Developable polymer composite material and method of making and use thereof

Abstract

This invention discloses a radiopaque polymer composite material, its preparation method, and its applications. The radiopaque polymer composite material of this invention comprises the following components by weight percentage: biodegradable polymer: 50%–75%; iodine-containing contrast agent: 20%–45%; dispersant: 5%–10%. The radiopaque polymer composite material of this invention has advantages such as good radiopaque effect, high mechanical strength, good biocompatibility, and safe degradability. It is suitable for medical products such as interventional medical devices and implantable materials / devices. Furthermore, its preparation method is simple, the raw materials are widely available, and the production cost is low, making it suitable for large-scale industrial production and application.

Description

Technical Field

[0001] This invention relates to the fields of polymer materials and medical imaging technology, specifically to a radiopaque polymer composite material, its preparation method, and its application. Background Technology

[0002] With the rapid development of interventional medicine, minimally invasive surgery, and medical imaging technology, an increasing number of medical devices (such as catheters, guidewires, and other interventional medical devices; stents, joints, and other implantable materials / devices) require excellent visualization capabilities in vivo to achieve precise positioning, real-time monitoring, and postoperative follow-up. Against this backdrop, incorporating imaging capabilities into polymer material systems to construct radiopaque polymer material systems has become one of the important research directions in the field of biomaterials.

[0003] Polyurethane, polylactic acid, polycaprolactone, and polyethylene glycol, among other polymers, possess excellent biocompatibility and processing properties. However, their response to X-ray or CT imaging is weak, making it difficult to meet the imaging monitoring requirements after interventional or implantation procedures. Therefore, it is often necessary to introduce radiopaque components containing high atomic number elements (e.g., iodine, barium, tungsten, bismuth) to endow polymers with radiopaque properties. However, existing radiopaque polymer systems still face the following problems in practical applications: 1) Under traditional physical blending methods, the amount of radiopaque component added to the polymer matrix is ​​limited. Excessive radiopaque component content can easily lead to material embrittlement, decreased mechanical properties, or deterioration of processing performance, making it difficult to balance radiopaque effect and material performance; 2) The interfacial compatibility between the radiopaque component and the polymer matrix is ​​poor, easily leading to aggregation, phase separation, or sedimentation, resulting in uneven radiopaque performance within the material and affecting imaging stability and clinical safety; 3) Some radiopaque fillers may migrate, precipitate, or detach in the body fluid environment, which not only weakens the long-term radiopaque effect but may also pose biosafety risks.

[0004] Therefore, it is of great significance to develop a polymer composite material with good development effect, high mechanical strength, good biocompatibility, and safe degradability. Summary of the Invention

[0005] The purpose of this invention is to provide a developable polymer composite material, its preparation method, and its application.

[0006] The technical solution adopted in this invention is: A developable polymer composite material comprising the following components by weight percentage: Biodegradable polymers: 50%–75%; Iodine-containing developing agents: 20%–45%; Dispersant: 5%–10%.

[0007] Preferably, the biodegradable polymer is at least one of poly(p-dioxanone) (PPDO), polylactic acid (PLA), polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA), and polyhydroxyalkanoate (PHA).

[0008] More preferably, the degradable polymer is poly(p-dioxanone).

[0009] Preferably, the number-average molecular weight of the poly(p-dioxanone) is 5000 g / mol to 50000 g / mol.

[0010] Preferably, the iodine-containing developing agent is at least one of iodixanol, iohexol, iopromide, iopamidol, and iomethol.

[0011] Preferably, the dispersant is at least one of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and polyethylene glycol-polypropylene glycol block copolymer (PEG-PPG).

[0012] More preferably, the dispersant is polyvinyl alcohol.

[0013] Preferably, the number-average molecular weight of the polyvinyl alcohol is 30,000 g / mol to 220,000 g / mol.

[0014] A method for preparing a developable polymer composite material as described above includes the following steps: 1) Mix chlorinated hydrocarbon solvent and fluorinated alcohol solvent, then add part of iodine-containing developer and dispersant and mix well, then add the remaining iodine-containing developer and mix well, then add biodegradable polymer and mix well to obtain spinning solution. 2) Add the spinning solution to the electrospinning device for electrospinning to obtain a developable polymer composite material.

