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CN118079080A - Preparation method of polymer valve leaflet material, polymer valve leaflet and artificial valve - Google Patents

Preparation method of polymer valve leaflet material, polymer valve leaflet and artificial valve
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Publication number
CN118079080A
CN118079080ACN202211491916.2ACN202211491916ACN118079080ACN 118079080 ACN118079080 ACN 118079080ACN 202211491916 ACN202211491916 ACN 202211491916ACN 118079080 ACN118079080 ACN 118079080A
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solvent
polymer
polyurethane
drying
solution
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王立超
卫星
邝大军
朱雨婷
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Hangzhou Qiming Medical Devices Co ltd
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Hangzhou Qiming Medical Devices Co ltd
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Priority to CN202211491916.2ApriorityCriticalpatent/CN118079080A/en
Priority to PCT/CN2023/112856prioritypatent/WO2024109180A1/en
Publication of CN118079080ApublicationCriticalpatent/CN118079080A/en
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Abstract

The application discloses a preparation method of a polymer valve leaflet material, a polymer valve leaflet and a prosthetic valve, wherein the preparation method of the polymer valve leaflet material comprises the following steps: step 1, impregnating a reinforcing material with a first polymer solution, and drying to obtain an initial pre-fixed polymer membrane; step 2, infiltrating the polymer membrane with a second polymer solution, and drying; the mass fraction of the second polymer solution is not higher than that of the first polymer solution, and the second polymer solution is a mixed solvent which comprises a first solvent and a second solvent which are mutually soluble, wherein the first solvent is a good solvent of a solute, and the second solvent is a poor solvent of the solute; and 3, repeating the step 2 until the surface of the reinforcing material is completely covered by the polymer, and obtaining the flat ultrathin polymer leaflet material. The polymer valve blade material is ultrathin and smooth, uniform in thickness and good in flexibility.

Description

Preparation method of polymer valve leaflet material, polymer valve leaflet and artificial valve
Technical Field
The application relates to the technical field of medical materials, in particular to a preparation method of a polymer valve leaflet material, a polymer valve leaflet and a prosthetic valve.
Background
Currently, prosthetic heart valves are gaining extensive attention and research as products for treating heart valve diseases. The artificial heart valve is divided into an aortic valve, a pulmonary valve, a mitral valve, a tricuspid valve and the like according to the action parts, and can replace the action of a natural heart valve to control the unidirectional flow of blood, thereby realizing the normal movement of heart organs of a human body.
Common artificial heart valves are mainly classified into mechanical valves, biological valves and polymer valves according to the types of leaflet materials. Firstly, the mechanical valve has long service life, but is mainly implanted in a surgical mode to cause great damage to human body, and meanwhile, the biocompatibility is poor, so that long-term anticoagulation is required to be taken to cause complications; the biological valve is widely used at present, has small damage to human body, but has the problems of short service life and poor tolerance. Therefore, in recent years, research on polymer valves has been paid much attention, mainly because the properties of the polymer materials themselves make them have better biocompatibility, longer service life, better flexibility and flexibility to obtain good hydrodynamic properties.
For example, the currently widely used polymeric leaflet materials are mainly polyurethanes, polyolefins, polysiloxanes, etc., which have been used in large quantities for the preparation of implantable medical devices and proved to have excellent high elasticity, good biocompatibility and flexibility. Meanwhile, compared with the biological membrane, the high molecular valve leaf has the advantages of simple processing technology, uniform thickness and performance and the like in batch production. In order to meet better strength and performance, polymers on the market at present are generally reinforced by adopting fabrics, so that the performance of the membrane can be effectively improved, and the strength and creep resistance of the valve leaflet are improved on the premise of not sacrificing the softness of the membrane.
Along with the continuous research of the preparation method of the polymer valve leaflet, the problems of uneven valve preparation, uneven thickness and excessive thick membrane in the process of reinforcing the polymer by adopting the fabric are also exposed, and the preparation method is specifically:
(1) The use of conventional extrusion compounding processes, which employ high temperatures, can cause yellowing of the polyurethane, lower molecular weight, poorer mechanical properties, and simultaneously cause degradation and increased cytotoxicity.
(2) When polyurethane is poured on the fabric, if the thickness of the poured material is too thick, the bending rigidity is larger, the softness is reduced, and the polyurethane cannot be completely compressed and loaded in the interventional instrument; if the thickness of the poured material is too thin, the surface of the fabric cannot be well covered, the fabric is easy to float on the final surface of the polyurethane surface to form fabric lines, thrombus calcification and the like are easy to form, meanwhile, the polyurethane is unevenly distributed on the two surfaces of the fabric, the polyurethane content on the upper surface is less, the interface bonding is unstable, and uneven microcrack stress points of the valve leaflet are increased, so that the fatigue resistance and the service life of the valve leaflet are reduced.
(3) When polyurethane is poured on the fabric, as the solvent volatilizes to gradually float the fabric in the polyurethane layer, the fabric is difficult to control at the position in the middle of the polyurethane, the fabric is easy to be thicker at one side and the fabric lines are not fully covered at the other side, so that the method is difficult to accurately and stably obtain the membrane surface with the fabric in the middle of the polyurethane layer, two sides of the membrane are smooth, the interface bonding degree is good, the uneven membrane surface of the macromolecular valve blade with less microcrack quantity can increase microcrack stress points on the surface of the valve blade, the parts of weaker stress points are damaged at first, and then the integral damage of the valve blade is caused, and the fatigue resistance is reduced.
