CN116036366B - Artificial heart valve - Google Patents

Abstract

The invention discloses a prosthetic heart valve, which is prepared from a hydrogenated styrene thermoplastic elastomer, wherein the hydrogenated styrene thermoplastic elastomer is a block polymer synthesized by ionic polymerization and subjected to selective catalytic hydrogenation; the disperse phase or solid phase of the block polymer is vinyl aromatic hydrocarbon polymer; the continuous or rubber phase of the block polymer is hydrogenated poly-conjugated diene or hydrogenated random copolymer of conjugated diene and vinyl aromatic hydrocarbon. The hydrogenated styrene elastomer used in the invention has excellent biostability, anticoagulation performance, calcification resistance and mechanical strength, and can be used for preparing artificial heart valves with more durable performance than biological valves.

Description

An artificial heart valve

This application is a divisional application of the invention entitled "Application of a hydrogenated styrene thermoplastic elastomer in the preparation of artificial heart valves". The application date of the original application is January 16, 2020, and the application number of the original application is 202010045344.X.

Technical Field

The invention belongs to the technical field of biomedical materials, and in particular relates to an artificial heart valve.

Background Art

Heart valves refer to valves between atria and ventricles or between ventricles and arteries, including the mitral valve between the left ventricle and the left atrium, the tricuspid valve between the right ventricle and the right atrium, the aortic valve at the outlet of the left ventricle, and the pulmonary valve at the outlet of the right ventricle. When the structure or function of the heart valve changes, the blood cannot be discharged smoothly, or the discharged blood flows back, which increases the heart load. The series of diseases caused by this are called valvular heart disease. There are many causes of valvular heart disease, mainly rheumatic and degenerative. Rheumatic valvular heart disease often recurs due to rheumatic fever, causing deformation of heart valves, causing stenosis or insufficiency of valves; rheumatic valvular heart disease often occurs between the ages of 20 and 40, mostly involving the mitral valve, followed by the aortic valve, and can also affect the mitral valve, aortic valve and tricuspid valve at the same time, and rarely involving the pulmonary valve. Degenerative valvular heart disease is mostly caused by valve calcification in the elderly population (generally over 60 years old), which manifests as valve thickening and hardening, deformation, and calcium salt deposition, leading to valve stenosis or insufficiency. In most patients, the aortic valve is first affected, and degenerative insufficiency or stenosis of the mitral valve may also occur.

For patients with severe calcification or damage to the valve structure, artificial valve replacement is the most effective treatment. Early artificial valve replacement required surgical thoracotomy, and artificial valve products are mainly divided into two categories: mechanical valves and biological valves. Mechanical valves are generally made of artificial materials such as titanium, graphite matrix and pyrolytic carbon. Although they have good durability, patients need to take anticoagulants for life. Biological valves are usually made from bovine or horse pericardium or pig valves and are artificially processed. Their characteristics are closer to the characteristics of human physiological valves. Although biological valves have good anticoagulant properties and patients do not need to take anticoagulant drugs for a long time, their durability is only 5-10 years due to aging and gradual wear. In recent years, transcatheter heart valve surgery has become the mainstream of heart valve replacement technology because of its low surgical damage [Ann Cardiothorac Surg (2017) 6 (5): 493–7]. Since mechanical valves cannot be inserted through catheters, this type of interventional treatment can only use foldable biological valves. In addition to poor durability, the raw material of biological valves - animal pericardium - is difficult to ensure consistency due to individual differences in animal-derived materials. It is also very expensive and difficult to achieve large-scale production. In addition, biological valves may even carry animal-derived diseases and cause patient death.

Therefore, there is an urgent need for artificial valve materials with better performance in clinical practice, which not only have the durability of mechanical valves and the biocompatibility of biological valves, but also can be treated through minimally invasive surgical intervention like biological valves, and can also solve the shortcomings of biological valves such as high cost and difficult to control raw material quality.