[0015] Preferably, the volume ratio of the chlorinated hydrocarbon solvent and the fluorinated alcohol solvent in step 1) is 1:0.1 to 2.

[0016] Preferably, the chlorinated hydrocarbon solvent in step 1) is at least one of dichloromethane and chloroform.

[0017] Preferably, the fluorinated alcohol solvent in step 1) is at least one of hexafluoroisopropanol, 2,2,2-trifluoroethanol, and tetrafluoropropanol.

[0018] Preferably, the electrospinning process parameters in step 2) include: feed rate of 0.5 mL / h to 2 mL / h, voltage of 4.5 kV to 20 kV, receiving distance of 8 cm to 12 cm, and spinning time of 4 h to 10 h.

[0019] Preferably, the electrospinning in step 2) is carried out at room temperature.

[0020] A medical product comprising the above-mentioned radiopaque polymer composite material.

[0021] Preferably, the medical product is one of interventional medical devices or implantable materials / devices.

[0022] The beneficial effects of the present invention are: the radiopaque polymer composite material of the present invention has the advantages of good radiopaque effect, high mechanical strength, good biocompatibility, safety and degradability, etc., and is suitable for medical products such as interventional medical devices and implantable materials / devices. Moreover, its preparation method is simple, the raw materials are widely available, and the production cost is low, making it suitable for large-scale industrial production and application.

[0023] Specifically: 1) This invention employs a composite solvent system composed of chlorinated hydrocarbon solvents and fluorinated alcohol solvents, and introduces iodine-containing developing agents stepwise, enabling the iodine-containing developing agents to achieve high loading and uniform dispersion in the polymer matrix (forming a uniform distribution at the nanoscale or microscale). This effectively avoids the aggregation or precipitation of developing agents (fundamentally ensuring the consistency of physical properties and stability of the molding process of the polymer composite material). The uniformly dispersed developing agent ensures that the polymer composite material exhibits a durable and stable developing effect during X-ray or CT imaging, avoiding the problem of image quality degradation or low contrast caused by uneven distribution of developing agents during the imaging process. 2) The radiopaque polymer composite material of the present invention uses an iodine-containing contrast agent with high atomic number characteristics, which can provide strong and clear imaging contrast during the imaging process and maintain stable performance in complex biological environments, thereby ensuring long-term stable imaging quality. It is suitable for interventional medical devices and implantable materials that require high-resolution imaging, and provides effective protection for precise positioning and monitoring. 3) The radiopaque polymer composite material of the present invention uses a biodegradable polymer as the matrix, which not only has a low risk of immune rejection, but also gradually degrades after completing the radiopaque function. The material can be safely absorbed by the body during the degradation process in vivo, reducing the long-term burden on patients and avoiding permanent foreign body reactions caused by long-term implantation. It is suitable for long-term treatment and monitoring. 4) The radiopaque polymer composite material of the present invention is prepared by electrospinning technology. It has excellent mechanical properties, high compressive strength and tensile strength, which enables it to maintain stable performance and structural integrity in complex biological environments. It can be adapted to various medical device forms (e.g., catheters, stents, emboli, etc.), expanding its applicability in different medical applications. 5) The radiopaque polymer composite material of the present invention can effectively enhance the resolution and accuracy of medical images by providing a stable imaging effect. Especially in interventional treatments such as embolization therapy, the treatment area can be accurately determined by using the composite material, ensuring that the embolized material is accurately placed in the target blood vessel, reducing the impact on normal tissues. Moreover, the image feedback system can be used to monitor the treatment process in real time, ensuring the accuracy and safety of the treatment effect. 6) The radiopaque polymer composite material of the present invention is not only applicable to X-ray and CT imaging, but can also be extended to other medical imaging technologies (e.g., MRI, ultrasound, etc.), providing a new solution for the diversification of medical imaging technology. Moreover, its radiopaque performance can remain consistent on different devices, making it widely applicable, meeting different clinical needs, and improving the accuracy of medical imaging. 7) The preparation method of the radiopaque polymer composite material of the present invention is simple to operate and the parameters are controllable. It can be widely adapted to a variety of polymers and types of iodine-containing contrast agents. The material can be processed into fiber, film and tube forms according to clinical needs. It can be widely used in multiple fields such as cardiovascular intervention, neurosurgical implantation and tumor markers, and has extremely high clinical promotion value. Attached Figure Description

[0024] Figure 1 This is a schematic diagram of an in vitro development test of the developable polymer composite material of Example 1.

