Degradable artificial heart valve, preparation method and artificial heart valve device

Abstract

The present invention provides a degradable artificial heart valve, a preparation method, and an artificial heart valve device. The valve comprises an upper oriented layer, a lower oriented layer, and an intermediate micropatterned layer disposed between the upper and lower oriented layers. The upper and lower oriented layers are fiber-oriented layers with anisotropic mechanical properties, with the fibers of the upper and lower oriented layers oriented perpendicularly to each other. The intermediate micropatterned layer is a polymer film layer with a predetermined array of micropatterns. The upper and lower oriented layers of the valve correspond to the fiber layer and ventricular layer of a natural valve, respectively, with their fibers oriented perpendicularly to each other. The intermediate micropatterned layer corresponds to the sponge layer of the natural valve and acts as a buffer layer in the in vivo environment, allowing shear and deformation between the inner and outer layers. Furthermore, this intermediate micropatterned layer structure absorbs energy during valve compression, reducing valve flutter during forward flow.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical materials, and in particular relates to a degradable artificial heart valve, a preparation method and an artificial heart valve device. Background Art

[0002] 9 out of every 1,000 newborns worldwide suffer from congenital heart disease. Unlike adults, infants and young children with congenital heart valve disease are more difficult to treat. In recent decades, the most commonly used valve types are mechanical valves and bioprosthetic valves. Although they have improved the quality of life of patients, their limitations, such as the inability to grow and adapt to hemodynamic changes, have restricted their application in patients with congenital heart disease. For this group of people, degradable artificial heart valves have the ability to regenerate and reshape, and they gradually grow as the patient ages and grows in size. In the past, other types of transplanted artificial valves lost their proper function because they could not grow synchronously, and repeated surgeries were required. Therefore, degradable artificial heart valves are the most urgently needed treatment for this type of patients and their development has the greatest prospects.

[0003] The mechanical properties of natural heart valves are highly anisotropic. The valve is primarily composed of a fibrous layer, a spongy layer, and a ventricular layer: the fibrous layer is primarily composed of densely packed type I collagen fibers along the circumference, which play a major load-bearing role during cardiac contraction; the ventricular layer is primarily composed of elastin fibers, most of which are arranged radially along the valve, limiting radial strain during valve opening and helping the valve rebound when closed; the spongy layer is primarily composed of proteoglycans and a small amount of collagen, with a foam-like structure that has a damping effect and acts as a buffer layer. The layered structure of the heart valve results in higher strength in the circumferential direction and greater deformation in the radial direction. The mechanical anisotropy ratio Eaxial / Eradial of natural heart valves is approximately 2-8. Existing published artificial heart valves often use a single-structure polymer membrane as the artificial heart valve material. For example, the extracellular matrix coating reinforced polymer valve disclosed in the Chinese patent (application number 202010506677.8) uses silicone rubber, polylactic acid, polyetheretherketone, polyurethane or styrene-b-isobutylene-b-styrene as the valve base material; the supramolecular polymer electrospun valve released by the Dutch company Xeltis also uses a single electrospun polycaprolactone-urea-pyrimidone (ePCL-UPy) as the valve material. This single valve structure design makes the valve lack anisotropic mechanical properties. Summary of the Invention

[0004] Therefore, the present invention provides a degradable artificial heart valve, a preparation method and an artificial heart valve device to solve the problem in the related art that the heart valve is a single structure and does not have anisotropic mechanical properties.

[0005] In order to solve the above problems, the present invention provides a degradable artificial heart valve with a composite structure, wherein the valve includes an upper oriented layer, a lower oriented layer, and an intermediate micro-pattern layer located between the upper oriented layer and the lower oriented layer, wherein the upper oriented layer and the lower oriented layer are fiber oriented arrangement layers with anisotropic mechanical properties, and the fiber directions of the upper oriented layer and the lower oriented layer are perpendicular to each other, and the intermediate micro-pattern layer is a polymer film layer with a preset array micro-pattern.

[0006] In some embodiments, the valve is made of a degradable synthetic polymer material.

[0007] In some embodiments, the upper and lower oriented layers are prepared by uniaxial electrospinning, and the degradable synthetic polymer material is one or more of polylactic acid, polycaprolactone, poly (L-lactide-caprolactone), and polyglycolic acid.

[0008] In some embodiments, the thickness of the lower alignment layer is 20-80 μm, and the thickness of the upper alignment layer is 2-8 times the thickness of the lower alignment layer.

[0009] In some embodiments, the thickness of the intermediate micro-pattern layer is 100-150 μm; and / or the predetermined array micro-pattern is formed by arranging regular polygonal patterns of one or more shapes.

[0010] In some embodiments, the diameter of the inscribed circle of the regular polygon is 0.3-1.5 mm; and / or, in the preset array pattern, each regular polygon has a common side with its adjacent regular polygons.

