CN106913909B - Dry artificial biological valve and preparation method thereof - Google Patents
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Abstract
The invention discloses a dry artificial biological valve and a preparation method thereof, wherein the preparation method comprises the following steps: and (3) immersing the artificial biological valve after cross-linking and fixing into a polymer solution containing hydroxyl, taking out after soaking for a preset time, and drying at the temperature of 5-45 ℃ to obtain the dried artificial biological valve. The dry artificial biological valve prepared by the preparation method has good physical and chemical properties and biocompatibility; the preparation method of the invention prolongs the service life of the valve, and leads the valve to still keep flexible property in a dry state, thereby reducing the production and transportation cost of the valve and simplifying the use flow of the valve.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a dry artificial biological valve and a preparation method thereof.
Background
With economic development and aging population, the incidence of senile Calcified Aortic Valve Disease (CAVD) is on the rise, second to coronary heart disease and hypertension. A retrospective non-stochastic research analysis in China suggests that the incidence of Aortic Valve Calcification (AVC) in middle-aged and elderly patients over 50 years old reaches 49.38%. With the aging of population, the incidence of Calcified Aortic Stenosis (CAS) is increasing, which is about to become the leading cause of valvular disease in our country.
Aortic Valve Replacement (AVR) using prosthetic valves is the gold standard for treating various types of aortic valve lesions. The use of transcatheter aortic biologic valve placement (TAVR, or TAVI) is increasing worldwide. This is probably because this technique has the potential to reduce mortality and morbidity compared to the high risk of traditional surgical AVR. Transcatheter aortic valve implantation offers new promise as a less invasive, less risky treatment for patients with severe aortic stenosis, particularly those who cannot undergo open thoracic surgery. With the wide use of the interventional artificial heart biological valve, how to improve the service life of the interventional artificial heart biological valve and reduce the decay of the biological valve are important problems facing people.
The existing biological valve is basically crosslinked by adopting a single glutaraldehyde solution, the mechanical property and durability of the use range are achieved under certain conditions, the biological valve has good biocompatibility, and then the biological valve is sewn on a memory metal bracket and then stored in glutaraldehyde storage solution with certain concentration. Prior to heart valve replacement surgery, the valve is transported to a hospital operating room, cleaned, and then delivered into the patient's heart by a delivery device. During the manufacturing, sewing, transporting and using processes of the valve, the valve must be preserved in a specific preservation solution and the valve is ensured to be in a wet state.
The existing crosslinked biological valve at home and abroad needs to be stored in a specific storage solution and ensures that the valve is in a wet state in the manufacturing, sewing, transporting and using processes, so that the valve needs additional conditions in the preparation process so as to be complicated in the preparation process, the valve needs to be separated from a conveyor in the transporting process, the valve needs to be loaded before an operation, the residual storage solution on the valve needs to be cleaned off in the loading process, the risk of easy damage and calcification caused inactivation and bacterial infection is increased, the clinical application and popularization of the valve are limited, and the storage, transportation and use costs of the biological valve are increased. Moreover, after the biological valve is cross-linked by glutaraldehyde, unpaired aldehyde groups from the glutaraldehyde and carboxyl groups on the valve protein tissue often remain on the valve, and the aldehyde groups and the carboxyl groups are easy to combine with calcium ions, so that calcification sites exist in the biological valve, which is an important reason for causing calcification of the biological valve. Meanwhile, due to wet film loading, the compressed size of the valve cannot be further reduced, the application range of a patient is reduced, the valve implantation path is limited, and vascular complications are increased.
