CN118059314A - Combined artificial heart valve and preparation method thereof - Google Patents
Combined artificial heart valve and preparation method thereof Download PDFInfo
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- CN118059314A CN118059314A CN202410176902.4A CN202410176902A CN118059314A CN 118059314 A CN118059314 A CN 118059314A CN 202410176902 A CN202410176902 A CN 202410176902A CN 118059314 A CN118059314 A CN 118059314A
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Classifications
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- 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
- A61L27/3604—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 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3629—Intestinal tissue, e.g. small intestinal submucosa
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/3604—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 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
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- 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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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- 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
- A61L27/3691—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 physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
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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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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Botany (AREA)
- Urology & Nephrology (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Surgery (AREA)
- Prostheses (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a combined artificial heart valve and a preparation method thereof, wherein the method comprises the steps of performing decellularization treatment on a natural biological membrane to obtain a protein skeleton; filling the cell gap generated after the treatment with a polymer; synthesizing the protein backbone with the polymer; and grafting the synthesized protein skeleton to the anticoagulant coating. Compared with a single polymer material, the invention combines with natural biological materials for manufacturing the valve, and the combined valve has the characteristics of better biocompatibility, blood compatibility, low immunogenicity and the like. Meanwhile, the material has stronger mechanical properties.
Description
Technical Field
The invention relates to the technical field of medical appliances, in particular to a combined artificial heart valve and a preparation method thereof.
Background
The current artificial heart valve mainly comprises two major types of mechanical valves and biological valves, and each valve product has corresponding advantages and disadvantages, such as wide applicable range of mechanical valves and strong durability, but needs to take anticoagulant drugs for life; the biological valve is mainly made of animal tissues, is made of pig pericardium and cattle pericardium materials, has the advantages of good biocompatibility, low immunogenicity, no need of taking anticoagulant medicines for life, and the like, but the durability of the valve is relatively low, and the valve is easy to calcifie, so that the service life of the valve is greatly reduced. At present, the heart valve prosthesis market mainly aims at improving the calcification resisting technology of biological valves and developing novel valve materials, wherein the high molecular polymer materials are used for manufacturing heart valves (preparing process polymer valves) and gradually become a new development trend.
The polymer valve adopts high molecular polymer materials and reasonable valve designs (valve leaflet shape design, suture mode and the like), so that the polymer valve has the same degree of biocompatibility and low immunogenicity as a biological valve, and has the advantages of better durability, good hemodynamics, larger effective opening area, difficult calcification and the like, and the research and development of the polymer valve can overcome the defects existing in the prior valve under the condition of keeping the advantages of the prior valve, thereby becoming a new development direction.
Currently, the company using polymer valves has Foldax, STRAIT ACCESS Technologies, etc., and related products are in clinical stages. Despite the good progress made by polymeric valves, there is still a great deal of room for development in perfecting the corresponding valve products.
Disclosure of Invention
The invention aims to provide a combined artificial heart valve and a preparation method thereof, so that the valve has better biocompatibility and stronger mechanical property, and the service performance is improved.
In order to achieve the above object, according to a first aspect of the present invention, there is provided a method for manufacturing a combination type artificial heart valve, comprising:
Performing cell removal treatment on the natural biological membrane to obtain a protein skeleton;
filling the cell gap generated after the treatment with a polymer;
The protein skeleton is synthesized with the polymer; and
And grafting an anticoagulant coating on the surface of the synthesized protein skeleton.
Further, the decellularization treatment includes:
The pretreatment is carried out on the natural biological membrane,
Performing pretreatment and then performing digestion;
Performing hypotonic solution treatment after digestion;
Treating the hypotonic solution and then treating the hypotonic solution;
carrying out nuclease solution removal treatment after hypertonic solution treatment; and
And (5) washing.
Further, the preprocessing includes: fat removal and surface impurity removal, followed by washing in balanced salt solution.
Further, the balanced salt solution comprises at least one of physiological saline, PBS solution and Hanks solution, wherein a bacteriostat and a protease inhibitor are added into the balanced salt solution, the mass ratio of the balanced salt solution to the bacteriostat is (10-150): 1, and the mass ratio of the balanced salt solution to the protease inhibitor is (50-150): 1.
Further, the digestion includes using a trypsin solution containing ethylenediamine tetraacetic acid in a mass concentration range of 0.05% -0.5%.
Further, the nuclease solution comprises DNase with a concentration of 100-250. Mu.g/mL and RNase with a concentration of 10-50. Mu.g/mL.
Further, the decellularization treatment includes: repeated freeze thawing or chemical treatment.
Further, the polymer includes at least one of polyurethane, polystyrene, polylactic acid, and polytetrafluoroethylene.
