Degradable plugging device and preparation method thereof
By heat treatment and cooling the blocking membrane or external mesh stent of the cardiac occluder under water and oxygen isolation conditions, and adjusting the material structure, the thrombosis problem caused by large differences in degradation time in the occluder is solved, and the synchronous degradation and safety improvement of the external mesh stent and the blocking membrane are achieved.
Patent Information
- Application Number
- CN202411351038.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-25
- Publication Date
- 2025-05-30
AI Technical Summary
Among the existing cardiac occlusion devices, the degradation time of the outer mesh stent and the occlusion membrane is quite different, which leads to the easy clinical problems such as thrombosis after the occlusion device is implanted into the body.
By heat treatment and rapid cooling of the blocking film or outer mesh scaffold embryo body under sealing conditions with water and oxygen barrier, the microstructure, hydrophilicity and crystallinity of polymer materials can be adjusted, thereby shortening the degradation time and reducing the difference in degradation time.
The synchronous degradation of the outer mesh stent and the blocking membrane is achieved, reducing the risk of thrombosis after the occluder is implanted in the body, and improving the safety and stability of the occluder.
Smart Images
Figure CN120053767A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the technical field of occluder manufacturing, and more specifically, to a biodegradable occluder and its preparation method. Background Art
[0002] A cardiac occluder is an important implantable device in the interventional treatment of structural heart diseases, generally composed of an outer network stent and a flow-blocking membrane. Traditional cardiac occluders are made of non-biodegradable materials such as nitinol, stainless steel, expanded polytetrafluoroethylene (ePTFE), and polyethylene terephthalate (PET), which can affect subsequent minimally invasive surgical access and may cause complications such as nickel ion allergy. Therefore, the research and development of biodegradable cardiac occluders has become one of the hotspots in this field.
[0003] In existing biodegradable occluders, the commonly used materials are mostly polylactic acid and poly(p-dioxanone), etc. For example, poly(p-dioxanone) is used as the outer network stent, and its degradation time (at 37°C) is usually about 365 days. Polylactic acid is used as the flow-blocking membrane, and its degradation time (at 37°C) is usually about 450 - 540 days. The difference in degradation time between the two is as high as 90 - 180 days. In addition, even if the outer network stent and the flow-blocking membrane use the same raw material, due to the large differences in factors such as their sizes, the degradation time of the outer network stent is usually 60 - 120 days longer than that of the flow-blocking membrane. Therefore, even when using the same material, there is still a large difference in degradation time between the two. In other words, existing occluders usually have a large difference in degradation time between the outer network stent and the flow-blocking membrane, which is likely to cause a series of clinical problems such as thrombosis after the occluder is implanted in the body. Therefore, it is urgent to adjust the degradation cycle of the outer network stent or the flow-blocking membrane in the occluder to reduce the difference in their degradation times. Summary of the Invention
[0004] The purpose of this application is to provide a biodegradable occluder and its preparation method, which can narrow the difference in degradation time between the outer network stent and the flow-blocking membrane, and to a certain extent achieve synchronous degradation of the two, thereby solving problems such as thrombosis caused after the occluder is implanted in the body.
[0005] The embodiments of this application are implemented as follows:
[0006] In a first aspect, an embodiment of the present application provides a method for preparing a degradable occluder. The occluder includes an outer network stent and a flow-blocking membrane. The preparation method includes the following steps: First, heat-treat the flow-blocking membrane embryo under a sealed condition of water isolation and oxygen isolation, and then perform a cooling treatment to obtain the flow-blocking membrane; wherein, in the step of heat treatment, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the flow-blocking membrane embryo is -10 to 10 °C; in the step of cooling treatment, the cooling rate is 10 to 30 °C / min until the temperature is reduced to 0 to 20 °C; then, set the flow-blocking membrane on the outer network stent to obtain the degradable occluder.
[0007] Alternatively, first heat-treat the stent embryo under a sealed condition of water isolation and oxygen isolation, and then perform a cooling treatment to obtain the outer network stent; wherein, in the step of heat treatment, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the stent embryo is 0 to 20 °C; in the step of cooling treatment, the cooling rate is 10 to 30 °C / min until the temperature is reduced to 0 to 20 °C; then, set the flow-blocking membrane on the outer network stent to obtain the degradable occluder.
[0008] In the prior art, the degradation time of the outer mesh stent and the degradation time of the occlusion membrane are usually not synchronized, and the difference in their degradation times is as high as more than 60 days, which easily causes a series of clinical problems such as thrombosis after the occluder is implanted into the body. The processing technology provided by the embodiments of the present application can shorten the degradation time of the outer mesh stent or the occlusion membrane, so as to reduce the difference in the degradation times of the outer mesh stent and the occlusion membrane, and to a certain extent achieve their synchronous degradation, thereby solving problems such as thrombosis caused after the occluder is implanted into the body. On the one hand, when the occlusion membrane material and the outer mesh stent material are different and the degradation period of the occlusion membrane material is longer than that of the outer mesh stent material, by sequentially performing heat treatment and rapid cooling treatment on the occlusion membrane embryo under a water- and oxygen-proof sealing condition. Specifically, in the heat treatment step, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the stent embryo is -10 to 10 °C; in the cooling treatment step, the cooling rate is 10 to 30 °C / min until the temperature drops to 0 to 20 °C, a occlusion membrane with a larger degradation rate and a shorter degradation time can be prepared to reduce the difference in the degradation times of the occlusion membrane and the outer mesh stent, and further achieve the synchronous degradation of the occlusion membrane and the outer mesh stent. On the other hand, when the occlusion membrane material and the outer mesh stent material are the same, but due to factors such as the size of the outer mesh stent or other factors, the degradation period of the outer mesh stent is longer than that of the occlusion membrane, by sequentially performing heat treatment and rapid cooling treatment on the stent embryo under a water- and oxygen-proof sealing condition. Specifically, in the heat treatment step, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the stent embryo is 0 to 20 °C; in the cooling treatment step, the cooling rate is 10 to 30 °C / min until the temperature drops to 0 to 20 °C, an outer mesh stent with a larger degradation rate and a shorter degradation time can be prepared to reduce the difference in the degradation times of the outer mesh stent and the occlusion membrane, and further achieve the synchronous degradation of the outer mesh stent and the occlusion membrane. Through the effect of one of the above aspects, the difference in the degradation times of the outer mesh stent and the occlusion membrane can be reduced, and their synchronous degradation can be achieved to a certain extent, thereby solving problems such as thrombosis caused after the occluder is implanted into the body.