[0011] The present invention also provides a method for preparing the above-mentioned degradable artificial heart valve having a composite structure, comprising the following steps:

[0012] Preparation of spinning solution: using one or more combinations of degradable synthetic polymer materials such as polylactic acid, polycaprolactone, poly (L-lactide-caprolactone), and polyglycolic acid as raw materials, and one or more combinations of chloroform, tetrahydrofuran, hexafluoroisopropanol, and 2,2,2-trifluoroethanol as solvents to prepare a spinning solution, wherein the concentration of the prepared spinning solution is 5-15 wt%;

[0013] Preparation of the intermediate micro-pattern layer: The intermediate micro-pattern layer is prepared using a template method, and a metal template with a preset array of micro-patterns is used as a collector for electrospinning;

[0014] Preparation of the lower alignment layer: The prepared middle micro-pattern layer is pasted on the receiving roller, and the spinning solution is evenly spun on the receiving roller using a uniaxial electrospinning process;

[0015] Preparation of the upper alignment layer: The prepared intermediate micro-pattern layer and the lower alignment layer are turned over and rotated 90 degrees and pasted on the receiving roller, and the spinning solution is evenly spun on the receiving roller using a uniaxial electrospinning process.

[0016] In some embodiments,

[0017] The process parameters used in the intermediate micro-pattern layer preparation step are: a feed rate of 0.5-2 mL / h, a vertical distance between the nozzle and the receiving plate of 10-15 cm, a 19-25G blunt-tip needle, a voltage of 13-18 kV, an ambient temperature of 25-40° C., and an ambient humidity of less than 45%;

[0018] The process parameters used in the lower alignment layer preparation step are as follows: the roller speed of the receiving roller is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving roller is 10-15 cm, the nozzle uses a 19-25G blunt-tip needle, the voltage is 13-18 kV, the ambient temperature is 25-40° C., and the ambient humidity is less than 45%;

[0019] The process parameters used in the upper oriented layer preparation step are: the roller speed of the receiving roller is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving roller is 10-15 cm, the nozzle uses a 19-25G blunt needle, the voltage is 13-18 kV, the ambient temperature is 25-40 ° C, and the ambient humidity is less than 45%.

[0020] In some embodiments, the metal template with the predetermined array of micropatterns is prepared by screen printing and etching.

[0021] In some embodiments, the metal template is prepared by the following steps:

[0022] Engineering drawing: drawing the preset array micro pattern;

[0023] Ink brushing and baking: evenly apply photosensitive ink on the surface of the metal plate, and then bake the plate;

[0024] Exposure and development: Use a metal halide lamp to expose the preset pattern area, and then develop it with a developer;

[0025] Etching: The etching solution is a mixed solution of 10-20% by mass nitric acid, 3.5-5.5% by mass hydrofluoric acid, and the remainder is deionized water. The metal plate after the exposure and development treatment is immersed and pulled at room temperature for 5-10 minutes.

[0026] The present invention also provides a degradable artificial heart valve device, which is formed by sewing the aforementioned degradable artificial heart valve with a composite structure into the interior of a valve stent; the in vivo degradation period of the degradable artificial heart valve device is 1-3 years.

[0027] In some embodiments, the valve stent is a polyetheretherketone stent or a nickel-titanium alloy stent; and / or the opening size of the valve stent is 17-35 mm; and / or the effective opening area of ​​the degradable artificial heart valve device is 0.70-2.5 cm 2 , reflux ratio ≤20%.

[0028] Compared with the prior art, the biodegradable artificial heart valve, preparation method and artificial heart valve device of the present invention have at least the following beneficial effects: ① The three-layer composite structure valve is compared with the three-layer structure of the natural valve, that is, the upper oriented layer and the lower oriented layer correspond to the fiber layer and the ventricular layer respectively, and the fiber directions of the two are perpendicular to each other. The middle micro-pattern layer corresponds to the sponge layer, which can act as a buffer layer in the in vivo environment, allowing shear and deformation between the inner and outer layers. In addition, this middle micro-pattern layer structure can also absorb energy during the valve compression process and play a role in reducing valve flutter during forward flow. ② The three-layer composite structure composed of the upper oriented layer, the lower oriented layer and the middle micro-pattern layer can adjust the valve's anisotropic mechanical properties by adjusting the thickness of each layer, so that it has mechanical anisotropy and has a mechanical anisotropy ratio (E) with the natural heart valve. 轴向 / E 径向 About 2-8) match, so that the entire artificial heart valve is more compatible with the human body. ③ The material used in the present invention is a degradable synthetic polymer material. Compared with natural materials, the composition and structure of the material can be more accurately regulated, batch differences are less, and the mechanical properties and degradation rate are easier to control. ④ The degradable artificial heart valve device provided by the present invention, in addition to having the aforementioned beneficial effects, also has the characteristics of simple and easy process, low cost, etc., which is suitable for mass production and can also be used for special customized services. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a flow chart of a method for preparing a degradable artificial heart valve with a composite structure according to an embodiment of the present invention;

