Degradable adjustable PLGA / PCL micro-injection implant interventional medical device and preparation method thereof

Abstract

The application discloses a kind of controllable degradability PLGA / PCL micro injection implant interventional medical device products and preparation method thereof, the preparation method is according to weight fraction 10~50 portions PCL, 0.1~1.0 portion ZIF-8 is added to appropriate organic solvent and stirred and mixed as intermediate mixed solution, then freeze-drying treatment is carried out to remove organic solvent, after recovering normal temperature, 50~90 portions PLGA are added as mixed material, and then the PLGA / PCL micro injection implant interventional medical device product is prepared by micro injection molding process.The PLGA / PCL micro injection implant interventional medical device product prepared by the application has biocompatibility, promotes vascular-osteogenic activity, controllable degradability, and it is found that the controllable degradability can be realized by adjusting the addition ratio of ZIF-8.

Description

Technical Field

[0001] This invention belongs to the field of implantable interventional medical device products and their molding and processing, and relates to a controllable degradable PLGA / PCL micro-injection molded implantable interventional medical device product and its preparation method. Specifically, it relates to a PLGA / PCL micro-injection molded implantable interventional medical device product with added zeolite imidazole framework-8 (ZIF-8) to improve degradation performance and controllable degradability. Background Technology

[0002] Implantable interventional medical devices are an important product category in the medical device industry and are among the most effective means of treating cardiovascular and cerebrovascular diseases and orthopedic conditions. For example, bone plates and screws, typical components of orthopedic fracture fixation devices, are used to stabilize and fix fractured bone segments, ensuring their proper alignment and healing. Traditional metal fracture fixation devices, such as those made of stainless steel or titanium, provide the necessary strength and rigidity for fracture fixation. However, these metal devices can cause complications including stress shielding and implant displacement, and may require a secondary surgery to remove the implant.

[0003] To address these issues, researchers have developed implantable medical device materials made from biocompatible polymers, such as polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA). These materials can gradually degrade within the body, eliminating the need for surgical removal; and they gradually transfer stress to human tissues, such as bone, reducing stress shielding. However, devices made from traditional PCL and PLGA materials suffer from the following problems: 1. Generally poor biocompatibility; degradation products can exacerbate local immune responses, affecting treatment outcomes such as osteogenic effects; 2. They do not promote bone function and cannot accelerate bone healing; 3. Slow degradation, failing to match the healing time characteristics of human tissues such as natural bone, often resulting in space-occupying effects and hindering normal bone healing; 4. As an amorphous polymer, PLGA's poor crystallinity and stiffness limit its use as medical devices such as bone plates or screws. Furthermore, degradation further weakens its mechanical properties, increasing the fatal risks associated with using PLGA as a medical device.

[0004] Therefore, there is an urgent need for improved implantable medical device materials that possess superior biocompatibility, promote osteogenic-angiogenic coupling, and exhibit excellent mechanical properties and a controllable degradation rate to achieve efficient bone healing. Ideally, the degradation rate of an implantable medical device should match the therapeutic objective, such as the osteogenic process. For example, it should provide sufficient mechanical strength in the initial bone healing stage to prevent bone fragment displacement, while also degrading completely in the later stages without causing a space-occupying effect, thus minimizing complications and promoting bone healing. Summary of the Invention

[0005] To address the problems in the prior art, this invention provides a controllable degradable PLGA / PCL micro-injection molded implantable interventional medical device and its preparation method, which combines biocompatibility, angiogenesis-promoting activity, and controllable degradability. It has also been found that controllable degradability can be achieved by adjusting the proportion of ZIF-8 added.

[0006] To achieve the above objectives, the present invention employs a technical solution consisting of the following technical measures.

[0007] On the one hand, this invention provides a method for preparing a controllable degradable PLGA / PCL micro-injection molded implantable interventional medical device, mainly including the following steps:

[0008] (1) Prepare the following raw materials by weight:

[0009] 50-90 parts of polylactic-co-glycolic acid copolymer (PLGA)

[0010]

[0011] The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts;

[0012] (2) Add the poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process.

[0013] The process parameters of the micro-injection molding process are as follows: melt temperature 170-200℃, injection speed 50-600mm / s, holding pressure temperature 20-120℃, and holding pressure and cooling time 1-7s.

[0014] In this paper, the polylactic acid-glycolic acid copolymer (PLGA) and poly(ε-caprolactone) (PCL) used in step (1) can be selected from conventional commercially available raw materials, such as conventional chemical raw material grade polylactic acid-glycolic acid copolymer and poly(ε-caprolactone); in one technical solution, in order to be better suited for the preparation of implantable interventional medical device products, the raw materials used are preferably medical grade chemical raw materials.

[0015] It should be noted that in the technical solution of this invention, the raw materials mentioned in step (1) are composed of polylactic acid-glycolic acid copolymer (PLGA), poly(ε-caprolactone) (PCL), zeolite imidazole framework-8 (ZIF-8), and organic solvent, without any other fillers / auxiliaries as a fourth raw material component, especially without the addition of compatibilizers / plasticizers / toughening agents. This ensures the biocompatibility, complete degradation, and controllable degradation of the prepared implantable interventional medical device products.

