during the grafting process. In this paper, the low molecular weight hyperbranched PEI modified hydrophilic polymer has good polymer chain flexibility, which can reduce the steric effect and increase the grafting amount of heparin.

6. The modification scheme used in this experiment in which the modification solution circulates through the body of the medical device has a simple preparation process, a controllable process, no solvent toxicity, environmentally friendly and suitable for industrial production.

Description of the drawings:

Figure 1 is an electron microscope photo of the surface topography of the unmodified material with a magnification of ×10K.

Figure 2 is an electron microscope photograph of the surface topography of the modified material prepared in Example 1, with a magnification of ×10K.

Specific implementation plan:

The present invention is described below through specific embodiments. The embodiments should be understood as illustrative rather than limiting the scope of the present invention, and the spirit and scope of the present invention are only defined by the claims. For those skilled in the art, without departing from the essence and scope of the present invention, various changes or modifications to the material components and dosages in these embodiments also belong to the protection scope of the present invention.

Example 1 A method for preparing a medical device based on ionic bond-covalent bond coordination surface heparinized anticoagulant blood

A medical device based on ionic bond-covalent bond coordination surface heparinized anticoagulant, and its preparation method is as follows:

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain is prepared: 5g ethylene oxide and 2g allyl glycidyl ether are opened by anion. Cyclic copolymerization reaction produces a hydrophilic polyethylene oxide (PEO) polymer with a large number of double bonds; 2g mercaptoethanol and 1g AIBN are added, and the addition reaction is carried out at 80℃ for 48h, so that all the double bonds of the side chain are converted into hydroxyl groups. ; Use 2g 4-NC to activate the hydroxyl in the hydrophilic polymer to obtain a hydrophilic PEO polymer whose side chain is NC modified; finally, 3g of low molecular weight PEI is added, and the amino group on the PEI reacts with NC to obtain the final product; Ion water dialysis was used to remove excess PEI and freeze-dried to obtain a hydrophilic PEO polymer modified with low molecular weight PEI.

(2) At 25°C, the medical device is activated with a 40wt% sulfuric acid solution for 30 minutes, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI-modified hydrophilic PEO polymer is formulated into a solution with a concentration of 3 mg/ml, and the solution is circulated through the surface of the medical device body for 1 hour, and the side chain is a low-molecular-weight PEI-modified hydrophilic PEO polymer. It is fixed on the surface of the medical device, washed with pure water and dried.

(4) Circulate the 3mg/ml heparin solution over the surface of the medical device body for 30 minutes, and then use a 0.5wt% glutaraldehyde solution to circulate over the surface of the medical device body at 55°C for 1 hour to ionic bond the heparin The combined method is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use an EDC·HCl solution with a concentration of 10 mg/ml to activate heparin sodium for 20 minutes, and then add NHS to the solution containing EDC·HCl, and control the concentration of the activator NHS in the mixed solution to 4 mg/ml. ml, activation treatment for 2h. After that, the solution is circulated through the surface of the modified medical device in step (4), and reacted for 24 hours. The stable heparin coating is further fixed on the surface of the medical device by covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Example 2 A method for preparing a medical device based on ionic bond-covalent bond synergy with surface heparinized anticoagulant

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, prepare a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain: 2g ethylene glycol and 0.5g allyl glycidyl ether are ring-opened through anion The copolymerization reaction produces a hydrophilic polyethylene glycol (PEG) polymer with a large number of double bonds in the side chain; 0.5g mercaptoethanol and 1g AIBN are added, and the addition reaction is carried out at 50°C for 24h, so that all the double bonds of the side chain are converted into Hydroxyl; 0.2g 4-NC is used to activate the hydroxyl in the hydrophilic polymer to obtain a hydrophilic PEG polymer whose side chain is NC modified; finally, 1g of low molecular weight PEI is added, and the amino group on PEI reacts with NC to obtain the final product; Excess PEI was removed by deionized water dialysis, and freeze-dried to obtain a hydrophilic PEG polymer modified with low molecular weight PEI on its side chain.

(2) At 80°C, the medical device is activated with a 10 wt% perchloric acid solution for 10 minutes, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI-modified hydrophilic PEG polymer was formulated into a solution with a concentration of 1 mg/ml, and it circulated through the surface of the medical device body for 10 minutes, and the side chain was a low-molecular-weight PEI-modified hydrophilic PEG polymer. It is fixed on the surface of the medical device, washed with pure water and dried.