[0009] In some alternative embodiments, during the heat treatment, the treatment duration is 10 to 60 min.
[0010] In the above technical solution, limiting the duration of the heat treatment within a specific range can achieve a better modification effect.
[0011] In some alternative embodiments, in the cooling treatment step, an ice-water bath or a refrigerator is used to cool the occlusion membrane embryo or the stent embryo.
[0012] In the above technical solution, cooling treatment is carried out by means of ice-water bath cooling or refrigerator cooling, so that the temperature of the flow-blocking film embryo or the stent embryo can drop rapidly and uniformly, and then the prepared flow-blocking film or outer network stent has high degradation stability and a relatively uniform degradation rate.
[0013] In some alternative embodiments, the material of the stent embryo includes at least one of polyglycolic acid, polylactic acid, and poly(p-dioxanone).
[0014] The above specific types of materials have advantages such as high safety and stable physical and chemical properties. Correspondingly, they have high safety and can be uniformly degraded after being implanted into the body.
[0015] In some alternative embodiments, the material of the flow-blocking film embryo includes at least one of poly(lactide-co-caprolactone), polyglycolic acid, polyurethane, polylactic acid, and polycaprolactone.
[0016] The above specific types of materials have advantages such as high safety and stable physical and chemical properties. Correspondingly, they have high safety and can be uniformly degraded after being implanted into the body.
[0017] In some alternative embodiments, the step of heat-treating the flow-blocking film embryo or the stent embryo under water- and oxygen-proof sealing conditions includes: placing the flow-blocking film embryo or the stent embryo and an open spiral-sealed stainless steel protective can in a glove box, and performing N cyclic operations to make the flow-blocking film embryo or the stent embryo and the stainless steel protective can be in an inert atmosphere; where N is a positive integer greater than 1; the cyclic operation includes: evacuating the glove box, and then filling the glove box with an inert gas to atmospheric pressure; after performing N cyclic operations, sealing the flow-blocking film embryo or the stent embryo in the stainless steel protective can in the glove box, and then placing the sealed stainless steel protective can in a drying oven for heat treatment.
[0018] In the above technical solution, the step of water- and oxygen-proof heat treatment is carried out according to a specific process, which has the advantage of being more thorough in water and oxygen isolation, so as to achieve a better modification effect on the flow-blocking film or the outer network stent, making the degradation times of the two closer.
[0019] In some alternative embodiments, N is 3.
[0020] In the above technical solution, limiting the number of cyclic operations within a specific range can create relatively thorough water- and oxygen-proof conditions. At the same time, a smaller number of cyclic operations can also take into account higher processing efficiency.
[0021] In some alternative embodiments, in the step of evacuating, the vacuum degree in the glove box is -0.06 to -0.1 Mpa until.
[0022] In the above technical solution, in the step of evacuating the air, limiting the vacuum degree in the glove box within a specific range can further play a role in isolating water and oxygen, thereby achieving a better modification effect on the flow-blocking membrane or the outer network support, so that the degradation times of the two are closer.
[0023] In some alternative embodiments, the flow-blocking membrane embryo is prepared by electrospinning technology, including the following steps: mixing the raw materials and solvents of the flow-blocking membrane embryo to obtain a mixed solution; using an electrospinning device to prepare the mixed solution into a flow-blocking membrane embryo. The electrospinning device includes a liquid outlet needle, a receiver, and a pressure supply unit. The liquid outlet needle and the pressure supply unit are connected by a sliding track, and the liquid outlet needle and the receiver are spaced apart.
[0024] Among them, the electrospinning device satisfies at least one of the following conditions A to D:
[0025] A The voltage of the pressure supply unit is 5 - 20 KV.
[0026] B The speed of the liquid outlet needle is 1 - 5 mL / h.
[0027] C The distance from the liquid outlet needle to the receiver is 4 - 5 cm.
[0028] D The rotation speed of the receiver is 200 - 2000 rpm.
[0029] In the above technical solution, the flow-blocking membrane embryo is prepared by electrospinning technology, and by limiting the relevant parameters in the electrospinning device within a specific range, a flow-blocking membrane embryo with relatively excellent physical and chemical properties can be prepared, thereby enabling the preparation of a better-quality occluder.
[0030] In the second aspect, the embodiments of the present application provide a degradable occluder, which is prepared by using the preparation method provided in the first aspect. The difference between the degradation time of the outer network support and the degradation time of the flow-blocking membrane is 0 - 30 days.
[0031] In the above technical solution, the degradable occluder is prepared by using the preparation method provided in the first aspect. The difference in the degradation times of the outer network support and the flow-blocking membrane therein is small, enabling the synchronous degradation of the outer network support and the flow-blocking membrane, and thus solving clinical problems such as blood clots caused by too large a difference in the degradation cycles of the outer network support and the flow-blocking membrane after the occluder is implanted into the body. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings required to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can also be obtained based on these drawings without creative efforts.