Disclosure of Invention
Based on the method, the preparation method of the high-molecular valve leaflet material can obtain the high-molecular valve leaflet material which is flat, uniform in thickness, good in flexibility and ultrathin.
A preparation method of a high molecular leaflet material comprises the following steps:
Step 1, infiltrating a reinforcing material with a first polymer solution in a die, and then drying to obtain an initial pre-fixed polymer membrane;
Step 2, infiltrating the polymer membrane with a second polymer solution, and drying;
The mass fraction of the second polymer solution is not higher than that of the first polymer solution, and the second polymer solution is a mixed solvent which comprises a first solvent and a second solvent which are mutually soluble, wherein the first solvent is a good solvent of a solute, and the second solvent is a poor solvent of the solute;
and 3, repeating the step 2 until the surface of the reinforcing material is completely covered by the polymer, and obtaining the flat ultrathin polymer leaflet material.
In step 2, the mass fraction of the second polymer solution (i.e., the mass fraction of the solute/(solute+first solvent)) is greater than the mass fraction of the first polymer solution, and is close to the saturated mass fraction of the solute in the first solvent.
The following provides several alternatives, but not as additional limitations to the above-described overall scheme, and only further additions or preferences, each of which may be individually combined for the above-described overall scheme, or may be combined among multiple alternatives, without technical or logical contradictions.
Optionally, a pretreatment step is further included before step 1, the pretreatment step including flattening the sheet-like reinforcing material and heating the pre-form.
Optionally, the thickness of the reinforcing material is 0.06-0.11 mm.
Optionally, the reinforcing material is in a fabric form, and the raw material is one of terylene, aramid fiber, chinlon, silk, polyurethane and polyolefin.
Optionally, the tensile strength of the fabric is more than or equal to 40MPa, and the tearing strength is more than or equal to 80N/mm.
Optionally, the solute of the first polymer solution is polyurethane, and the solvent is at least one of N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, N-dimethylpropionamide and N, N' -dimethylacrylamide.
Optionally, the mass fraction of the first polymer solution is 1% -20%.
Optionally, in the second polymer solution, the solubility of the solute in the first solvent is greater than 1.5g/100g, and the solubility of the solute in the second solvent is less than 0.5g/100g.
Optionally, the solute of the second polymer solution is polyurethane, the boiling point of the second solvent is lower than that of the first solvent, and the boiling point of the second solvent is not lower than 40 ℃.
Optionally, the volume ratio of the first solvent to the second solvent is 1:0.5 to 8.
Optionally, the first solvent is at least one of N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, N-dimethylpropionamide, N' -dimethylacrylamide, and the second solvent is at least one of ethyl acetate, acetone, toluene, and isopropanol.
Optionally, the mass fraction of the second polymer solution is 0.5% -10%.
Optionally, in step 1, the drying mode is drying, the drying temperature is 60-80 ℃, and the drying time is 10-60 min.
Optionally, in the step 2, the drying mode is drying, the drying temperature is 5-50 ℃ lower than the boiling point of the second solvent, and the drying time is 30-180 min.
Optionally, in the step 2, the drying mode is drying, the drying temperature is 40-80 ℃, and the drying time is 60-120 min.
The application also provides a polymer valve leaflet, which is obtained by cutting the polymer valve leaflet material prepared by the preparation method according to a preset shape, wherein the thickness of the polymer valve leaflet is 0.12-0.2 mm.
The present application also provides a prosthetic valve comprising:
A blood flow channel is arranged in the bracket;
The valve comprises one or more valve leaves, wherein the valve leaves adopt the valve leaves, the edge parts of the valve leaves comprise opposite free edges and fixed edges, the fixed edges of the valve leaves are fixed with a bracket, and the free edges of the valve leaves are matched with the inner wall of the bracket or the free edges of the valve leaves to control a blood flow channel.
The prepared high molecular valve leaflet material can realize the expected strength, flatness, softness and ultrathin thickness, the surface of the reinforcing material is completely covered by the high polymer, better flatness can be realized, the softness of the membrane is not sacrificed while the reinforcement of the valve leaflet is realized, the full combination of the high polymer and the interface of the reinforcing material is realized, and the ultrathin reinforced high molecular valve with better overall mechanical property is obtained.
Drawings
FIG. 1 is a schematic view of a mold;
FIG. 2a is a SEM schematic of a cross-section of a polymeric leaflet prepared in comparative example 1;
FIG. 2b is a SEM schematic of the upper surface of a polymeric leaflet prepared in comparative example 1;
FIG. 2c is a SEM schematic of the lower surface of a polymeric leaflet prepared in comparative example 1;
FIG. 3a is a SEM schematic of a cross-section of a polymeric leaflet prepared in example 1;
FIG. 3b is a SEM schematic of the upper surface of a polymeric leaflet prepared in example 1;
Fig. 3c is an SEM schematic of the lower surface of the polymeric leaflet prepared in example 1.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
For a better description and illustration of embodiments of the application, reference should be made to one or more of the accompanying drawings, but the additional details or examples used to describe the drawings should not be construed as limiting the scope of any of the inventive, presently described embodiments or preferred modes of carrying out the application.