[0030] Figure 2 This is a schematic diagram of the preset array micro-pattern described in Example 1 of the present invention, wherein: Figure 2 Figure (a) is a schematic diagram of the regular hexagonal pattern arrangement. Figure 2 Figure (b) is a schematic diagram of the arrangement of equilateral triangle patterns;

[0031] Figure 3This is the laser confocal topography of a preset array micro-pattern (regular hexagon) processed on the surface of a Ti-6Al-4V metal plate in Example 1 of the present invention;

[0032] Figure 4 (a) and (b) are scanning electron microscope (SEM) images of the hexagonal middle micro-pattern layer prepared in Example 1 of the present invention, (c) is an SEM image of the fiber orientation direction arrangement of the lower oriented layer prepared in Example 1 of the present invention, and (d) is a statistical frequency distribution histogram of the fiber diameter of the lower oriented layer;

[0033] Figure 5 (a) is a uniaxial tensile curve of a control example (a material having a single structure prepared from polycaprolactone (molecular weight: 80,000) using the same electrospinning parameters as in Example 1 of the present invention, specifically using a flat plate as a collector, a feed rate of 1 mL / h, a vertical distance of 15 cm between the nozzle and the receiver, a 19G blunt-tip needle, a voltage of 15 kV, an ambient temperature of 30°C, and an ambient humidity of less than 45%, ultimately producing a single structure material having a thickness of 300 μm). (b) and (c) are uniaxial tensile curves of a degradable artificial heart valve having a composite structure prepared in Example 1 of the present invention along the fiber directions of the upper and lower oriented layers, respectively; (d) is a bar graph of the elastic modulus of the material.

[0034] Figure 6 (a) is a stress-strain curve of a dynamic tensile test of a control example; (b) and (c) are stress-strain curves of a dynamic tensile test of a degradable artificial heart valve having a composite structure prepared in Example 1 of the present invention along the fiber directions of the upper and lower oriented layers, respectively; (d) is a bar graph of the storage modulus of the material;

[0035] Figure 7 A physical photograph of a degradable artificial heart valve device sewn from a degradable artificial heart valve having a composite structure prepared in Example 1 of the present invention;

[0036] Figure 8 The fluid dynamics detection curves of a degradable artificial heart valve device sewn with a composite structure prepared in Example 1 of the present invention, wherein (a) is a curve showing changes in aortic pressure, ventricular pressure and fluid flow rate over time, and (b) is an image of the valve when it is opened and closed. DETAILED DESCRIPTION

[0037] See also Figures 1 to 8As shown, according to an embodiment of the present invention, a biodegradable artificial heart valve with a composite structure is provided, comprising an upper oriented layer, a lower oriented layer, and an intermediate micropatterned layer disposed between the upper and lower oriented layers. The upper and lower oriented layers are fiber-oriented layers with anisotropic mechanical properties, and the fibers of the upper and lower oriented layers are perpendicular to each other. The intermediate micropatterned layer is a polymer film layer with a predetermined array of micropatterns. Natural heart valves have a distinct corrugated structure, which maintains the stability of the entire valve during contraction and relaxation. The polymer film layer with the predetermined array of micropatterns has a surface morphology similar to that of a corrugated structure, which helps maintain valve stability during contraction and relaxation. The intermediate micropatterned layer, having a certain thickness, corresponds to the sponge layer in a natural valve and can serve as a buffer layer in the in vivo environment. The predetermined array of micropatterns is composed of one or more regular polygonal patterns, such as single regular hexagons, regular quadrilaterals, regular triangles, or a combination of regular hexagons and regular triangles. Regular polygons ensure that the patterns are densely packed across a plane, while irregular polygons are difficult to combine. Furthermore, based on the accuracy of fabricating a metal template with a preset array micropattern using a screen printing and etching method, the diameter of the inscribed circle of the regular polygon is 0.3-1.5 mm, balancing ease of fabrication with a high buffering effect. Below this range, fabrication becomes difficult, while above this range, the micropattern becomes too large, resulting in a loose spatial structure in the intermediate micropattern layer, weakening its role as a buffer layer. The preset array micropattern includes: and / or, within the preset array pattern, each regular polygon shares a common edge with its adjacent regular polygons. This common edge arrangement mimics the corrugated structure of a natural valve; on the other hand, it forms a certain spatial structure that acts as a buffer layer in the in vivo environment, allowing shear and deformation between the inner and outer layers. Furthermore, this intermediate micropattern layer structure can absorb energy during valve compression, reducing valve flutter during forward flow.