[0033] Figure 1 Microstructure test diagram of the flow-blocking membrane provided in Embodiment 1 of the present application;
[0034] Figure 2 Microstructure test diagram of the flow-blocking membrane provided in Comparative Example 1 of the present application;
[0035] Figure 3 Microstructure test diagram of the flow-blocking membrane provided in Comparative Example 3 of the present application;
[0036] Figure 4 Test diagram of the water contact angle of the flow-blocking membrane provided in Embodiment 2 of the present application;
[0037] Figure 5 Test diagram of the water contact angle of the flow-blocking membrane provided in Comparative Example 2 of the present application;
[0038] Figure 6 Summary diagram of the XRD test results of the flow-blocking membranes provided in Embodiment 2 and Comparative Example 2 of the present application;
[0039] Figure 7 Summary diagram of the XRD test results of the outer network brackets provided in Embodiment 3 and Comparative Example 4 of the present application;
[0040] Figure 8 Mass degradation curve of the flow-blocking membrane and the outer network bracket provided in Embodiment 2 of the present application;
[0041] Figure 9 Intrinsic viscosity curve of the flow-blocking membrane and the outer network bracket provided in Embodiment 2 of the present application. Detailed implementation manners
[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. For those not specified in the embodiments, the conventional conditions or the conditions recommended by the manufacturer are followed. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.
[0043] It should be noted that the "and / or" in the present application, such as "feature 1 and / or feature 2", refers to the three cases of "feature 1" alone, "feature 2" alone, and "feature 1" plus "feature 2".
[0044] In addition, in the description of the present application, unless otherwise specified, the "multiple" in "one or more" means two or more; the range of "numerical value a to numerical value b" includes the two end values "a" and "b", and the "measurement unit" in "numerical value a to numerical value b + measurement unit" represents the "measurement unit" of both "numerical value a" and "numerical value b".
[0045] Currently, among the mainstream commercially available degradable occluders, the difference in the degradation time between the outer network stent and the occlusion membrane is usually as high as more than 60 days. Such a large difference in degradation time may cause clinical problems such as thrombosis after the degradable occluder is implanted into the body. Therefore, the synchronous degradation of the outer network stent and the occlusion membrane has become an important problem that urgently needs to be solved at present.
[0046] Research has found that the degradation time of related components prepared from polymer materials is not only determined by their own chemical structure, but is also closely related to the microstructure, hydrophilicity, and crystal properties (such as crystallinity) of the polymer materials. At the same time, it is also related to the final size of the corresponding components. Based on this, by optimizing the preparation process of the outer network stent or the occlusion membrane, it is possible to adjust the properties such as the microstructure, hydrophilicity, and crystal properties (such as crystallinity) of the polymer materials, so that the degradation times of the outer network stent and the occlusion membrane in the occluder are close enough to solve the clinical problem that the existing occluders are prone to cause thrombosis after being implanted into the body.
[0047] The following specifically describes the degradable occluder and its preparation method according to the embodiments of the present application.
[0048] In a first aspect, the embodiments of the present application provide a preparation method of a degradable occluder. The occluder includes an outer network stent and an occlusion membrane. The preparation method includes the following steps: First, heat-treat the occlusion membrane embryo under a sealed condition of water isolation and oxygen isolation, and then perform a cooling treatment to obtain the occlusion membrane. In the step of heat treatment, the heating rate is 3 to 10 °C / min (for example, but not limited to, any one of the heating rates of 3 °C / min, 4 °C / min, 5 °C / min, 6 °C / min, 7 °C / min, 8 °C / min, 9 °C / min, and 10 °C / min or the range value between any two of them), and the difference between the treatment temperature and the melting point of the occlusion membrane embryo is -10 to 10 °C (for example, but not limited to, any one of the difference values of -10 °C, -5 °C, 0 °C, 5 °C, and 10 °C or the range value between any two of them); in the step of cooling treatment, the cooling rate is 10 to 30 °C / min (for example, but not limited to, any one of the heating rates of 10 °C / min, 15 °C / min, 20 °C / min, 25 °C / min, and 30 °C / min or the range value between any two of them), until the temperature is reduced to 0 to 20 °C (for example, but not limited to, any one of the difference values of 0 °C, 5 °C, 10 °C, 15 °C, and 20 °C or the range value between any two of them); then, set the occlusion membrane on the outer network stent to obtain the degradable occluder.
[0049] Alternatively, first heat-treat the stent embryo under sealed conditions of water isolation and oxygen isolation, and then perform a cooling treatment to obtain an outer network stent; wherein, in the step of heat treatment, the heating rate is 3 to 10 °C / min (for example, but not limited to, the heating rate is any one of 3 °C / min, 4 °C / min, 5 °C / min, 6 °C / min, 7 °C / min, 8 °C / min, 9 °C / min, and 10 °C / min or the range value between any two of them), and the difference between the treatment temperature and the melting point of the stent embryo is 0 to 20 °C (for example, but not limited to, the difference is any one of 0 °C, 5 °C, 10 °C, 15 °C, and 20 °C or the range value between any two of them); in the step of cooling treatment, the cooling rate is 10 to 30 °C / min (for example, but not limited to, the heating rate is any one of 10 °C / min, 15 °C / min, 20 °C / min, 25 °C / min, and 30 °C / min or the range value between any two of them), until the temperature is reduced to 0 to 20 °C (for example, but not limited to, the difference is any one of 0 °C, 5 °C, 10 °C, 15 °C, and 20 °C or the range value between any two of them); then, set the flow-blocking film on the outer network stent to obtain a degradable occluder.