It will be understood that when an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present. When an element is referred to as being "disposed on" another element, it can be directly on the other element or intervening elements may also be present.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
A preparation method of a high molecular leaflet material comprises the following steps:
Step 1, impregnating a reinforcing material with a first polymer solution, and then drying to obtain an initial pre-fixed polymer membrane;
step 2, infiltrating the polymer membrane with a second polymer solution, and drying;
The mass fraction of the second polymer solution is not higher than that of the first polymer solution, and the second polymer solution is a mixed solvent which comprises a first solvent and a second solvent which are mutually soluble, wherein the first solvent is a good solvent of a solute, and the second solvent is a poor solvent of the solute;
And step3, repeating the step 2 until the surface of the reinforcing material is completely covered by the polymer, and obtaining the flat ultrathin polymer leaflet material.
The flat and ultrathin high-molecular valve leaflet material is prepared by the method, wherein the surfaces of both sides of the valve leaflet material are planes formed by the high-molecular material, at least no reinforcing material is exposed on the surface of the valve leaflet material, and the flat and ultrathin high-molecular valve leaflet material has uniform thickness and no warpage and wrinkles and is a sheet-shaped material which can be well attached to the planes. The ultra-thin polymer valve leaflet material has a thickness of not more than 0.2mm (the thickness of the reinforcing material is 0.06-0.11 mm), and is usually between 0.12mm and 0.2mm (the thickness difference between the reinforcing material and the polymer valve material is 0.06-0.09 mm).
The reinforcing material is kept as flat as possible before step 1, and can be flattened after cutting based on the material characteristics of the reinforcing material itself, in order to further consolidate this flattened state, ready for the subsequent step, a pretreatment step may be added before step 1, which comprises flattening the sheet-like reinforcing material and heating the preformed shape.
In the pretreatment step, because the reinforcing material is a flexible sheet material, possible warpage or wrinkles are eliminated through flattening and presetting, so that the edge of the reinforcing material is flattened, and the whole body is kept in a flattened state so as to be prepared for the subsequent process.
In step 1, the main purpose of preparing the initial pre-fixed polymer membrane is to primarily fix the flattened form of the reinforcing material, so as to prevent edge warpage and integral deflection in the process. Meanwhile, the infiltrated first polymer solution can effectively enable the reinforcing material to be flatly attached to the bottom of the die, and through drying and shaping, the reinforcing material can be effectively fixed at a rough position (namely, the reinforcing material is positioned in the first polymer solidified after drying) and keeps a corresponding form (such as curling and tilting of the reinforcing material), and the first polymer solution not only meets the leveling requirement, but also does not adversely affect the flattening form of the reinforcing material. And meanwhile, the basic thickness of one side of the polymer membrane close to the die is basically fixed, so that the reinforcing material is positioned in the middle position of the thickness of the polymer valve blade material through repeated infiltration adjustment in the later stage.
In the step 2, the mass fraction concentration of the second polymer solution is not greater than that of the first polymer solution, and the solvent of the second polymer solution is not a single good solvent with better solubility selected conventionally, but is a mixed solvent with mutual solubility, and the design of the mixed solvent comprises a first solvent and a second solvent, wherein the first solvent is a good solvent of a solute, the second solvent is a poor solvent of the solute, and the first solvent and the second solvent have obvious performance differences.
Optionally, the good solvent used as the first solvent is a solvent with a higher melting boiling point and a relatively higher polarity, the poor solvent used as the second solvent is an organic reagent with a lower melting boiling point, and is relatively volatile and lower in polarity, the addition of the second solvent does not influence the solubility of the solute in the first solvent, the generation of bubbles is reduced, meanwhile, the viscosity of the second polymer solution is effectively reduced, and the second polymer solution is favorable for fully leveling and filling gaps and lines of the reinforcing material under lower viscosity so as to obtain better ductility and flatness.
In the step 2, the second solvent volatilizes before the first solvent, and in the process of volatilizing the second solvent, the solute mass fraction of the second polymer solution is gradually increased, the viscosity of the second polymer solution is gradually increased, the fluidity is deteriorated, and the film is gradually dried. In this process, it is necessary to strictly control the ratio of the first solvent and the second solvent to control the gradient volatilization rate of the mixed solvent. In order to ensure that the second polymer solution does not dissolve the membrane after the previous drying and curing, the solute/(the first solvent+solute) in the second polymer solution is higher than the solute/(the solvent+solute) in the first polymer solution, and is close to the solubility of the solute in the first solvent, so that the viscosity of the second polymer solution is relatively viscous and cannot be leveled under the condition that the second solvent is not added, at the moment, if the proportion of the first solvent is too high, the viscosity of the second polymer solution cannot be effectively reduced, so that the solution is difficult to level, the surface thickness of the reinforced material is uneven, and if the proportion of the second solvent is too high, a large number of pores are formed in the second polymer by the second solvent, and the first solvent does not have enough time to fill the pores, so that a large number of pore structures are easy to form. Similarly, too fast a volatilization rate will form a similar effect, while too slow a volatilization rate will cause the solution to absorb water vapor in the air, thereby forming bubbles on the surface of the polyurethane (i.e. the solute of the second polymer solution) due to water evaporation.
