CN116712601B

CN116712601B - Implantable material, artificial prosthesis, artificial heart valve and preparation method

Info

Publication number: CN116712601B
Application number: CN202310961038.4A
Authority: CN
Inventors: 卫星; 邝大军; 王成红; 王立超; 朱雨婷
Original assignee: Hangzhou Qiming Medical Devices Co ltd
Current assignee: Hangzhou Qiming Medical Devices Co ltd
Priority date: 2022-12-23
Filing date: 2023-08-02
Publication date: 2023-12-26
Anticipated expiration: 2043-08-02
Also published as: CN116712601A

Abstract

The application discloses an implantable material, an artificial prosthesis, an artificial heart valve and a preparation method, wherein the preparation method of the implantable material comprises the following steps: step S100, providing a polymer film; step S200, swelling the polymer film; and step S300, maintaining the polymer film in a preset three-dimensional shape and drying to obtain the implantable material. In the application, the high polymer membrane is in a three-dimensional shape for swelling treatment, molecular chain segment movement in the membrane can be increased, and secondary shaping is carried out under the condition of no internal stress, so that the stress distribution of the material is improved, the deformation in the valve movement period is reduced, the uniformity of the thickness of the membrane is considered, and the degradation caused by high temperature is reduced.

Description

Implantable material, artificial prosthesis, artificial heart valve and preparation method

Technical Field

The present application relates to the field of prosthetic valve technology, and in particular to implantable materials, prosthetic prostheses, prosthetic heart valves, and methods of making.

Background

In artificial prostheses, polymer materials are increasingly used as prosthetic materials, and in the case of heart valves, the polymer materials can be applied to the positions of valve leaflets or skirts and the like, but the implantable polymer material devices have better biocompatibility but have the problem of insufficient fatigue performance, for example, the polymer valve leaflets are easy to tear at the center of free edges with large deformation or at the joint of the polymer valve leaflets and a stent.

Some devices are prepared in the prior art in a three-dimensional molding mode, so that the stress and strain of materials are optimized; two relatively common ways include dip coating of the mold surface and hot press molding in the mold cavity.

The surface dip coating of the mold is to dip coat the polymer solution on the surface of the mold in a three-dimensional shape, and the polymer is solidified on the surface of the mold to form the polymer membrane with a three-dimensional structure along with the volatilization of the polymer solution. However, since the mold is three-dimensional, the polymer solution has a certain fluidity on the surface of the mold under the influence of gravity, resulting in uncontrollable thickness of the membrane at different positions. Finally, the uniformity and consistency of the membrane are affected; thereby affecting the fatigue performance and qualification rate of the valve.

The hot press molding of the die is to form a film sheet with a three-dimensional shape in the cavity of the female die and the male die by melting polymer. This approach generally requires heating the polymer above 190 ℃, where the polymer undergoes various levels of degradation at high temperatures, resulting in reduced molecular weight and even the production of toxic small molecule components. Further, the biological, mechanical and aging properties of the valve are affected.

Disclosure of Invention

The application provides a preparation method of an implantable material, which comprises the following steps:

step S100, providing a polymer film;

step S200, swelling the polymer film;

and step S300, maintaining the polymer film in a preset three-dimensional shape and drying to obtain the implantable material.

The implantable material can be applied to a prosthetic heart valve, namely, the application provides a preparation method of the prosthetic heart valve material.

Optionally, the preparation method of the polymer film comprises the following steps:

dissolving raw materials in a first solvent to prepare a solution with the mass percent concentration of 3% -40%;

forming a film on the surface of the die by using the solution;

and drying to obtain the polymer film.

Optionally, the raw material is at least one of polyurethane, polyolefin, polysiloxane, polyvinyl alcohol and Pebax.

Optionally, the first solvent is selected from good solvents of the raw materials. For example, at least one selected from DMAc, DMF, tetrahydrofuran, DMSO, toluene, cyclohexane, xylene, and dichloromethane.

Optionally, the temperature of the drying is 25-80 ℃. The drying time is 1-48 hours, for example 6-24 hours.

Optionally, inert gas is used for protection during drying.

Optionally, the thickness of the polymer film is 0.1-0.6 mm, preferably 0.1-0.3 mm.

Optionally, the polymer film is a cylindrical structure, and each leaflet corresponds to one part of the side wall in the cylindrical structure.

Optionally, the tubular structure is a prefabricated integral structure, and the swelling treatment and the drying treatment are performed under the tubular structure.

Optionally, the polymer film is prefabricated into a sheet structure, and then the sheet structure is curled to fix two opposite sides to each other to form a cylindrical structure.

Optionally, the swelling treatment and the drying treatment of the polymer film are performed under a sheet structure, and the polymer film is enclosed into a cylindrical structure after the swelling treatment and the drying treatment are completed.

Optionally, the polymer film has a predetermined three-dimensional shape with a bending portion, and the swelling treatment is at least directed to the bending portion or swells the polymer film as a whole.

Optionally, the polymer film is kept in a predetermined three-dimensional shape when the polymer film is subjected to swelling treatment; or after swelling the polymer film, maintaining the polymer film in a predetermined three-dimensional shape.

Optionally, before the polymer film is swelled, the polymer film is first installed in a mold matching the predetermined three-dimensional shape, and then a treatment liquid for swelling is injected into the mold.

Optionally, in the swelling treatment, the part to be treated is soaked with a treatment liquid, and the treatment liquid is a poor solvent of the polymer membrane. For example, a second solvent or an aqueous solution of the second solvent, the second solvent being at least one selected from ethanol, propanol, isopropanol, tetrahydrofuran, acetone, toluene, and the total concentration of the second solvent in the aqueous solution being 30% by mass or more.

