CN113117139A

CN113117139A - Application of hydrogenated styrene thermoplastic elastomer in preparation of artificial heart valve

Info

Publication number: CN113117139A
Application number: CN202010045344.XA
Authority: CN
Inventors: 王云兵; 雷洋; 杨立; 周永华
Original assignee: Beijing Huiyu Biomedical Technology Co ltd
Current assignee: Hangzhou Xinju Medical Technology Co ltd; Sichuan University
Priority date: 2020-01-16
Filing date: 2020-01-16
Publication date: 2021-07-16
Anticipated expiration: 2040-01-16
Also published as: CN116036366A; CN113117139B

Abstract

The invention discloses an application of hydrogenated styrene thermoplastic elastomer in preparing a prosthetic heart valve. The thermoplastic elastomer is a block polymer synthesized by living anionic polymerization, wherein the solid phase or dispersed phase is polystyrene, and the rubber phase is hydrogenated conjugated diene polymer or hydrogenated conjugated diene and styrene random copolymer. The hydrogenated styrene elastomer used in the invention has excellent biological stability, anticoagulation performance, calcification resistance and mechanical strength, and can be used for preparing a heart valve prosthesis with more durable performance than a biological valve.

Description

Application of hydrogenated styrene thermoplastic elastomer in preparation of artificial heart valve

Technical Field

The invention belongs to the technical field of biomedical materials, and particularly relates to an application of hydrogenated styrene thermoplastic elastomer in preparation of a heart valve prosthesis.

Background

The heart valve refers to a valve between an atrium and a ventricle or between a ventricle and an artery, and comprises a mitral valve positioned between a left ventricle and a left atrium, a tricuspid valve positioned between a right ventricle and a right atrium, an aortic valve positioned at an outlet of the left ventricle, and a pulmonary valve positioned at an outlet of the right ventricle. When the heart valve has structural or functional changes, blood cannot be discharged smoothly, or the discharged blood returns reversely, so that the heart load is increased, and a series of diseases caused by the heart load are called valvular heart diseases. There are many causes of valvular heart disease, mainly including both rheumatic and degenerative. Rheumatic fever caused by rheumatic valvular heart disease frequently recurs, leads to the deformation of the heart valve, and causes the stenosis or incomplete closure of the valve; rheumatic valvular heart disease commonly occurs in 20-40 years old, involving the mitral valve, then the aortic valve, and also involving the mitral valve, aortic valve and tricuspid valve, and rarely involving the pulmonary valve. Degenerative valvular heart disease is mostly caused by calcification of the valves in the elderly population (generally over sixty years), manifested by stiffening of the valves, deposition of deformed calcium salts, etc., resulting in stenosis or insufficiency of the valves; most patients first involve the aortic valve, and degenerative insufficiency or stenosis may also occur at the mitral valve.

Prosthetic valve replacement is the most effective treatment for patients with severely calcified or damaged valve structures. Early prosthetic valve replacement required surgical open chest surgery, and prosthetic valve products were mainly of two major types: mechanical valves and biological valves. The mechanical valve is made of artificial materials such as titanium, graphite matrix, pyrolytic carbon and the like, and although the mechanical valve is good in durability, a patient needs to take anticoagulant drugs for the whole life. The biological valve is generally made by taking bovine or equine pericardium or porcine valve and artificially processing, and is characterized by being closer to the characteristic of a human physiological valve; although the biological valve has good anticoagulation and the patient does not need to take anticoagulation medicine for a long time, the durability is only 5-10 years due to aging and gradual abrasion. In recent years, transcatheter heart valve placement surgery has become the mainstream of heart valve replacement technology due to small surgical injuries [ Ann Cardiotorac Surg (2017)6(5): 493-7 ]. Because mechanical valves cannot be placed through a catheter, such interventional treatment approaches can only employ a foldable biological valve. Besides poor durability, the raw material of the biological valve, namely the animal pericardium, is difficult to ensure the consistency of the raw material due to the individual difference of animal source materials, has high cost and is difficult to realize large-scale production; in addition, the biovalve may even carry diseases of animal origin and cause death of the patient.

Therefore, a more excellent artificial valve material is needed clinically, which not only has the durability of the mechanical valve and the biocompatibility of the biological valve, but also can be used for interventional therapy through minimally invasive surgery like the biological valve, and can solve the defects of high cost, difficult control of raw material quality and the like of the biological valve.

