CN111569152A - Biological valve with anticoagulation and calcification resistance and preparation method thereof - Google Patents
Biological valve with anticoagulation and calcification resistance and preparation method thereof Download PDFInfo
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
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- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
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- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0076—Chemical modification of the substrate
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
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- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
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Abstract
The invention discloses a biological valve with anticoagulation and calcification resistance and a preparation method thereof. The method comprises the following specific processes: glutaraldehyde is adopted to carry out cross-linking treatment on the biological valve, and functional molecules containing amino groups are adopted to carry out at least one time of functional modification treatment on the biological valve before and/or after the cross-linking treatment, so that the functional molecules are fixed on the biological heart valve in a chemical grafting manner to obtain the biological valve with anticoagulation and anti-calcification functions. The biological valve prepared by the invention not only has good mechanical property, but also has excellent anticoagulation and anti-calcification effects.
Description
Technical Field
The invention belongs to the technical field of preparation of medical materials and medical instruments, and particularly relates to a biological valve with anticoagulation and calcification resistance and a preparation method thereof.
Background
Valvular heart disease is a cardiovascular disease and is one of the important causes of high morbidity and mortality of cardiovascular diseases. Conventional valve replacement surgery needs to be performed through an open chest, but because the open chest surgery requires extracorporeal circulation to be established, the risk of surgery is high, and the recovery time of the patient is long, which cannot be tolerated by some elderly patients and patients who are not suitable for opening the chest. In recent years, transcatheter interventional heart valve replacement techniques have brought about patient patency with the development of minimally invasive interventional techniques. The intervention heart valve replacement operation does not need to open the chest, has low operation risk and short recovery time, and provides a new treatment scheme for old patients and patients who are not suitable for opening the chest. Biological heart valves refer to a class of biomedical materials used to replace diseased heart valves in humans. Based on the characteristics and advantages of the biological valve material, the biological valve is the first choice for the intervention valve.
Compared with the aortic valve, the pulmonary valve has the characteristics of slow pulmonary blood flow speed and generally low age in the range of applied patients, so that higher requirements are provided for the antithrombotic and anticalcification performances of the interventional pulmonary valve. At present, the existing interventional biological valves generally adopt glutaraldehyde cross-linked biological valve materials, and the problem of blood coagulation and calcification of the glutaraldehyde cross-linked pulmonary valve in vivo becomes a very important factor for causing clinical valve failure. Therefore, the anticoagulation and anti-calcification treatment of the existing biological valve material can effectively prolong the service life of the interventional pulmonary valve, and has important significance for clinical use of the interventional pulmonary valve and improvement of the life quality of patients.
At present, heparin modification is mainly carried out on the strategy aiming at anticoagulation of glutaraldehyde cross-linked valves, and the following two methods are mainly used: (1) through a direct soaking mode, soaking the glutaraldehyde cross-linked valve into a solution containing heparin to realize modification of the heparin on a valve material; (2) the valve material surface is modified by electrostatic assembly with an electropositive compound in an electrostatic adsorption assembly mode. Because the methods modify heparin on the surface of the valve material through weak binding force such as physical adsorption and the like, the storage time of the heparin on the surface of the material is short, and the purpose of long-term anticoagulation cannot be realized.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a biological valve with anticoagulation and calcification-resistant performances, in particular a pulmonary valve and a preparation method thereof, aiming at solving the problems of coagulation and calcification of the existing interventional biological valve, improving the anticoagulation and calcification-resistant effects of a valve material and prolonging the service life of the valve while ensuring the mechanical performance of the biological valve material.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of a biological valve with anticoagulation and calcification resistance is characterized in that glutaraldehyde is adopted to perform cross-linking treatment on the biological valve, functional molecules containing amino groups are adopted to perform at least one time of functional modification treatment on the biological valve before and/or after the cross-linking treatment, and the functional molecules are fixed on the biological heart valve in a chemical grafting mode to obtain the biological valve with anticoagulation and calcification resistance.
Further, the specific process of the functional modification treatment is as follows: and (3) placing the biological valve in a mixed solution of the functional molecules and the condensing agent, and reacting for 1-7 days at 4-37 ℃.
Further, the mass concentration of the functional molecules in the mixed solution is 0.1-30%; the mass concentration of the condensing agent is 0.1-20%.
Further, the mass concentration (mass percentage concentration) of the functional molecule is preferably 0.5 to 20%, and may be, for example, 0.5%, 8%, 15%, 20%, or the like.
Further, the mass concentration (mass percentage concentration) of the appropriate amount of the condensing agent is preferably 0.1 to 20%, and may be, for example, 0.1%, 1%, 5%, 10%, 15%, or the like.