Further, the synthesizing the protein scaffold with the polymer comprises: and the end of the amino acid residue in the protein skeleton is subjected to a crosslinking reaction with the polymer in an impregnation mode.
Further, the synthesizing the protein scaffold with the polymer comprises: and filling the polymer into the gaps of the protein skeleton by spraying.
Further, the synthesized protein skeleton is grafted with an anticoagulant coating through a plasma treatment and solution soaking mode.
Further, the method further comprises, after synthesizing the protein scaffold with the polymer: cutting and sewing according to the designed shape of the valve leaflet to obtain the combined artificial heart valve.
Further, the natural biological film comprises at least one of pericardial material, fascia material and animal small intestine submucosa.
According to a second aspect of the present invention, there is provided a combination prosthetic heart valve obtainable by the method of manufacturing a combination prosthetic heart valve according to the first aspect.
Further, the combined type artificial heart valve comprises a protein skeleton and a polymer filled in gaps of the protein skeleton.
Further, an anticoagulant coating is also included on the surface layer.
Compared with a single polymer material, the combined artificial heart valve and the preparation method thereof are combined with natural biological materials for manufacturing the valve, and the combined valve has the characteristics of better biocompatibility, blood compatibility, low immunogenicity and the like. Meanwhile, the natural biological material has a natural structure, and the intermolecular bonding modes such as Van der Waals force, hydrogen bond and hydrophobic acting force are more diversified, which are incomparable with the polymeric material, so that the valve has stronger mechanical property by combining the two materials, and the valve and the bracket can be combined by adopting a sewing mode, so that the structure is finer, and the valve is beneficial to playing a function.
Drawings
Fig. 1 is a flowchart of a method of manufacturing a combination prosthetic heart valve in accordance with an embodiment of the present invention.
Detailed Description
The method and system for making a combination prosthetic heart valve of the present invention will be described in more detail below with reference to the drawings, in which preferred embodiments of the invention are shown, it being understood that one skilled in the art could modify the invention described herein while still achieving the beneficial effects of the invention. Accordingly, the following description is to be construed as broadly known to those skilled in the art and not as limiting the invention.
As described in the background art, the valve is generally manufactured by a dipping casting process, so that the internal structure of the valve is relatively single, and the natural structure of pericardial tissue is lacking, which easily affects the mechanical properties of the valve, the hemodynamic properties of the valve, and the like.
Based on the above, the invention provides a preparation method of the combined artificial heart valve. Referring to fig. 1, fig. 1 is a flowchart illustrating a method for manufacturing a combined prosthetic heart valve according to an embodiment of the invention.
In this embodiment, the method includes:
S100, performing cell removal treatment on the natural biological membrane to obtain a protein skeleton;
s200, filling the cell gap generated after the treatment with a polymer;
s300, synthesizing the protein skeleton and the polymer; and
S400, grafting the synthesized protein skeleton into an anticoagulant coating.
Because the valve is manufactured by adopting a mode of combining natural materials and polymers, compared with a single polymer component, the natural component can improve the biocompatibility and blood compatibility of the valve, reduce immunogenicity and improve shearing resistance, and the valve can be combined with the bracket by adopting a sewing mode, so that the valve is finer in structure and beneficial to the valve to play a role.
Selected natural biological membranes include, but are not limited to, pericardial materials, fascia materials, animal small intestine submucosa, and the like. Preferably, a pericardial material is used, which is bovine pericardium or porcine pericardium. The bovine pericardium is described below as an example.
In S100, the decellularization treatment may be performed in various ways, for example, repeated freeze thawing, hypotonic treatment, chemical treatment, or the like. In this example, a high-low permeability treatment was used.
Specifically, the high-low permeability treatment method comprises the following steps:
s101, preprocessing a natural biological film, which mainly comprises the following steps:
Fresh bovine pericardium is washed in cold (0-4 ℃) balanced salt solutions, including but not limited to, for example, physiological saline, PBS solution, hanks solution, and the like, preferably PBS solution, after removing excess fat and surface impurities. The balanced salt solution is added with a corresponding bacteriostat and a protease inhibitor, and the mass ratio of the balanced salt solution to the bacteriostat is (10-150): 1, preferably 100:1; the mass ratio of the balanced salt solution to the protease inhibitor is (50-150): 1, preferably 100:1.
And a bacteriostatic agent and a protease inhibitor are added into the balanced salt solution, the bacteriostatic agent can inhibit certain microorganisms, and the protease inhibitor can inhibit degradation of proteases existing between tissues on valve materials.