The use of polymeric materials to make prosthetic heart valves has several distinct advantages: 1) the polymer material can be produced in a large scale, and the performance and the quality can be stably controlled, so that the cost is greatly reduced; 2) the polymer material has wide mechanical properties, and can achieve the required performance (including soft and foldable characteristics to meet the requirements of minimally invasive surgery such as catheterization) of a heart valve product through the design of molecular structure and chemical composition; 3) the polymer material can obtain heart valves with different sizes and shapes through different processing modes, and the biological valve can not be basically processed again to change the thickness and the shape except cutting and sewing; 4) polymeric materials generally do not carry diseases of animal origin. The biocompatibility, durability, and fatigue resistance of polymeric materials are major challenges for their use in heart valve products.

Polymeric materials have been used for several decades to develop artificial heart valves, but have not been successfully used clinically [ Biomaterials 36(2015)6-25 ]. Polymeric materials used to make prosthetic heart valves include silica gel, expanded polytetrafluoroethylene, polyurethane, SIBS (styrene-isobutylene-styrene triblock polymer), ethylene propylene rubber, and polyvinyl alcohol hydrogel. The mechanical properties of the silica gel and the expanded polytetrafluoroethylene can not meet the use requirement of the heart valve, and the polyurethane material can not meet the durability requirement due to poor hydrolytic stability. SIBS (styrene-isobutylene-styrene triblock polymer) is an elastic material excellent in biocompatibility and biostability, but is easily subject to creep deformation under long-term applied force due to its thermoplastic characteristics. In sheep animal model experiments, calcification and blood coagulation phenomena were caused by exposure of the polyester fibers embedded inside due to polymer creep in heart valves made of polyester fiber reinforced SIBS material. The thermally crosslinked SIBS material (XSIBS) has creep resistance, and the heart valve made of the material has improved hemodynamics and anticoagulation performance, but is in the laboratory development stage at present and has not been clinically applied. No clinical trials have been reported for both ethylene propylene rubber and polyvinyl alcohol hydrogels, no product registration and commercialization.

Hydrogenated styrenic block polymers (HSBC) are block polymer materials synthesized by anionic polymerization followed by selective catalytic hydrogenation, and have the characteristics of thermoplastic elastomers (i.e., both as easy to process as thermoplastics and as elastic as thermoset rubbers). HSBC includes hard block polymers such as polystyrene, and soft blocks such as hydrogenated polybutadiene or polyisoprene; the hard segments are the dispersed phase at both ends of the polymer and the soft segments are the continuous phase in the middle of the polymer, so that the dispersed hard segments form physical crosslinks in the continuous soft segments to give the material rubber elasticity while the material can be melt or solution processed to give thermoplastic processability. The commercial HSBC polymers are mainly classified into SEBS and SEPS, wherein SEBS uses butadiene monomer and SEPS uses isoprene monomer. The rubber phase of the HSBC can be randomly copolymerized by introducing styrene and a conjugated diene monomer to obtain a rubber phase containing a styrene monomer unit; after the rubber phase of the HSBC is introduced into a styrene monomer unit through random copolymerization, the mechanical properties (such as tensile modulus, abrasion resistance and tear resistance) of the elastomer can be greatly improved and are close to the properties of a polyurethane elastomer, so that the application range of the elastomer is expanded [ U.S. Pat. No. 5, 7169848 ].

HSBC materials are ideal medical materials, with the following advantages: contains no plasticizer and allergen, has low amount of leachables and leachables, is not hydrolyzed and degraded, does not cause human body irritation reaction, is convenient for processing and forming, and is suitable for various disinfection means (ethylene oxide, gamma ray, electron beam, ultraviolet ray, high temperature) and the like [ https:// kraton, com/products/pdf/Medical% 20Brochure. HSBC materials can pass all relevant medical standard tests such as ISO10993 biocompatibility tests and USP class 6 certification of the united states pharmacopeia. The biomedical applications of HSBC materials are currently limited to less risky medical instruments (one and two types) or consumables. In the medical field, HSBC is typically blended with other components (e.g., polyolefins, polyurethanes, engineering plastics, mineral oils, etc.) and then processed into medical articles (e.g., infusion tubes, infusion bags, syringes, seals, medical connectors, drug stoppers and caps, medical packs 6, wound bandages, skin patches, surgical drapes, medical gowns, etc.). Although the applications relate to human body implantation, the applications are limited to 30 days, and the applications of the implant in the human body for a long time are not available.