Optionally, the polymer membrane is subjected to swelling treatment locally or wholly until the volume change rate of the part to be treated is 0.1% -10%.

Optionally, the swelling treatment is performed for 0.1 to 24 hours, for example, 0.1 to 12 hours.

Optionally, at least one side of the polymer film is supported by a mold to maintain a predetermined three-dimensional shape.

Optionally, the temperature of the drying treatment is 25-80 ℃. The drying time is 0.5 to 48 hours, for example 1 to 16 hours.

Optionally, inert gas is used for protection during drying.

Alternatively, the predetermined three-dimensional shape of the polymer film is always maintained during the drying process, for example, the mold always supports the polymer film, or the predetermined three-dimensional shape of the polymer film is maintained only for a part of the time period.

Optionally, the drying process includes a relative early stage and a late stage, wherein the early stage occupies at least 15% of the total drying process time, and the polymer film maintains a predetermined three-dimensional shape at least in the early stage.

Optionally, the leaflet has opposite open and closed shapes under fluid action, and a transitional shape during switching, the predetermined three-dimensional shape corresponding to the closed or transitional shape of the leaflet.

Optionally, the leaflet of the prosthetic heart valve has an opening area corresponding to S1 in the open shape, the leaflet has an opening area corresponding to S2 in the transitional shape, and the percentage of S2 in S1 is greater than 0 and less than or equal to 85%.

The application also provides an implantable material and a prosthetic heart valve material, which respectively adopt a polymer film, wherein at least a part of areas of the polymer film are preformed into a three-dimensional shape.

The implantable material and the prosthetic heart valve material can be obtained by the preparation method.

The present application also provides a prosthetic prosthesis and a prosthetic heart valve. At least a portion of the prosthesis employs the implantable material. The artificial heart valve comprises a bracket and valve blades connected to the bracket, wherein the valve blades adopt the artificial heart valve material.

The application also provides a preparation method of the artificial heart valve, wherein the artificial heart valve comprises a bracket and a plurality of valve leaflets connected to the bracket, and the preparation method comprises the following steps of:

providing a polymeric film for preparing a leaflet;

swelling the polymer film;

maintaining the polymer film in a preset three-dimensional shape and drying the polymer film;

and mounting the dried polymer membrane to the bracket to obtain the artificial heart valve.

Optionally, the polymer film after the drying treatment is cut in an arbitrary step in accordance with the outline shape of the leaflet before being mounted as the leaflet to the stent.

Optionally, the leaflet is mounted to the scaffold either before the swelling process or after the drying process.

Optionally, a plurality of petals are respectively prepared and then mounted on the stent.

Optionally, after a plurality of valve leaves are respectively prepared, the valve leaves are connected in sequence head and tail to form a cylindrical structure, and then the valve leaves are mounted on the bracket.

Optionally, the plurality of valve leaflets are integrally formed.

providing a polymeric membrane having the contour shape of a leaflet;

the polymer membrane is arranged on the bracket, and swelling treatment is carried out on the polymer membrane;

the artificial heart valve is obtained by maintaining the preset three-dimensional shape of the polymer membrane and drying the polymer membrane together with a bracket.

Optionally, the prosthetic heart valve further comprises a cover attached to the stent, the cover being made of the prosthetic heart valve material.

Optionally, the covering film and the valve leaflet are connected in a split mode or are of an integral structure.

Optionally, the stent is in a radially deformable cylinder shape, a blood flow channel is arranged in the stent, the valve leaflet is positioned at the inner side of the stent to control the blood flow channel, and the covering film is positioned at the blood flow inflow side of the valve leaflet.

Optionally, the covering film is located at the inner side and/or the outer side of the radial direction of the bracket.

Optionally, further comprising heat treating the prosthetic heart valve. The heat treatment temperature is 80-160 ℃, and inert gas is adopted for protection during the heat treatment. The heat treatment time is 0.5-4 h.

The application also provides a leaflet prefabricated product of the artificial heart valve, wherein the leaflet prefabricated product is tubular and comprises a plurality of leaflets connected end to end in sequence.

In the application, the swelling treatment is carried out on the polymer film in a three-dimensional shape, so that the molecular chain segment movement in the film can be increased, and the secondary shaping is carried out under the condition of no internal stress. The stress distribution of the material can be improved, and meanwhile, the uniformity of the thickness of the membrane is also considered, so that the degradation caused by high temperature is reduced.

Drawings

FIG. 1 is a flow chart of a method of preparing an implantable material of the present application;

fig. 2-6 are schematic diagrams of different embodiments of the prosthetic heart valve.

Detailed Description

The following description of the technical solutions in the embodiments of the present application will be made clearly and completely with reference to the drawings in the embodiments of the present application, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.

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 present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

The concentration of the solution mentioned hereinafter is the concentration in percent by mass (weight) unless otherwise specified, and the solvent in the solution is water when no solvent is mentioned. The prosthetic and implantable material in the various embodiments are exemplified by, but not strictly limited to, the field of prosthetic heart valves, e.g., the prosthetic may be a prosthetic heart valve, and the implantable material may be a leaflet, skirt, or auxiliary material in a prosthetic heart valve, etc.

An embodiment of the present application provides a method for preparing an implantable material, which can be applied to a prosthetic heart valve, namely, a method for preparing a prosthetic heart valve material.