In step 2, the polymer membrane is infiltrated with a second polymer solution, and dried, and the solute is dissolved in the second polymer solution by adopting a mixed solvent, wherein the mixed solvent comprises: the first solvent serving as the good solute solvent and the second solvent serving as the poor solute solvent can reduce the viscosity of the second polymer solution in the dip-coating process to ensure the leveling of the solution, ensure the uniform distribution of the solute on the surface of the reinforced material, and simultaneously prevent the membrane after the previous drying and solidification from being rapidly redissolved by the good solvent.
The use of the mixed solvent in the second polymer solution in the step 2 ensures that the solute keeps the fluidity required by leveling while approaching the solubility of the mixed solvent, and new polymers can be gradually deposited according to dip-coating times while avoiding the re-dissolution of the membrane after the previous drying and solidification, so that the thickness of the material is gradually increased and lines and gaps of the reinforcing material are covered on the basis of the polymer membrane prepared in the step 1.
Since the surface of the reinforcing material (usually fabric) has a large number of concave-convex undulations (the concave-convex undulations depend on the knitting structure of the reinforcing material, in general, the places where the knitting material is located correspond to the protrusions, and the places where the knitting material is adjacent form the depressions), the distribution of the leveling polyurethane (solute in the second polymer solution) on the surface of the uneven fabric is uneven, more polyurethane solution is accumulated in the pits, and the number of the convex points is relatively small. The uneven fabric lines are again displayed on the leveling surface due to different solvent volatilization amounts at different positions, more polyurethane is deposited on concave points, a relatively small amount of polyurethane is deposited on convex points, the degree of uneven fluctuation is reduced, and the uneven fluctuation on the fabric surface is almost smoothed after repeated infiltration and drying, so that the leaflet material with even two surfaces (without uneven fluctuation) is finally formed.
According to the preparation method of the polymer leaflet material, the form of the reinforcing material is fixed through the step 1, and then the small increment of the thickness of the membrane is realized each time through the operation of the step 2, so that the final thickness of the membrane can be effectively controlled, and the expected strength, flatness, softness and ultrathin thickness are realized. The surface of the reinforcing material is completely covered by the polymer, so that better flatness can be realized, the soft degree of the diaphragm is not reduced while the reinforcement of the valve leaf is realized, and the full combination of the interface is realized, thereby obtaining the ultrathin reinforced polymer valve with better overall mechanical property.
The thickness of the reinforcing material is 0.06-0.11 mm.
Too small a thickness of the reinforcing material may result in insufficient strength, failing to meet the strength requirement as a leaflet, too large a thickness of the reinforcing material may lose compression performance, and is not easily loaded in an interventional instrument.
The reinforcing material is in the form of fabric, and the raw material is at least one of terylene, aramid fiber, chinlon, silk, polyurethane and polyolefin. The reinforcing material is in a fabric form, the surface of the fabric is provided with an uneven structure, and solutes of the first polymer solution and the second polymer solution are deposited in the uneven structure. The reinforcing material in the form of a fabric has voids, the porosity of the fabric being 30-80%, i.e. depressions in the surface of the fabric.
The knitting form of the fabric is not limited, and for example, a nonwoven fabric or a knitted fabric may be used. The fabric is of a knitting structure, and the raw material of the fabric is terylene or chinlon. The fabric is used for increasing the polymer material and needs to have proper strength, and generally, the tensile strength of the fabric is more than or equal to 40MPa, and the tearing strength of the fabric is more than or equal to 80N/mm.
The reinforcing material has anisotropy and elasticity in a direction perpendicular to the free edge. The reinforcement material is resilient in a direction perpendicular to the free edge, which feature facilitates leaflet opening and closing during actual use.
The solute of the first polymer solution is polyurethane, and the solvent is at least one of N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, N-dimethylpropionamide and N, N' -dimethylacrylamide.
The solvent of the first high polymer solution is a good solvent of polyurethane, the mass fraction of the first high polymer solution is too high, the viscosity is too high, the leveling is not easy, and the polyurethane layer on one side of the reinforcing material is too thick after the drying, so that the final valve leaflet material is too thick; the mass fraction of the first polymer solution is too low, and although the first polymer solution is easy to level, the polyurethane layer on one side of the reinforcing material close to the die after drying is too thin, so that the edge is easy to warp, the effect of fixing the flattened form of the reinforcing material cannot be achieved, and in the step 2, the too thin polyurethane layer is easy to be excessively dissolved, the presetting of the reinforcing material cannot be achieved, and the reinforcing material cannot be effectively fixed on a grinding tool to prevent floating. Therefore, the mass fraction of the first polymer solution needs to be appropriate.
The first polymer solution needs to have a proper mass fraction, and an excessive mass fraction may result in a thicker polymer membrane material, failing to meet the use requirement, and an insufficient mass fraction may not provide a sufficient solute layer to fix the morphology of the reinforcing material, preferably, the mass fraction of the first polymer solution is 1% -20%. More preferably, the mass fraction of the first polymer solution is 1% to 10%. More preferably, the mass fraction of the first polymer solution is 5% to 10%.