With the gradual accumulation of TAVR clinical experience, complications are gradually reduced, and the indications tend to be gradually expanded to younger patients and patients with low or medium risk. Potential problems are gradually highlighted in the application process of all commercial transcatheter aortic valves at present, and mainly include the following:
1. the valve has insufficient durability and cannot meet the trend of valve patients to be younger;
2. the compressed size of the valve can not be further reduced, the adaptation range of a patient is reduced, the implantation path of the valve is limited, and vascular complications are increased;
3. the valve needs to be loaded before operation, is easy to calcify and inactivate, has poor durability, harsh manufacturing, storing and transporting conditions and the like, and limits the clinical application and popularization;
4. the biocompatibility of the existing artificial biological valve is still insufficient; the biocompatibility of the artificial biological valve is an important reason influencing the service life of the valve, and the elimination of the immunogenicity of the valve can enhance the creeping function of endothelial cells of a host and reduce the occurrence probability of perivalvular leakage.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, the present invention aims to provide a dry bioprosthetic valve and a preparation method thereof, and aims to solve the problems that the existing bioprosthetic valve is not durable enough, the compressed size of the valve cannot be further reduced, the valve needs to be loaded before operation, is easy to calcify and inactivate, and has harsh conditions for manufacturing, storage and transportation and poor biocompatibility.
The technical scheme of the invention is as follows:
a method for preparing a dry bioprosthetic valve, comprising the steps of: and (3) immersing the artificial biological valve after cross-linking and fixing into a polymer solution containing hydroxyl, taking out after soaking for a preset time, and drying at the temperature of 5-45 ℃ to obtain the dried artificial biological valve.
The preparation method of the dry artificial biological valve comprises the step of preparing a hydroxyl-containing polymer solution, wherein the hydroxyl-containing polymer solution is one or a mixture of polyethylene glycol, polyvinyl alcohol and polyether glycol solution.
The preparation method of the dry artificial biological valve comprises the step of preparing a hydroxyl-containing polymer solution, wherein the concentration of the hydroxyl-containing polymer solution is 10-50%.
The preparation method of the dry artificial biological valve comprises the step of carrying out drying for 1-7 days.
The preparation method of the dry artificial biological valve comprises the step of soaking the artificial biological valve after cross-linking and fixing in a polymer solution containing hydroxyl at the temperature of 25-45 ℃.
The preparation method of the dry artificial biological valve comprises the step of adding hydrochloric acid to control the pH value of a solution to be 3.0-5.5 when the artificial biological valve after cross-linking and fixing is immersed in a polymer solution containing hydroxyl groups.
The preparation method of the dry artificial biological valve comprises the step of carrying out cross-linking fixation on the artificial biological valve by adopting a glutaraldehyde solution.
The preparation method of the dry artificial biological valve comprises the step of carrying out cross-linking fixation on the artificial biological valve for 2-5 days at normal temperature by adopting 0.1% -5% glutaraldehyde solution.
A dry bioprosthetic valve made by the method of any of the above.
Has the advantages that: the dry artificial biological valve prepared by the preparation method has good physical and chemical properties and biocompatibility; the preparation method of the invention prolongs the service life of the valve, and leads the valve to still keep flexible property in a dry state, thereby reducing the production and transportation cost of the valve and simplifying the use flow of the valve.
Drawings
FIG. 1 is a schematic representation of the reaction equations for aldehyde and carboxyl groups with hydroxyl groups in the polymer in a valve of the present invention.
Detailed Description
The invention provides a dry artificial biological valve and a preparation method thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention creatively treats the cross-linked and fixed artificial biological valve (valve for short) by the polymer solution containing hydroxyl, chemical functional groups contained in the solution and groups in the valve are subjected to chemical reaction, and meanwhile, the polymer has a softening and modifying effect on the valve, and then the valve is subjected to low-temperature drying treatment, so that the valve has good physical and chemical properties and biocompatibility, and the service life of the valve is prolonged.
The method for preparing the dry artificial biological valve of the preferred embodiment of the invention comprises the following steps: and (3) immersing the artificial biological valve after cross-linking and fixing into a polymer solution containing hydroxyl, taking out after soaking for a preset time, and drying at the temperature of 5-45 ℃ to obtain the dried artificial biological valve.
In the embodiment, the valve is dried at a low temperature of 5-45 ℃. The artificial biological valve treated by the hydroxyl-containing polymer mixed solution is taken out and dried at a low temperature, so that the completely dried artificial biological valve still can ensure good flexibility and mechanical property.