[0038] In this technical solution, a biodegradable artificial heart valve with a composite structure can be constructed through electrospinning to form a composite valve with different fiber morphologies and arrangements. The three-layer composite valve structure is similar to the three-layer structure of a natural valve: the upper and lower oriented layers correspond to the fiber layer and ventricular layer, respectively, with the fibers oriented perpendicularly to each other. The middle micropatterned layer corresponds to the sponge layer and acts as a buffer layer in the in vivo environment, allowing shear and deformation between the inner and outer layers. Furthermore, this middle micropatterned layer structure absorbs energy during valve compression, reducing valve flutter during forward flow. The three-layer composite structure, consisting of the upper, lower, and middle micropatterned layers, can be adjusted to adjust the mechanical properties of the valve in various directions by adjusting the thickness of each layer, resulting in mechanical anisotropy that matches the mechanical anisotropy ratio of a natural heart valve, making the entire artificial heart valve more compatible with the human body. Furthermore, the composite artificial heart valve provided by the present invention, in addition to the aforementioned beneficial effects, also features simple and easy processing and low cost, making it suitable for mass production and custom customization.

[0039] It should be noted that the fiber directions of the upper oriented layer and the lower oriented layer in the present invention are perpendicular to each other, and the two oriented layers each contain only one type of oriented fiber. This is similar to the situation in a natural heart valve where the upper fiber layer is mainly composed of collagen fibers (mainly distributed along the circumferential direction), the lower ventricular layer is mainly composed of elastin fibers (mainly distributed along the radial direction), and the fibers of the upper fiber layer and the lower ventricular layer are perpendicular to each other, thereby achieving the bionic purpose of the present invention.

[0040] In some embodiments, the valve is made of a degradable synthetic polymer. Such a degradable synthetic polymer is one or more of polylactic acid (PLA), polycaprolactone (PCL), poly-L-lactide-caprolactone (PLCL), and polyglycolic acid (PGA). In other words, the valve of the present invention can be made of one or more degradable synthetic polymers.

[0041] In some embodiments, the upper and lower oriented layers are prepared using a uniaxial electrospinning process, with a fiber diameter of 0.3-5 μm. The fibers formed in this way have both high flexibility and high strength. The thickness of the upper and lower oriented layers is different, so that the mechanical properties of each layer are different in two different directions, that is, anisotropy is achieved, achieving a design goal similar to that of a natural heart valve. In a specific embodiment, the thickness of the lower oriented layer is 20-80 μm, and the thickness of the upper oriented layer is 2-8 times the thickness of the lower oriented layer, so that its mechanical anisotropy ratio (E) is similar to that of a natural heart valve. 轴向 / E 径向The biodegradable artificial heart valve is made with a simple, easy-to-use uniaxial electrospinning process, resulting in nanofibers with excellent properties such as large surface area and porosity. Furthermore, the surface morphology exhibits advantages such as small pore size, high porosity, fiber uniformity, and good orientation.

[0042] In some embodiments, the thickness of the middle micropatterned layer is 100-150 μm to match the thickness of the sponge layer of a natural heart valve.

[0043] According to an embodiment of the present invention, there is also provided a method for preparing the above-mentioned degradable artificial heart valve having a composite structure, comprising the following steps:

[0044] Preparation of spinning solution: using one or more combinations of degradable synthetic polymer materials (such as polylactic acid (PLA), polycaprolactone (PCL), poly-L-lactide-caprolactone (PLCL), polyglycolic acid (PGA)) as raw materials, and one or more combinations of chloroform, tetrahydrofuran, hexafluoroisopropanol, 2,2,2-trifluoroethanol as solvent to prepare the spinning solution, the concentration of the prepared spinning solution is 5-15wt%, the spinning solution has good spinnability, and it is easy to prepare nanofiber film by electrospinning;

[0045] Preparation of the intermediate micro-pattern layer: The intermediate micro-pattern layer is prepared using a template method, and a metal template with a preset array micro-pattern is used as a collector for electrospinning;

[0046] Preparation of the lower alignment layer: The prepared middle micro-pattern layer is pasted on the receiving roller, and the spinning solution is evenly spun on the receiving roller using a uniaxial electrospinning process;

[0047] Preparation of the upper alignment layer: The prepared intermediate micro-pattern layer and the lower alignment layer are turned over and rotated 90 degrees and pasted on the receiving roller, and the spinning solution is evenly spun on the receiving roller using a uniaxial electrospinning process.

[0048] It should be noted that the present invention first prepares the middle micro-pattern layer and then prepares the lower oriented layer and the upper oriented layer. This is because the middle micro-pattern layer is prepared by a template method. The template is a metal plate with a preset pattern. This plate is flat and cannot be bent. If the upper oriented layer or the lower oriented layer is prepared first, the pattern of the middle micro-pattern layer cannot be printed because the upper oriented layer and the lower oriented layer are collected by rollers.