In the second polymer solution, the solubility of the solute in the first solvent is more than 1.5g/100g (solvent), and the solubility of the solute in the second solvent is less than 0.5g/100g (solvent).
The first solvent in the second polymer solution is the same as or different from the solvent of the first polymer solution. The solvent of the second polymer solution includes a first solvent and a second solvent, and the first solvent and the first polymer solution are not related.
When preparing the second polymer solution, firstly dissolving polyurethane in a first solvent to obtain a solution with the mass fraction of 1.5% -30%, and then mixing the solution with the second solvent to obtain the second polymer solution with the mass fraction of 0.5% -9.9%.
The solute of the second polymer solution is polyurethane, the boiling point of the second solvent is lower than that of the first solvent, and the boiling point of the second solvent is not lower than 40 ℃.
The first solvent and the second solvent can be completely miscible, and the first solvent and the second solvent can not cause precipitation of polyurethane polymer after being miscible. Further preferably, the boiling point of the second solvent is not lower than 50 ℃. The boiling point of the second solvent is far lower than that of the first solvent, when drying is carried out, the second solvent volatilizes in preference to the first solvent, otherwise, the first solvent volatilizes first to cause partial polyurethane precipitation, the film thickness is uneven, the boiling point of the second solvent is not lower than 50 ℃, otherwise, the second solvent volatilizes too fast, the first solvent does not have enough time to fill the position of the second solvent, and therefore a large number of void structures are formed, and the mechanical property and the surface flatness of the membrane are affected.
The first solvent and the second solvent need to have a proper volume ratio to satisfy the use requirement, and preferably, the volume ratio of the first solvent to the second solvent is 1:0.5 to 8. Further preferably, the volume ratio of the first solvent to the second solvent is 1:3 to 8.
The volume of the second solvent is much larger than that of the first solvent, and the solubility of polyurethane, the leveling property of the second polymer solution and the first solvent are required to be considered simultaneously when the volume ratio of the first solvent to the second solvent is selected.
When the first solvent is only used, if the mass fraction of polyurethane is too high, the viscosity is too high, the leveling is difficult, if the solution dosage required by the leveling is met, the thickness of the formed membrane is too thick, if the mass fraction of polyurethane is too low, the cured polyurethane membrane is easily leveled, but the first solvent can dissolve the cured polyurethane membrane, so that the fabric loses fixation and floats on the surface of the membrane, and by adding the second solvent, the viscosity of the solution can be reduced while the dissolving capacity of the polyurethane is not increased, and the leveling is realized.
The first solvent is at least one of N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, N-dimethylpropionamide and N, N' -dimethylacrylamide, and the second solvent is at least one of ethyl acetate, acetone, toluene and isopropanol.
The mass fraction of the second polymer solution is not greater than that of the first polymer solution, and the mass fraction of the second polymer solution is in a proper range, and at least the following factors need to be considered:
A. the solubility that polyurethane can actually achieve after the second solvent is added;
B. whether the second polymer solution can be sufficiently leveled;
C. Whether the second solvent in the second polymer solution volatilizes too much or not brings bubbles;
D. The first solvent content in the second polymeric solution is so high as to dissolve the cured polyurethane film.
Preferably, the mass fraction of the second polymer solution is 0.5% -10%. More preferably, the mass fraction of the second polymer solution is 0.5% to 8%. More preferably, the mass fraction of the second polymer solution is 3% to 6%.
The polyurethane in the second polymer solution is the same as the polyurethane in the first polymer solution.
The polyurethane has a number average molecular weight of more than 5w and a hard segment content of 35-55%.
The polyurethane at least needs to meet the biocompatibility of the implant materials in the medical appliance industry, and currently, common implantable polyurethane materials disclosed in the industry comprise: PDMS-PU, PIB-PU, POSS-PCU and the like with good compatibility with human bodies.
In the pretreatment step, a sheet-shaped reinforcing material is paved on a flat supporting surface, and is flattened by a heat conducting metal plate.
The flattening temperature of the heat conducting metal plate is 40-80 ℃, and the flattening time of the heat conducting metal plate is 5-10 min.
The polymer valve blade can be prepared by adopting a die 1 shown in fig. 1, placing a sheet-shaped reinforcing material into the die 1, providing a flat supporting surface at the bottom 11 of the die 1, leaving a gap of at least 1-2 mm between the edge of the reinforcing material and the frame of the die so as to ensure that the whole reinforcing material can be in a flat state, pressing a metal heat conducting plate on the surface of the reinforcing material, heating at least one of the die and a metal heating plate (heating to a flattening temperature), and presetting the reinforcing material by hot pressing.
The die can also be made of a heat-conducting metal material, and the die and the metal heating plate are heated simultaneously, so that the pre-shaping effect is better.
The flattening temperature needs to be well below the melting point of the reinforcement material to avoid adversely affecting the molecular structure and properties of the reinforcement material.
In the step 1, the drying mode is drying, the drying temperature is 60-80 ℃, and the drying time is 10-60 min.