Both HSBC and SIBS are non-hydrolyzable hydrocarbons, free of small-molecule leachables and leachables that are biologically toxic, and therefore have good biocompatibility. The only substantial difference between the two is the monomeric 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 the polyisobutene, which has no readily available hydrogen atoms to generate degradation reactions and is therefore completely biologically inert [ US 6102939 ]. In fact, however, SIBS materials are susceptible to degradation under uv, gamma, e-beam, etc. irradiation (and thus are generally suitable for sterilization with ethylene oxide), whereas HSBC is more stable under these rays. This suggests that HSBC may have better stability in humans, at least as useful as SIBS for long-term human implantation. In fact, HSBC should have a wider range of applications due to superior mechanical properties.

In summary, the current heart valve prosthesis products need new polymer elastic materials to overcome the defects of the existing products, and the HSBC product, as an excellent biomaterial, has not been used for medical devices (including heart valve prostheses) implanted into human bodies for a long time.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the application of hydrogenated styrene thermoplastic elastomer in preparing the artificial heart valve, which can be used for preparing a novel artificial heart valve to overcome the defects of a mechanical valve and a biological valve.

In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:

an application of hydrogenated styrene thermoplastic elastomer in preparing artificial heart valve. 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 hydrogenated poly-conjugated diene or hydrogenated random copolymer of conjugated diene and vinyl aromatic hydrocarbon.

Further, the hydrogenated styrene thermoplastic elastomer is a block polymer which is synthesized by active anion polymerization and is subjected to selective catalytic hydrogenation.

Further, the dispersed phase or solid phase of the block polymer is a 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.

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

Further, the vinyl aromatic hydrocarbon is styrene.

Further, 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 conjugated diene isoprene and 1, 3-butadiene.

Further, the prosthetic 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.

Further, the prosthetic heart valve may be implanted via an open chest procedure or a small incision minimally invasive replacement procedure.

The invention has the beneficial effects that:

the hydrogenated styrene thermoplastic elastomer (HSBC) used in the invention has excellent biological stability, anticoagulation performance, anti-calcification performance and mechanical strength, so that the artificial heart valve prepared from the material can overcome the defects of other artificial heart valves (such as mechanical valves and biological valves).

The polymer material used in the invention can be produced in large scale, and the performance and quality can be stably controlled, thereby greatly reducing the cost of heart valve products. The polymer material used in the invention has wide mechanical properties, and can achieve the required properties of the heart valve product (including soft and foldable characteristics, and can be placed through minimally invasive surgery such as catheterization) 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 the biological valve can not be substantially processed and changed in thickness and shape except for cutting and sewing. Furthermore, the polymeric materials used in the present invention do not carry diseases of animal origin.

Drawings

FIG. 1 is a diagram illustrating the platelet adhesion test results of the polymeric elastic material and the biological valve material of the present application;

FIG. 2 is a graph showing the results of whole blood adhesion tests of the polymeric elastic material and the bioprosthetic valve material of the present application;

FIG. 3 is a diagram showing four results of blood coagulation tests of the polymeric elastic material and the biological valve material according to the present invention; wherein A is a PT detection result graph; b is an APTT detection result graph; c is a TT detection result graph; d is an FIB detection result graph;

FIG. 4 is a graph showing the results of the calcification-resistant performance test of the polymeric elastic material and the biological valve material of the present application;

fig. 5 shows the results of the suture strength simulation test of the polymeric elastic material and the biological valve material according to the present invention.

Detailed Description

The following description of the embodiments of the present invention is provided to facilitate 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. 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 changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Example 1

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

then placing the membrane in a mould with the thickness of 0.1mm, and carrying out mould pressing for 30min at 240 ℃ to obtain the macromolecular valve.

Example 2

A hydrogenated styrene elastomer (sample number is HW010), the styrene content of which is 58 percent, and the molecular structure of which is as follows:

Example 3: accelerated in vitro testing of biostability

One accelerated in vitro test for biostability is to subject the sample to boiling concentrated nitric acid (65%) because nitric acid is not only a strong acid but also a strong oxidizer [ US patent US 6102939 ]. For experimental safety, the test temperature for this example was room temperature and the sample and concentrated nitric acid were mixed for 6 hours (if not otherwise indicated) by a teflon coated rotor and magnetic stirrer.

The elastic material prepared in the embodiment 2 of the invention is subjected to biological stability detection together with other elastic materials and biological valves, and the detection results are shown in table 1.