(4) Circulate the 1mg/ml heparin solution over the surface of the medical device body for 2h, and then use 0.5wt% formaldehyde to circulate it over the surface of the medical device body for 2h at 40°C to bond the heparin by ion bonding It is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use a DCC solution with a concentration of 5 mg/ml to activate heparin sodium for 20 minutes, then add DMAP to the solution containing DCC, control the concentration of the activator DMAP in the mixed solution to 3 mg/ml, and activate the treatment 2h. After that, the solution is circulated through the surface of the modified medical device in step (4), and reacted for 24 hours. The stable heparin coating is further fixed on the surface of the medical device by covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Example 3 A method for preparing a medical device based on ionic bond-covalent bond coordination surface heparinized anticoagulant blood

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, prepare a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain: shrink 10g α,ω-aminopropyl-ethylene glycol and 5g allyl group Glyceryl ether through anionic ring-opening copolymerization reaction to obtain hydrophilic α,ω-aminopropyl-polyethylene glycol polymer with double bond modification; add 10g mercaptoethanol and 5g AIBN, carry out the addition reaction at 100℃ for 48h, make The double bonds of the side chains are all converted into hydroxyl groups; 5g 4-NC is used to activate the hydroxyl groups in the hydrophilic polymer to obtain a hydrophilic polymer with NC-modified side chains; finally, 10g of low molecular weight PEI is added, and the amino groups on the PEI are combined with The final product is obtained by NC reaction; excess PEI is removed by deionized water dialysis and freeze-dried to obtain hydrophilic α,ω-aminopropyl-polyethylene glycol polymer modified with low molecular weight PEI on the side chain.

(2) At 25° C., the medical device is activated with a 10 wt% hydrochloric acid solution for 2 hours, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI modified hydrophilic α,ω-aminopropyl-polyethylene glycol polymer is formulated into a solution with a concentration of 5mg/ml, and it flows through the surface of the medical device body for 2h, and the side chain The hydrophilic α,ω-aminopropyl-polyethylene glycol polymer modified for low molecular weight PEI is fixed on the surface of the medical device, washed with pure water, and dried.

(4) Circulate the 5mg/ml heparin solution over the surface of the medical device body for 10 minutes, and then use a 0.5wt% periodic acid solution to circulate it over the surface of the medical device body for 20 minutes at 80°C. The heparin is ionic bond The combined method is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use an EDC·HCl solution with a concentration of 15 mg/ml to activate heparin sodium for 50 minutes, and then add NHS to the solution containing EDC·HCl, and control the concentration of the activator NHS in the mixed solution to 6 mg/ml. ml, activation treatment 4h. Afterwards, the solution was circulated through the surface of the modified medical device in step (4) and reacted for 48 hours. The stable heparin coating was further fixed on the surface of the medical device through covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Example 4 A method for preparing a medical device based on ionic bond-covalent bond synergy with surface heparinized anticoagulant

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, prepare a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain: 3g vinyl alcohol and 2g allyl glycidyl ether are subjected to anionic ring-opening copolymerization reaction The hydrophilic polyvinyl alcohol polymer with double bond modification is obtained; 1g mercaptoethanol and 2g AIBN are added, and the addition reaction is carried out at 80℃ for 24h, so that all the double bonds of the side chain are converted into hydroxyl groups; 2g4-NC is used to activate the hydrophilic The hydroxyl group in the polymer obtains a hydrophilic polymer with NC-modified side chain; finally, 5g of low molecular weight PEI is added, and the amino group on the PEI reacts with the NC to obtain the final product; the excess PEI is removed by deionized water dialysis and frozen After drying, a hydrophilic polyvinyl alcohol polymer whose side chain is modified with low molecular weight PEI is obtained.

(2) At 60° C., the medical device is activated with 30 wt% acetic acid solution for 1 hour, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI-modified hydrophilic polyvinyl alcohol polymer was formulated into a solution with a concentration of 3 mg/ml, and it was circulated through the surface of the medical device body for 30 minutes, and the side chain was a low-molecular-weight PEI-modified hydrophilic polymer. The vinyl alcohol polymer is fixed on the surface of the medical device, washed with pure water, and dried.