[0025] Figure 2 The image shows the in vitro development test results of the developable polymer composite material of Example 1.

[0026] Figure 3 This is a graph showing the results of an in vitro long-term development test of the developable polymer composite material of Example 1.

[0027] Figure 4 This is a SEM image of the cross-section of the developable polymer composite material of Example 1.

[0028] Figure 5 This is an EDXS image of the developable polymer composite material of Example 1.

[0029] Figure 6 The figure shows the tensile properties test results of the developable polymer composite material in Example 1.

[0030] Figure 7 The image shows the results of a long-term imaging test of the radiopaque polymer composite material of Example 1 in SD rats. Detailed Implementation

[0031] The present invention will be further explained and described below with reference to specific embodiments.

[0032] Example 1: A developable polymer composite material is prepared by the following method: 1) Mix 10 mL of dichloromethane and 2 mL of hexafluoroisopropanol and stir at room temperature for 10 min at a stirring rate of 500 r / min. Then add 500 mg of iodixanol and 50 mg of polyvinyl alcohol (PVA; number average molecular weight of 146000 g / mol) and continue stirring for 30 min. Then add another 500 mg of iodixanol and continue stirring for 30 min. Finally, add 2 g of poly(p-dioxanone) (PPDO; number average molecular weight of 50000 g / mol) and continue stirring for 1 h to obtain the spinning solution. 2) Add the spinning solution to the electrospinning device and perform electrospinning at room temperature. The process parameters for electrospinning are as follows: feed rate is 1.5 mL / h, voltage is 15 kV, receiving distance is 10 cm, and spinning time is 5 h. After peeling off from the receiving device, place it in a vacuum drying environment at room temperature for 24 h to obtain a developable polymer composite material (fiber membrane).

[0033] Performance testing: 1) Cut the radiopaque polymer composite material of this embodiment into circular films with a diameter of 0.5 cm (maintaining a consistent thickness). Then, lay the circular films (ensuring a smooth surface) flat in the sample tray of the CT scanning equipment. Next, stack pigskin (approximately 6 cm thick) on top of the circular films to simulate tissue thickness. Then, use a medical X-ray computed tomography (CT) scanner to scan the sample (without introducing other radiopaque materials during the scanning process) to perform an in vitro radiopaque test (as shown in the test diagram). Figure 1 As shown in the figure), after scanning, image analysis software was used to measure the grayscale value of the image to evaluate the material's developing ability and developing uniformity under X-ray conditions. The test results are as follows. Figure 2 As shown.

[0034] Depend on Figure 2 It can be seen that the radiopaque polymer composite material can exhibit good imaging effect under X-ray irradiation in pigskin tissue with a thickness of about 6 cm, indicating that it has good imaging effect.

[0035] 2) The developable polymer composite material of this embodiment was cut into circular films with a diameter of 0.5 cm, and then subjected to in vitro development testing to determine the gray value (as above). The circular films were then completely immersed in phosphate buffer solution at 37°C for 14 days (simulating in vivo physiological conditions). After 14 days, the films were removed, cleaned, and dried. The samples were then subjected to in vitro development testing again under the same CT scanning conditions as the initial test to determine the gray value (to evaluate the stability of the material's development performance over time in a physiological environment). The results of the long-term in vitro development test are as follows: Figure 3 As shown.

[0036] It can be seen from Figure 3 that: The gray-scale values measured before and after the immersion of the developable polymer composite material for 14 days did not change significantly (indicating that the development performance remained stable under simulated physiological environmental conditions), indicating that the developer was firmly bound in the polymer matrix and there was no obvious migration or loss in the aqueous phase environment. The developable polymer composite material could maintain a continuous and reliable imaging effect during in vivo application.

[0037] 3) Cut the developable polymer composite material of this embodiment into a size suitable for observation by a scanning electron microscope (SEM), then fix it on the sample stage for gold spraying and conductive treatment on the sample surface, and then observe the surface and cross-sectional morphology of the sample through a scanning electron microscope, and use the energy dispersive X-ray spectroscopy (EDXS) analysis system supporting the scanning electron microscope to perform elemental analysis on the sample (perform point scanning or area scanning on the surface and cross-sectional areas of the sample to obtain the characteristic signal distribution of iodine element to evaluate the spatial distribution state and uniformity of the developer in the polymer matrix). The SEM image of the cross-section of the obtained developable polymer composite material is as Figure 4 shown, and the EDXS image is as Figure 5 shown.