Referring to fig. 1, the preparation method comprises the following steps:

step S100, providing a polymer film;

step S200, swelling the polymer film;

step S300, the polymer film is kept in a preset three-dimensional shape and is subjected to drying treatment, so that the implantable material is obtained.

The polymer membrane in the step S100 can be made of a polymer material with biocompatibility in the conventional technology, and at least one raw material of polyurethane, polyolefin, polysiloxane, polyvinyl alcohol and Pebax is adopted in the application in combination with the characteristic of long-time periodic movement of the artificial heart valve, so that the artificial prosthesis is especially suitable for implantation in an interventional mode, and is generally required to be radially compressed when being delivered in an interventional mode, the relative deformation position between the polymer material and the bracket generates internal stress for traction and even deformation, and the stress can be absorbed by the good elasticity, so that the risk of local damage is reduced.

An embodiment of the present application also provides a method for preparing a polymer film, including:

volatilizing the solution on the surface of the die to form a film; and then drying to obtain the polymer film.

The first solvent is a good solvent of raw materials, for example polyurethane, and is at least one selected from DMAc, DMF, DMSO, tetrahydrofuran, toluene, cyclohexane, xylene and dichloromethane. According to the different modes of the subsequent application, the molding surface provided by the mold can be a plane or a curved surface, when the curved surface is adopted, in order to ensure the uniformity of the thickness, a cylindrical surface and other regular shapes are preferably adopted, particularly the inner surface or the outer surface of the rotating body can rotate the mold during film forming so as to overcome the uneven thickness caused by the action of gravity.

When the paint is applied to the surface of the mold, the paint can be sprayed, brushed, poured, leveled and the like, and the drying condition is 25-80 ℃ for example. The drying time is 1-48 hours, for example 6-24 hours. The baking process can also adopt inert gases such as nitrogen and the like for protection. The thickness of the polymer film is 0.1-0.6 mm according to the use environment of the implantation material, and can be preferably 0.1-0.3 mm when the polymer film is applied to a heart valve prosthesis.

The prepared polymer film is of a cylindrical structure by combining the space characteristics of the valve leaflets in the artificial heart valve or similar structure, each valve leaflet corresponds to one part of the side wall in the cylindrical structure, a plurality of valve leaflets can be formed at one time, and the workload of reconnecting the valve leaflets with each other is reduced. The tubular structure may be a prefabricated integral structure, i.e., molded with a mold surface in the shape of a rotating body, and in the subsequent step, a swelling treatment and a drying treatment are performed based on the tubular structure

The polymer film can also be prefabricated into a sheet structure, namely a planar film, the subsequent swelling treatment and drying treatment are carried out in a sheet state, after the completion, the sheet structure is curled to enable the two opposite sides to be mutually fixed and enclosed into a cylindrical structure, and the cylindrical structure is cut and mounted to a bracket.

The polymer film provided in step S100 needs to be shaped according to a predetermined three-dimensional shape, and there are bending portions in the predetermined three-dimensional shape, wherein the bending portions may be smooth curved surfaces or may be folding with a relatively obvious trend, and the swelling treatment is at least directed at the bending portions, which does not mean that all the bending portions need to be swelled, and the swelling treatment can be performed according to the expected performance requirements, and for convenience of operation, the whole polymer film may be placed into the swelling system even together with the mold.

When the polymer film is swelled, the polymer film can be firstly kept in a preset three-dimensional shape by using a mode such as a mould support and the like, and then the polymer film is swelled; the swelling may be performed first, that is, the swelling is not performed with three-dimensional shaping, but the polymer film may be dried after the step S200 by maintaining the polymer film in a predetermined three-dimensional shape.

Before swelling treatment is carried out on the polymer film, the polymer film is firstly arranged in a mould matched with a preset three-dimensional shape, then treatment liquid for swelling is injected into the mould, and a liquid injection hole can be reserved in the mould, and a mode of soaking the whole mould can be adopted.

Drying the polymer film after swelling treatment or drying the polymer film and the mold, namely removing solvent molecules in a polymer film system, so that the whole polymer film or at least the bending part is in a state of uniform stress distribution, and the fatigue resistance of the bending part is improved.

Aiming at the problem of poor fatigue resistance of the polymer, the method performs three-dimensional shaping under the condition that the whole polymer film or at least the bending part has no internal stress, can optimize stress distribution of the valve leaflet when being applied to the artificial heart valve, also reduces the maximum deformation of the valve leaflet, has controllable thickness, simultaneously has no high-temperature degradation problem in the preparation process, and improves the fatigue resistance of the valve.

Compared with the existing dip-coating three-dimensional molding, the thickness of the product is controllable, the batch difference is avoided, and the qualification rate of the finished product is greatly improved. Compared with the existing hot press molding, the predetermined die structure is simpler, the process is free from high-temperature melting, the high polymer material is free from degradation, the biocompatibility risk is reduced, and the service life of the high polymer material is prolonged.

In the swelling treatment, the part to be treated is soaked by the treatment liquid, and the treatment liquid is a second solvent or an aqueous solution of the second solvent.

Wherein the second solvent is at least one selected from ethanol, propanol, isopropanol, tetrahydrofuran, acetone and toluene, and when an aqueous solution of the second solvent is adopted, the total concentration of the second solvent in the aqueous solution is more than or equal to 30% by mass percent. For example 30% -90%, and for example 40% -80%.