Polymer materials have several obvious advantages in making artificial heart valves: 1) Polymer materials can be mass-produced, and their performance and quality can be stably controlled, which greatly reduces costs; 2) Polymer materials have a wide range of mechanical properties, and can be designed with molecular structure and chemical composition to achieve the performance required for heart valve products (including soft and foldable properties to meet the requirements of minimally invasive surgeries such as transcatheter implantation); 3) Polymer materials can be processed in different ways to obtain heart valves of different sizes and shapes, while biological valves basically cannot be processed to change thickness and shape except for cutting and sewing; 4) Polymer materials generally do not carry animal-borne diseases. The biocompatibility, durability and fatigue resistance of polymer materials are the main challenges for their use in heart valve products.

Polymer materials have been used to develop artificial heart valves for several decades, but there has been no successful clinical application [Biomaterials 36 (2015) 6-25]. Polymer materials used to make artificial heart valves include silicone, expanded polytetrafluoroethylene, polyurethane, SIBS (styrene-isobutylene-styrene triblock polymer), ethylene propylene rubber and polyvinyl alcohol hydrogel. The mechanical properties of silicone and expanded polytetrafluoroethylene do not meet the requirements for heart valve use, while polyurethane materials do not meet the durability requirements due to poor hydrolytic stability. SIBS (styrene-isobutylene-styrene triblock polymer) is an elastic material with excellent biocompatibility and biostability, but due to its thermoplastic characteristics, it is prone to creep deformation under long-term forces. In sheep animal model experiments, heart valves made of polyester fiber-reinforced SIBS material were exposed to the internal embedded polyester fibers due to polymer creep, resulting in calcification and coagulation. Thermally cross-linked SIBS material (XSIBS) has anti-creep properties, and heart valves made of this material have improved hemodynamics and anti-coagulation properties, but it is still in the laboratory development stage and has not yet entered clinical application. There are no clinical trial reports on EPDM rubber and polyvinyl alcohol hydrogel, let alone product registration and commercialization.

Hydrogenated styrene block polymer (HSBC) is a block polymer material synthesized by anionic polymerization and then selectively catalytically hydrogenated. It has the characteristics of a thermoplastic elastomer (i.e., it can be easily processed like a thermoplastic, and has the same elasticity as a thermosetting rubber). HSBC contains hard segment polymers such as polystyrene, and soft segments such as hydrogenated polybutadiene or polyisoprene; the hard segment is a dispersed phase, located at both ends of the polymer, while the soft segment is a continuous phase, located in the middle of the polymer. In this way, the dispersed hard segment forms a physical crosslink in the continuous soft segment, making the material have rubber elasticity. At the same time, the material can be melt or solution processed and has the processability of thermoplastics. Commercial HSBC polymers are mainly divided into two categories: SEBS and SEPS. SEBS uses butadiene monomers, while SEPS uses isoprene monomers. The rubber phase of HSBC can be obtained by introducing styrene and randomly copolymerizing with conjugated diene monomers to obtain a rubber phase containing styrene monomer units; after the styrene monomer units are introduced into the rubber phase of HSBC by random copolymerization, the mechanical properties of the elastomer (such as tensile modulus, wear resistance and tear resistance) can be greatly improved, approaching the properties of polyurethane elastomers, thereby expanding its application range [U.S. Patent US 7169848].

HSBC materials are ideal medical materials with the following advantages: no plasticizers and allergens, very low amounts of leachables and leachables, no hydrolysis or degradation, no irritation to the human body, easy processing and molding, suitable for various disinfection methods (ethylene oxide, gamma rays, electron beams, ultraviolet rays, high temperatures), etc. [https://kraton.com/products/pdf/Medical%20Brochure.pdf]. HSBC materials can pass all relevant medical standard tests, such as ISO10993 biocompatibility test and USP Class 6 certification. At present, the biomedical application of HSBC materials is limited to medical devices (Class I and Class II) or consumables with lower risks. In the medical field, HSBC is generally blended with other components (such as polyolefins, polyurethanes, engineering plastics, mineral oils, etc.), and then processed into medical products (such as infusion tubes, infusion bags, syringes, seals, medical connectors, drug bottle stoppers and caps, medical packs, wound bandages, skin patches, surgical drapes, medical clothing, etc.). Although some of these applications involve human implantation, they are limited to 30 days and there are no long-term human implantation applications.