(4) Circulate the 2mg/ml heparin solution over the surface of the medical device body for 50 minutes, and then use a 0.1wt% glutaraldehyde solution to circulate over the surface of the medical device body for 40 minutes at 50°C to ionic bond the heparin The combined method is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use the DCC solution with a concentration of 6mg/ml to activate the sodium heparin for 30, then add DMAP to the solution containing DCC, control the concentration of the activator DMAP in the mixed solution to 6mg/ml, and activate the treatment 2h. After that, the solution is circulated through the surface of the modified medical device in step (4), and reacted for 24 hours. The stable heparin coating is further fixed on the surface of the medical device by covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Example 5 A method for preparing a medical device based on ionic bond-covalent bond synergy surface heparinized anticoagulant

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain is prepared: 8g of ethylene oxide and 4g of allyl glycidyl ether are opened by anion. Cyclic copolymerization reaction produces hydrophilic PEO polymer with double bond modification; 6g mercaptoethanol and 2g AIBN are added, and the addition reaction is carried out at 80℃ for 48h, so that all the double bonds of the side chain are converted into hydroxyl groups; 5g4-NC is used to activate the affinity The hydroxyl group in the water polymer obtains a hydrophilic PEO polymer whose side chain is NC modified; finally, 6g of low molecular weight PEI is added, and the amino group on the PEI reacts with the NC to obtain the final product; the excess PEI is removed by deionized water dialysis , Freeze-drying, to obtain a hydrophilic PEO polymer with a low molecular weight PEI modified side chain.

(2) At 30° C., the medical device is activated with a 40 wt% nitric acid solution for 30 minutes, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI-modified hydrophilic PEO polymer was formulated into a solution with a concentration of 5 mg/ml, and it was circulated through the surface of the medical device body for 20 minutes, and the side chain was a low-molecular-weight PEI-modified hydrophilic PEO polymer. It is fixed on the surface of the medical device, washed with pure water and dried.

(4) Circulate a 5mg/ml heparin solution over the surface of the medical device body for 30 minutes, and then use a 1.2wt% formaldehyde solution to circulate it over the surface of the medical device body for 1.5 hours at 70°C to bond the heparin with ionic bonds The method is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use a solution of EDC·HCl with a concentration of 5mg/ml to activate heparin sodium for 20 minutes, then add DMAP to the solution containing EDC·HCl, and control the concentration of the activator DMAP in the mixed solution to 3mg /ml, activation treatment 2h. Afterwards, the solution was circulated through the surface of the modified medical device in step (4) and reacted for 48 hours. The stable heparin coating was further fixed on the surface of the medical device through covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Example 6 A method for preparing a medical device based on ionic bond-covalent bond synergistic surface heparinized anticoagulant

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, a hydrophilic polymer with a low molecular weight hyperbranched PEI in the side chain is prepared: 10g ethylene oxide and 5g allyl glycidyl ether are opened by anion. Cyclic copolymerization reaction produces a hydrophilic PEO polymer with a large number of double bonds in the side chain; 8g mercaptoethanol and 3g AIBN are added, and the addition reaction is carried out at 100°C for 24h, so that all the double bonds in the side chain are converted into hydroxyl groups; 4g 4- NC activates the hydroxyl group in the hydrophilic polymer to obtain a hydrophilic PEO polymer whose side chain is NC modified; finally, 8g of low molecular weight PEI is added, and the amino group on the PEI reacts with NC to obtain the final product; it is removed by deionized water dialysis Excess PEI is freeze-dried to obtain a hydrophilic PEO polymer whose side chain is modified by low molecular weight PEI.

(2) At 35° C., the medical device is activated with a 30 wt% acid solution for 2 hours, washed with pure water, and dried.

(3) The obtained low-molecular-weight PEI-modified hydrophilic PEO polymer was formulated into a solution with a concentration of 4 mg/ml, and circulated through the surface of the medical device body for 40 minutes, and the side chain was a low-molecular-weight PEI-modified hydrophilic PEO polymer. It is fixed on the surface of the medical device, cleaned with pure water and dried.