[0049] In some embodiments,

[0050] The process parameters used in the preparation step of the intermediate micro-pattern layer are: a feed rate of 0.5-2 mL / h, a vertical distance between the nozzle and the receiving plate of 10-15 cm, a 19-25G blunt-tip needle, a voltage of 13-18 kV, an ambient temperature of 25-40°C, and an ambient humidity of less than 45%.

[0051] The process parameters used in the preparation step of the lower alignment layer are as follows: the drum speed of the receiving drum is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving drum is 10-15 cm, the nozzle uses a 19-25G blunt-tip needle, the voltage is 13-18 kV, the ambient temperature is 25-40°C, and the ambient humidity is less than 45%;

[0052] The process parameters used in the preparation step of the upper oriented layer are: the drum speed of the receiving drum is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving drum is 10-15 cm, the nozzle uses a 19-25G blunt needle, the voltage is 13-18 kV, the ambient temperature is 25-40 ° C, and the ambient humidity is less than 45%.

[0053] The above-mentioned preparation parameters can ensure the optimal parameters obtained from experiments to prepare uniform nanofiber morphology. If the parameters are too small or too large, the nanofiber morphology will be uneven or even impossible to spin.

[0054] Metal templates with preset array micropatterns are prepared using screen printing and etching. Compared with other feasible methods such as femtosecond laser and mechanical finishing, this preparation method is fast, efficient, simple and easy.

[0055] In some embodiments, the metal template is prepared using the following steps:

[0056] Engineering drawing: drawing the preset array micro pattern;

[0057] Ink brushing and baking: evenly apply photosensitive ink on the surface of the metal plate, and then bake the plate;

[0058] Exposure and development: Use a metal halide lamp to expose the preset pattern area, and then develop it with a developer;

[0059] Etching: The etching solution is a mixed solution of 10-20% by mass nitric acid, 3.5-5.5% by mass hydrofluoric acid, and the remainder is deionized water. The metal plate after the exposure and development treatment is immersed and pulled at room temperature for 5-10 minutes.

[0060] According to an embodiment of the present invention, there is also provided a degradable artificial heart valve device, which is formed by sewing the aforementioned degradable artificial heart valve with a composite structure into the interior of a valve stent;

[0061] In some embodiments, the biodegradable artificial heart valve device has an in vivo degradation period of 1-3 years;

[0062] In some embodiments, the valve stent is a polyetheretherketone stent or a nickel-titanium alloy stent; and / or the opening size of the valve stent is 17-35 mm; and / or the effective opening area of ​​the degradable artificial heart valve device is 0.70-2.5 cm 2 , reflux ratio ≤20%.

[0063] The present invention is further described below by means of specific experimental examples:

[0064] Example 1

[0065] (1) Spinning solution preparation: 14 wt% polycaprolactone (molecular weight: 80,000) 2,2,2-trifluoroethanol solution was prepared as the spinning solution;

[0066] (2) Preparation of metal template of preset array micro pattern: Preparation is carried out by screen printing and etching method, specifically a. Engineering drawing: Drawing the preset array micro pattern, the micro pattern is a regular hexagon, such as Figure 2 As shown in (a), the diameter of the inscribed circle of the regular hexagon is 1.0 mm; b. Ink brushing and baking: evenly apply photosensitive ink on the surface of the Ti-6Al-4V metal plate, and then bake the plate; c. Exposure and development: use a metal halide lamp to expose the preset pattern area, and then develop it with a developer; d. Etching: At room temperature, the Ti-6Al-4V plate after exposure and development is immersed in a mixed solution of 10% nitric acid, 3.5% hydrofluoric acid, and the rest deionized water for 5 minutes. Figure 3 Shown is the laser confocal topography image of a regular hexagonal pattern machined on the surface of a Ti-6Al-4V metal plate;

[0067] (3) Preparation of the intermediate micro-pattern layer: The metal template prepared in step (2) was used as a collector for electrospinning. The feed rate was 1 mL / h, the vertical distance between the nozzle and the receiving plate was 15 cm, the nozzle used a 19G blunt-tip needle, and the voltage was 15 kV. The ambient temperature was 30°C, the ambient humidity was less than 45%, and an intermediate micro-pattern layer with a thickness of about 150 μm was prepared. Figure 4 (a-b) show the SEM images of the hexagonal middle micro-pattern layer;

[0068] (4) Preparation of lower alignment layer: The intermediate micro-pattern layer prepared in step (3) was pasted onto a receiving roller, and the solution was evenly spun onto the receiving roller using a uniaxial electrospinning process at a roller speed of 2000 rpm. The feed rate was 1 mL / h, the vertical distance between the nozzle and the receiving roller was 15 cm, the nozzle used a 19G blunt-tip needle, and the voltage was 15 kV. The ambient temperature was 30°C, the ambient humidity was less than 45%, and an intermediate micro-pattern layer with a thickness of about 50 μm was prepared. Figure 4 As shown in Figure (c), the fibers are arranged along the directional direction, as shown in Figure 4 (d) As shown in the figure, the fiber diameter is 2.014 ± 0.930 μm;