[0038] It can be seen from Figure 4 and Figure 5 that: The hydrophilic iodixanol was embedded in the hydrophobic poly(p-dioxanone) matrix in the form of a discrete phase, showing a typical "sea-island structure" distribution characteristic, and was evenly distributed within the overall range. No obvious local enrichment or element deficiency phenomenon was observed, indicating that by adopting a composite solvent system and combining a stepwise introduction strategy of the developer, the present invention can effectively inhibit the aggregation and phase separation behavior of the developer during the material preparation process, thereby promoting the uniform dispersion of the developer in the polymer matrix and being beneficial to constructing a structurally stable and continuous composite polymer network.

[0039] 4) Place the developable polymer composite material of this embodiment in a flat vulcanizing machine, and then hot-press it at 200 °C to prepare standard dumbbell-shaped mechanical test specimens. Then use an electronic universal material testing machine to perform uniaxial tensile testing on the test specimens, with a tensile rate of 15 mm / min. Parallel testing is performed on no less than 3 specimens, and statistical analysis is performed on the test results. The obtained tensile property test results are as Figure 6 (The control group was exactly the same as the developable polymer composite material of this embodiment except that polyvinyl alcohol was not added) shown.

[0040] It can be seen from Figure 6It can be seen that the tensile strength of the developable polymer composite material is significantly improved compared with the control group without dispersant. This indicates that the introduction of dispersant not only improves the dispersion state of developer in polymer matrix, but also helps to enhance the mechanical properties of composite material. The uniformly dispersed developer phase can effectively reduce local stress concentration and improve the load transfer efficiency inside the fiber, thus macroscopically manifesting as an increase in the tensile strength of the material.

[0041] 5) Imaging effect test: Animals: SPF-grade male SD rats, purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.

[0042] Under aseptic conditions, rats were anesthetized either generally or locally to ensure anesthesia. After anesthesia, the rats were placed on a sterile operating table, and the subcutaneous tissue on their backs was selected as the implantation site. The implantation area was shaved, and the skin was routinely disinfected with a disinfectant. Within the disinfected area, an incision of appropriate length was made on the skin surface using sterile surgical instruments, and a subcutaneous pouch was formed through blunt dissection. The radiopaque polymer composite material of this embodiment was sterilized and then implanted into the subcutaneous pouch (ensuring it was completely located within the subcutaneous tissue and in a stable position). The incision was then repositioned layer by layer and sutured with medical sutures. After suturing, the incision surface was disinfected again, and the rats were transferred to a clean environment for postoperative recovery.

[0043] Medical imaging was performed on rats at predetermined time points after material implantation. Imaging tests were conducted on rats at different time points. Before imaging tests, rats were appropriately anesthetized to reduce motion artifacts. Rats were placed on the scanning table of the medical imaging equipment, ensuring the scanning area covered the implanted material site. Computed tomography (CT) was used to acquire image data of the implanted area, and the imaging intensity of the implanted area was quantitatively or semi-quantitatively analyzed using image analysis software to evaluate the imaging effect and imaging stability of the radiopaque polymer composite material at different time points in vivo. The long-term imaging test results of the radiopaque polymer composite material in SD rats are as follows: Figure 7 As shown.

[0044] Depend on Figure 7 It can be seen that after 3 and 6 months of implantation of the radiopaque polymer composite material into SD rats, clear and identifiable high-contrast radiopaque signals can still be observed at the implantation site, indicating that it can maintain good imaging visibility in the long-term physiological environment in vivo. The contrast agent did not undergo rapid migration or burst release, but was retained in the local area as the polymer matrix slowly degraded, thus maintaining a stable imaging effect over a long time scale.