It should be noted that the bioprosthetic valve of the present invention includes, but is not limited to, animal pericardial valves such as porcine pericardial valve and bovine pericardial valve.
Before being immersed into the hydroxyl-containing polymer solution, the artificial biological valve needs to be crosslinked to obtain a crosslinked and fixed artificial biological valve. In this example, glutaraldehyde solution was used for cross-linking fixation of the bioprosthetic valve.
Preferably, glutaraldehyde solution with the concentration of 0.1% -5% is adopted to carry out cross-linking fixation on the artificial biological valve for 2-5 days at normal temperature. Firstly, glutaraldehyde crosslinking and fixing are carried out on the biological valve, so that the biological activity of the biological valve can be eliminated, and the mechanical property and the durability of the biological valve can meet the requirements.
When the method is specifically implemented, the artificial biological valve can be immersed in 0.1-5% glutaraldehyde solution and kept for 2-5 days at normal temperature, and meanwhile, the valve is ensured to be flatly unfolded.
In general, the preparation method of the invention comprises: 1. cross-linking of the biological valve; 2. chemical treatment and softening treatment of the biological valve; 3. and (5) drying at low temperature. The method mainly comprises the step of immersing the artificial biological valve which is fixed by crosslinking into a polymer solution containing hydroxyl for soaking so as to enable the polymer containing hydroxyl to chemically react with the artificial biological valve.
The invention adopts valve cross-linking, then chemical treatment is carried out by hydroxyl-containing polymer, and low-temperature drying and dehydration are carried out to prepare the dry artificial biological valve. The polymer solution containing hydroxyl is combined with the surface of the valve through a chemical covalent bond, so that the valve has good flexibility, and can still keep good flexibility under a dry condition, and the dry storage of the valve is realized. Meanwhile, chemical functional groups of the polymer solution and residual aldehyde groups or carboxyl groups in the biological valve carry out chemical reaction, so that the free chemical groups are sealed, the binding force between the biological valve and calcium ions is reduced, the thickness of the valve material is obviously reduced, the valve material has a fold self-leveling function, tissue deactivation is realized, the immunogenicity of the material is reduced, the host endothelial cell climbing capacity is enhanced, the occurrence rate of long-term perivalvular leakage is reduced, and the service life of the biological valve is prolonged.
Further, in this embodiment, the hydroxyl group-containing polymer solution is one or more of a mixture of polyethylene glycol, polyvinyl alcohol, and polyether glycol solution. The polymer solution containing hydroxyl is a liquid which is non-toxic and harmless to human bodies, and is an excellent toughening agent.
As shown in figure 1, the hydroxyl-containing polymer of the present invention covers the surface of the valve with a layer of polymer by chemical reaction of the terminal hydroxyl with the aldehyde and carboxyl groups remaining in the valve. The larger molecular weight of the polymer also allows a larger coverage of the single polymer molecule on the valve surface, so that the hydroxyl-containing polymer can easily impart the chemical and physical properties of the hydroxyl-containing polymer to the bioprosthetic valve.
The invention adopts the polymer containing hydroxyl with the toughening effect, and can be combined with the surface of the valve through a chemical covalent bond, so that the valve also has good flexibility, and the valve can still keep excellent flexibility under a dry condition, thereby realizing the dry storage of the valve.
Further, in this embodiment, the concentration of the hydroxyl group-containing polymer solution is 10% to 50%. Namely, the invention immerses the artificial biological valve after cross-linking and fixing into the polymer solution containing hydroxyl with the concentration of 10 to 50 percent for soaking.
Further, in this embodiment, the artificial biological valve after being cross-linked and fixed is immersed in the polymer solution containing hydroxyl groups for 1 to 7 days, and then taken out and dried, that is, the predetermined time is 1 to 7 days.
Further, in this embodiment, when the cross-linked and fixed bioprosthetic valve is immersed in a polymer solution containing hydroxyl groups, the immersion temperature is 25 to 45 ℃.