Further, the functional molecule is an anticoagulant functional component containing amino, and comprises anticoagulant natural molecules, anticoagulant drugs and anticoagulant polymers.
Further, the functional molecule includes at least one of heparan, chitosan-like heparin, hirudin, protamine, dabigatran, bivalirudin, taurine, 2-cyclohexylaminoethanesulfonic acid, aminopropanesulfonic acid, Tris ethanesulfonic acid, polylysine-heparin, ethylenediamine-grafted polyglycidyl methacrylate-polyacrylamide-2-methylpropanesulfonic acid, ethylenediamine-grafted polyglycidyl methacrylate-poly (styrene) sulfonic acid, ethylenediamine-grafted polyglycidyl methacrylate-poly (2-methacryloyloxyethanesulfonic acid), ethylenediamine-grafted polyglycidyl methacrylate-poly (3-methacryloyloxy) -2-hydroxypropyl sulfonic acid, ethylenediamine-grafted polyglycidyl methacrylate-polyallylsulfonic acid, and ethylenediamine-grafted polyglycidyl methacrylate-poly (3-methacryloyloxypropanesulfonic acid, etc One kind of the medicine.
Further, the condensing agent is dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole or the like.
Further, when glutaraldehyde is adopted for cross-linking treatment, the volume concentration of the glutaraldehyde is 0.1-10%, and the pH value is 7-8.
Further, the volume concentration of the glutaraldehyde aqueous solution is preferably 0.1 to 10%, and may be, for example, 0.1%, 1%, 5%, 10%, etc., and the pH of the glutaraldehyde aqueous solution is preferably 7 to 8, and may be, for example, 7, 7.4, 8, etc.
Furthermore, the crosslinking reaction temperature is 4-37 ℃, and the reaction time is 1-7 days.
Further, cleaning pretreatment is carried out on the biological valve between the glutaraldehyde crosslinking or functional modification treatment; the cleaning pretreatment process comprises the following steps: the cleaning process may include: fresh porcine or bovine pericardial tissue was collected and stored in a low temperature humidified state at 4 ℃. The pericardial tissue was washed with deionized (distilled) water using gentle friction and fluid pressure under shaking conditions to remove adherent non-pericardial and non-collagenous tissue. The washing described in the present invention achieves effective decellularization of pericardial tissue by osmotic shock, preferably washing continues until there is no visible adherent non-pericardial or non-collagenous tissue. In specific implementation, preferably, the step of cleaning the animal pericardium includes: cleaning fresh animal pericardium with deionized water for 1.5-3 h at 3-5 ℃ and at the rotating speed oscillation condition of 80-120 RPM. For example, the clean fresh animal (pig or cattle) pericardium can be subjected to cross-linking treatment or functionalization treatment after being washed with deionized water for 2h under the condition of 4 ℃ and 100RPM rotational speed oscillation.
Further, the biological valve is a pulmonary valve, aortic valve, venous valve, mitral valve, or tricuspid valve replacement and repair material.
The biological valve prepared by the method has anticoagulation and calcification resistance.
The invention has the beneficial effects that:
1. because the untreated biological membrane material has poor anticoagulation and anti-calcification capacities, the anticoagulation functional molecules are creatively fixed on the biological heart valve in a chemical grafting manner before and after the glutaraldehyde crosslinking fixation of the biological membrane tissue, so that the biological heart valve has excellent anticoagulation capacity. Meanwhile, the functional modification treatment can also seal the valve calcification sites such as carboxyl, aldehyde group and the like of the glutaraldehyde valve, so that the calcification-resistant capability of the valve is further improved, and the prepared biological valve material, particularly the pulmonary valve, has long-acting anticoagulation and calcification-resistant performances, so that the durability of the pulmonary valve is further improved, and the clinical requirement of the pulmonary valve is met.
2. According to the method, the biological valve is placed in a mixed solution of functional molecules and a condensing agent, then grafting reaction is carried out for 1-7 days at 4-37 ℃, anticoagulation functional molecules can be grafted on the biological valve as much as possible, then stable crosslinking of most collagen tissues on the biological valve can be realized through crosslinking treatment of glutaraldehyde, the structural stability of the whole pericardial tissue is improved, and the immunogenicity is reduced so as to be eliminated.
3. The biological valve prepared by the method has good mechanical properties and shows excellent anticoagulation and calcification-resistant effects in coagulation tests, animal experiments and other tests. The valve material is suitable for pulmonary valve, and can also be used as replacement and repair material for aortic valve, venous valve, mitral valve, tricuspid valve, etc.