[0016] In one of the technical solutions, the polylactic acid-glycolic acid copolymer (PLGA) mentioned in step (1) is preferably a polylactic acid-glycolic acid copolymer with a molecular weight of 250,000 to 450,000 and a lactic acid content of 40% to 80% in the comonomer.

[0017] In one of the technical solutions, the poly(ε-caprolactone) (PCL) mentioned in step (1) is preferably a poly(ε-caprolactone) with a molecular weight of 40,000 to 80,000 and a particle size of 10 to 1,000 μm.

[0018] In this paper, the zeolite imidazole framework-8 (ZIF-8) used in step (1) can be a commercially available zeolite imidazole framework-8, or it can be a zeolite imidazole framework-8 prepared by conventional preparation processes known in the art or preparation methods described in existing literature.

[0019] It should be noted that, since zeolite imidazole framework-8 (ZIF-8) has certain biotoxicity, in order to reduce the biotoxicity caused by zeolite imidazole framework-8, on the one hand, this invention limits the addition of only a very small amount (≤1%) of zeolite imidazole framework-8, and on the other hand, it adopts a micro-injection molding process after blending, thereby reducing the contact density between zeolite imidazole framework-8 and biological cells, thereby further reducing the biotoxic side effects of zeolite imidazole framework-8.

[0020] In one of the technical solutions, the zeolite imidazole framework-8 (ZIF-8) mentioned in step (1) is preferably a zeolite imidazole framework-8 with a metal core of Zn ions and a particle size of 20 to 500 nm.

[0021] To better illustrate the present invention and provide a technical solution for reference, the zeolite imidazole framework-8 (ZIF-8) described in step (1) is prepared as follows:

[0022] Weigh 0.811 g of dimethylimidazole and dissolve it in 25 mL of methanol to obtain solution A. Weigh 0.734 g of zinc nitrate hexahydrate and dissolve it in 25 mL of methanol to obtain solution B. Place solutions A and B separately under an ultrasonic instrument and sonicate for 5 min to obtain homogenized solutions A and B. Add solution B to solution A and let it stand at room temperature for 24 h. Centrifuge at high speed (8000 rpm, 10 min) and collect the white precipitate. Add methanol to the white precipitate again, shake to mix, and centrifuge again (8000 rpm, 10 min). Repeat the above centrifugation operation 3 times. Place the precipitate in a vacuum drying oven (60℃, 24 h) to remove excess methanol solvent. The resulting white solid powder is zeolite imidazole framework-8, which is stored in a refrigerator at 4℃ for later use.

[0023] The zeolite imidazole framework-8 (ZIF-8) prepared by the above method has a nanoscale and more uniform particle size, which can further reduce the biotoxicity of the final product and improve its biocompatibility.

[0024] In this document, the organic solvent mentioned in step (1) is a conventional organic solvent described in this technical field that can be used to dissolve poly(ε-caprolactone) (PCL). It should be noted that poly(ε-caprolactone) (PCL) is a conventional chemical raw material, and the organic solvent that can dissolve it should be chosen based on common knowledge in the art. In one technical solution, in order to better suit the preparation of implantable interventional medical device products, the organic solvent used is preferably a non-biotoxic medical-grade chemical reagent.

[0025] In one of the technical solutions, the organic solvent in step (1) is selected from any one of 1,4-dioxane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate.

[0026] In one of the technical solutions, in order to improve the overall mechanical properties of the prepared PLGA / PCL micro-injection molded implantable interventional medical device, the following raw materials are prepared by weight in step (1):

[0027]

[0028] The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts.

[0029] It should be noted that the preparation method of this invention is based on micro-injection molding, especially the principle of in-situ fiber formation. By applying strong shear force conditions through micro-injection molding, PCL is induced to form fibers in PLGA in situ, thereby enhancing the mechanical properties of the composite material. The process conditions of the micro-injection molding process described in step (2) are all necessary for in-situ fiber formation.

[0030] For a detailed explanation of the in-situ fiber formation principle and the reasons for the necessity of the process conditions of the micro-injection molding process described in step (2), please refer to the applicant's prior authorized invention patents "Method for preparing PLA biomedical micro-devices by micro-injection molding process" (CN110815700B) and "Method for preparing high-performance PLA / PBSA micro-products based on micro-injection molding process" (CN114228086B).

[0031] In one preferred embodiment, to improve the overall performance of the prepared implantable interventional medical device, the melt temperature in step (2) is preferably 175-195°C.

[0032] In one preferred embodiment, to improve the overall performance of the prepared implantable interventional medical device, the injection speed in step (2) is preferably 100-500 mm / s.

[0033] In one preferred embodiment, to improve the overall performance of the prepared implantable interventional medical device, the pressure holding temperature in step (2) is preferably 30-90°C.

[0034] In one preferred embodiment, to improve the overall performance of the prepared implantable interventional medical device, the pressure holding and cooling time in step (2) is preferably 2 to 6 seconds.

[0035] The inventive point of this invention lies in the fact that, during the further research and development of the applicant's prior authorized invention patent "A method for preparing open-cell ZIF-8 / polymer composite foam material using solid-phase shear grinding technology" (CN112940342B), it was accidentally discovered that when ZIF-8 is directly added to the PLGA / PCL system, it significantly promotes the degradation performance of micro-injection molded samples of the PLGA / PCL system, especially the degradation performance in vivo. Further comparative experimental analysis revealed that the degradation rate of the sample in vivo is positively correlated with the addition ratio of ZIF-8. Thus, the degradation can be controlled by adjusting the addition ratio of ZIF-8, so that the degradation rate of implantable interventional medical devices can be matched with the therapeutic purpose, such as the osteogenic process.