(4) Circulate the 4mg/ml heparin solution over the surface of the medical device body for 20 minutes, and then use a 0.1wt% glutaraldehyde solution to circulate over the surface of the medical device body for 2 hours at 80°C to ionic bond the heparin The combined method is fixed on the surface of the medical device, washed with pure water, and dried.

(5) Use a solution of DCC with a concentration of 5 mg/ml to activate heparin sodium for 40 minutes, and then add NHS to the solution containing DCC, control the concentration of the activator NHS in the mixed solution to 5 mg/ml, activate Process for 2h. Afterwards, the solution was circulated through the surface of the modified medical device in step (4) and reacted for 48 hours. The stable heparin coating was further fixed on the surface of the medical device through covalent bonds, washed with pure water, and dried to obtain a new type of anticoagulant. Medical device.

Claims

A surface heparinized anticoagulant medical device based on ionic bond-covalent bond coordination is characterized in that it comprises the following steps:

(1) Based on a hydrophilic polymer with a large number of double bonds in the side chain, prepare a hydrophilic polymer with a low molecular weight hyperbranched polyethyleneimine (PEI) in the side chain: 2-10g hydrophilic monomer and 0.5- 5.0g of allyl glycidyl ether was obtained through anionic ring-opening copolymerization to obtain a hydrophilic polymer with a large number of double bonds in the side chain; 0.5-10.0g of mercaptoethanol and 1-5g of azobisisobutyronitrile (AIBN) were added to 50 The addition reaction is carried out at -100℃ for 24-48h, so that all the double bonds of the side chain are converted into hydroxyl groups; 0.2-5.0g of p-nitrophenyl chloroformate (4-NC) is used to activate the hydroxyl groups in the hydrophilic polymer to obtain The side chain is a hydrophilic polymer of NC; finally, 1-10g of low molecular weight PEI is added, and the amino group on the PEI reacts with NC to obtain the final product; the excess PEI is removed by deionized water dialysis and freeze-dried to obtain the side chain Low molecular weight hyperbranched PEI modified hydrophilic polymer.

(2) Use 10-60wt% acid solution to activate the medical device for 10min-2h at 25-80°C, wash with pure water and dry.

(3) Prepare the low molecular weight PEI modified hydrophilic polymer prepared in step (1) into a solution with a concentration of 1-5 mg/ml, and circulate it over the surface of the medical device body for 10 minutes to 2 hours, and change the side chain to low molecular weight. The PEI modified hydrophilic polymer is fixed on the surface of the medical device, washed with pure water, and dried.

(4) Circulate 1-5mg/ml heparin solution over the surface of the medical device body for 10min-2h, and then use 0.1-2.0wt% crosslinking agent to circulate over the surface of the medical device body at 40-80℃ 20min-2h, fix the heparin on the surface of the medical device in an ionic bond, wash with pure water, and dry.

(5) Use a solution of activator A with a concentration of 5-15 mg/ml to activate heparin sodium for 20-50 minutes, and then add activator B to the solution containing activator A to control the mixing of the activator B The concentration in the solution is 3-6mg/ml, and the activation treatment is 2-4h. Afterwards, the solution is circulated through the surface of the modified medical device in step (4), and reacted for 24-48h. The stable heparin coating is further fixed on the surface of the medical device through covalent bonds, washed with pure water, and dried to obtain a new type of anti Blood coagulation medical device.
The hydrophilic monomer in step (1) of claim 1 is selected from at least one of ethylene glycol, ethylene oxide, α,ω-aminopropyl-ethylene glycol, and vinyl alcohol.
The acid solution in step (1) according to claim 1 is selected from at least one of sulfuric acid, hydrochloric acid, acetic acid, nitric acid, and perchloric acid.
The medical device in step (2) according to claim 1 is a device that is suitable for living organisms (mainly human bodies) and can come into contact with blood.
In step (4) of claim 1, the crosslinking agent is selected from at least one of formaldehyde, glutaraldehyde, and periodic acid.
The activator A in step (5) according to claim 1 is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC . HCl) or N, N' -At least one of dicyclohexyl carboimide (DCC).
In the solution of the activator A in the step (5) according to claim 1, the solvent is a buffer solution of 2-morpholineethanesulfonic acid with a concentration of 8-10 g/L.
The activator B in the step (5) of claim 1 is at least one of 4-dimethylaminopyridine (DMAP) or N-hydroxysuccinimide (NHS).