S102, performing pretreatment and then performing digestion; the step may be, for example, digestion of cleaned bovine pericardium in trypsin containing ethylenediamine tetraacetic acid in a mass concentration range of 0.05% -0.5% for 1-3 hours at 20-40 ℃. As an example, the temperature is 37 ℃ and the reaction time is 2h.
By digestion, the use of pancreatin reduces the connection between cells and extracellular matrix, facilitating subsequent decellularization treatments.
S103, performing hypotonic solution treatment after digestion; treating in hypotonic solution at low temperature for 5-10 hr, and replacing fresh solution at intervals. As an example, the preferable reaction time is 8 hours, the intermediate liquid is changed 1 to 2 times, and the shaking treatment is performed. Wherein the low temperature environment can be 2-8 ℃, preferably 4 ℃.
Under the action of hypotonic solution, the cell membrane has permeability, so that the cell absorbs water and swells, and the cell membrane can be broken and the intracellular substances exude. And collagen and elastin are fibrous structures, and the hypotonic solution treatment can lead to the swelling of the collagen and elastin by water absorption, and the structure of the collagen and elastin is not destroyed.
S104, performing hypertonic solution treatment after the hypotonic solution treatment;
Treating the solution in the hypertonic solution for 5 to 10 hours at low temperature, and replacing the fresh solution at intervals. As an example, the preferable reaction time is 8 hours, the intermediate liquid is changed 1 to 2 times, and the shaking treatment is performed. Wherein the low temperature environment can be 2-8 ℃, preferably 4 ℃. The hypertonic solution can be the solution of inorganic salt substances such as NaCl or KCl.
Under the action of the hypertonic solution, the excessive water absorbed in the tissue treated by the hypotonic solution is released outside the fiber again and is recovered to the previous level.
By treatment of hypotonic and hypertonic solutions, the foreign cells in the valve tissue can be removed, while retaining the basic framework structures of collagen, elastin, and the like.
S105, carrying out nuclease solution removal treatment after hypertonic solution treatment; the nuclease solution comprises DNase with the concentration of 100-250 mug/mL and RNase with the concentration of 10-50 mug/mL. As an example, the DNase is preferably at a concentration of 200. Mu.g/mL and the RNase is preferably at a concentration of 20. Mu.g/mL, and the reaction conditions may be incubated at 37℃for 1 to 4 hours, preferably 2 hours.
S106, washing. For example, the washing is carried out by adopting buffer salt solution, the washing is repeated for 3 to 8 times, each time lasts for 1 to 2 hours, the cold storage can be carried out under the low-temperature environment after the cell removal treatment, and the antibacterial agent is added for standby.
In S200, the polymer includes at least one of polyurethane, polystyrene, polylactic acid, and polytetrafluoroethylene. The polymer can be the existing finished polymer, and can also be a polymer material with good biocompatibility and mechanical properties, which is synthesized artificially.
The filling of the polymer may be performed by impregnating or spraying the polymer into the gaps where the protein backbone is to be filled. The impregnation method will be described below as an example.
At normal temperature, adding a catalyst into the same or mixed polymer solution for soaking, and forming a combined valve through a crosslinking reaction between the tail end of an amino acid residue in the bovine pericardium and the polymer; the amino and carboxyl in the collagen react with the carboxyl, amino and carbonyl in the polymer in a crosslinking way.
In S300, the synthesis mode can be carried out by dipping, and the ox pericardium after cell removal is respectively soaked in polymer solution with a certain mass concentration of, for example, 1-5% such as polyurethane, polylactic acid and the like, wherein the polymer solution contains 0.5-3% of catalyst, preferably EDC/NHS, the soaking time is 1-5 hours, preferably 2 hours, the temperature is 4-30 ℃, preferably 15 ℃, and the pH value of the solution is 4-7, preferably the pH value is 5.5.
In S400, the synthesized protein skeleton is grafted with an anticoagulation coating in a plasma treatment and solution soaking mode, so that the biocompatibility and anticoagulation effect of the valve are improved.
In this embodiment, the bovine pericardium filled with the polymer is subjected to low-temperature plasma treatment for 1s to 20s, preferably 10s, at a power of 300W to 800W, at a moving speed of 100mm/s to 300mm/s, and at a plasma treatment height of 8mm to 15mm.
After plasma treatment, the pericardial tissue is placed in a solution containing phosphorylcholine, heparin or sodium citrate and other small molecular substances for 2-48 h, the temperature is 20-40 ℃, preferably 30 ℃, and the biological-high molecular composite material with an anticoagulated surface is obtained.
Thereafter, S500 is performed, and the prosthetic heart valve of the composite material is obtained by cutting and sewing the prosthetic heart valve in accordance with the shape of the leaflet design using a picosecond laser cutter.