Both HSBC and SIBS are non-hydrolyzable hydrocarbons, do not contain small molecular leachables and leachables with biological toxicity, and therefore have good biocompatibility. The only substantial difference between the two is the monomer composition of the rubber phase in the molecular structure. The rubber phase of SIBS is polyisobutylene, while the rubber phase of HSBC is a copolymer of ethylene and 1-butene or a copolymer of ethylene and propylene. The biological stability of SIBS is attributed to the molecular structure of polyisobutylene, which has no easily accessible hydrogen atoms to produce degradation reactions, and therefore has complete biological inertness [US Patent US 6102939]. However, in fact, SIBS materials are prone to degradation under irradiation with ultraviolet rays, gamma rays, electron beams, etc. (thus generally suitable for disinfection with ethylene oxide), while HSBC is more stable under these rays. This suggests that HSBC may have better stability in the human body, at least like SIBS, can be used for long-term human implantation. In fact, HSBC should have a wider range of applications due to its superior mechanical properties.

In summary, current artificial heart valve products require new polymer elastic materials to overcome the shortcomings of existing products, and HSBC products, as an excellent biomaterial, have not yet been used in medical devices (including artificial heart valves) that are implanted in the human body for a long time.

Summary of the invention

In view of the above-mentioned deficiencies in the prior art, the present invention provides an application of a hydrogenated styrene-based thermoplastic elastomer in the preparation of an artificial heart valve, which can be used to make a new type of artificial heart valve to overcome the deficiencies of mechanical valves and biological valves.

To achieve the above purpose, the technical solution adopted by the present invention to solve the technical problem is:

A hydrogenated styrene thermoplastic elastomer is used in the preparation of artificial heart valves. The thermoplastic elastomer is a block polymer synthesized by anionic polymerization and formed by selective catalytic hydrogenation; the dispersed phase or solid phase of the block polymer is a vinyl aromatic hydrocarbon polymer, and the continuous phase or rubber phase of the block polymer is a hydrogenated polyconjugated diene or a hydrogenated conjugated diene and vinyl aromatic hydrocarbon random copolymer.

Furthermore, the hydrogenated styrene-based thermoplastic elastomer is a block polymer synthesized by living anionic polymerization and subjected to selective catalytic hydrogenation.

Furthermore, the dispersed phase or solid phase of the block polymer is a vinyl aromatic hydrocarbon polymer; the continuous phase or rubber phase of the block polymer is a hydrogenated polyconjugated diene or a hydrogenated conjugated diene and vinyl aromatic hydrocarbon random copolymer.

Furthermore, the vinyl aromatic hydrocarbon is at least one of styrene, 4-vinylbenzocyclobutene, α-methylstyrene, 4-methylstyrene, vinylnaphthalene, 1,1-diphenylethylene and divinylbenzene.

Furthermore, the vinyl aromatic hydrocarbon is styrene.

Furthermore, the conjugated diene is at least one of isoprene, 1,3-butadiene, 1,3-pentadiene, 4-methylpentadiene and 2-methylpentadiene.

Further, at least one of the conjugated dienes isoprene and 1,3-butadiene.

Further, the artificial heart valve is an aortic valve, a pulmonary valve, a mitral valve or a tricuspid valve.

Furthermore, the thickness of the artificial heart valve is 0.02-0.40 mm.

Furthermore, the thickness of the artificial heart valve is 0.08-0.15 mm.

Furthermore, artificial heart valves can be implanted through open-chest surgery or minimally invasive replacement surgery with a small incision.