[0050] In the prior art, the degradation time of the outer mesh stent is usually not synchronized with that of the occlusion membrane, and the difference in their degradation times is as high as more than 60 days, which easily causes a series of clinical problems such as thrombosis after the occluder is implanted into the body. The processing technology provided by the embodiments of the present application can shorten the degradation time of the outer mesh stent or the occlusion membrane, so as to reduce the difference in the degradation times of the outer mesh stent and the occlusion membrane, and to a certain extent achieve synchronous degradation of the two, thereby solving problems such as thrombosis caused after the occluder is implanted into the body. On the one hand, when the occlusion membrane material and the outer mesh stent material are different and the degradation period of the occlusion membrane material is longer than that of the outer mesh stent material, by sequentially performing heat treatment and rapid cooling treatment on the occlusion membrane embryo under a water- and oxygen-proof sealing condition. Specifically, in the heat treatment step, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the stent embryo is -10 to 10 °C; in the cooling treatment step, the cooling rate is 10 to 30 °C / min until the temperature drops to 0 to 20 °C, a occlusion membrane with a larger degradation rate and a shorter degradation time can be prepared to reduce the difference in the degradation times of the occlusion membrane and the outer mesh stent, and further achieve synchronous degradation of the occlusion membrane and the outer mesh stent. On the other hand, when the occlusion membrane material and the outer mesh stent material are the same, but due to factors such as the size of the outer mesh stent or other factors, the degradation period of the outer mesh stent is longer than that of the occlusion membrane, by sequentially performing heat treatment and rapid cooling treatment on the stent embryo under a water- and oxygen-proof sealing condition. Specifically, in the heat treatment step, the heating rate is 3 to 10 °C / min, and the difference between the treatment temperature and the melting point of the stent embryo is 0 to 20 °C; in the cooling treatment step, the cooling rate is 10 to 30 °C / min until the temperature drops to 0 to 20 °C, an outer mesh stent with a larger degradation rate and a shorter degradation time can be prepared to reduce the difference in the degradation times of the outer mesh stent and the occlusion membrane, and further achieve synchronous degradation of the outer mesh stent and the occlusion membrane.
[0051] It should be noted that after the polymer materials of the occlusion membrane and the outer mesh stent are determined, if the occluder is prepared according to the normal process, the lengths of the degradation periods of the outer mesh stent and the occlusion membrane in the occluder can be obtained. Specifically, there are mainly two cases. The first is that the materials of the occlusion membrane and the outer mesh stent are different, and the degradation period of the occlusion membrane material is longer than that of the outer mesh stent material; the second is that the materials of the occlusion membrane and the outer mesh stent are the same, but due to factors such as the size of the outer mesh stent or other factors, the degradation period of the outer mesh stent material is longer than that of the occlusion membrane.
[0052] Based on this, the essence of the preparation process provided by the embodiments of the present application lies in that: according to the processing process provided by the embodiments of the present application, the degradation rate of the component with a longer degradation time among the two can be increased, thereby shortening its degradation time to achieve the purpose of substantially synchronous degradation of the two. It should be noted that specifically in the present application, the inventors further found that by sequentially performing heat treatment and rapid cooling treatment on the flow-blocking membrane embryo under water-proof and oxygen-proof sealing conditions, the degradation time of the corresponding flow-blocking membrane is adjusted mainly from one, two or three aspects of the microstructure, crystallinity and hydrophilicity of the polymer material; by sequentially performing heat treatment and cooling treatment on the stent embryo under water-proof and oxygen-proof sealing conditions, the degradation time of the corresponding outer network stent is adjusted mainly from one or two aspects of the crystallinity and hydrophilicity of the polymer material.
[0053] As an example, during the heat setting process, the treatment duration is 10 - 60 min, such as but not limited to any one of the point values of 10 min, 20 min, 30 min, 40 min, 50 min and 60 min or the range values between any two of them.
[0054] In this embodiment, limiting the duration of the heat treatment within a specific range can achieve a better modification effect.
[0055] It should be noted that the specific cooling method is not limited and can be set according to the conventional selection in the art.
[0056] As an example, in the step of the cooling treatment, an ice-water bath or a refrigerator is used to cool the stent embryo or the flow-blocking membrane embryo.
[0057] In this embodiment, the ice-water bath cooling or refrigerator cooling method is used for the cooling treatment, so that the temperature of the flow-blocking membrane embryo or the stent embryo can drop rapidly and evenly, and thus the prepared flow-blocking membrane or outer network stent has high degradation stability and a relatively uniform degradation rate.
[0058] As an example, the material of the stent embryo includes at least one of polyglycolic acid, polylactic acid and poly-p-dioxanone.
[0059] In this embodiment, the above-mentioned specific types of materials have advantages such as high safety and stable physical and chemical properties. Correspondingly, they have high safety and can be degraded uniformly after being implanted into the body.
[0060] As an example, the material of the flow-blocking membrane embryo includes at least one of poly(lactide-caprolactone) copolymer, polyglycolic acid, polyurethane, polylactic acid and polycaprolactone.
[0061] In this embodiment, the above-mentioned specific type of material has advantages such as high safety and stable physical and chemical properties. Correspondingly, it has high safety and can be uniformly degraded after being implanted into the body.
[0062] As an example, the steps of heat-treating the flow-blocking membrane embryo or the stent embryo under water- and oxygen-isolated sealing conditions include: placing the flow-blocking membrane embryo or the stent embryo and an opened spiral-sealed stainless-steel protective tank in a glove box, and performing N cyclic operations to make the flow-blocking membrane embryo or the stent embryo and the stainless-steel protective tank under an inert atmosphere; where N is a positive integer greater than 1; the cyclic operation includes: evacuating the glove box, and then filling the glove box with an inert gas to atmospheric pressure; after performing N cyclic operations, sealing the flow-blocking membrane embryo or the stent embryo in the stainless-steel protective tank in the glove box, and then placing the sealed stainless-steel protective tank in a drying oven for heat treatment.