The polymer film is swelled locally or wholly until the volume change rate of the part to be treated is 0.1-30%, such as 0.1-15%, such as 5-10%, and swelling time can be intuitively controlled, such as 0.1-24h, such as 0.1-12h, such as 1-10 h, such as 2-8 h.

In order to eliminate stress at the bending part, a predetermined three-dimensional shape is required to be maintained during swelling, drying and shaping, for example, in one embodiment, a mold is used to support at least one side (thickness direction) of the polymer film, and the polymer film is attached to the surface of the mold by means of gravity, a clamp or the like, and the mold may be a buckling structure, i.e. a mold cavity is surrounded, and both sides of the polymer film are limited.

In order to facilitate the drying treatment after the swelling is finished, the mold can be in a non-fully closed type, for example, only one side of the polymer film is fully supported, and the other side adopts a mode of multipoint fixing or edge clamping and the like.

The drying treatment in step S300 is performed at a temperature of 25 to 80 ℃, for example, 40 to 60 ℃. The drying treatment can be performed under the protection of inert gas such as nitrogen, and the drying time is 0.5-48 h, for example 1-16h, and for example 2-6 h.

The predetermined three-dimensional shape of the polymer film is always maintained during the drying process, for example, the mold always supports the polymer film, or the predetermined three-dimensional shape of the polymer film is maintained only for a part of the time period, that is, the mold supports the polymer film for a part of the time period.

The support force which is maintained, i.e. maintains, the three-dimensional shape only during a part of the time period is releasable during the drying process, e.g. the configuration is basically maintained after the polymer film has been dried for a period of time, and the removal of the mould may accelerate the volatilization process of the residual volatiles and increase the overall efficiency, e.g. the whole drying process comprises a relatively early stage and a relatively late stage, wherein in an embodiment the mould supports the polymer film at least in the early stage, wherein the early stage comprises at least 15%, e.g. 20-60%, of the whole drying process time, and for the first 3 hours the polymer film is always bound and supported to the mould, and for the last 3 hours the polymer film is separated from the mould, but without strictly requiring any support, or supporting the polymer film by means of hanging, leveling, multipoint support, etc., but no longer in full surface contact.

The predetermined three-dimensional shape is implemented in connection with the design of the product, for example, a leaflet having opposite open and closed shapes under the influence of a fluid, and a transition shape during switching, the predetermined three-dimensional shape corresponding to the closed or transition shape of the leaflet. In one embodiment, a transition shape is preferred, and the shape characteristics thereof can be described by an opening area, for example, the opening area corresponding to the leaflet in the prosthetic heart valve in the open shape is S1, the opening area corresponding to the leaflet in the transition shape is S2, and the percentage of S2 in S1 is greater than 0 and less than or equal to 85%. A closed shape is understood to be 0.

The ultimate bending angle of the valve leaflet in the transitional shape is obviously reduced no matter the valve leaflet tends to be in an open shape or a closed shape in the opening and closing period, and the deformation amount of the valve leaflet in the movement process is greatly reduced, so that the bending times are enhanced, and the service life is prolonged.

Based on the above preparation method, a corresponding implantable material, in particular a prosthetic heart valve material, can be obtained. With respect to its application, the prosthetic prosthesis and prosthetic heart valve may be further processed. Wherein at least a portion of the prosthesis employs an implantable material.

The implantable material of the present application may contain, in addition to the polymeric membrane as the main body portion, a reinforcing fabric locally or wholly as needed, and may be directly embedded in the process of synthesizing the polymeric membrane, or may be formed into a film by dip coating or the like on the reinforcing fabric, and at this time, the reinforcing fabric may be understood as a mold to support the shape of the polymeric membrane without affecting the subsequent swelling or drying operation process or the like.

The following embodiments take a prosthetic heart valve as an example, and in particular, a prosthetic heart valve capable of being delivered through catheter intervention, which specifically includes a stent and leaflets connected to the stent, the stent is made of a memory material, such as nickel-titanium alloy, and is in a cylindrical structure capable of being deformed in radial direction as a whole, the sidewall is provided with a hollowed-out area, for example, the hollowed-out area is formed by laser cutting or braiding, a blood flow channel is located inside the stent, the leaflets are connected in the stent, and a plurality of the leaflets are mutually matched to control the opening and closing degree of the blood flow channel, and the leaflets can be made of the prosthetic heart valve material of the present application. The artificial heart valve material can also be used for processing a tectorial membrane, the tectorial membrane is positioned on the blood inflow side of the valve leaflet, can be positioned on the radial inner side and/or the radial outer side of the stent, has the functions of keeping sealing, preventing peripheral leakage, protecting safety and the like, is in a split connection or integrated structure with the valve leaflet, and can be formed by integrally rolling the tectorial membrane on the inner side of the stent.

Based on this, an embodiment of the present application further provides a method for preparing a prosthetic heart valve, the prosthetic heart valve including a stent and a plurality of leaflets attached to the stent, the method comprising:

providing a polymeric film for preparing a leaflet;

the method comprises the steps of keeping a polymer film in a preset three-dimensional shape, swelling at least a bending part, keeping the three-dimensional shape of the polymer film after swelling, and drying; or swelling the polymer film directly, and then keeping the polymer film in a preset three-dimensional shape for drying treatment;

and mounting the dried polymer membrane on a bracket to obtain the artificial heart valve.

The preparation of the polymer film, and the swelling treatment and the drying treatment may be combined with the foregoing, and the polymer film after the drying treatment is cut in an arbitrary step in accordance with the outline shape of the leaflet before the polymer film is mounted as the leaflet to the stent, which will not be described in detail. The method can be used for cutting and shaping (comprising swelling treatment and drying treatment) or cutting and shaping.