Based on the above embodiments, in another embodiment of the present invention, a combination type heart valve prosthesis is also provided.
Specifically, the combined type artificial heart valve comprises a protein skeleton and a polymer filled in gaps of the protein skeleton.
Wherein the collagen skeleton is about 95m%, the elastin is about 0.5m%, and the polymer is about 4.5m%
Further, the combined artificial heart valve further comprises an anticoagulation coating layer positioned on the surface layer.
Table 1 below shows the following results obtained after data conditioning using 20 sets of the inventive combined prosthetic heart valves compared to 20 sets of pure biological valves:
TABLE 1
| Test item | Maximum tensile strength | Elongation at break | Maximum load | Biocompatibility of |
| Unit (B) | MPa | ％ | N | / |
| Reference standard | GB/T1040.1-2006 | GB/T 6344-2008 | GB/T 6344-2008 | GB/T16886 |
| Fixed bovine pericardium (control) | 12±0.4 | 56±4.8 | 20±5.3 | No rejection |
| Inventive samples | 45±0.8 | 75±5.3 | 30±6.9 | No rejection |
The combined artificial heart valve obtained by the invention has greatly improved mechanical performance and better biocompatibility.
Compared with a simple biological valve, the valve made of the biological tissue combined with the high polymer material can increase the durability of the valve; compared with a pure polymer valve, the anti-calcification performance, the anticoagulation performance and the biocompatibility of the valve are improved by combining natural materials and coating the surface of the valve.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (16)
1. A method of making a combination prosthetic heart valve, comprising:
Performing cell removal treatment on the natural biological membrane to obtain a protein skeleton;
filling the cell gap generated after the treatment with a polymer;
synthesizing the protein backbone with the polymer; and
And grafting the synthesized protein skeleton with the anticoagulant coating.
2. The method of claim 1, wherein the decellularizing process comprises:
Pretreating a natural biological film;
Performing pretreatment and then performing digestion;
Performing hypotonic solution treatment after digestion;
Treating the hypotonic solution and then treating the hypotonic solution;
carrying out nuclease solution removal treatment after hypertonic solution treatment; and
And (5) washing.
3. The method of manufacturing a combination prosthetic heart valve of claim 2, wherein the pre-treatment comprises: fat removal and surface impurity removal, followed by washing in balanced salt solution.
4. The method for preparing a combined artificial heart valve according to claim 3, wherein the balanced salt solution comprises at least one of physiological saline, PBS solution and Hanks solution, wherein a bacteriostatic agent and a protease inhibitor are added into the balanced salt solution, the mass ratio of the balanced salt solution to the bacteriostatic agent is (10-150): 1, and the mass ratio of the balanced salt solution to the protease inhibitor is (50-150): 1.
5. The method of claim 2, wherein the digestion comprises using a trypsin solution containing ethylenediamine tetraacetic acid in a mass concentration range of 0.05% -0.5%.
6. The method of claim 2, wherein the nuclease solution comprises dnase at a concentration of 100 μg/mL to 250 μg/mL and rnase at a concentration of 10 μg/mL to 50 μg/mL.
7. The method of claim 1, wherein the decellularizing process comprises: repeated freeze thawing or chemical treatment.
8. The method of claim 1, wherein the polymer comprises at least one of polyurethane, polystyrene, polylactic acid, and polytetrafluoroethylene.
9. The method of claim 1, wherein the synthesizing the protein scaffold with the polymer comprises: and the end of the amino acid residue in the protein skeleton is subjected to a crosslinking reaction with the polymer in an impregnation mode.
10. The method of claim 1, wherein the synthesizing the protein scaffold with the polymer comprises: and filling the polymer into the gaps of the protein skeleton by spraying.
11. The method for preparing a combined artificial heart valve according to claim 1, wherein the synthesized protein skeleton is grafted with an anticoagulant coating by means of plasma treatment and solution soaking.
12. The method of claim 1, further comprising, after synthesizing the protein scaffold with the polymer: cutting and sewing according to the designed shape of the valve leaflet to obtain the combined artificial heart valve.
13. The method of claim 1, wherein the natural biological film comprises at least one of pericardial material, fascia material, and animal small intestine submucosa.
14. A combination prosthetic heart valve obtained by the method of manufacturing a combination prosthetic heart valve according to any one of claims 1-13.
15. The combination prosthetic heart valve of claim 14, wherein the combination prosthetic heart valve comprises a protein scaffold and a polymer filled in interstices of the protein scaffold.
16. The combination prosthetic heart valve of claim 15, further comprising an anticoagulant coating on the surface layer.
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