[0063] In this embodiment, the steps of water- and oxygen-isolated heat treatment are carried out according to a specific process, which has the advantage of being more thorough in water and oxygen isolation, so as to be able to achieve a better modification effect on the outer mesh stent or the flow-blocking membrane, making the degradation times of the two closer.
[0064] As an example, N is 3.
[0065] In this embodiment, limiting the number of cyclic operations within a specific range can create relatively thorough water- and oxygen-isolated conditions. At the same time, a smaller number of cyclic operations can also take into account higher processing efficiency.
[0066] As an example, in the step of evacuating, until the vacuum degree in the glove box is -0.06 to -0.1 Mpa.
[0067] In this embodiment, in the step of evacuating, limiting the vacuum degree in the glove box within a specific range can further play a role in water and oxygen isolation, so as to be able to achieve a better modification effect on the outer mesh stent or the flow-blocking membrane, making the degradation times of the two closer.
[0068] As an example, the flow-blocking membrane embryo is prepared by electrospinning technology, including the following steps: mixing the raw materials and the solvent of the flow-blocking membrane embryo to obtain a mixed solution; using an electrospinning device to prepare the mixed solution into a flow-blocking membrane embryo, the electrospinning device includes a liquid outlet needle, a receiver and a pressure supply unit, the liquid outlet needle and the pressure supply unit are connected by a sliding track, and the liquid outlet needle and the receiver are spaced apart; where the electrospinning device satisfies at least one of the following conditions A to D:
[0069] A The voltage of the pressure supply unit is 5 to 20 KV.
[0070] B The speed of the liquid outlet needle is 1 to 5 mL / h.
[0071] The distance from the C liquid outlet needle to the receiver is 4-5 cm.
[0072] D The rotation speed of the receiver is 200-2000 rpm.
[0073] In this embodiment, the flow-blocking membrane embryo is prepared by electrospinning technology, and each relevant parameter in the electrospinning device is limited within a specific range, so that a flow-blocking membrane embryo with relatively excellent physical and chemical properties can be prepared, and thus a better-quality occluder can be prepared.
[0074] It should be noted that for the processes or steps not specifically described or limited in the preparation process, they can be set according to the conventional selection in the art.
[0075] As an example, the solvent is selected from at least one of hexafluoroisopropanol, acetone, dichloroethane, chloroform, and dimethylformamide.
[0076] As an example, in the mixed solution, the mass concentration of the raw material of the flow-blocking membrane embryo is 50-80 mg / mL, such as but not limited to any one point value of 50 mg / mL, 60 mg / mL, 70 mg / mL, and 80 mg / mL or the range value between any two of them.
[0077] In a second aspect, an embodiment of the present application provides a degradable occluder, which is prepared by using the preparation method provided in the first aspect embodiment, and the difference between the degradation time of the outer network stent and the degradation time of the flow-blocking membrane is 0-30 days.
[0078] In the present application, the degradable occluder is prepared by using the preparation method provided in the first aspect embodiment, and the difference in the degradation time between the outer network stent and the flow-blocking membrane is small, which can realize the synchronous degradation of the outer network stent and the flow-blocking membrane, and further solve the clinical problems such as thrombosis caused by the too large difference in the degradation cycle between the outer network stent and the flow-blocking membrane after the occluder is implanted into the body.
[0079] The features and performance of the present application will be further described in detail below in conjunction with embodiments.
[0080] Example 1
[0081] An embodiment of the present application provides a preparation method for a degradable occluder, including the following steps:
[0082] S1 Preparation of the outer network stent
[0083] The PDO raw material wire is knitted and knotted and then placed in a shaping jig, and then placed in a drying oven and heated to 95 °C, heat-insulated for 50 minutes, then the heating is turned off, and it is naturally cooled in the drying oven for 3 hours to room temperature. After removing the jig, two upper and lower umbrella-shaped disk surfaces of the outer network stent are obtained.
[0084] Preparation of S2 Blocking Membrane
[0085] Mix a degradable polymer (polylactic acid PL38, with a melting point of 180 °C) and a solvent to obtain a mixed solution. Here, the solvent is hexafluoroisopropanol, and the mass concentration of the degradable polymer in the mixed solution is 70 mg / mL. Then, use the electrospinning technique to prepare a blocking membrane embryo from the mixed solution. Among them, the spinning voltage is 15 KV, the liquid feeding speed is 1.5 mL / h, the liquid discharging speed is 3 mL / h, the distance from the liquid discharging needle to the receiver is 5 cm, and the rotation speed of the receiver is 1000 rpm.
[0086] Place the blocking membrane embryo (including the receiving paper) and the opened spiral-sealed stainless steel protective canister in a glove box, and perform 3 cyclic operations to make the blocking membrane embryo and the stainless steel protective canister under an inert atmosphere. The cyclic operations include: evacuating the glove box (until the vacuum degree reaches -0.08 Mpa), and then filling the glove box with inert gas to atmospheric pressure. After performing 3 cyclic operations, seal the blocking membrane embryo in the stainless steel protective canister inside the glove box, and then place the sealed stainless steel protective canister in a drying oven for heat treatment. Among them, in the heat treatment step, the heating rate is 5 °C / min, the treatment temperature is 190 °C, and the holding time is 30 min.
[0087] Then, take out the spiral-sealed stainless steel protective canister from the drying oven and place it in an ice-water bath for cooling treatment until the temperature drops to 20 °C to obtain the blocking membrane. Among them, the cooling rate is 15 °C / min.
[0088] After using tweezers and other fixtures to peel the blocking membrane from the receiving paper, put it inside the upper and lower umbrella trays, and then use wire to sew and fix the blocking membrane along the edge of the umbrella tray to obtain a cardiac occluder.