[0036] The above research findings, especially the tests based on in vivo degradation rates, point to ZIF-8 accelerating the degradation of PLGA / PCL materials in vivo through chemical catalysis.

[0037] Zeolite imidazole framework-8 (ZIF-8) is a metal-organic framework (MOF) material. It is a porous material with a high specific surface area and a regular pore structure, formed by the complexation between metal ions and organic ligands. In recent years, due to its excellent physicochemical properties, more and more MOF materials have been applied in the field of bone tissue engineering. ZIF-8, due to its osteoinductive properties, is frequently mentioned in recent research reports on implantable and interventional medical devices.

[0038] However, a search revealed that current literature on the catalytic activity of ZIF-8 focuses primarily on its photocatalytic and electrocatalytic properties. Clearly, when added to a PLGA / PCL blend and placed in an implantable medical device within a living organism, it cannot exert its photocatalytic and electrocatalytic properties. Some literature also reports that ZIF-8 degrades in acidic environments, and the resulting pores in the matrix accelerate water molecule intrusion, thus accelerating the degradation of organic materials. However, in the technical solution of this invention, the PLGA / PCL micro-injection molded implantable medical device, prepared through a micro-injection molding process, has a more compact structure to improve its mechanical properties. The blended ZIF-8 is unlikely to come into contact with an acidic environment for degradation, and subsequent thermogravimetric-infrared-mass spectrometry analysis suggests that it is a chemical catalyst. Based on the above analysis, testing, and simulation experiments, it is speculated that the main principle is that ZIF-8, as a metal-organic framework compound, contains low-coordinate Zn-based complexes in its structure. Zn is exposed in these low-coordinate Zn-based complexes. Analysis using HOMO-LUMO theory shows that LUMOs are mainly located on Zn, creating reaction sites. Simultaneously, PLGA, due to its large molecular weight and strong steric hindrance, is unlikely to form covalent bonds with ZIF-8. Therefore, the exposed Zn... 2+ The ions can contact the ester bonds in polylactic-co-glycolic acid copolymer (PLGA), Zn 2+ The ions can act as Lewis acids, serving as attack sites to attack the ester bonds in polylactic acid-glycolic acid copolymers (PLGA), thereby stealing electrons to carry out the reaction and promoting its degradation.

[0039] Comparative experiments revealed that when the amount of ZIF-8 added was 0.1–0.12 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 20–50 °C lower than that of the control sample without ZIF-8.

[0040] Comparative experiments revealed that when the amount of ZIF-8 added was 0.48–0.52 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 40–80 °C lower than that of the control sample without ZIF-8.

[0041] Comparative experiments revealed that when the amount of ZIF-8 added was 0.98–1.02 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 150–200 °C lower than that of the control sample without ZIF-8.

[0042] It should be noted that the reason for measuring the pyrolysis temperature of the sample is that the pyrolysis temperature can usually reflect the rate of degradation at room temperature. Therefore, by comparing the pyrolysis temperatures of the samples, the changes in degradation rate between different samples can be effectively explained.

[0043] Furthermore, in vivo experiments based on the mouse femoral unilateral cortical bone defect model showed that, compared to the control group and the PLGA / PCL group without ZIF-8, the PLGA / PCL@0.5Z group with ZIF-8 added exhibited a good effect in promoting angiogenesis-osteogenic coupling, thereby promoting bone healing. The experiments also demonstrated that the material degradation in the PLGA / PCL@0.5Z group was more complete than that in the PLGA / PCL group.

[0044] The present invention has the following beneficial effects:

[0045] (1) The PLGA / PCL micro-injection molded implantable interventional medical device products provided by the present invention have the significant advantage of adjustable degradation rate, which can match the healing time characteristics of different natural bone tissues. It can provide sufficient mechanical strength in the initial bone healing stage to prevent bone block displacement, and can degrade in time in the later stage without producing space-occupying effect, so as to minimize complications and promote bone healing. It is expected to be transformed and applied as a new type of implantable interventional medical device.

[0046] (2) The PLGA / PCL micro-injection molded implantable interventional medical device products provided by the present invention, when used as bone nails and other fracture fixation products as one of the optional applications, make up for the shortcomings of domestic and foreign biodegradable absorbable materials for femoral fracture fixation. It can achieve the technical effects of simple manufacturing process, avoidance of secondary surgery, good fixation effect, promotion of fracture recovery and low cost.

[0047] (3) The PLGA / PCL micro-injection molded implantable interventional medical device products provided by the present invention have higher biocompatibility, avoid the aggravation of local immune response caused by degradation products, and do not affect osteogenesis; at the same time, they have the property of promoting angiogenesis-osteogenesis, which can accelerate bone healing and avoid complications such as stress shielding and implant displacement. Attached Figure Description

[0048] Figure 1 The following are evaluation charts based on the molecular dynamics (MD) simulations used in this invention. A) Schematic diagram of the HOMO-LUMO orbitals of PLGA and ZIF-8 in DFT simulation; B) Schematic diagram of MD simulations of PLGA and ZIF-8-supported PLGA before and after heating from 300K to 1650K; C) Curves showing the change of OC=O dissociation number and initial temperature during MD simulations for four different MD models; D) Curves showing the change of molecular species number and initial temperature during MD simulations for four different MD models; E) Schematic diagram of the reasoning mechanism by which ZIF-8 promotes PLGA degradation.