Drawings
FIG. 1 shows the results of mechanical testing of a biological valve prepared in example 1 of the present application;
FIG. 2 shows the results of a platelet adhesion test between a glutaraldehyde valve (left) and a biological valve prepared in example 1 of the present application (right);
fig. 3 shows the results of quantitative in vivo calcification analysis of glutaraldehyde valves (left) and biological valves prepared in example 1 of the present application (right).
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning porcine pericardium valve with deionized water, and soaking in 5% hirudin and 1% condensing agent water solution at 4 deg.C for 2 days;
(2) soaking in 5% glutaraldehyde solution at 4 deg.C for 7 days;
(3) soaking in 3% aminoheparin water solution at 4 deg.C for 2 days to obtain target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile break stress of 34N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by over 600 percent.
Example 2
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning a bovine pericardial valve by deionized water, and soaking the bovine pericardial valve in an aqueous solution of taurine with the concentration of 3% and a condensing agent with the concentration of 5% for 2 days at the temperature of 4 ℃;
(2) soaking in 5% glutaraldehyde solution at 4 deg.C for 7 days;
(3) soaking in 5% chitosan heparinoid water solution at 4 deg.C for 2 days to obtain target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile breaking stress greater than 30N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by more than 500 percent.
Example 3
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning porcine pericardium valve with deionized water, and soaking in 5% glutaraldehyde solution at 4 deg.C for 7 days;
(2) soaking in aqueous solution of 20% Tris-ethanesulfonic acid and 5% condensing agent at 4 deg.C for 5 days;
(3) soaking in 3% concentration water solution of ethylenediamine grafted poly glycidyl methacrylate-polyacrylamide-2-methyl propane sulfonic acid at 4 deg.c for 5 days to obtain the target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile breaking stress greater than 30N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by over 600 percent.
Example 4
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning porcine pericardium valve with deionized water, and soaking in aqueous solution of heparin with concentration of 2% and condensing agent with concentration of 5% at 37 deg.C for 3 days;
(2) soaking in 5% glutaraldehyde solution at 4 deg.C for 7 days;
(3) soaking in 50% ethylenediamine grafted poly (glycidyl methacrylate) -poly (3-methacryloyloxy) -2-hydroxypropyl sulfonic acid aqueous solution at 37 deg.C for 3 days to obtain the target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile breaking stress greater than 30N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by more than 400 percent.
Example 5
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning porcine pericardium valve with deionized water, and soaking in 5% bivalirudin and 10% condensating agent water solution at 4 deg.C for 3 days;
(2) soaking in 5% glutaraldehyde solution at 4 deg.C for 7 days;
(3) soaking in 3% aminoheparin water solution at 4 deg.C for 3 days to obtain target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile breaking stress greater than 30N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by more than 400 percent.
Example 6
A preparation method of a biological valve with anticoagulation and calcification resistance performance comprises the following specific steps:
(1) cleaning a porcine pericardium valve with deionized water, and soaking the porcine pericardium valve in an aqueous solution of 1% polylysine-heparin and 1% condensing agent for 5 days at room temperature;
(2) soaking in 5% glutaraldehyde solution at 37 deg.C for 7 days;
(3) and soaking the valve body in 2% dabigatran aqueous solution at room temperature for 5 days to obtain the target biological valve material.
The calcification-resistant bioprosthetic heart valve prepared in this example had a tensile breaking stress greater than 30N under uniaxial tensile testing (1 x 5cm sample size).
Platelet adhesion experiments show that compared with the traditional glutaraldehyde cross-linked valve, the biological valve prepared by the implementation method has obviously improved anticoagulation performance.
The subcutaneous implantation experiment of animal rats shows that compared with the traditional glutaraldehyde cross-linked valve, the calcification-resistant effect of the biological valve prepared by the implementation is improved by over 600 percent.
As shown in fig. 1, it can be seen that the biological valve prepared by the present application has excellent mechanical properties; according to fig. 2, almost no platelets adhere to the biological valve prepared by the method, and platelets adhere to the biological valve treated by glutaraldehyde obviously, so that the biological valve prepared by the method has excellent anticoagulation performance.
Fig. 3 is a result of calcification-resistant performance detection, and as can be seen from fig. 3, the amount of calcium on the biological valve prepared by the method is only about 22 μ g/mg, while the amount of calcium on the biological valve treated by glutaraldehyde reaches about 154 μ g/mg, which is far lower than that of the biological valve treated by glutaraldehyde.