Further, in this embodiment, when the crosslinked and fixed bioprosthetic valve is immersed in a polymer solution containing hydroxyl groups, the pH of the solution is controlled to 3.0 to 5.5 by adding hydrochloric acid. Due to the steric hindrance effect, the polymer has the defects of slow reaction rate, long reaction time and the like, so that aldehyde groups and carboxyl groups in the artificial biological valve are activated by adjusting the pH value of the solution to be 3.0-5.5, and the reactivity of the hydroxyl groups in the polymer containing the hydroxyl groups and the aldehyde groups and the carboxyl groups in the valve is enhanced.
In specific implementation, the biological valve crosslinked by glutaraldehyde can be immersed in 10% -50% of hydroxyl-containing polymer solution for 1-7 days, the temperature is controlled to be 25-45 ℃, meanwhile, the pH value of the solution is controlled to be 3.0-5.5 by adding hydrochloric acid, and the valve is ensured to be flatly unfolded.
Furthermore, the invention also provides a dry artificial biological valve which is prepared by adopting the preparation method of the dry artificial biological valve.
The invention makes the valve leaf thinner, firmer, more durable, better biocompatibility and more stable by a unique dry film processing technology. The reduction of the thickness of the valve leaflet reduces the overall dimension of the valve after being compressed by 80%, and the dry film treatment process realizes that the valve can be preassembled into a conveying system for delivery, can be used at any time, does not need preoperative installation, shortens the operation time, and reduces the death risk of a patient during the period of waiting for the valve to be implanted in the operation. The tissue is deactivated by drying treatment, a preinstallation system stored in a storage solution containing glutaraldehyde is not needed, the problem of valve durability is thoroughly solved, the biocompatibility of the valve is improved, the endocarditis occurrence probability caused by immunogen risks is reduced, the host endothelial cell climbing function is enhanced, and the perivalvular leakage occurrence probability is reduced.
The invention is illustrated in detail below with specific examples:
example 1
Soaking the porcine pericardium valve in a glutaraldehyde solution with the concentration of 5% for 2 days, taking out and washing to obtain a cross-linked and fixed artificial biological valve; and then soaking the cross-linked and fixed artificial biological valve in a mixed solution of polyethylene glycol and polyvinyl alcohol with the pH value of 5.5 and the concentration of 20% for 7 days at the temperature of 45 ℃, taking out the artificial biological valve, and finally completely drying the artificial biological valve at the temperature of 20 ℃ to obtain the dried artificial biological valve.
The detection shows that the dry artificial biological valve prepared by the embodiment has excellent flexibility, the external dimension of the compressed valve is reduced by 80%, the biocompatibility is good, and the properties are stable.
Example 2
Soaking the porcine pericardium valve in a glutaraldehyde solution with the concentration of 4% for 3 days, taking out and washing to obtain a cross-linked and fixed artificial biological valve; and then soaking the cross-linked and fixed artificial biological valve in a mixed solution of polyethylene glycol and polyvinyl alcohol with the pH value of 4.5 and the concentration of 30% for 5 days at the temperature of 40 ℃, taking out the artificial biological valve, and finally completely drying the artificial biological valve at the temperature of 25 ℃ to obtain the dried artificial biological valve.
The detection shows that the dry artificial biological valve prepared by the embodiment has excellent flexibility, the external dimension of the compressed valve is reduced by 80%, the biocompatibility is good, and the properties are stable.
Example 3
Soaking the porcine pericardium valve in a glutaraldehyde solution with the concentration of 3% for 4 days, taking out and washing to obtain a cross-linked and fixed artificial biological valve; and then soaking the cross-linked and fixed artificial biological valve in 40% polyethylene glycol solution with the pH value of 4.0 at the temperature of 35 ℃ for 3 days, taking out the artificial biological valve, and finally completely drying the artificial biological valve at the temperature of 30 ℃ to obtain the dried artificial biological valve.
The detection shows that the dry artificial biological valve prepared by the embodiment has excellent flexibility, the external dimension of the compressed valve is reduced by 80%, the biocompatibility is good, and the properties are stable.