[0069] (5) Preparation of the upper alignment layer: The intermediate micro-pattern layer + lower alignment layer prepared in step (4) were flipped over and rotated 90°, and then attached to a receiving roller. The solution was evenly spun onto the receiving roller using a uniaxial electrospinning process at a roller speed of 2000 rpm. The feed rate was 1 mL / h, the vertical distance between the nozzle and the receiving roller was 15 cm, the nozzle used a 19G blunt-tip needle, and the voltage was 15 kV. The ambient temperature was 30°C, and the ambient humidity was less than 45%. An upper alignment layer with a thickness of approximately 100 μm (twice the thickness of the lower alignment layer) was prepared.

[0070] In order to demonstrate that the mechanical properties of the embodiments of the present invention are comparable to those of natural heart valves, the three-layer composite structure material prepared in Example 1 is subjected to static / dynamic mechanical testing. The control example is a material with a single structure prepared by polycaprolactone (molecular weight: 80,000) using the same electrospinning parameters. Specifically, a flat plate is used as the collector, the feed rate is 1 mL / h, the vertical distance between the nozzle and the receiver is 15 cm, the nozzle uses a 19G blunt needle, the voltage is 15 kV, the ambient temperature is 30°C, and the ambient humidity is less than 45%. Finally, a single structure material with a thickness of 300 μm is prepared (equivalent to the total thickness of the material prepared in Example 1).

[0071] The static mechanical properties of the material were evaluated by using a strip sample with a size of 20×5mm and a gauge length of 10mm, and performing three repeated tensile tests in each direction at a tensile speed of 0.02mm / s. Figure 5 As shown in (a) and (d), the control sample has no mechanical anisotropy and the elastic modulus is 12.67±1.46MPa; Figure 5 As shown in (bd), the elastic modulus of the three-layer composite structure material prepared in Example 1 along the fiber direction of the lower oriented layer is 19.46±0.43 MPa, and the elastic modulus along the fiber direction of the upper oriented layer is 38.10±0.45 MPa. The anisotropy ratio is about 1.96, which is comparable to that of a natural valve.

[0072] Similarly, a strip sample with a size of 20×5mm and a gauge length of 10mm was used to stretch the sample with a sinusoidal wave with a maximum strain of 30% at a frequency of 1-5Hz, and the test was repeated 3 times in each direction to evaluate the dynamic mechanical properties of the material. Figure 6 As shown in (a) and (d), at 1 Hz (the approximate value of the human heart rate), the storage modulus of the control sample has no mechanical anisotropy and is 11.23 ± 1.16 MPa; Figure 6 As shown in (bd), the three-layer composite structure material prepared in Example 1 has a storage modulus of 25.34±5.93 MPa along the fiber direction of the lower oriented layer, and a storage modulus of 52.57±2.95 MPa along the fiber direction of the upper oriented layer. The anisotropy ratio is about 2.07, which is comparable to that of a natural valve.

[0073] Figure 7 This is a physical photo of the degradable artificial heart valve device prepared in Example 1 of the present invention; Figure 8 The hydrodynamic test curve of the degradable artificial heart valve device prepared for Example 1 of the present invention was calculated. The reflux ratio of the degradable artificial heart valve device of the present invention was 9.6%, and the effective opening area was 1.8 cm 2 The results show that it has low energy loss, and the regurgitation ratio and effective opening area of ​​the valve meet the requirements of ISO 5840-2 standard (for surgical valves with a diameter of 25 mm, the effective opening area is ≥1.45 cm 2 and reflux ratio ≤15%).

[0074] Example 2

[0075] (1) Spinning solution preparation: 13 wt% polyglycolide-caprolactone (PGCL) hexafluoroisopropanol solution was prepared as the spinning solution;

[0076] (2) Preparation of metal template of preset array micro pattern: Preparation is carried out by screen printing and etching method, specifically a. Engineering drawing: Drawing the preset array micro pattern, the micro pattern is an equilateral triangle, such as Figure 2 (b) shows that the inscribed circle of the equilateral triangle has a diameter of 0.5 mm. b. Ink brushing and baking: The surface of the Ti metal plate is evenly coated with photosensitive ink, followed by baking. c. Exposure and development: The preset pattern area is exposed using a metal halide lamp, followed by development using a developer. d. Etching: The Ti plate after exposure and development is dipped and pulled using a mixed solution of 15% by mass nitric acid, 4% by mass hydrofluoric acid, and the remainder deionized water at room temperature for 8 minutes.