For the mounting timing of the leaflet, it may be mounted to the stent before the swelling treatment or after the drying treatment. Since the valve leaflet also has a plurality of valve leaflets, the plurality of valve leaflets can be prepared (including shaping) respectively and then mounted on the bracket. Or after a plurality of valve leaves are respectively prepared, the valve leaves are connected in sequence head and tail to form a cylindrical structure, and then the cylindrical structure is mounted on a bracket. Of course, the multiple valve leaves can be in an integrated structure, namely, the same polymer film is cut and connected with each other. For example, in one embodiment, there is also provided a leaflet preform for a prosthetic heart valve, the leaflet preform being tubular and comprising a plurality of leaflets joined end-to-end in sequence.

The valve vane prefabricated product is obtained by adopting a cylindrical polymer film after swelling treatment and drying treatment, and the polymer film can be cut in advance according to the outline of the valve vane or cut after shaping.

An embodiment also provides a method of preparing a prosthetic heart valve comprising a stent and a plurality of leaflets attached to the stent, for the leaflets to be mounted to the stent prior to a swelling process, the method comprising:

providing a polymeric membrane having the contour shape of a leaflet;

installing a polymer film on a bracket, keeping the polymer film in a preset three-dimensional shape and swelling at least the bending part;

after the swelling treatment, the three-dimensional shape of the polymer film is maintained and the polymer film and the stent are dried to obtain the artificial heart valve.

The polymer film may be directly swelled after being mounted on the bracket, and then the polymer film may be kept in a predetermined three-dimensional shape by a mold and then dried.

The artificial heart valve can be subjected to heat treatment after being assembled, wherein the heat treatment temperature is 80-160 ℃, for example, inert gas is adopted for protection during heat treatment at 120-140 ℃, and the heat treatment time is 0.5-4 h, for example, 2h.

Various embodiments are provided below in connection with specific parameters, such as prosthetic heart valves, for example, valves that may be in the aortic valve position.

Example 1

Polyurethane was dissolved in DMAc to form a 10wt% polyurethane solution, 10mL of the polyurethane solution was poured into a flat mold (e.g., 50mm x 50mm metal box) and the mold was baked at 60 ℃ for 12h. A polyurethane film having a thickness of 0.2mm was formed.

In fig. 2 (a), a part of the polyurethane film is laser-cut according to a predetermined contour shape to obtain a leaflet semi-finished product (corresponding to a single leaflet), the leaflet semi-finished product is placed in a mold having a three-dimensional configuration with a supporting surface adapted to the predetermined three-dimensional shape, and the mold is immersed in a 50wt% ethanol solution together with the leaflet semi-finished product for 2 hours to complete the swelling treatment.

After the swelling treatment, the mold and the semi-finished product of the valve blade are dried for 2 hours in a dry nitrogen atmosphere at 60 ℃, and the semi-finished product of the valve blade, namely the semi-finished product of the valve blade, is taken out and separated from the mold, and is dried for 2 hours again, so that the valve blade is obtained, see the part (b) in fig. 2.

Taking a plurality of valve leaflets to be mutually connected to form a cylindrical structure, sewing the valve leaflets to a bracket to obtain a heart valve prosthesis, wherein the part (c) in fig. 2 is shown, and the part (d) in fig. 2 is shown, so that the relative postures of the valve leaflets and the bracket are mutually adapted to the preset three-dimensional shape.

Example 2

A0.2 mm polyurethane film was prepared as in example 1.

Referring to part (a) of fig. 3 to part (b) of fig. 3, a polyurethane film is laser cut into a semi-finished leaflet (corresponding to a single leaflet) according to a predetermined contour shape, a plurality of leaflets are taken to be connected with each other to form a cylindrical structure, and then the cylindrical structure is sewn to a support to obtain a prosthetic heart valve preform.

The prosthetic heart valve preform is placed in a mold having a solid configuration that is generally cylindrical and extends into the stent to maintain the leaflet support in a predetermined three-dimensional shape, as shown in fig. 3 at (c), and the mold is soaked with the prosthetic heart valve preform in a 50wt% ethanol solution for 2 hours to complete the swelling process.

After the swelling treatment, the mold together with the prosthetic heart valve preform was dried in a dry nitrogen atmosphere at 60 ℃ for 2 hours.

Further performing heat treatment on the obtained prosthetic heart valve preform, and heating the prosthetic heart valve preform to 120 ℃ in a dry nitrogen atmosphere for 2 hours; and then slowly cooled to room temperature.

Example 3

A0.2 mm polyurethane film was prepared as in example 1.

And cutting the polyurethane film by laser according to a preset contour shape to obtain a semi-finished product of the valve leaf, wherein a plurality of valve leaves can be cut out by the semi-finished product of the valve leaf, and the semi-finished product of the valve leaf is connected end to form a cylindrical structure.

The cylindrical structure was placed in a mold having a three-dimensional configuration, the mold being substantially cylindrical, and the cylindrical structure was fitted around the outer periphery of the mold and immersed in an 80wt% ethanol solution together with the mold for 1 hour.

After the swelling treatment, the semi-finished valve leaflet and the mould are dried for 2 hours in a dry nitrogen atmosphere at 60 ℃, and the semi-finished valve leaflet and the mould are separated and are further dried for 2 hours to obtain a plurality of valve leaflets which are connected together, as shown in the part (a) of fig. 4. And may be further mounted to a stent to obtain a prosthetic heart valve, as shown in part (b) of fig. 4.