[0045] Example 2: A developable polymer composite material is prepared by the following method: 1) Mix 8 mL of chloroform and 2 mL of hexafluoroisopropanol and stir at room temperature for 10 min at a stirring rate of 500 r / min. Then add 400 mg of iohexol and 20 mg of polyvinyl alcohol (number average molecular weight of 30000 g / mol) and continue stirring for 20 min. Then add 150 mg of iohexol and continue stirring for 30 min. Then add 1 g of polydioxanone (number average molecular weight of 10000 g / mol) and continue stirring for 1 h to obtain the spinning solution. 2) Add the spinning solution to the electrospinning device and perform electrospinning at room temperature. The process parameters for electrospinning are as follows: feed rate is 2 mL / h, voltage is 12 kV, receiving distance is 10 cm, spinning time is 5 h. After peeling off from the receiving device, place it in a vacuum drying environment at room temperature for 24 h to obtain a developable polymer composite material (fiber membrane).

[0046] According to the test (the test method is the same as in Example 1), the tensile strength of the developable polymer composite material in this example is about 17 MPa, and it also has excellent developing effect.

[0047] Example 3: A developable polymer composite material is prepared by the following method: 1) Mix 5 mL of chloroform and 5 mL of hexafluoroisopropanol and stir at room temperature for 10 min at a stirring rate of 100 r / min. Then add 800 mg of iodixanol and 50 mg of polyvinyl alcohol (number average molecular weight of 60000 g / mol) and continue stirring for 30 min. Then add 200 mg of iohexol and continue stirring for 1 h. Then add 1 g of polydioxanone (number average molecular weight of 50000 g / mol) and 1 g of polylactic acid (number average molecular weight of 146000 g / mol) and continue stirring for 1 h to obtain the spinning solution. 2) Add the spinning solution to the electrospinning device and perform electrospinning at room temperature. The process parameters for electrospinning are as follows: feed rate is 1.5 mL / h, voltage is 8 kV, receiving distance is 10 cm, and spinning time is 8 h. After peeling off from the receiving device, place it in a vacuum drying environment at room temperature for 24 h to obtain a developable polymer composite material (fiber membrane).

[0048] According to the test (the test method is the same as in Example 1), the tensile strength of the developable polymer composite material in this example is about 17 MPa, and it also has excellent developing effect.

[0049] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A developable polymer composite material, characterized in that, Includes the following components by mass percentage: Biodegradable polymers: 50%–75%; Iodine-containing developing agents: 20%–45%; Dispersant: 5%–10%.

2. The developable polymer composite material according to claim 1, characterized in that: The biodegradable polymer is at least one of polydioxanone, polylactic acid, polycaprolactone, polylactic acid-hydroxyacetic acid copolymer, and polyhydroxy fatty acid ester.

3. The developable polymer composite material according to claim 1 or 2, characterized in that: The iodine-containing developing agent is at least one of iodixanol, iohexol, iopromide, iopamidol, and iomethol.

4. The developable polymer composite material according to claim 1 or 2, characterized in that: The dispersant is at least one of polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, and polyethylene glycol-polypropylene glycol block copolymer.

5. A method for preparing a developable polymer composite material as described in any one of claims 1 to 4, characterized in that, Includes the following steps: 1) Mix chlorinated hydrocarbon solvent and fluorinated alcohol solvent, then add part of iodine-containing developer and dispersant and mix well, then add the remaining iodine-containing developer and mix well, then add biodegradable polymer and mix well to obtain spinning solution. 2) Add the spinning solution to the electrospinning device for electrospinning to obtain a developable polymer composite material.

6. The preparation method according to claim 5, characterized in that: In step 1), the volume ratio of the chlorinated hydrocarbon solvent and the fluorinated alcohol solvent is 1:0.1 to 2.

7. The preparation method according to claim 5 or 6, characterized in that: The chlorinated hydrocarbon solvent in step 1) is at least one of dichloromethane and chloroform; the fluorinated alcohol solvent in step 1) is at least one of hexafluoroisopropanol, 2,2,2-trifluoroethanol and tetrafluoropropanol.

8. The preparation method according to claim 5, characterized in that: Step 2) The electrospinning process parameters include: feed rate of 0.5 mL / h to 2 mL / h, voltage of 4.5 kV to 20 kV, receiving distance of 8 cm to 12 cm, and spinning time of 4 h to 10 h.

9. The preparation method according to claim 5 or 8, characterized in that: Step 2) The electrospinning is carried out at room temperature.

10. A medical product, characterized in that, The invention comprises the developable polymer composite material according to any one of claims 1 to 4.

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