[0077] (3) Preparation of the intermediate micro-pattern layer: Electrospinning was performed using the metal template prepared in step (2) as a collector. The feed rate was 0.8 mL / h, the vertical distance between the nozzle and the receiving plate was 10 cm, the nozzle used a 21G blunt-tip needle, and the voltage was 13 kV. The ambient temperature was 25°C and the ambient humidity was less than 45%. An intermediate micro-pattern layer with a thickness of approximately 120 μm was prepared.

[0078] (4) Preparation of the lower alignment layer: The intermediate micro-pattern layer prepared in step (3) was pasted onto a receiving roller, and the solution was evenly spun onto the receiving roller using a uniaxial electrospinning process. The roller speed was 1000 rpm, the feed rate was 0.8 mL / h, the vertical distance between the nozzle and the receiving plate was 10 cm, the nozzle used a 21G blunt-tip needle, and the voltage was 13 kV. The ambient temperature was 25°C, the ambient humidity was less than 45%, and an intermediate micro-pattern layer with a thickness of approximately 40 μm was prepared.

[0079] (5) Preparation of the upper oriented layer: The intermediate micro-pattern layer + the lower oriented layer prepared in step (4) were turned over and rotated 90° and pasted on the receiving roller. The solution was evenly spun on the receiving roller using a uniaxial electrospinning process. The roller speed was 1000 rpm, the feeding rate was 0.8 mL / h, the vertical distance between the nozzle and the receiving plate was 10 cm, the nozzle used a 21G blunt needle, and the voltage was 13 kV. The ambient temperature was 25°C, the ambient humidity was less than 45%, and an upper oriented layer with a thickness of about 120 μm was prepared (the thickness was 3 times that of the lower oriented layer).

[0080] Example 3

[0081] (1) Spinning solution preparation: 15 wt% poly (L-lactide-caprolactone) (PLCL) hexafluoroisopropanol solution was prepared as the spinning solution;

[0082] (2) Preparation of metal templates for preset array micropatterns: Preparation is performed using a screen printing and etching method, specifically: a. Engineering drawing: Drawing the preset array micropattern, the micropattern is a regular quadrilateral, and the inscribed circle diameter of the regular quadrilateral is 1.2 mm; b. Ink brushing and baking: Evenly apply photosensitive ink on the surface of the NiTi metal plate, and then bake the plate; c. Exposure and development: Expose the preset pattern area with a metal halide lamp, and then develop it with a developer; d. Etching: At room temperature, the NiTi plate after exposure and development is immersed and pulled with a mixed solution of 10% by mass nitric acid, 4.5% by mass hydrofluoric acid, and the rest deionized water for 10 minutes;

[0083] (3) Preparation of the intermediate micro-pattern layer: Electrospinning was performed using the metal template prepared in step (2) as a collector. The feed rate was 1.5 mL / h, the vertical distance between the nozzle and the receiving plate was 13 cm, the nozzle used a 20G blunt-tip needle, and the voltage was 18 kV. The ambient temperature was 40°C and the ambient humidity was less than 45%. An intermediate micro-pattern layer with a thickness of approximately 120 μm was prepared.

[0084] (4) Preparation of the lower alignment layer: The intermediate micro-pattern layer prepared in step (3) was pasted onto a receiving roller, and the solution was evenly spun onto the receiving roller using a uniaxial electrospinning process. The roller speed was 1500 rpm, the feed rate was 1.5 mL / h, the vertical distance between the nozzle and the receiving plate was 13 cm, the nozzle used a 20G blunt-tip needle, and the voltage was 18 kV. The ambient temperature was 40°C, the ambient humidity was less than 45%, and an intermediate micro-pattern layer with a thickness of approximately 30 μm was prepared.

[0085] (5) Preparation of the upper oriented layer: The intermediate micro-pattern layer + the lower oriented layer prepared in step (4) were turned over and rotated 90° and pasted on the receiving roller. The solution was evenly spun on the receiving roller using a uniaxial electrospinning process. The roller speed was 1500 rpm, the feeding rate was 1.5 mL / h, the vertical distance between the nozzle and the receiving plate was 13 cm, the nozzle used a 20G blunt needle, and the voltage was 18 kV; wherein the ambient temperature was 40°C and the ambient humidity was less than 45%, and an upper oriented layer with a thickness of about 120 μm was prepared (the thickness was 4 times that of the lower oriented layer).

[0086] It is easy for those skilled in the art to understand that, under the premise of no conflict, the advantageous technical features of the above-mentioned methods can be freely combined and superimposed.

[0087] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention. The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art may make various improvements and variations without departing from the technical principles of the present invention, and such improvements and variations shall also be considered within the scope of protection of the present invention.