Example 4

Polyurethane was dissolved in DMF to form a 15wt% polyurethane solution, 60mL of the 15wt% polyurethane solution was poured into a flat mold (150 mm x 150mm metal box), and the mold was baked at 60 ℃ under dry nitrogen atmosphere for 8h. A polyurethane film of 0.2mm was formed as in part (a) of FIG. 5.

The polyurethane film was placed in a mold, for example, three leaflets, having at least three adjacent mold cavities for one-shot molding of three leaflets, as shown in part (b) of fig. 5, and the polyurethane film and mold were placed in a 50wt% isopropyl alcohol solution and immersed for 0.5h.

Taking out the mould and drying for 5h at 50 ℃. The prefabricated integrated membrane (sheet-shaped and comprising three valve leaves) is obtained, the redundant part is trimmed, the membrane is rolled into a cylinder shape as shown in the part (c) of fig. 5, and the initial valve She Fengzhi and the final valve She Fengzhi are connected to form a cylinder shape and are mounted on a bracket, so that the artificial heart valve is obtained.

Optionally performing heat treatment, heating the artificial heart valve to 120deg.C in dry nitrogen atmosphere, and maintaining for 2 hr; and then slowly cooled to room temperature.

Example 5

Dissolving polyurethane in DMF to form a 15wt% polyurethane solution; providing a cylindrical mold according to the size requirement of valve products, wherein one end of the cylindrical mold is connected with power, for example, the cylindrical mold is linked with a motor capable of rotating at a constant speed, the prepared polyurethane solution is uniformly coated on the outer surface or the inner surface of the mold (the inner surface of the mold can be used as a molding surface if the mold is of a hollow structure), the mold is kept to rotate around the axis (the axis is horizontally placed) at a constant speed, and the mold is dried for 2 hours at 50 ℃; repeating the dip-coating and drying processes 5 times; finally drying for 24 hours; after being separated from the mold, the polymer cylinder with uniform thickness is formed, as shown in part (a) of fig. 6, and the thickness of the cylinder is 0.2mm.

The polymeric cylinder was placed into another pre-set mold matching the three-dimensional shape of the valve leaflet, and the pre-set mold was placed into a 30wt% aqueous solution of tetrahydrofuran, and immersed in 0.5. 0.5h.

Taking out the pre-shaping mold, and drying for 6h at 40 ℃. The prefabricated integral membrane (cylindrical and comprising three valve leaflets) shown in part (b) of fig. 6 is obtained, and the redundant part is trimmed to obtain integral valve leaflets which are then fixed on a bracket, so that the artificial heart valve is obtained.

Further heat treating the obtained artificial heart valve, and heating the artificial heart valve to 140 ℃ in a dry nitrogen atmosphere, and maintaining 0.5 h; and then slowly cooled to room temperature.

Example 6

Dissolving polyurethane in DMF to form a 15wt% polyurethane solution; providing a cylindrical mold according to the size requirement of valve products, wherein one end of the cylindrical mold is connected with power, for example, the cylindrical mold is linked with a motor capable of rotating at a constant speed, the prepared polyurethane solution is uniformly coated on the outer surface or the inner surface of the mold, the mold is kept to rotate around the axis (the axis is horizontally arranged) at a constant speed, and the cylindrical mold is dried for 2 hours at 50 ℃; repeating the dip-coating and drying processes 5 times; finally drying for 24 hours; and the polymer cylinder with uniform thickness is formed after being separated from the die, and the wall thickness of the cylinder is 0.2mm.

The polymer cylinder was put into 70wt% ethanol aqueous solution and immersed for 2 hours. And placing the swelled macromolecule cylinder into another preset mould matched with the three-dimensional shape of the valve blade.

The pre-shaping mold was dried at 40℃for 6 hours. The method comprises the steps of obtaining a pre-set integrated diaphragm (cylindrical and comprising three valve leaflets), trimming redundant parts to obtain integrated valve leaflets, and fixing the integrated valve leaflets on a bracket to obtain the artificial heart valve.

Performing heat treatment, heating the artificial heart valve to 150 ℃ in a dry nitrogen atmosphere, and maintaining 0.5 h; and then slowly cooled to room temperature.

Example 7

Polyurethane was dissolved in DMAc to form a 10wt% polyurethane solution, 10mL of the polyurethane solution was poured into a flat mold (e.g., 50mm x 50mm metal box) and the mold was baked at 60 ℃ for 12h. A polyurethane film of 0.2mm was formed.

The polyurethane film is laser cut according to a predetermined profile shape to obtain a leaflet semi-finished product (corresponding to a single leaflet), the leaflet semi-finished product is placed in a mold having a three-dimensional configuration with a female and male mold cavity, the leaflet semi-finished product is placed in the mold and closed, and the mold cavity has an opening, and the mold has a support surface conforming to the predetermined three-dimensional shape. From the open hole, 50% propanol solution was injected into the cavity and immersed for 3 hours to complete the swelling treatment.

After the swelling treatment, the propanol solution was poured out and dried at 60℃for 4 hours. Opening the mould and continuously drying for 3 hours at 60 ℃ to obtain the valve blade.

And (3) connecting a plurality of valve leaflets to each other to form a cylindrical structure, and then sewing the cylindrical structure to the bracket to obtain the artificial heart valve, wherein the relative postures of the valve leaflets and the bracket are mutually adapted to the preset three-dimensional shape.