In the step 1, the thickness of the initial membrane (namely the polymer membrane prepared in the step 1) is controlled by controlling the casting amount of the first polymer solution, the thickness of the initial membrane not only needs to meet the function of fixing the flattening form of the reinforcing material, but also cannot be too thick, so that the thickness of the valve leaflet cannot meet the requirement, and the thickness of the initial membrane is 0.06-0.11 mm.
The drying temperature in the step 1 is required to be far lower than the melting temperature of polyurethane, and the structure and the performance of the polyurethane are not influenced while the solvent is volatilized.
In the step 2, the drying mode is drying, the drying temperature is 5-50 ℃ lower than the boiling point of the second solvent, and the drying time is 30-180 min.
In the step 2, the drying mode is drying, the drying temperature is 10-40 ℃ lower than the boiling point of the second solvent, and the drying time is 60-120 min.
In the step 2, the drying mode is drying, the drying temperature is 40-80 ℃, and the drying time is 60-120 min.
In the step 2, the casting amount of the second polymer solution depends on the leveling condition, and when each casting is performed, the mass fraction of polyurethane is as high as possible under the leveling condition, so that the first solvent is prevented from dissolving the cured polyurethane film of the previous layer, and meanwhile, the excessive volatilization of the second solvent and the bubbles caused by the volatilization of the second solvent are also avoided.
The drying temperature in step 2 needs to be lower than the boiling point of the second solvent by more than 10 ℃, but is not lower than 40 ℃, if the drying temperature is higher, the second solvent volatilizes too fast, so that pores are easily caused, and if the drying temperature is too low, the first solvent volatilizes too slowly, and the polyurethane solidified in the previous layer may be dissolved.
When N, N-dimethylacetamide is used as the first solvent, the N, N-dimethylacetamide has water absorption, so that the drying temperature is too low, the first solvent can absorb water, and the polyurethane membrane is not compact.
The thickness of the diaphragm is controlled by controlling the casting quantity of the second polymer solution, and the casting quantity of the second polymer solution is as small as possible on the premise of ensuring leveling, so that the diaphragm thickness is prevented from exceeding the expected thickness due to the overlarge thickness of the diaphragm.
The preparation method of the polymer leaflet material provided by the application comprises the following steps:
(1) Placing square fabric (i.e. reinforcing material) with a side length of 47-49cm and a thickness of 0.06-0.11mm in a 50 x 50cm (bottom area) metal mold (see figure 1);
(2) Placing a heat conducting metal plate with a flat surface on the fabric, wherein the heat conducting metal plate is square and has a side length of 49-50cm;
(3) Heating the metal mold and the heat conducting metal plate at 60-80 ℃ for 5-10min, and removing the heat conducting metal plate;
(4) Pouring 0.5-10mL of polyurethane solution (namely first polymer solution, wherein the solvent of the first polymer solution is one or more of DMAc (N, N-dimethylacetamide), DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), tetrahydrofuran, N-methylpyrrolidone, N-dimethylpropionamide and N, N' -dimethylacrylamide) with the mass fraction of 1-20% into a metal mold;
(5) Drying in a drying oven at 60-80deg.C for 30-180 min;
(6) Pouring 1-3mL of polyurethane solution with the mass fraction of 0.5% -10% (namely second polymer solution, wherein the first solvent of the second polymer solution is the same as the solvent of the first polymer solution, the second solvent is at least one of ethyl acetate, toluene, acetone and isopropanol, and the volume ratio of the first solvent to the second solvent is 1:0.5-8) into a metal mold, and leveling.
(7) Drying in a drying oven at a temperature 5-50 ℃ lower than the boiling point of the second solvent;
(8) Repeating the step (6) and the step (7) for 3-20 times to obtain the polymer valve leaflet material. The thickness of the polymer valve leaflet material is 0.12-0.2 mm, and the two sides of the polymer valve leaflet material are smooth and have no fabric texture.
Example 1
The preparation method of the polymer valve leaflet material comprises the following steps:
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in fig. 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is PET, the woven material is 0.09mm thick;
(2) Pressing a heat-conducting metal plate on the fabric after flattening the fabric, wherein the surface of the heat-conducting metal plate is in a mirror surface level, and the heat-conducting metal plate is square with the length of 50 cm;
(3) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(4) Pouring 1mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(5) Drying in a drying oven at 80 ℃ for 1h;
(6) Preparing a polyurethane solution with the mass fraction of 6% (the polyurethane is dissolved in a mixed solution of DMAc (namely a first solvent) and acetone (namely a second solvent), wherein the volume ratio is DMAc: acetone=1:2);
(7) Pouring 1.5mL of the polyurethane solution prepared in the step (6) into a metal mold, and leveling;
(8) Drying in a drying oven at 50 ℃ for 1h;
(9) Repeating the step (7) and the step (8) for 5 times to obtain the high molecular valve leaflet material.
The thickness of the macromolecular valve leaflet material is 0.15mm, and the two sides of the macromolecular valve leaflet material are smooth and have no fabric texture.
In this embodiment, the polyurethane used in step (3) and step (6) is the same polyurethane, and the polyurethane components are: 48% PDMS (molecular weight 1000), 12% PHMO (molecular weight 700), 6.6% BDO,33.4% MDI.