The beneficial effects of the present invention are:

The hydrogenated styrene thermoplastic elastomer (HSBC) used in the present invention has excellent biological stability, anti-coagulation performance, anti-calcification performance and mechanical strength. Therefore, the artificial heart valve prepared by using this material can overcome the shortcomings of other artificial heart valves (such as mechanical valves and biological valves).

The polymer material used in the present invention can be mass-produced, and the performance and quality can be stably controlled, thereby greatly reducing the cost of heart valve products. The polymer material used in the present invention has a wide range of mechanical properties, and can achieve the performance required for heart valve products (including soft and foldable properties, which can be implanted through minimally invasive surgeries such as catheter implantation) through the design of molecular structure and chemical composition. The polymer material used in the present invention can be processed in different ways to obtain heart valves of different sizes and shapes, while biological valves basically cannot be processed and the thickness and shape cannot be changed except for cutting and sewing. Moreover, the polymer material used in the present invention does not carry animal-borne diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a graph showing platelet adhesion test results of the polymer elastic material and the biological valve material of the present application;

FIG2 is a graph showing the whole blood adhesion test results of the polymer elastic material and the biological valve material of the present application;

FIG3 is a graph showing four coagulation test results of the polymer elastic material and the biological valve material of the present application; wherein A is a PT test result graph; B is an APTT test result graph; C is a TT test result graph; and D is a FIB test result graph;

FIG4 is a graph showing the anti-calcification performance test results of the polymer elastic material and the biological valve material of the present application;

FIG5 is a simulation test result of the suture strength of the polymer elastic material and the biological valve material of the present application.

DETAILED DESCRIPTION

The specific embodiments of the present invention are described below to facilitate those skilled in the art to understand the present invention, but it should be clear that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, as long as various changes are within the spirit and scope of the present invention defined and determined by the attached claims, these changes are obvious, and all inventions and creations using the concept of the present invention are protected.

Example 1

A hydrogenated styrene elastomer (sample number HW009) has a styrene content of 42% and a molecular structure as follows:

Then, the polymer valve is prepared by placing it in a mold with a thickness of 0.1 mm and molding it at 240° C. for 30 minutes.

Example 2

A hydrogenated styrene elastomer (sample number HW010) has a styrene content of 58% and a molecular structure as follows:

Then, the polymer valve is prepared by placing it in a mold with a thickness of 0.1 mm and molding it at 240° C. for 30 minutes.

Example 3: In vitro accelerated testing of biological stability

An accelerated in vitro test of biological stability is to place the sample in boiling concentrated nitric acid (65%), because nitric acid is not only a strong acid but also a strong oxidant [US Patent US 6102939]. For experimental safety considerations, the test temperature in this example is room temperature, and the sample and concentrated nitric acid are mixed for 6 hours by a Teflon-coated rotor and a magnetic stirrer (unless otherwise specified).

The elastic material prepared in Example 2 of the present invention was tested for biological stability together with other elastic materials and biological valves. The test results are shown in Table 1.

As shown in the test results of Table 1, the bioprosthetic valve material (pig pericardium) will curl up, change color, form many tiny depressions on the surface, and greatly reduce the strength in concentrated nitric acid; polyether polyurethane is completely corroded by concentrated nitric acid in about 35 minutes; although polycarbon polyurethane is not corroded, it completely loses its elasticity, indicating that the molecular structure, especially the soft segment, has undergone serious structural changes; other elastomers (including SIBS, polyolefin elastomer, polyolefin block polymer, sample 2 of this embodiment, SEPS) are obviously much more stable. Although SEPS has yellowing, all samples have not changed in form, and the rubber elasticity is basically maintained (except for the SEPS sample, the rubber elasticity is basically unchanged or only decreased by 10%). Based on the biological stability of the test, although polycarbon polyurethane is significantly better than polyether polyurethane, these two polyurethane samples are far inferior to other elastic materials based on hydrocarbon polymers (including SEBS, SEPS, copolymer elastomers based on polyethylene, polyolefin block elastomers based on polyethylene, SIBS based on polyisobutylene, and the thermal cross-linked elastic material of the present invention). This indicates that the elastic material prepared according to the present invention has better biostability than biological valve materials and polyurethane materials.