Claims

1. A degradable artificial heart valve with a composite structure, characterized in that: The valve includes an upper oriented layer, a lower oriented layer, and an intermediate micro-pattern layer located between the upper oriented layer and the lower oriented layer, wherein the upper oriented layer and the lower oriented layer are fiber oriented arrangement layers with anisotropic mechanical properties, and the fiber directions of the upper oriented layer and the lower oriented layer are perpendicular to each other, and the intermediate micro-pattern layer is a polymer film layer with a preset array micro-pattern; the preset array micro-pattern is composed of one or more regular polygonal patterns, and the diameter of the inscribed circle of the regular polygon is 0.3-1.5 mm.

2. The degradable artificial heart valve with a composite structure according to claim 1, characterized in that: The material of the valve is a degradable synthetic polymer material; and / or, the upper oriented layer and the lower oriented layer are prepared by a uniaxial electrospinning process, and the fiber diameter is 0.3-5 μm; wherein, the thickness of the upper oriented layer and the lower oriented layer are different; and / or, the degradable synthetic polymer material is one or more of polylactic acid, polycaprolactone, poly L-lactide-caprolactone, and polyglycolic acid.

3. The degradable artificial heart valve with a composite structure according to claim 2, characterized in that: The thickness of the lower alignment layer is 20-80 μm, and the thickness of the upper alignment layer is 2-8 times the thickness of the lower alignment layer.

4. The degradable artificial heart valve with a composite structure according to claim 1, characterized in that: The thickness of the intermediate micro-pattern layer is 100-150 μm.

5. The degradable artificial heart valve with a composite structure according to claim 4, characterized in that: In the preset array pattern, each regular polygon has a common side with its adjacent regular polygons.

6. A method for preparing a degradable artificial heart valve with a composite structure according to any one of claims 1 to 5, characterized in that: The steps include: Preparation of spinning solution: using one or more combinations of degradable synthetic polymer materials as raw materials and one or more combinations of chloroform, tetrahydrofuran, hexafluoroisopropanol, and 2,2,2-trifluoroethanol as solvents to prepare a spinning solution, wherein the concentration of the prepared spinning solution is 5-15 wt%; Preparation of the intermediate micro-pattern layer: The intermediate micro-pattern layer is prepared using a template method, and a metal template with a preset array of micro-patterns is used as a collector for electrospinning; Preparation of the lower alignment layer: pasting the prepared intermediate micro-pattern layer on a receiving roller, and using a uniaxial electrospinning process to evenly spin the spinning solution on the receiving roller; Preparation of the upper alignment layer: The prepared intermediate micro-pattern layer and the lower alignment layer are turned over and rotated 90 degrees to be pasted on the receiving roller, and the spinning solution is evenly spun on the receiving roller using a uniaxial electrospinning process.

7. The preparation method according to claim 6, characterized in that The process parameters used in the intermediate micro-pattern layer preparation step are: a feed rate of 0.5-2 mL / h, a vertical distance between the nozzle and the receiving plate of 10-15 cm, a 19-25G blunt-tip needle, a voltage of 13-18 kV, an ambient temperature of 25-40° C., and an ambient humidity of less than 45%; The process parameters used in the lower alignment layer preparation step are as follows: the roller speed of the receiving roller is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving roller is 10-15 cm, the nozzle uses a 19-25G blunt-tip needle, the voltage is 13-18 kV, the ambient temperature is 25-40° C., and the ambient humidity is less than 45%; The process parameters used in the upper oriented layer preparation step are: the roller speed of the receiving roller is 500-3000 rpm, the feeding rate is 0.5-2 mL / h, the vertical distance between the nozzle and the receiving roller is 10-15 cm, the nozzle uses a 19-25G blunt needle, the voltage is 13-18 kV, the ambient temperature is 25-40 ° C, and the ambient humidity is less than 45%.

8. The preparation method according to claim 6, characterized in that The metal template with the preset array micro-pattern is prepared by screen printing and etching; the preparation of the metal template adopts the following steps: Engineering drawing: drawing the preset array micro pattern; Ink brushing and baking: evenly apply photosensitive ink on the surface of the metal plate, and then bake the plate; Exposure and development: Use a metal halide lamp to expose the preset pattern area, and then develop it with a developer; Etching: The etching solution is a mixed solution of 10-20% by mass nitric acid, 3.5-5.5% by mass hydrofluoric acid, and the remainder is deionized water. The metal plate after the exposure and development treatment is immersed and pulled at room temperature for 5-10 minutes.

9. A degradable artificial heart valve device, characterized in that: The degradable artificial heart valve device is prepared by the preparation method described in claims 6-8, and a degradable artificial heart valve with a composite structure is sewn into the interior of a valve stent, wherein the in vivo degradation period of the degradable artificial heart valve device is 1-3 years.

10. The degradable artificial heart valve device according to claim 9, characterized in that: The valve stent is a polyetheretherketone stent or a nickel-titanium alloy stent; and / or, The opening size of the valve stent is 17-35 mm; and / or, The effective opening area of ​​the degradable artificial heart valve device is 0.70-2.5 cm 2 , reflux ratio ≤20%.

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