[0049] Figure 2 These are comparative graphs showing the thermogravimetric-infrared spectroscopy (TG-FTIR) analysis of the products prepared in Examples 1-3 and Comparative Example 1 of this invention. In the graphs, F) is the TG-FTIR curve of each sample; G) is the 1750 cm⁻¹ curve of each sample. -1 TG-FTIR curves and initial degradation temperature.

[0050] Figure 3 These are comparative images of in vivo test sections taken in a mouse femoral unilateral cortical bone defect model using the products prepared in Example 1 and Comparative Example 1 of this invention. In the images, arrows indicate residual degradation material, dashed boxes represent magnified images of biological tissue near the implanted device, and CONTROL represents the control group. Detailed Implementation

[0051] To further understand the present invention, preferred embodiments are described below with reference to examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims. Those skilled in the art can refer to the content of this document to appropriately improve the process parameters. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make modifications or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention. Although it is believed that those skilled in the art will fully understand the following terms, the following definitions are set forth to help illustrate the subject matter disclosed in the present invention.

[0052] On the one hand, this invention provides a method for preparing a controllable degradable PLGA / PCL micro-injection molded implantable interventional medical device, mainly including the following steps:

[0053] (1) Prepare the following raw materials by weight:

[0054]

[0055]

[0056] The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts;

[0057] (2) Add the poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process.

[0058] The process parameters of the micro-injection molding process are as follows: melt temperature 170-200℃, injection speed 50-600mm / s, holding pressure temperature 20-120℃, and holding pressure and cooling time 1-7s.

[0059] In this paper, the polylactic acid-glycolic acid copolymer (PLGA) and poly(ε-caprolactone) (PCL) used in step (1) can be selected from conventional commercially available raw materials, such as conventional chemical raw material grade polylactic acid-glycolic acid copolymer and poly(ε-caprolactone); in one embodiment, in order to be more suitable for the preparation of implantable interventional medical device products, the raw materials used are preferably medical grade chemical raw materials.

[0060] It should be noted that in the technical solution of this invention, the raw materials mentioned in step (1) are composed of polylactic acid-glycolic acid copolymer (PLGA), poly(ε-caprolactone) (PCL), zeolite imidazole framework-8 (ZIF-8), and organic solvent, without any other fillers / auxiliaries as a fourth raw material component, especially without the addition of compatibilizers / plasticizers / toughening agents. This ensures the biocompatibility, complete degradation, and controllable degradation of the prepared implantable interventional medical device products.

[0061] In one embodiment, the polylactic acid-hydroxyacetic acid copolymer (PLGA) mentioned in step (1) is preferably a polylactic acid-hydroxyacetic acid copolymer with a molecular weight of 250,000 to 450,000 and a lactic acid content of 40% to 80% in the comonomer.

[0062] In one embodiment, the poly(ε-caprolactone) (PCL) mentioned in step (1) is preferably a poly(ε-caprolactone) with a molecular weight of 40,000 to 80,000 and a particle size of 10 to 1,000 μm.

[0063] In this paper, the zeolite imidazole framework-8 (ZIF-8) used in step (1) can be a commercially available zeolite imidazole framework-8, or it can be a zeolite imidazole framework-8 prepared by conventional preparation processes known in the art or preparation methods described in existing literature.

[0064] It should be noted that, since zeolite imidazole framework-8 (ZIF-8) has certain biotoxicity, in order to reduce the biotoxicity caused by zeolite imidazole framework-8, on the one hand, this invention limits the addition of only a very small amount (≤1%) of zeolite imidazole framework-8, and on the other hand, it adopts a micro-injection molding process after blending, thereby reducing the contact density between zeolite imidazole framework-8 and biological cells, thereby further reducing the biotoxic side effects of zeolite imidazole framework-8.

[0065] In one embodiment, the zeolite imidazole framework-8 (ZIF-8) mentioned in step (1) is preferably a zeolite imidazole framework-8 with a metal core of Zn ions and a particle size of 20 to 500 nm.

[0066] To better illustrate the present invention and provide a reference embodiment, the zeolite imidazole framework-8 (ZIF-8) described in step (1) is prepared as follows:

[0067] Weigh 0.811 g of dimethylimidazole and dissolve it in 25 mL of methanol to obtain solution A. Weigh 0.734 g of zinc nitrate hexahydrate and dissolve it in 25 mL of methanol to obtain solution B. Place solutions A and B separately under an ultrasonic instrument and sonicate for 5 min to obtain homogenized solutions A and B. Add solution B to solution A and let it stand at room temperature for 24 h. Centrifuge at high speed (8000 rpm, 10 min) and collect the white precipitate. Add methanol to the white precipitate again, shake to mix, and centrifuge again (8000 rpm, 10 min). Repeat the above centrifugation operation 3 times. Place the precipitate in a vacuum drying oven (60℃, 24 h) to remove excess methanol solvent. The resulting white solid powder is zeolite imidazole framework-8, which is stored in a refrigerator at 4℃ for later use.