[0089] Example 2
[0090] S1 Preparation of Outer Mesh Support
[0091] Weave and knot with PDO raw material wire, then put it into a shaping jig, and then put it into a drying oven and heat it to 105 °C for heat preservation treatment for 50 minutes. Then turn off the heating and let it cool naturally in the drying oven for 3 hours to room temperature. After removing the jig, obtain an outer mesh support with upper and lower umbrella-shaped disk surfaces.
[0092] S2 Preparation of Blocking Membrane
[0093] Mix a degradable polymer ((L-lactide-co-caprolactone PLC7015 (with a melting point of 110 °C) is mixed with a solvent to obtain a mixed solution. Here, the solvent is hexafluoroisopropanol, and the mass concentration of the degradable polymer in the mixed solution is 80 mg / mL. Then, an electrospinning technique is used to prepare a flow-blocking membrane embryo from the mixed solution. Among them, the spinning voltage is 14 KV, the liquid feeding speed is 2 mL / h, the liquid discharging speed is 3 mL / h, the distance from the liquid discharging needle to the receiver is 5 cm, and the rotation speed of the receiver is 1000 rpm.
[0094] The flow-blocking membrane embryo (including the receiving paper) and the opened spiral-sealed stainless steel protective can are placed in a glove box, and three cyclic operations are performed to make the flow-blocking membrane embryo and the stainless steel protective can under an inert atmosphere. The cyclic operations include: evacuating the glove box (until the vacuum degree reaches -0.08 Mpa), and then filling the glove box with an inert gas to atmospheric pressure. After performing the three cyclic operations, the flow-blocking membrane embryo is sealed in the stainless steel protective can inside the glove box, and then the sealed stainless steel protective can is placed in a drying oven for heat treatment. Among them, in the heat treatment step, the heating rate is 4 °C / min, the treatment temperature is 120 °C, and the heat preservation time is 20 min.
[0095] Then, the spiral-sealed stainless steel protective can is taken out of the drying oven and placed in an ice-water bath for cooling treatment until the temperature drops to 20 °C to obtain a flow-blocking membrane. Among them, the cooling rate is 15 °C / min.
[0096] S3 After using tweezers and other jigs to peel the flow-blocking membrane from the receiving paper, it is placed inside the upper and lower umbrella discs, and then the flow-blocking membrane is fixed by sewing along the edge of the umbrella disc with wire, and a heart occluder can be obtained.
[0097] Example 3
[0098] The embodiment of the present application provides a preparation method of a degradable occluder, including the following steps:
[0099] S1 Preparation of the outer network stent
[0100] The PDO raw material wire is woven and knotted and then placed in a shaping jig, and then placed in a drying oven and heated to 95 °C for 45 minutes. Then, the heating is turned off, and it is naturally cooled in the drying oven for 3 hours to room temperature. After removing the jig, upper and lower umbrella-shaped disc-shaped stent embryos (with a melting point of 100 °C) are obtained.
[0101] Place the scaffold embryo and the opened spiral-sealed stainless-steel protective canister in a glove box, and perform three cyclic operations to bring the scaffold embryo and the stainless-steel protective canister under an inert atmosphere; the cyclic operations include: evacuating the glove box (until the vacuum degree reaches -0.08 Mpa), and then filling the glove box with inert gas up to atmospheric pressure; after performing the three cyclic operations, seal the scaffold embryo in the stainless-steel protective canister inside the glove box, and then place the sealed stainless-steel protective canister in an oven for heat treatment; wherein, in the heat treatment step, the heating rate is 5 °C / min, the treatment temperature is 110 °C, and the holding time is 30 min.
[0102] Then, take out the spiral-sealed stainless-steel protective canister from the oven and place it in an ice-water bath for cooling treatment until the temperature drops to 20 °C to obtain the outer network scaffold; wherein, the cooling rate is 15 °C / min.
[0103] S2 Preparation of the blocking film
[0104] Mix the PDO raw material and the solvent to obtain a mixed solution, wherein the solvent is hexafluoroisopropanol, and the mass concentration of the degradable polymer in the mixed solution is 70 mg / mL; then, use the electrospinning technique to prepare the mixed solution into a blocking film; wherein, the spinning voltage is 15 KV, the liquid feeding speed is 1.5 mL / h, the liquid discharging speed is 3 mL / h, the distance from the liquid discharging needle to the receiver is 5 cm, and the rotation speed of the receiver is 1000 rpm.
[0105] Use tweezers and other jigs to place the blocking film inside the upper and lower umbrella disks, and then use wire to sew and fix the blocking film along the edge of the umbrella disk to obtain a cardiac occluder.
[0106] Comparative Example 1
[0107] The comparative example of this application provides a preparation method of a degradable occluder, including the following steps:
[0108] S1 Preparation of the outer network scaffold
[0109] Weave and tie a PDO raw material wire, then place it in a shaping fixture, and then place it in an oven and heat it to 95 °C for 45 minutes. Turn off the heating and let it cool naturally in the oven for 3 hours to room temperature. After removing the fixture, obtain an outer network scaffold with upper and lower umbrella-shaped disks. In an in vitro PBS (pH = 7.2 - 7.4) buffer solution at 37 °C, its degradation time is about 360 days.
[0110] S2 Preparation of the blocking film
[0111] Mix the degradable polymer (polylactic acid PL38 (with a melting point of 180 °C) is mixed with a solvent to obtain a mixed solution. Here, the solvent is hexafluoroisopropanol, and the mass concentration of the degradable polymer in the mixed solution is 70 mg / mL. Then, an electrospinning technique is used to prepare a flow-blocking membrane from the mixed solution. Among them, the spinning voltage is 15 KV, the liquid feeding speed is 1.5 mL / h, the liquid discharging speed is 3 mL / h, the distance from the liquid discharging needle to the receiver is 5 cm, and the rotation speed of the receiver is 1000 rpm. In a PBS (pH = 7.2 - 7.4) buffer solution at 37 °C in vitro, the degradation time of the flow-blocking membrane is 450 days.
