VALVE MATERIAL WITH LONG-ACTING ANTITHROMBOSIS PROPERTY AND PREPARATION METHOD THEREFOR

Abstract

The present invention provides a valve material having a long-acting antithrombosis property and a preparation method therefor. The preparation method therefor comprises the following steps: performing glutaraldehyde cross-linking treatment on an animal-derived biological valve material, so that the valve material can resist decomposition for a long time; soaking the treated valve material in a formulation solution containing a cross-linking agent and a modifier for 10-60 min, then increasing the temperature to 30-60° C., and performing heat treatment for 1-12 h; and rinsing the valve material after heat treatment, so as to obtain the valve material. The valve material prepared by the method has excellent antithrombosis and anti-calcification properties, and can effectively solve the problem of calcification and thrombosis in the valve material treated by existing means of glutaraldehyde cross-linking. The valve material prepared by the present method can be used as a valve material required for aortic valve, pulmonary valve, venous valve, mitral valve and tricuspid valve replacement.

Claims

1. A method for preparing a valve material having a long-acting antithrombosis property, comprising steps of: (1) crosslinking an animal-derived biological valve material with glutaraldehyde; (2) immersing the valve material treated in step (1) into a formulated solution containing a cross-linking agent and a modifier which is a phosphocholine compound or a copolymer of a phosphocholine compound and an auxiliary monomer compound, and performing heat treatment; and (3) rinsing the valve material treated in step (2), thereby obtaining the valve material having a long-acting antithrombosis property.

2. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is one or more selected from a group consisting of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide, metaphosphate, isocyanate and maleimide hydrazide.

3-4. (canceled)

5. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the phosphocholine compound is at least one selected from a group consisting of glycerophosphate choline, lecithin, dimyristoyl phosphatidylcholine, 1,2-diacyl-sn-glycero-3-phosphocholine, 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate, and methylacryloyloxyethyl sulfobetaine.

6. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the auxiliary monomer compound is one or more selected from a group consisting of lauryl methacrylate, butyl methacrylate, N-(3-aminopropyl) methacrylamide and methacrylamide.

7. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is sodium hexametaphosphate and the modifier is glycerophosphate choline.

8. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is isocyanate, the modifier is a copolymer of methylacryloyloxyethyl sulfobetaine, lauryl methacrylate and butyl methacrylate.

9. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is sodium metaphosphate, and the modifier is a copolymer of lauryl methacrylate and 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate.

10. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and the modifier is a copolymer of 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate and N-(3-aminopropyl) methacrylamide.

11. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent is a mixture solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide and sodium metaphosphate, and the modifier is a mixture solution of lecithin and dimyristoyl phosphatidylcholine.

12. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the cross-linking agent of the formulated solution in step (2) has a mass concentration in a range of 0.05 wt % to 5 wt %.

13. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the modifier of the formulated solution in step (2) has a mass concentration in a range of 0.2 wt % to 2 wt %.

14. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein a molar ratio of the cross-linking agent to the modifier of the formulated solution in step (2) is 0.5-2:0.2-1.

15. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein a solvent of the formulated solution in step (2) is one or more selected from a group consisting of hexafluoroisopropanol, isopropanol, ethanol, methanol and water.

16. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, further comprising, in step (2), immersing the treated valve material in the formulated solution containing the cross-linking agent and the modifier for 10-60 min and then performing the heat treatment.

17. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, further comprising, in step (2), immersing the treated valve material in the formulated solution containing the cross-linking agent and the modifier, and then heating to 30-60° C. for the heat treatment for 1-12 h.

18. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, further comprising, in step (2), immersing the treated valve material in the formulated solution containing the cross-linking agent and the modifier for 10-60 min, and then heating to 30-60° C. for the heat treatment for 1-12 h.

19. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the animal-derived biological valve material comprises one of porcine pericardium, bovine pericardium and small intestinal submucosa.

20. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, wherein the glutaraldehyde in step (1) has a concentration in a range of 0.3-3%.

21. The method for preparing a valve material having a long-acting antithrombosis property of claim 1, further comprising crosslinking the animal-derived biological valve material with glutaraldehyde for 24-96 h at a pH value in a range of 6-9.

22. A valve material having a long-acting antithrombosis property, which is prepared by the method according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0046] FIG. 1 shows thrombosis on the surface of glutaraldehyde cross-linked valve material;

[0047] FIG. 2 shows thrombosis on the surface of modified valve material; and

[0048] FIG. 3 (left figure) shows calcification of glutaraldehyde cross-linked valve material after subcutaneous implantation for 3 months, and FIG. 3 (right figure) shows calcification of modified valve material after subcutaneous implantation for 3 months.

DESCRIPTION OF THE EMBODIMENTS

[0049] The specific embodiments of the present invention will be described in detail with reference to the drawings.

Example 1

[0050] A valve material having a long-acting antithrombosis property is prepared through the following steps: [0051] (1) Cut a defatted porcine pericardium material into an appropriate size, stretch the material and then immerse it into a glutaraldehyde solution with a concentration of 1%, renew the solution after 24 hours, and repeat the treatment for 72 hours; [0052] (2) Wash the obtained cross-linked valve material, and immerse the valve material into a formulated solution for 30 minutes, wherein the solvent of the formulated solution is hexafluoroisopropanol, the cross-linking agent is sodium hexametaphosphate, and the modifier is glycerophosphate choline. The concentration of the sodium hexametaphosphate is 1 wt %, and the concentration of the glycerophosphate choline is 0.5 wt %; then the valve immersed in the formulated solution is heated to 40° C. for 4 h; and [0053] (3) Wash the valve material obtained in step (2) sufficiently with deionize water to obtain the desired valve material, and preserve the material in a glutaraldehyde solvent for use.