[0068] The zeolite imidazole framework-8 (ZIF-8) prepared by the above method has a nanoscale and more uniform particle size, which can further reduce the biotoxicity of the final product and improve its biocompatibility.

[0069] In this document, the organic solvent mentioned in step (1) is a conventional organic solvent described in this technical field that can be used to dissolve poly(ε-caprolactone) (PCL). It should be noted that poly(ε-caprolactone) (PCL) is a conventional chemical raw material, and the organic solvent that can dissolve it should be chosen based on common knowledge in the art. In one embodiment, in order to better suit the preparation of implantable interventional medical device products, the organic solvent used is preferably a non-biotoxic medical-grade chemical reagent.

[0070] In one embodiment, the organic solvent in step (1) is selected from any one of 1,4-dioxane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate.

[0071] In one embodiment, in step (1), the polylactic acid-glycolic acid copolymer (PLGA) is 50 to 90 parts by weight, for example, 50, 55, 60, 65, 70, 75, 80, 85, 90 parts, or any range or point value between them; the poly(ε-caprolactone) (PCL) is 10 to 50 parts, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50 parts, or any range or point value between them; and the zeolite imidazole framework-8 (ZIF-8) is 0.1 to 1.0 parts, for example, 0.1, 0.2, 0. 3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1.0 parts, or any range or point value between them; the organic solvent is 35 to 175 parts, for example 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, or any range or point value between them.

[0072] In one embodiment, in order to improve the overall mechanical properties of the prepared PLGA / PCL micro-injection molded implantable interventional medical device, the following raw materials are prepared by weight in step (1):

[0073]

[0074] The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts.

[0075] It should be noted that the preparation method of this invention is based on micro-injection molding, especially the principle of in-situ fiber formation. By applying strong shear force conditions through micro-injection molding, PCL is induced to form fibers in PLGA in situ, thereby enhancing the mechanical properties of the composite material. The process conditions of the micro-injection molding process described in step (2) are all necessary for in-situ fiber formation.

[0076] For a detailed explanation of the in-situ fiber formation principle and the reasons for the necessity of the process conditions of the micro-injection molding process described in step (2), please refer to the applicant's prior authorized invention patents "Method for preparing PLA biomedical micro-devices by micro-injection molding process" (CN110815700B) and "Method for preparing high-performance PLA / PBSA micro-products based on micro-injection molding process" (CN114228086B).

[0077] In one embodiment, the process parameters of the micro-injection molding process in step (2) are: melt temperature 170-200℃, for example 170℃, 175℃, 180℃, 185℃, 190℃, 195℃, 200℃ or any range or point value between them; injection speed 50-600mm / s, for example 50mm / s, 60mm / s, 70mm / s, 80mm / s, 90mm / s, 100mm / s, 110mm / s, 120mm / s, 130mm / s, 140mm / s, 150mm / s 200mm / s, 250mm / s, 300mm / s, 350mm / s, 400mm / s, 450mm / s, 500mm / s, 550mm / s, 600mm / s or any range or point value between them; holding temperature 20~120℃, for example 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃ or any range or point value between them; holding and cooling time 1~7s, for example 1s, 2s, 3s, 4s, 5s, 6s or 7s.

[0078] In one preferred embodiment, in order to improve the overall performance of the prepared implantable interventional medical device product, the melt temperature in step (2) is preferably 175-195°C.

[0079] In one preferred embodiment, in order to improve the overall performance of the prepared implantable interventional medical device, the injection speed in step (2) is preferably 100-500 mm / s.

[0080] In one preferred embodiment, in order to improve the overall performance of the prepared implantable interventional medical device, the pressure holding temperature in step (2) is preferably 30 to 90°C.

[0081] In one preferred embodiment, in order to improve the overall performance of the prepared implantable interventional medical device, the pressure holding and cooling time in step (2) is preferably 2 to 6 seconds.

[0082] The inventive point of this invention lies in the fact that, during the further research and development of the applicant's prior authorized invention patent "A method for preparing open-cell ZIF-8 / polymer composite foam material using solid-phase shear grinding technology" (CN112940342B), it was accidentally discovered that when ZIF-8 is directly added to the PLGA / PCL system, it significantly promotes the degradation performance of micro-injection molded samples of the PLGA / PCL system, especially the degradation performance in vivo. Further comparative experimental analysis revealed that the degradation rate of the sample in vivo is positively correlated with the addition ratio of ZIF-8. Thus, the degradation can be controlled by adjusting the addition ratio of ZIF-8, so that the degradation rate of implantable interventional medical devices can be matched with the therapeutic purpose, such as the osteogenic process.

[0083] The above research findings, especially the tests based on in vivo degradation rates, point to ZIF-8 accelerating the degradation of PLGA / PCL materials in vivo through chemical catalysis.

[0084] Zeolite imidazole framework-8 (ZIF-8) is a metal-organic framework (MOF) material. It is a porous material with a high specific surface area and a regular pore structure, formed by the complexation between metal ions and organic ligands. In recent years, due to its excellent physicochemical properties, more and more MOF materials have been applied in the field of bone tissue engineering. ZIF-8, due to its osteoinductive properties, is frequently mentioned in recent research reports on implantable and interventional medical devices.