Example 2
The preparation method of the polymer valve leaflet material comprises the following steps:
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in fig. 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is PET, the woven material is 0.09mm thick;
(2) Pressing a heat-conducting metal plate on the fabric after flattening the fabric, wherein the surface of the heat-conducting metal plate is in a mirror surface level, and the heat-conducting metal plate is square with the length of 50 cm;
(3) Dissolving polyurethane in DMF (N, N-dimethylformamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(4) Pouring 1mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(5) Drying in a drying oven at 80 ℃ for 1h;
(6) Preparing a polyurethane solution with a mass fraction of 4.5% (the polyurethane is dissolved in a mixed solution of DMF (namely a first solvent) and toluene (namely a second solvent), wherein the volume ratio is DMF: toluene=1:3);
(7) Pouring 2mL of the polyurethane solution prepared in the step (6) into a metal mold, and leveling;
(8) Drying in a drying oven at 70 ℃ for 1h;
(9) Repeating the step (7) and the step (8) for 5 times to obtain the high molecular valve leaflet material.
The thickness of the macromolecular valve leaflet material is 0.15mm, and the two sides of the macromolecular valve leaflet material are smooth and have no fabric texture.
In this embodiment, the polyurethane used in step (3) and step (6) is the same polyurethane, and the polyurethane components are: 48% PDMS (molecular weight 1000), 12% PHMO (molecular weight 700), 6.6% BDO,33.4% MDI.
Example 3
The preparation method of the polymer valve leaflet material comprises the following steps:
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in fig. 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is PET, the woven material is 0.09mm thick;
(2) Pressing a heat-conducting metal plate on the fabric after flattening the fabric, wherein the surface of the heat-conducting metal plate is in a mirror surface level, and the heat-conducting metal plate is square with the length of 50 cm;
(3) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(4) Pouring 1mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(5) Drying in a drying oven at 80 ℃ for 1h;
(6) Preparing a polyurethane solution with the mass fraction of 6% (the polyurethane is dissolved in a mixed solution of DMAc (namely a first solvent) and acetone (namely a second solvent), wherein the volume ratio is DMAc: acetone=1:2);
(7) Pouring 2mL of the polyurethane solution prepared in the step (6) into a metal mold, and leveling;
(8) Drying in a drying oven at 60 ℃ for 1h;
(9) Repeating the step (7) and the step (8) for 4 times to obtain the polymer valve leaflet material.
The thickness of the polymer valve leaflet material is 0.16mm, and the two sides of the polymer valve leaflet material are smooth and have no fabric texture.
In this embodiment, the polyurethane used in step (3) and step (6) is the same polyurethane, and the polyurethane components are: 48% PDMS (molecular weight 1000), 12% PHMO (molecular weight 700), 6.6% BDO,33.4% MDI.
Example 4
The preparation method of the polymer valve leaflet material comprises the following steps:
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in figure 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is polyolefin, and the thickness of the woven material is 0.08mm;
(2) Pressing a heat-conducting metal plate on the fabric after flattening the fabric, wherein the surface of the heat-conducting metal plate is in a mirror surface level, and the heat-conducting metal plate is square with the length of 50 cm;
(3) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(4) Pouring 1mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(5) Drying in a drying oven at 80 ℃ for 1h;
(6) Preparing a polyurethane solution with the mass fraction of 6% (the polyurethane is dissolved in a mixed solution of DMAc (namely a first solvent) and acetone (namely a second solvent), wherein the volume ratio is DMAc: acetone=1:2);
(7) Pouring 1.5mL of the polyurethane solution prepared in the step (6) into a metal mold, and leveling;
(8) Drying in a drying oven at 50 ℃ for 1h;
(9) Repeating the step (7) and the step (8) for 5 times to obtain the high molecular valve leaflet material.
The thickness of the polymer valve leaflet material is 0.13mm, and the two sides of the polymer valve leaflet material are smooth and have no fabric texture.
In this embodiment, the polyurethane used in step (3) and step (6) is the same polyurethane, and the polyurethane components are: 48% PDMS (molecular weight 1000), 12% PHMO (molecular weight 700), 6.6% BDO,33.4% MDI.
Example 5
The preparation method of the polymer valve leaflet material comprises the following steps:
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in fig. 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is PET, the woven material is 0.09mm thick;
(2) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(3) Pouring 1mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(4) Drying in a drying oven at 80 ℃ for 1h;
(5) Preparing a polyurethane solution with the mass fraction of 6% (the polyurethane is dissolved in a mixed solution of DMAc (namely a first solvent) and acetone (namely a second solvent), wherein the volume ratio is DMAc: acetone=1:2);
(6) Pouring 1.5mL of the polyurethane solution prepared in the step (6) into a metal mold, and leveling;
(7) Drying in a drying oven at 50 ℃ for 1h;
(8) Repeating the step (6) and the step (7) for 5 times to obtain the high molecular valve leaflet material.
The thickness of the polymer valve leaflet material is 0.14mm, and the two sides of the polymer valve leaflet material are smooth and have no fabric texture. The leaflet material exhibits a curved condition.
In this embodiment, the polyurethane used in step (3) and step (6) is the same polyurethane, and the polyurethane components are: 48% PDMS (molecular weight 1000), 12% PHMO (molecular weight 700), 6.6% BDO,33.4% MDI.