Control group 1

Control group 2

1g of polyurethane solid is taken and placed in a mould with an inner cavity of 50mm and a height of 0.25mm, and preheated at 210 ℃ for 5min. Pressurized to 1000 psi and held for 1 minute. The film with the thickness of 0.21mm is obtained by a preparation method of mould pressing.

Experiment group 1

Polyurethane was dissolved in DMAc to form a 10wt% polyurethane solution, 10mL of the polyurethane solution was poured into a flat mold (e.g., 50mm x 50mm metal box) and the mold was baked at 60 ℃ for 12h. A polyurethane film of 0.2mm was formed. The membrane was fixed on a flat mold, and the mold together with the membrane was immersed in a 50wt% ethanol solution for 2 hours to complete the swelling treatment. After the swelling treatment, the mould and the semi-finished product of the valve blade are dried for 2 hours in a dry nitrogen atmosphere at 60 ℃ to obtain the membrane material.

Performance comparison

The polyurethane film was tested for breaking strength, elongation at break, and sewing force, and the test results are shown in Table 1 below.

TABLE 1 Performance test results

As can be seen from the results of the control groups 1 and 2, the breaking strength, breaking elongation and sewing force of the film sheet were reduced slightly after the hot press molding. During the hot press molding process, the pressure causes residual stress or material molecular weight reduction inside the membrane. Data of the control group 1 and the experimental group 1 are compared, and the mechanical properties of the materials subjected to the pre-molding condition treatment are not significantly different; the pretreatment process can effectively improve the uniformity and qualification rate of the thickness of the valve leaflet, but does not reduce the mechanical strength of the diaphragm.

TABLE 2 comparison of hydrodynamic Properties

Comparative example 1

Polyurethane was dissolved in DMAc to form a 10wt% polyurethane solution, 10mL of the polyurethane solution was poured into a flat mold (e.g., 50mm x 50mm metal box) and the mold was baked at 60 ℃ for 12 hours to form a 0.2mm polyurethane film. Cutting polyurethane film by laser to obtain preset shape of valve leaf and skirt, sewing and installing on the bracket to obtain the polymer valve.

From the hydrodynamic results, the hydrodynamic contrast data between the examples were not significantly different, indicating the sequence and form of the swelling process, and had little effect on the hydrodynamic properties of the final valve. However, the effective opening area in comparative example 1 was reduced, possibly due to more deflection of the bending type when the leaflet was opened, resulting in a reduction in the leaflet opening area; the reflux of comparative example 1 increased, resulting in an increased leakage due to incomplete flap She Tiege; the valve-crossing pressure difference of comparative example 1 is remarkably increased, the deformation of the valve She Wanshe in the opening and closing process in comparative example 1 is large, and the stress of the valve leaflet is large, so that the valve-crossing pressure difference is remarkably increased.

According to ISO5840 related standard, the fatigue resistance of examples 1-7 and comparative example 1 is measured, and the final test results are as follows:

example 1:2.4 hundred million times, no tearing occurs, and the pores at the suture line are larger;

example 2:2.1 hundred million times, the suture is torn;

example 3:2.8 hundred million times, no tearing occurs, and the pores at the suture line are larger;

example 4:4.4 hundred million times, the tip of the flap blade is worn; no change is made at the suture;

example 5:4.8 hundred million times, the free edge of the valve leaflet is torn; no change is made at the suture;

example 6:4.5 hundred million times, the free edge of the valve leaflet is torn; no change is made at the suture;

example 7:2.5 hundred million times, no tearing occurs, and the pores at the suture line are larger;

comparative example 1:1.2 hundred million times, the tip of the valve tip is torn, the valve She Wanshe is torn, and the hole at the suture line of the valve is larger.

From the above results, it can be seen that the valves prepared in examples 1-3 and 7, the leaflet active area was not torn, but the fatigue life was affected by the suture portions; the results of examples 4-6 were excellent in fatigue properties; it was demonstrated that the valve significantly improved the stress distribution of the leaflet active region by swelling the pre-form, and that the leaflet active region life was higher than that of comparative example 1. The leaflet of comparative example 1 had multiple tears at the cusps and the folds. Therefore, the embodiment swelling-presetting method can effectively avoid the fatigue problem of the bending part of the valve leaflet, and ensure the uniformity of the thickness of the material.

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. When technical features of different embodiments are embodied in the same drawing, the drawing can be regarded as a combination of the embodiments concerned also being disclosed at the same time.

The above examples only represent a few embodiments of the present application, which are described in more detail and are not to be construed as limiting the scope of the claims. It should be noted that it would be apparent to those skilled in the art that various modifications and improvements could be made without departing from the spirit of the present application, which would be within the scope of the present application.

Claims

1. A method of preparing an implantable material, comprising the steps of:

step S100, providing a polymer film for preparing valve leaflets, wherein the polymer film is prepared into a solution by corresponding raw materials in advance, and then is formed into a film and dried, and the polymer film is at least one of polyurethane, polyolefin, polysiloxane, polyvinyl alcohol and Pebax;

step S200, firstly, the polymer film is arranged in a mould matched with a preset three-dimensional shape, and then the polymer film is subjected to swelling treatment, in the swelling treatment, a part to be treated is soaked by using a treatment liquid until the volume change rate of the part to be treated is 0.1% -30%, wherein the treatment liquid is a poor solvent of the polymer film;

and step S300, maintaining the polymer film in a preset three-dimensional shape and performing drying treatment at the temperature of 25-80 ℃ to obtain the implantable material, wherein the preset three-dimensional shape of the polymer film is provided with a bending part, the swelling treatment is at least aimed at the bending part or the whole polymer film is swelled, the drying treatment process comprises a relative early stage and a relative later stage, the preset three-dimensional shape of the polymer film is maintained at least in the early stage, and the early stage accounts for at least 15% of the whole drying treatment time.