[0085] However, a search revealed that current literature on the catalytic activity of ZIF-8 focuses primarily on its photocatalytic and electrocatalytic properties. Clearly, when added to a PLGA / PCL blend and placed in an implantable medical device within a living organism, it cannot exert its photocatalytic and electrocatalytic properties. Some literature also reports that ZIF-8 degrades in acidic environments, and the resulting pores in the matrix accelerate water molecule intrusion, thus accelerating the degradation of organic materials. However, in the technical solution of this invention, the PLGA / PCL micro-injection molded implantable medical device, prepared through a micro-injection molding process, has a more compact structure to improve its mechanical properties. The blended ZIF-8 is unlikely to come into contact with an acidic environment for degradation, and subsequent thermogravimetric-infrared-mass spectrometry analysis suggests that it is a chemical catalyst. Based on the above analysis, testing, and simulation experiments, it is speculated that the main principle is that ZIF-8, as a metal-organic framework compound, contains low-coordinate Zn-based complexes in its structure. Zn is exposed in these low-coordinate Zn-based complexes. Analysis using HOMO-LUMO theory shows that LUMOs are mainly located on Zn, creating reaction sites. Simultaneously, PLGA, due to its large molecular weight and strong steric hindrance, is unlikely to form covalent bonds with ZIF-8. Therefore, the exposed Zn... 2+ The ions can contact the ester bonds in polylactic-co-glycolic acid copolymer (PLGA), Zn 2+ The ions can act as Lewis acids, serving as attack sites to attack the ester bonds in polylactic acid-glycolic acid copolymers (PLGA), thereby stealing electrons to carry out the reaction and promoting its degradation.

[0086] Comparative experiments revealed that when the amount of ZIF-8 added was 0.1–0.12 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 20–50 °C lower than that of the control sample without ZIF-8.

[0087] Comparative experiments revealed that when the amount of ZIF-8 added was 0.48–0.52 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 40–80 °C lower than that of the control sample without ZIF-8.

[0088] Comparative experiments revealed that when the amount of ZIF-8 added was 0.98–1.02 wt%, the pyrolysis temperature of the prepared PLGA / PCL micro-injection molded implantable interventional medical device was 150–200 °C lower than that of the control sample without ZIF-8.

[0089] It should be noted that the reason for measuring the pyrolysis temperature of the sample is that the pyrolysis temperature can usually reflect the rate of degradation at room temperature. Therefore, by comparing the pyrolysis temperatures of the samples, the changes in degradation rate between different samples can be effectively explained.

[0090] Furthermore, in vivo experiments based on the mouse femoral unilateral cortical bone defect model showed that, compared to the control group and the PLGA / PCL group without ZIF-8, the PLGA / PCL@0.5Z group with ZIF-8 added exhibited a good effect in promoting angiogenesis-osteogenic coupling, thereby promoting bone healing. The experiments also demonstrated that the material degradation in the PLGA / PCL@0.5Z group was more complete than that in the PLGA / PCL group.

[0091] The present application will be further explained in detail below with reference to embodiments. However, those skilled in the art should understand that these embodiments are provided for illustrative purposes only and are not intended to limit the present application.

[0092] Example

[0093] The embodiments of this application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of this application. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Where the manufacturers of reagents or instruments are not specified, they are all commercially available conventional products. This application should not be construed as being limited to the specific embodiments described.

[0094] 1. Raw materials

[0095] Polylactic acid-glycolic acid copolymer (PLGA, DG-75DLG200) has a weight-average molecular weight (Mw) of 2.4 × 10⁵ g·mol⁻¹. -1 Purchased from China Daigang Biotechnology Co., Ltd.

[0096] Poly(ε-caprolactone) (PCL, 600c, Mw = 60000) was supplied by Shenzhen Guanghua Industrial Co., Ltd. (China).

[0097] Zeolite imidazole framework-8 (ZIF-8) was prepared according to the following method:

[0098] Weigh 0.811 g of dimethylimidazole (M104839, Alladin) and dissolve it in 25 mL of methanol solution as solution A. Weigh 0.734 g of zinc nitrate hexahydrate (Z111703, Alladin) and dissolve it in 25 mL of methanol solution as solution B. Place solutions A and B separately under an ultrasonic instrument and sonicate for 5 min to obtain homogenized solutions A and B. Add solution B to solution A and let it stand at room temperature for 24 h. Centrifuge at high speed (8000 rpm, 10 min) and collect the white precipitate. Add methanol to the white precipitate again, shake to mix, and centrifuge again (8000 rpm, 10 min). Repeat the above centrifugation operation 3 times. Place the precipitate in a vacuum drying oven (60℃, 24 h) to remove excess methanol solvent. The resulting white solid powder is zeolite imidazole framework-8, which is stored in a refrigerator at 4℃ for later use.

[0099] Example 1

[0100] This embodiment provides a method for preparing a controllable and degradable PLGA / PCL micro-injection molded implantable interventional medical device, which mainly includes the following steps:

[0101] (1) Prepare the following raw materials by weight:

[0102]

[0103] (2) Add the poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process, denoted as PLGA / PCL@0.5Z or PLGA / PCL-0.5Z.

[0104] The process parameters for the micro-injection molding process are as follows: MicroPower-5 micro-injection molding machine, melt temperature 190℃, injection speed 200mm / s, holding pressure temperature 40℃, and holding and cooling time 4s.