Comparative example 1
(1) Placing a fabric (namely a sheet-shaped reinforcing material) in a metal mold (shown in fig. 1) with 50cm and 50cm (bottom area), wherein the fabric is square with the length of 48cm, the material is PET, the woven material is 0.09mm thick;
(2) Pressing a heat-conducting metal plate on the fabric after flattening the fabric, wherein the surface of the heat-conducting metal plate is in a mirror surface level, and the heat-conducting metal plate is square with the length of 50 cm;
(3) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(4) Pouring 5.5mL of the polyurethane solution obtained in the step (3) into a metal mold, and slightly shaking to enable the solution to fully spread and cover the whole fabric;
(5) And (5) drying for 3 hours at 80 ℃ in a drying oven to obtain the polymer leaflet material.
The thickness of the macromolecular valve leaflet material is 0.15mm, the metallic surface of the macromolecular valve leaflet material is smooth, and the upper surface has obvious fabric lines.
SEM observation was performed for comparative example 1, see fig. 2a, in which the fabric floats on the upper layer, closer to the surface, in a cross-sectional view. Referring to fig. 2b and 2c, the upper surface of the polymeric leaflet material is uneven, wrinkles exist, and the lower surface is relatively flat, so that it is known that polyurethane on the upper surface and the lower surface of, fabric is unevenly distributed, the polyurethane content on the upper surface is less, the polyurethane content on the lower surface is more, and the lower upper surface has obvious lines.
The same SEM observation was performed on the polymer leaflet material prepared in example 1, and as shown in fig. 3a, 3b and 3c, the fabric was positioned in the middle of the polyurethane in the thickness direction, the polyurethane on the upper and lower surfaces of the fabric was uniformly distributed, and both the upper and lower surfaces were in a flat state.
Comparative example 2
(1) Dissolving polyurethane in DMAc (namely N, N-dimethylacetamide) to form a polyurethane solution with the mass fraction of 10 percent (namely a first polymer solution);
(2) Pouring 2ml of polyurethane solution into the metal mold, and slightly shaking to enable the solution to fully spread to cover the whole metal mold;
(3) Drying for 1h at 80 ℃ in a drying oven to obtain a polyurethane film A;
(4) Repeating the steps (2) and (3) to obtain a polyurethane film B, wherein the polyurethane film A and the polyurethane film B are respectively and independently prepared by adopting the same method;
(5) Placing the fabric between the polyurethane film A and the polyurethane film B, and hot-pressing for 1min in a flat plate hot press at 200 ℃ and 2 MPa;
(6) The thickness of the macromolecular valve leaflet material is 0.15mm, the macromolecular valve leaflet material is smooth in metal surface adhesion, and no obvious fabric lines are formed on the upper surface.
Bovine serum albumin adsorption assay: a1 mg/mL solution of bovine serum albumin was prepared in PBS (pH 7.4), the polyurethane leaflet material was immersed in the solution, the leaflet material was adsorbed by shaking at 37℃for 3 hours, the leaflet material was rinsed with PBS, and the remaining protein on the surface of the fabric was adsorbed with a 1wt% aqueous solution of sodium dodecyl sulfate, and the BSA contentTM was measured using a spectrophotometer and then the amount of BSA adsorbed on the sample was calculated.
Softness test: cutting the macromolecular valve leaflet material into 45mm 10mm valve leaflets, placing the valve leaflets on a test bench in bilateral symmetry, and observing the sagging angle of the fabric.
The test results of example 1 and comparative example 2 are shown in table 1.
TABLE 1
Bovine serum albumin adsorptionStrength ofSoftness degree
Example 15.4.+ -. 1.1 Micrograms/cm238.5MPa26°
Comparative example 287+ -7.5 Micrograms/cm238.3MPa27°
From the results shown in Table 1, the high molecular valve leaflet material prepared by the preparation method provided by the application is similar to the hot-pressing mode in terms of strength and softness, but the bovine serum albumin adsorption amount is much smaller, and the biocompatibility advantage is obvious, and the preparation method is mainly based on the fact that the whole process of the preparation method provided by the application is carried out at a lower temperature, so that polyurethane chain breakage and MDI yellowing are not easy to cause.
The application also provides a polymer valve leaflet, which is obtained by cutting the polymer valve leaflet material prepared by the preparation method according to a preset shape, wherein the thickness of the polymer valve leaflet is 0.12-0.2 mm. Further preferably, the thickness of the polymeric leaflet is 0.13 to 0.16mm.
The application also provides a prosthetic valve, which comprises a bracket, wherein the inside of the bracket is a blood flow channel;
The edge part of the valve leaf comprises a free edge and a fixed edge which are opposite, the fixed edge of the valve leaf is fixed with the bracket, and the free edge of the valve leaf is matched with the inner wall of the bracket or the free edges of the valve leaves to control the blood flow channel.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the application, which are described in detail and are not to be construed as limiting the scope of the application. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the application, which are all within the scope of the application. Accordingly, the scope of protection of the present application is to be determined by the appended claims.

Claims (17)

CN202211491916.2A2022-11-252022-11-25Preparation method of polymer valve leaflet material, polymer valve leaflet and artificial valvePendingCN118079080A (en)

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