[0112] S3 Use fixtures such as tweezers to place the flow-blocking membrane inside the upper and lower umbrella disks, and then use wires to sew and fix the flow-blocking membrane along the edge of the umbrella disk to obtain a cardiac occluder.
[0113] Comparative Example 2
[0114] The comparative example of this application provides a preparation method of a degradable occluder, and the difference from Example 2 is only that: an electrospinning technique is used to prepare a flow-blocking membrane from the mixed solution, and subsequent water-proof and oxygen-proof heating and cooling treatments are not carried out.
[0115] Comparative Example 3
[0116] The comparative example of this application provides a preparation method of a degradable occluder, and the difference from Example 1 is only that: in the heat treatment step, the heating rate is 15 °C / min, and the treatment temperature is 160 °C.
[0117] Comparative Example 4
[0118] The comparative example of this application provides a preparation method of a degradable occluder, and the difference from Example 3 is only that:
[0119] S1 Preparation of the outer network stent
[0120] Weave and knot the PDO raw material wire, then put it into a shaping jig, and then put it into a drying oven and heat it to 95 °C for 45 minutes. Then turn off the heating and let it cool naturally in the drying oven for 3 hours to room temperature. After removing the jig, two umbrella-shaped disk-shaped stent embryos (with a melting point of 100 °C) are obtained, and subsequent water-proof and oxygen-proof heating and cooling treatments are not carried out.
[0121] Test Example 1
[0122] Microstructure test of the flow-blocking membrane
[0123] Test method
[0124] Number the flow-blocking membranes prepared in Example 1, Comparative Example 1, and Comparative Example 3 respectively, and then use a scanning electron microscope to test the microstructure of each sample.
[0125] Refer toFigure 1 (Corresponding to Example 1) and Figure 2 (Corresponding to Comparative Example 1), it can be seen that among them, Figure 1 and Figure 2 the scales in are both 20 microns. According to the preparation process provided by the embodiments of the present application, it is possible to form a continuous network structure from the original fibrous flow-blocking membrane, thereby changing the microstructure of the flow-blocking membrane, and further enabling the flow-blocking membrane to have a larger degradation rate and a shorter degradation time, so as to narrow the degradation time difference between the outer network stent and the flow-blocking membrane, and further achieve the synchronous degradation of the outer network stent and the flow-blocking membrane.
[0126] Referring to Figure 1 (Corresponding to Example 1) and Figure 3 (Corresponding to Comparative Example 3), it can be seen that among them, Figure 1 and Figure 3 the scales in are both 20 microns. In the step of heat-treating the flow-blocking membrane embryo, if the heating rate is too fast and the heat-treatment temperature is too high, it will cause the network structure formed by the flow-blocking membrane to be damaged, and it is difficult to effectively adjust its degradation rate.
[0127] Test Example 2
[0128] Water contact angle test of the flow-blocking membrane
[0129] Test method
[0130] The flow-blocking membranes prepared in Example 2 and Comparative Example 2 were numbered respectively, and then the water contact angles of each sample were tested under the same conditions.
[0131] Referring to Figure 4 (Corresponding to Example 2) and Figure 5 (Corresponding to Comparative Example 2), it can be seen that for the flow-blocking membrane prepared according to the preparation process provided by the embodiments of the present application, the smaller its water contact angle, that is, the better its hydrophilicity, so that the flow-blocking membrane has a larger degradation rate and a shorter degradation time, so as to narrow the degradation time difference between the outer network stent and the flow-blocking membrane, and further achieve the synchronous degradation of the outer network stent and the flow-blocking membrane.
[0132] Test Example 3
[0133] Crystallinity test of the flow-blocking membrane
[0134] Test method
[0135] The flow-blocking membranes prepared in Example 2 and Comparative Example 2, and the outer network stents prepared in Example 3 and Comparative Example 4 were numbered respectively, and then the XRD patterns of each sample were tested using an XRD device, and the two groups of experimental results were respectively plotted into XRD spectra.
[0136] Referring to Figure 6It can be seen that the flow-blocking film prepared according to the preparation process provided in the embodiments of the present application has a relatively blunt peak shape at 16.8° and a weaker intensity compared to the flow-blocking film prepared by the conventional process. According to the fitting calculation of software Jade6.0, its crystallinity is lower (from 55.2% to 47.8%), that is, it is more easily invaded by water and degraded, so that the flow-blocking film has a larger degradation rate and a shorter degradation time, so as to narrow the degradation time difference between the outer network stent and the flow-blocking film, and then realize the synchronous degradation of the outer network stent and the flow-blocking film.
[0137] Refer to Figure 7 It can be seen that the outer network stent prepared according to the preparation process provided in the embodiments of the present application has smaller diffraction peak intensities at 22° and 24° compared to the outer network stent prepared by the conventional process. According to the fitting calculation of software Jade6.0, its crystallinity is lower (from 62.6% to 52.8%), that is, it is more easily invaded by water and degraded, so that the outer network stent has a larger degradation rate and a shorter degradation time, so as to match the flow-blocking film with a shorter degradation period, be able to narrow the degradation time difference between the outer network stent and the flow-blocking film, and then realize the synchronous degradation of the outer network stent and the flow-blocking film.
[0138] Test Example 4
[0139] Degradation time test of the flow-blocking film and the outer network stent
[0140] Test method
[0141] Step 1: Place the outer network stent and the flow-blocking film prepared in Example 2 in a PBS buffer solution with pH = 7.4 ± 0.02 respectively, and then transfer the corresponding samples to a constant temperature and humidity chamber, where the humidity is 50 ± 2% and the temperature is 50 ± 1°C; then, set the sampling times to 12 days, 24 days, 36 days, 48 days, 60 days, 72 days, 84 days, 96 days, 104 days, 108 days, and 118 days.