Table 1 Results of in vitro accelerated biological stability test

Example 4 Blood compatibility test

Using biological valve materials as controls, three polymer materials (HW010, HW014 and HZ009) were subjected to various blood compatibility tests. HW010 is the polymer material used in Example 2, which is a HSBC; HW014 is a polyolefin elastomer; and HZ009 is a cross-linkable SIBS (XSIBS) material.

Figure 1 shows the results of the platelet adhesion test, Figure 2 shows the results of the whole blood adhesion test, and Figure 3 shows the results of the four coagulation tests. These test results show that there is no significant difference in the blood compatibility of these polymer materials and biological valve materials, so these materials will not cause coagulation problems when used in heart valves, just like biological valves.

Example 5 Anti-calcification performance test

Using biological valve materials as controls, three polymer materials (HW010, HW014 and HZ009) were implanted in rats for 90 days for calcification experiments. HW010 is the polymer material used in Example 2, which is a HSBC; HW014 is a polyolefin elastomer; and HZ009 is a cross-linkable SIBS (XSIBS) material. The results of the calcification experiment in Figure 4 show that the calcification of these polymer materials (HW010, HW014 and HZ009) is significantly lower than that of biological valve materials. Therefore, artificial heart valves made of these materials can overcome the problem that biological valves are prone to calcification.

Example 6 Suture Strength Test

Taking biological valve materials as a control, three polymer materials (HW010, HW014 and HZ009) were prepared into films with a thickness of about 0.15 mm by a hot pressing method, and then their suture strength was tested by simulation experiments. HW010 is the polymer material used in Example 2, which is a HSBC; HW014 is a polyolefin elastomer; HZ009 is a cross-linkable SIBS (XSIBS) material. Figure 5 is the suture strength result, which shows that the suture strength of polymer materials HW010 and HW014 is close to that of biological valve materials, while the suture strength of HZ009 is significantly lower. This shows that the polymer material of the present invention has the necessary suture strength and can be sewn into qualified artificial heart valve products like biological valve materials.

Claims (8)

1. An artificial heart valve, characterized in that it is prepared by hydrogenated styrene-based thermoplastic elastomer, wherein the hydrogenated styrene-based thermoplastic elastomer is a block polymer synthesized by ion polymerization and selectively catalytically hydrogenated; the dispersed phase or solid phase of the block polymer is a vinyl aromatic hydrocarbon polymer; the continuous phase or rubber phase of the block polymer is a random copolymer of hydrogenated conjugated dienes and vinyl aromatic hydrocarbons, and the thickness of the artificial heart valve is 0.02 to 0.40 mm. 2. The artificial heart valve according to claim 1, characterized in that the vinyl aromatic hydrocarbon is at least one of styrene, 4-vinylbenzocyclobutene, α-methylstyrene, 4-methylstyrene, vinylnaphthalene, 1,1-diphenylethylene and divinylbenzene. 3. The artificial heart valve according to claim 2, characterized in that the vinyl aromatic hydrocarbon is styrene. 4. The artificial heart valve according to claim 1, characterized in that the conjugated diene is at least one of isoprene, 1,3-butadiene, 1,3-pentadiene, 4-methylpentadiene and 2-methylpentadiene. 5 . The artificial heart valve according to claim 4 , wherein the conjugated diene is at least one of isoprene and 1,3-butadiene. 6 . The artificial heart valve according to claim 1 , wherein the artificial heart valve is an aortic valve, a pulmonary valve, a mitral valve or a tricuspid valve. 7. The artificial heart valve according to claim 6, characterized in that the thickness of the artificial heart valve is 0.08-0.15 mm. 8. The artificial heart valve according to claim 6 is characterized in that the artificial heart valve can be implanted through open-chest surgery or minimally invasive replacement surgery with a small incision.