2. The method of preparing an implantable material according to claim 1, wherein the method of preparing a polymer film comprises:

forming a film on the surface of the die by using the solution;

and drying to obtain the polymer film.

3. The method of preparing an implantable material according to claim 2, wherein the first solvent is selected from good solvents for the starting materials.

4. The method for preparing an implantable material according to claim 1, wherein the thickness of the polymer film is 0.1 to 0.6mm.

5. The method for producing an implantable material according to claim 1, wherein the polymer film has a tubular structure, and the swelling treatment and the drying treatment are performed under the tubular structure; the cylindrical structure is a prefabricated integral structure or the polymer film is prefabricated into a sheet-shaped structure, and then the sheet-shaped structure is curled to enable two opposite sides to be mutually fixed and enclosed into the cylindrical structure.

6. The method of claim 1, wherein the swelling and drying of the polymer film is performed under a sheet-like structure, and the polymer film is enclosed into a cylindrical structure after completion.

7. The method of producing an implantable material according to claim 1, wherein the polymer film is put in a mold matching the predetermined three-dimensional shape before swelling treatment is performed on the polymer film, and a treatment liquid for swelling is injected into the mold.

8. The method of claim 1, wherein the treatment fluid is a second solvent or an aqueous solution of a second solvent, and the second solvent is at least one selected from the group consisting of ethanol, propanol, isopropanol, tetrahydrofuran, acetone, and toluene.

9. The method of preparing an implantable material according to claim 8, wherein the total concentration of the second solvent in the aqueous solution is 30% by mass or more.

10. The method of preparing an implantable material according to claim 1, wherein the polymer film is partially or wholly swelled until the volume change rate of the portion to be treated is 0.1% to 10%.

11. The method of claim 1, wherein the swelling treatment is performed for a period of 0.1 to 24 hours.

12. The method of preparing an implantable material according to claim 1, wherein at least one side of the polymer film is supported by a mold for maintaining a predetermined three-dimensional shape.

13. The method of claim 1, wherein the drying time of the drying treatment is 0.5 to 48 hours; and the drying treatment adopts inert gas for protection.

14. The method of preparing an implantable material according to claim 1, wherein a predetermined three-dimensional shape of the polymer film is maintained throughout the drying process.

15. An implantable material characterized by being obtained by the method for producing an implantable material according to any one of claims 1 to 14.

16. The implantable material of claim 15, wherein the implantable material is a leaflet in an artificial heart valve; the leaflets have opposite open and closed shapes under the influence of a fluid, and a transitional shape during switching, with a predetermined three-dimensional shape corresponding to the closed or transitional shape of the leaflets.

17. The implantable material of claim 16, wherein the leaflet has an open area corresponding to S1 in the open shape, the leaflet has an open area corresponding to S2 in the transitional shape, and the percentage of S2 to S1 is greater than 0 and less than or equal to 85%.

18. A prosthetic prosthesis employing the implantable material of claim 15.

19. A prosthetic heart valve comprising a stent and a leaflet attached to the stent, the leaflet employing the implantable material of claim 16 or 17.

20. The prosthetic heart valve of claim 19, further comprising a cover attached to the stent, the cover employing the implantable material;

the covering film and the valve leaflet are connected in a split mode or are of an integrated structure; the stent is in a radially deformable cylinder shape, a blood flow channel is arranged in the stent, the valve leaflet is positioned at the inner side of the stent to control the blood flow channel, and the covering film is positioned at the blood flow inflow side of the valve leaflet.

21. A method of making a prosthetic heart valve, the prosthetic heart valve comprising a stent and a plurality of leaflets attached to the stent, the method comprising:

providing a polymeric film for preparing a leaflet;

firstly, the polymer film is arranged in a mould matched with a preset three-dimensional shape, then the polymer film is subjected to swelling treatment, and in the swelling treatment, the part to be treated is soaked by using a poor solvent of the polymer film until the volume change rate of the part to be treated is 0.1% -30%;

maintaining the polymer film in a preset three-dimensional shape and drying the polymer film in an environment of 25-80 ℃;

22. The method of manufacturing a prosthetic heart valve of claim 21, further comprising cutting the polymer film according to the contour shape of the leaflet in any step before attaching the dried polymer film as the leaflet to the stent.

23. The method of claim 21, wherein after each of the plurality of leaflets is prepared, the plurality of leaflets are sequentially connected end to form a tubular structure, and then the tubular structure is attached to the stent;

or a plurality of valve leaves are integrated.

24. A method of making a prosthetic heart valve, the prosthetic heart valve comprising a stent and a plurality of leaflets attached to the stent, the method comprising:

providing a polymeric membrane having the contour shape of a leaflet;

the polymer film is arranged on the bracket, swelling treatment is carried out on the polymer film, and in the swelling treatment, the part to be treated is soaked by using a poor solvent of the polymer film until the volume change rate of the part to be treated is 0.1% -30%;

and maintaining the preset three-dimensional shape of the polymer film and drying the polymer film and the bracket in an environment of 25-80 ℃ to obtain the artificial heart valve.

25. The method of making a prosthetic heart valve of claim 21 or 24, further comprising heat treating the prosthetic heart valve; the temperature of the heat treatment is 80-160 ℃.