Example 4
Soaking the porcine pericardium valve in 1% glutaraldehyde solution for 5 days, taking out and washing to obtain a cross-linked and fixed artificial biological valve; and then soaking the cross-linked and fixed artificial biological valve in a polyethylene glycol solution with the pH value of 3.0 and the concentration of 50% for 1 day at the temperature of 25 ℃, taking out the artificial biological valve, and finally completely drying the artificial biological valve at the temperature of 45 ℃ to obtain the dried artificial biological valve.
The detection shows that the dry artificial biological valve prepared by the embodiment has excellent flexibility, the external dimension of the compressed valve is reduced by 80%, the biocompatibility is good, and the properties are stable.
Example 5
Soaking the porcine pericardium valve in 0.1% glutaraldehyde solution for 5 days, taking out and washing to obtain a cross-linked and fixed artificial biological valve; and then soaking the cross-linked and fixed artificial biological valve in a polyether glycol solution with the pH value of 3.0 and the concentration of 10% for 7 days at the temperature of 25 ℃, taking out the artificial biological valve, and finally completely drying the artificial biological valve at the temperature of 5 ℃ to obtain the dried artificial biological valve.
The detection shows that the dry artificial biological valve prepared by the embodiment has excellent flexibility, the external dimension of the compressed valve is reduced by 80%, the biocompatibility is good, and the properties are stable.
In summary, the present invention provides a dry bioprosthetic valve and a preparation method thereof, wherein the preparation method comprises the steps of: and (3) immersing the artificial biological valve after cross-linking and fixing into a polymer solution containing hydroxyl, taking out after soaking for a preset time, and drying at the temperature of 5-45 ℃ to obtain the dried artificial biological valve. The dry artificial biological valve prepared by the preparation method has good physical and chemical properties and biocompatibility; the preparation method of the invention prolongs the service life of the valve, and leads the valve to still keep flexible property in a dry state, thereby reducing the production and transportation cost of the valve and simplifying the use flow of the valve.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (6)
1. A method for preparing a dry bioprosthetic valve is characterized by comprising the following steps: immersing the artificial biological valve after cross-linking and fixing into a polymer solution containing hydroxyl, adjusting the pH value of the solution to 3.0-5.5, activating aldehyde groups and carboxyl groups in the artificial biological valve, and enhancing the reactivity of the hydroxyl groups in the polymer containing hydroxyl groups and the aldehyde groups and carboxyl groups in the valve; taking out the artificial biological valve after soaking for a preset time and drying the artificial biological valve at the temperature of 5-45 ℃ to obtain a dried artificial biological valve;
the concentration of the polymer solution containing hydroxyl is 10-50%;
the polymer solution containing hydroxyl is one or more mixed solution of polyethylene glycol, polyvinyl alcohol and polyether glycol solution;
the preset time is 1-7 days.
2. The method for preparing the dried artificial bioprosthetic valve according to claim 1, wherein the soaking temperature is 25-45 ℃ when the crosslinked and fixed artificial bioprosthetic valve is soaked in the hydroxyl-containing polymer solution.
3. The method for preparing the dried artificial bioprosthetic valve according to claim 1, wherein when the crosslinked and fixed artificial bioprosthetic valve is immersed in a polymer solution containing hydroxyl groups, the pH value of the solution is controlled to 3.0-5.5 by adding hydrochloric acid.
4. The method of claim 1, wherein the cross-linking of the bioprosthetic valve is performed using a glutaraldehyde solution.
5. The method for preparing the dry artificial biological valve according to the claim 4, characterized in that the glutaraldehyde solution with the concentration of 0.1% -5% is used for the cross-linking and fixing of the artificial biological valve for 2-5 days at normal temperature.
6. A dry bioprosthetic valve characterized by being produced by the production method according to any one of claims 1 to 5.
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| US11857441B2 (en) | 2018-09-04 | 2024-01-02 | 4C Medical Technologies, Inc. | Stent loading device |
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| CN106913909A (en) | 2017-07-04 |
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