Example 2

[0054] A valve material having a long-acting antithrombosis property is prepared through the following steps: [0055] (1) Cut a defatted porcine pericardium material into an appropriate size, stretch the material and then immerse it into a glutaraldehyde solution with a concentration of 0.5% for 24 hours, and then transfer the material into a glutaraldehyde solution with a concentration of 1% for 48 hours; [0056] (2) Wash the obtained cross-linked valve material, and immerse the valve material into a formulated solution for 60 minutes, wherein the solvent of the formulated solution is isopropanol, the cross-linking agent is isocyanate, and the modifier is a copolymer of methylacryloyloxyethyl sulfobetaine, lauryl methacrylate and butyl methacrylate. The concentrations of the isocyanate and the methylacryloyloxyethyl sulfobetaine, lauryl methacrylate and butyl methacrylate in the copolymer are 0.1 wt %, 0.1 wt %, 0.2 wt % and 0.2 wt %, respectively; and then the valve immersed with the formulated solution is heated to 60° C. for 3 h; and [0057] (3) Wash the valve material obtained in step (2) sufficiently with deionize water to obtain the desired valve material, and preserve the material in a glutaraldehyde solvent for use.

Example 3

[0058] A valve material having a long-acting antithrombosis property is prepared through the following steps: [0059] (1) Cut a defatted bovine pericardium material into an appropriate size, stretch the material and then immerse it into a glutaraldehyde solution with a concentration of 1% for 24 hours, and then transfer the material into a glutaraldehyde solution with a concentration of 0.5% for 48 hours; [0060] (2) Wash the obtained cross-linked valve material, and immerse the valve material into a formulated solution for 20 minutes, wherein the of the formulated solution is water, and the cross-linking agent is sodium metaphosphate, and the modifier is a copolymer of lauryl methacrylate and 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate. The concentrations of sodium metaphosphate, and the lauryl methacrylate and 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate in the copolymers are 1 wt %, 0.2 wt % and 0.3 wt %, respectively; and then the valve immersed with the formulated solution is heated to 50° C. for 8 h; and [0061] (3) Wash the valve material obtained in step (2) sufficiently with deionize water to obtain the desired valve material, and preserve the material in a mixed solvent of isopropanol and glycerol for use.

Example 4

[0062] A valve material having a long-acting antithrombosis property is prepared through the following steps: [0063] (1) Peel off and cut a small intestinal submucosa into an appropriate size, stretch the material and then immerse it into a glutaraldehyde solution with a concentration of 1% for 72 hours; [0064] (2) Wash the obtained cross-linked valve material, and immerse the valve material into a formulated solution for 40 min, wherein the solvent of the formulated solution is isopropanol, the cross-linking agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and the modifier is a copolymer of 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate and N-(3-aminopropyl) methacrylamide. The concentrations of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and the 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate and N-(3-aminopropyl) methacrylamide in the copolymer are 0.05 wt %, 0.2 wt % and 0.5 wt %, respectively; and then the valve immersed with the formulated solution is heated to 60° C. for 8 h; and [0065] (3) Wash the valve material obtained in step (2) sufficiently with deionize water to obtain the desired valve material, and preserve the material in a glutaraldehyde solvent for use.

Example 5

[0066] A valve material having a long-acting antithrombosis property is prepared through the following steps: [0067] (1) Cut a defatted porcine pericardium material into an appropriate size, stretch the material and then immerse it into a glutaraldehyde solution with a concentration of 1% for 72 hours; [0068] (2) Wash the obtained cross-linked valve material, and immerse the valve material into a formulated solution for 10 minutes, wherein the solvent of the formulated solution is water, the cross-linking agent is a mixture solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide and sodium metaphosphate with concentrations of 0.1 wt % and 2 wt %, respectively, and the modifier is a mixture solution of lecithin and dimyristoyl phosphatidylcholine with concentrations of 0.3 wt % and 0.4 wt %, respectively; and then the valve immersed with the formulated solution is heated to 40° C. for 12 h; and [0069] (3) Wash the valve material obtained in step (2) sufficiently with deionize water to obtain the desired valve material, and preserve the material in a mixed solvent of isopropanol and glycerol for use.

Test Example

[0070] Taking the valve material prepared in EXAMPLE 4 as an example, the structure on the surface of the glutaraldehyde cross-linked valve material is observed, as shown in FIG. 1; then the valve material is treated by modifier and cross-linking agent, the treated valve material suffers from a blood circulation test of rabbit ex vivo for 2 hours, and then thrombosis on the surface of the valve material is observed, as shown in FIG. 2.

[0071] As can be seen from FIG. 1, the conventional glutaraldehyde cross-linked valve material without modification is deposited with a large amount of thrombus, red blood cells and a large amount of criss-crossed fibrous. However, FIG. 2 shows that after the anti-clotting modification described in EXAMPLE 4, the surface of the valve material is still smooth without significant thrombosis, proving the excellent blood compatibility of the modified valve material.

[0072] As shown in FIG. 3, after subcutaneous implantation for 3 months and staining with alizarin red, there are significant calcified plaques on the glutaraldehyde cross-linked valve material (left figure), while the modified valve material (right figure) is still smooth without significant calcified plaques, which proves the anti-calcification property of the valve material.