[0105] Example 2

[0106] This embodiment provides a method for preparing a controllable and degradable PLGA / PCL micro-injection molded implantable interventional medical device, which mainly includes the following steps:

[0107] (1) Prepare the following raw materials by weight:

[0108]

[0109] (2) Add the poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process, denoted as PLGA / PCL@0.1Z or PLGA / PCL-0.1Z.

[0110] The process parameters for the micro-injection molding process are as follows: MicroPower-5 micro-injection molding machine, melt temperature 190℃, injection speed 200mm / s, holding pressure temperature 40℃, and holding and cooling time 4s.

[0111] Example 3

[0112] This embodiment provides a method for preparing a controllable and degradable PLGA / PCL micro-injection molded implantable interventional medical device, which mainly includes the following steps:

[0113] (1) Prepare the following raw materials by weight:

[0114]

[0115]

[0116] (2) Add poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process, denoted as PLGA / PCL@1.0Z or PLGA / PCL-1.0Z.

[0117] The process parameters for the micro-injection molding process are as follows: MicroPower-5 micro-injection molding machine, melt temperature 190℃, injection speed 200mm / s, holding pressure temperature 40℃, and holding and cooling time 4s.

[0118] Comparative Example 1

[0119] This comparative example provides a method for preparing a PLGA / PCL micro-injection molded implantable interventional medical device, which mainly includes the following steps:

[0120] (1) Prepare the following raw materials by weight:

[0121] 70 parts of polylactic-co-glycolic acid copolymer (PLGA)

[0122] Poly(ε-caprolactone) (PCL) 30 parts,

[0123] 105 parts of organic solvent (1,4-dioxane);

[0124] (2) Add the poly(ε-caprolactone) from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process, denoted as PLGA / PCL.

[0125] The process parameters for the micro-injection molding process are as follows: MicroPower-5 micro-injection molding machine, melt temperature 190℃, injection speed 200mm / s, holding pressure temperature 40℃, and holding and cooling time 4s.

[0126] 2. Testing Methods

[0127] To clarify the degradation process of the samples in Examples 1-3 and Comparative Example 1, thermogravimetric-infrared spectroscopy (TG-FTIR) analysis was performed in a Clarus SQ 8T (PerkinElmer, USA). The sample weight was 10 mg, and the heating rate was 50 °C / min. -1 The test results are as follows Figure 2 As shown.

[0128] Classical molecular dynamics (MD) simulations were used to explore the pyrolysis behavior of PLGA block copolymers under various settings. Here, we investigated four different MD models: pure PLGA copolymer, hydrous PLGA copolymer, ZIF-8-supported PLGA, ZIF-8-supported hydrous PLGA, and 10 PLGA copolymer chains placed in an MD model. Each PLGA copolymer chain consisted of 40 monomers, including PCL and PLGA monomers. For the hydrous case, 500 water molecules were incorporated into the copolymer. For the ZIF-8-containing case, a 2×2×1 ZIF-8 superunit was generated and placed at the bottom. To eliminate potential surface effects, periodic boundary conditions (PBCs) were applied in three orthogonal directions.

[0129] To characterize the atomic interactions in the studied system containing PLGA copolymers, a reactive force field (ReaxFF) was used. The ReaxFF force field has proven effective in capturing the breaking and formation of covalent bonds in various carbon-based structures under conditions such as heating and strain. In this work, we investigated the pyrolysis behavior of PLGA copolymers under different conditions using a parameterized version of ReaxFF. Energy minimization was first performed to relax the PLGA system before MD simulations. Then, MD simulations were performed at 300.15 K for 500,000 time steps to further relax the sample. Following MD relaxation, the relaxed sample was heated to 1673.15 K over 10,000,000 time steps to observe the pyrolysis behavior of the PLGA block copolymers. All MD simulations were run in a gauge ensemble (NVT) with temperature controlled by a Nose-Hoover thermostat. Atomic motions in the system followed classical Newton's equations, solved using the Velocity-Verlet algorithm with a time step of 0.1 fs. All MD simulations were performed using the Large Atomic / Molecular Massive Parallel Simulator (LAMMPS) software package. The ChemTraYzer chemical trajectory analyzer was used to identify, quantify, and evaluate the elementary reactions in our ReaxFF MD simulations, and the test results are as follows: Figure 1 As shown.

[0130] Eight-week-old mice had their hind limbs shaved and disinfected with povidone-iodine. A 5mm longitudinal incision was made along the femoral axis to expose the midshaft. A 3×1mm rectangular cortical defect was created in the mid-femur using a high-speed dental motor. In the control group, the muscles were repositioned and the skin sutured immediately after defect preparation. In the experimental group, matched-size PLGA / PCL and PLGA / PCL@0.5Z micro-injection implantation devices were implanted at the defect site. Postoperatively, the muscles were repositioned and the skin sutured, and penicillin was administered intramuscularly to prevent infection. On postoperative day 28, the mice were euthanized, the femur was completely removed and fixed with 4% paraformaldehyde, the femoral sample was demineralized and embedded, and frozen sections (100μm) were prepared along the longitudinal axis for RUNX2 / EMCN / DAPI triple immunostaining. Imaging was then performed using a rotating confocal microscope (Andor, Oxford) at 20x magnification. The test results are as follows: Figure 3 As shown.