From the detection results in table 1, the biological valve material (porcine pericardium) is curled and discolored in concentrated nitric acid, and a plurality of tiny depressions are formed on the surface, and the strength is greatly reduced; the polyether polyurethane is completely eroded by the concentrated nitric acid within about 35 minutes; the polycarbon polyurethane is not eroded by the pin, but loses elasticity completely, which indicates that the molecular structure, particularly the soft segment, is seriously structurally changed; other elastomers (including SIBS, polyolefin elastomers, polyolefin block polymers, sample of example 2, SEPS) are clearly much more stable, all samples did not undergo morphological changes and rubber elasticity was substantially maintained (rubber elasticity was substantially unchanged or decreased by only 10% except for SEPS samples) despite the yellowing of SEPS. Based on the biostability of this test, while the polycarbonate polyurethane is significantly superior to the polyether polyurethane, these two polyurethane samples are far inferior to other hydrocarbon polymer-based elastic materials (including SEBS, SEPS, polyethylene-based copolymer elastomers, polyethylene-based polyolefin block elastomers, polyisobutylene-based SIBS, and the thermally crosslinked elastic material of the present invention). This shows that the elastic material prepared according to the present invention has more excellent biostability than the bioprosthetic valve material and the polyurethane material.

TABLE 1 in vitro accelerated biostability test results

Example 4 blood compatibility test

Three polymer materials (HW010, HW014 and HZ009) were tested for various blood compatibility using biological valve material as control. HW010 is the polymer material used in example 2, which is HSBC; HW014 is a polyolefin elastomer; HZ009 is a cross-linkable sibs (xsibs) material.

Fig. 1 shows the results of the platelet adhesion test, fig. 2 shows the results of the whole blood adhesion test, and fig. 3 shows the results of the four blood coagulation tests. These test results show that these polymeric materials have no significant difference in blood compatibility with the biological valve material, and thus these materials will not cause coagulation problems when used in heart valves as well as biological valves. .

Example 5 anticalcification Performance test

Three polymeric materials (HW010, HW014 and HZ009) were implanted in rats for 90 days for calcification experiments with biological valve material as control. HW010 is the polymer material used in example 2, which is HSBC; HW014 is a polyolefin elastomer; HZ009 is a cross-linkable sibs (xsibs) material. Fig. 4 shows the calcification test result, which indicates that the calcification of these high polymer materials (HW010, HW014 and HZ009) is significantly lower than that of the biological valve material, so the artificial heart valve made of these materials can overcome the problem that the biological valve is easy to be calcified.

Example 6 seam Strength testing

Three polymeric materials (HW010, HW014 and HZ009) were prepared as thin films of about 0.15mm thickness by hot pressing method with a biological valve material as a control, and then tested for suture strength by simulation. HW010 is the polymer material used in example 2, which is HSBC; HW014 is a polyolefin elastomer; HZ009 is a cross-linkable sibs (xsibs) material. Fig. 5 shows the suture strength results, indicating that the suture strength of polymer materials HW010 and HW014 is close to that of biological valve material, while the suture strength of HZ009 is significantly lower. The polymer material has necessary suture strength, and can be sewn into qualified artificial heart valve products like biological valve materials.

Claims

1. An application of hydrogenated styrene thermoplastic elastomer in preparing artificial heart valve.

2. Use according to claim 1, characterized in that the hydrogenated styrenic thermoplastic elastomer is a block polymer synthesized by living anionic polymerization and subjected to selective catalytic hydrogenation.

3. Use according to claim 2, wherein the dispersed or solid phase of the block polymer is a vinyl aromatic 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.

4. Use according to claim 3, wherein the vinyl aromatic hydrocarbon is at least one of styrene, 4-vinylbenzocyclobutene, α -methylstyrene, 4-methylstyrene, vinylnaphthalene, 1-stilbene and divinylbenzene.

5. Use according to claim 4, wherein the vinyl aromatic hydrocarbon is styrene.

6. Use according to claim 3, wherein the conjugated diene is at least one of isoprene, 1, 3-butadiene, 1, 3-pentadiene, 4-methylpentadiene and 2-methylpentadiene.

7. Use according to claim 6, wherein said at least one of the conjugated dienes isoprene and 1, 3-butadiene.

8. The use according to any one of claims 1 to 7, wherein the prosthetic heart valve is an aortic valve, a pulmonary valve, a mitral valve or a tricuspid valve.

9. The use of claim 8, wherein the prosthetic heart valve has a thickness of 0.05 to 0.40 mm.

10. The use of claim 8, wherein the prosthetic heart valve is implantable via an open chest procedure or a small incision minimally invasive replacement procedure.