[0142] Step 2: Mass loss determination
[0143] 1. Weigh the initial masses of the outer network stent and the flow-blocking film respectively and record them.
[0144] 2. At each sampling point, filter and separate the outer network stent and the flow-blocking film with a funnel respectively. After the leakage liquid has completely leaked down, wash them three times with purified water. After the washing is completed, place the outer network stent and the flow-blocking film in a vacuum drying condition at 50 ± 2°C for 4 h ± 15 min respectively.
[0145] 3. After drying, weigh the masses of the outer network stent and the flow-blocking film after degradation respectively and record them.
[0146] 4. Calculate, the mass retention rate of the outer network stent and the flow-blocking film = mass after degradation / initial mass.
[0147] Step 3: Sort out the corresponding data of each sample and plot the corresponding degradation curves.
[0148] Refer to Figure 8 and Figure 9 It can be seen that (d in the figure represents days), when the plugging device is prepared according to the process provided in the embodiments of the present application, the degradation times of the outer network stent and the flow blocking membrane are 108 days and 118 days respectively, and are consistent with the decreasing trend of their intrinsic viscosities, that is, the degradation times of the outer network stent and the flow blocking membrane in the prepared plugging device are basically the same, and synchronous degradation can be achieved.
[0149] The embodiments described above are some, but not all, of the embodiments of the present application. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application claimed, but merely represents selected embodiments of the present application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts fall within the scope of protection of the present application.
Claims
1. A method for preparing a degradable occluder, characterized in that: The occluder comprises an external mesh support and a flow-blocking membrane, and the preparation method comprises the following steps: The flow-blocking membrane embryo is first subjected to heat treatment under water-proof and oxygen-proof sealing conditions, and then subjected to cooling treatment to obtain the flow-blocking membrane; wherein, in the heat treatment step, the heating rate is 3 to 10°C / min, and the difference between the treatment temperature and the melting point of the flow-blocking membrane embryo is -10 to 10°C; in the cooling treatment step, the cooling rate is 10 to 30°C / min, until the temperature drops to 0 to 20°C; then, the flow-blocking membrane is set on an external network bracket to obtain a degradable occluder; or, The stent embryo is first subjected to heat treatment under water-proof and oxygen-proof sealing conditions, and then subjected to cooling treatment to obtain an outer network stent; wherein, in the heat treatment step, the heating rate is 3 to 10°C / min, and the difference between the treatment temperature and the melting point of the stent embryo is 0 to 20°C; in the cooling treatment step, the cooling rate is 10 to 30°C / min, until the temperature drops to 0 to 20°C; then, a flow-blocking membrane is set on the outer network stent to obtain a degradable occluder.
2. The preparation method according to claim 1, characterized in that: In the step of heat treatment, the treatment time is 10 to 60 minutes.
3. The preparation method according to claim 1, characterized in that: In the cooling treatment step, an ice water bath or a refrigerator is used to cool the flow-blocking membrane embryo or the bracket embryo.
4. The preparation method according to any one of claims 1 to 3, characterized in that The material of the scaffold embryo body includes at least one of polyglycolic acid, polylactic acid and polydioxanone.
5. The preparation method according to any one of claims 1 to 3, characterized in that The material of the flow-blocking membrane embryo body includes at least one of polylactide-caprolactone copolymer, polyglycolic acid, polyurethane, polylactic acid and polycaprolactone.
6. The preparation method according to any one of claims 1 to 3, characterized in that: The step of heat treating the flow-blocking film embryo or the stent embryo under water-proof and oxygen-proof sealing conditions comprises: The flow-blocking film embryo or the bracket embryo and the opened spiral-sealed stainless steel protective tank are placed in a glove box, and N cycles are performed to place the flow-blocking film embryo or the bracket embryo and the stainless steel protective tank in an inert atmosphere; wherein N is a positive integer greater than 1; the cycle operation comprises: evacuating the glove box, and then filling the glove box with an inert gas to atmospheric pressure; After N cycles of operation are performed, the flow-blocking membrane embryo or the bracket embryo is sealed in the stainless steel protective can in the glove box, and then the sealed stainless steel protective can is placed in a drying oven for heat treatment.
7. The preparation method according to claim 6, characterized in that: The N is 3.
8. The preparation method according to claim 6, characterized in that: In the step of evacuating the vacuum, the vacuum degree in the glove box is -0.06 to -0.1 MPa.
9. The preparation method according to any one of claims 1 to 3, characterized in that: The flow-blocking membrane embryo is prepared by electrostatic spinning technology, comprising the following steps: Mixing the raw materials of the flow-blocking membrane embryo with a solvent to obtain a mixed solution; The mixed solution is prepared into the flow-blocking membrane embryo using an electrospinning device, wherein the electrospinning device comprises a liquid outlet needle, a receiver and a pressure supply unit, wherein the liquid outlet needle and the pressure supply unit are connected via a sliding track, and the liquid outlet needle and the receiver are spaced apart; Wherein, the electrospinning device satisfies at least one of the following conditions A to D: The voltage of the pressure supply unit A is 5-20KV; B. The speed of the liquid discharge needle is 1 to 5 mL / h; C. The distance from the liquid discharge needle to the receiver is 4 to 5 cm; D. The rotation speed of the receiver is 200-2000 rpm.
10. A degradable occluder, characterized in that: The method according to any one of claims 1 to 9 is used to prepare the external network support, wherein the difference between the degradation time of the external network support and the degradation time of the flow-blocking membrane is 0 to 30 days.