[0131] 3. Test Results

[0132] like Figure 1 As shown, DFT analysis indicates that ZIF-8's LUMO is low-coordinated with Zn. 2+ The Zn in ZIF-8 is centered around an ester bond structure, while the HOMO of PLGA is centered around an ester bond structure. 2+ZIF-8 can act as a Lewis acid site, promoting various chemical reactions and adsorption processes. MD analysis showed that as temperature increased, the more mobile short chains of PLGA occupied the simulated space. Due to the lack of long-chain molecular entanglement, PLGA tended towards a high-entropy state. In contrast, ZIF-8 maintained its molecular shape throughout the degradation process. Compared to pure PLGA samples, PLGA samples containing ZIF-8 and water showed several left-shifted OC=O dissociation curves. Furthermore, the initial temperature of OC=O dissociation was also lower than that of pure PLGA. These results indicate that ZIF-8 can promote the degradation of PLGA ester bonds autonomously or in conjunction with water. As a Lewis acid, ZIF-8 attacks the ester bonds of PLGA, thereby promoting its degradation.

[0133] like Figure 3 As shown, RUNX2 / EMCN / Ki67 staining results indicated that the bone defect areas of mice in the control group and PLGA / PCL group healed more slowly, with obvious coarse callus morphology and a small amount of RUNX2 within the callus. + Signal expression, and a small number of scattered EMCNs + Blood vessels were observed. Furthermore, in the PLGA / PCL group, clearly defined strip-shaped material was visible in the bone defect area, indicating a low degree of material degradation. In contrast, the PLGA / PCL@0.5Z group showed more complete bone healing with no obvious callus structure, indicating more complete material degradation with only a small amount remaining, and abundant RUNX2 surrounding the material. + Signal representation, and dense EMCN + The presence of blood vessels indicates that ZIF-8-modified PLGA / PCL materials promote angiogenesis-osteogenic coupling. These results suggest that ZIF-8 can promote bone healing by facilitating the degradation of PLGA / PCL materials and angiogenesis-osteogenic coupling.

Claims

1. A method for preparing a tunable degradable PLGA / PCL micro-injection molded implantable interventional medical device, characterized in that... The main steps include: (1) Prepare the following raw materials by weight: 50-90 parts of polylactic acid-glycolic acid copolymer, Poly(ε-caprolactone) 10~50 parts, Zeolite imidazole framework-8 0.1~1.0 parts, Organic solvent 35~175 parts, The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts; the zeolite imidazole framework-8 is a zeolite imidazole framework-8 with a metal core of Zn ions and a particle size of 20~500nm. (2) Add the poly(ε-caprolactone) and zeolite imidazole framework-8 from step (1) to an organic solvent and stir to mix evenly as an intermediate mixture. Then freeze-dry to remove the organic solvent. After restoring to room temperature, add polylactic acid-glycolic acid copolymer to mix as a mixture. Then prepare PLGA / PCL micro-injection molded implantable interventional medical device products through micro-injection molding process. The process parameters of the micro-injection molding process are as follows: melt temperature 170~200℃, injection speed 50~600mm / s, holding pressure temperature 20~120℃, and holding pressure and cooling time 1~7s.

2. The preparation method according to claim 1, characterized in that: The zeolite imidazole framework-8 described in step (1) is prepared as follows: Weigh 0.811 g of dimethylimidazole and dissolve it in 25 mL of methanol solution as solution A. Weigh 0.734 g of zinc nitrate hexahydrate and dissolve it in 25 mL of methanol solution as solution B. Place solutions A and B separately under an ultrasonic instrument and sonicate for 5 min to obtain homogenized solutions A and B. Add solution B to solution A and let it stand at room temperature for 24 h. Centrifuge using a high-speed centrifuge and collect the white precipitate. Add methanol to the white precipitate again, shake to mix, and centrifuge again. Repeat the above centrifugation operation 3 times. Place the precipitate in a vacuum drying oven to remove excess methanol solvent. The resulting white solid powder is zeolite imidazole framework-8, which is stored in a refrigerator at 4℃ for later use.

3. The preparation method according to claim 1, characterized in that: The organic solvent selected in step (1) includes any one of 1,4-dioxane, dimethyl sulfoxide, tetrahydrofuran, and ethyl acetate.

4. The preparation method according to claim 1, characterized in that... In step (1), the following raw materials are prepared by weight: 65-75 parts of polylactic acid-glycolic acid copolymer, Poly(ε-caprolactone) 25-35 parts, Zeolite imidazole framework-8 0.1~1.0 parts, Organic solvent 35~175 parts, The polylactic acid-glycolic acid copolymer and poly(ε-caprolactone) together comprise 100 parts.

5. The preparation method according to claim 1, characterized in that: The melt temperature in step (2) is 175~195℃.

6. The preparation method according to claim 1, characterized in that: The injection speed in step (2) is 100~500mm / s.

7. The preparation method according to claim 1, characterized in that: The pressure holding temperature in step (2) is 30~90℃.

8. The PLGA / PCL micro-injection molded interventional medical device product prepared by the preparation method of the adjustable degradable PLGA / PCL micro-injection molded implantable interventional medical device product according to claim 1.

9. The application of the PLGA / PCL micro-injection molded implantable interventional medical device product as an implantable interventional medical device according to claim 8.

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