Claims (10)
1. A preparation method of a biological valve with anticoagulation and calcification resistance is characterized in that glutaraldehyde is adopted to carry out cross-linking treatment on the biological valve, and functional molecules containing amino groups are adopted to carry out at least one time of functional modification treatment on the biological valve before and/or after the cross-linking treatment.
2. The method for preparing the biological valve with the anticoagulation and the anti-calcification performances according to claim 1, wherein the specific process of the function modification treatment is as follows: and (3) placing the biological valve in a mixed solution of the functional molecules and the condensing agent, and reacting for 1-7 days at 4-37 ℃.
3. The method for preparing the biological valve with the anticoagulation and the anti-calcification performances according to claim 2, wherein the mass concentration of the functional molecules in the mixed solution is 0.1-30%; the mass concentration of the condensing agent is 0.1-20%.
4. The method of claim 1 or 3, wherein the functional molecules comprise heparan, heparan chitosan, hirudin, protamine, dabigatran, bivalirudin, taurine, 2-cyclohexylaminoethanesulfonic acid, aminopropanesulfonic acid, Tris ethanesulfonic acid, polylysine-heparin, ethylenediamine grafted polyglycidyl methacrylate-polyacrylamide-2-methylpropanesulfonic acid, ethylenediamine grafted polyglycidyl methacrylate-poly (p-styrenesulfonic acid), ethylenediamine grafted polyglycidyl methacrylate-poly (2-methacryloxyethanesulfonic acid), ethylenediamine grafted polyglycidyl methacrylate-poly (3-methacryloyloxy-2-hydroxypropylsulfonic acid), and mixtures thereof, At least one of ethylenediamine grafted polyglycidyl methacrylate-polyallylsulfonic acid and ethylenediamine grafted polyglycidyl methacrylate-poly 3-methacryloxypropanesulfonic acid.
5. The method for preparing a biological valve having both anticoagulation and anti-calcification performances according to claim 2 or 3, wherein the condensing agent is dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or 1-hydroxybenzotriazole.
6. The method for preparing the biological valve with the anticoagulation and the calcification-resisting performances according to claim 1, wherein when glutaraldehyde is adopted for the crosslinking treatment, the volume concentration of the glutaraldehyde is 0.1-10%, and the pH value is 7-8.
7. The method for preparing the biological valve with the anticoagulation and the anti-calcification performances as claimed in claim 6, wherein the cross-linking reaction temperature is 4-37 ℃ and the reaction time is 1-7 days.
8. The method for preparing the biological valve with the anticoagulation and the calcification-resisting performances as claimed in claim 1, wherein before the glutaraldehyde crosslinking or functional modification treatment, the method further comprises a cleaning pretreatment on the biological valve; the cleaning pretreatment process comprises the following steps: and (3) placing the biological valve in a rotating speed oscillation condition of 3-5 ℃ and 80-120 rpm, and cleaning for 1.5-3 h by using deionized water.
9. The method of claim 1, wherein the biological valve is a replacement and repair material for a pulmonary valve, an aortic valve, a venous valve, a mitral valve, or a tricuspid valve.
10. The biological valve prepared by the method of any one of claims 1 to 9 and having both anticoagulation and calcification-resistant properties.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010466435.0A CN111569152A (en) | 2020-05-28 | 2020-05-28 | Biological valve with anticoagulation and calcification resistance and preparation method thereof |
| PCT/CN2021/096560 WO2021239080A1 (en) | 2020-05-28 | 2021-05-27 | Biological heart valve with both anticoagulation and anti-calcification properties, and preparation method therefor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010466435.0A CN111569152A (en) | 2020-05-28 | 2020-05-28 | Biological valve with anticoagulation and calcification resistance and preparation method thereof |
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| CN111569152A true CN111569152A (en) | 2020-08-25 |
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| CN202010466435.0A Pending CN111569152A (en) | 2020-05-28 | 2020-05-28 | Biological valve with anticoagulation and calcification resistance and preparation method thereof |
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| CN (1) | CN111569152A (en) |
| WO (1) | WO2021239080A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112472871A (en) * | 2020-12-08 | 2021-03-12 | 四川大学 | Biological valve crosslinking method for improving mechanical and anticoagulant properties |
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| CN112472871A (en) * | 2020-12-08 | 2021-03-12 | 四川大学 | Biological valve crosslinking method for improving mechanical and anticoagulant properties |
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| WO2024103392A1 (en) * | 2022-11-15 | 2024-05-23 | 四川大学 | Method for preparing biological valve material by copolymerization and crosslinking, biological valve material, and use |
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