Developing bracket based on hafnium oxide nanoparticles and preparation method thereof

Abstract

The invention discloses a developing stent based on hafnium oxide nanoparticles and a preparation method of the developing stent, and belongs to the technical field of biomedical materials. The developing stent comprises a stent base body, and a developing coating and a high polymer material protective layer which sequentially cover the stent base body from inside to outside, wherein the developing coating consists of flaky hafnium dioxide nanoparticles. The flaky hafnium dioxide nano-particles are prepared by controlling the temperature, the reaction time and the pH value of the hydrothermal reaction and are used as the developing coating of the developing bracket. Developing effect comparison under X-rays shows that the developing coating formed by the flaky hafnium oxide has a good X-ray shielding effect, the stent can be developed integrally, and observation of the state of the stent and postoperative monitoring in the implanting process are facilitated.

Description

Technical Field

[0001] The present invention relates to a developing stent based on hafnium dioxide nanoparticles and a preparation method thereof, belonging to the technical field of biomedical materials. Background Art

[0002] A stent is generally a prosthesis or implant that can be inserted into a patient's blood vessel or passage and adheres to the blood vessel or passage when it is deployed. In the field of modern medicine, as a key medical device for treating diseases such as vascular stenosis and occlusion, its importance is self-evident. During the operation, doctors need to clearly and in real time master the position, shape and deployment of the stent. After the operation, imaging techniques are also required to track the state of the stent in the body for a long time to evaluate the treatment effect and timely detect and handle possible complications. Therefore, the developability of the stent plays a decisive role in the precise implementation of the operation and the effective monitoring after the operation.

[0003] Currently, the stents widely used clinically are non-degradable stents. However, since non-degradable stents remain in the human body for a long time, they may cause thrombosis or rejection reactions of the human body, and patients need to take medicine for a long time. Degradable stents are designed to gradually degrade and be absorbed by the human body after completing the mission of supporting blood vessels, avoiding the potential risks of permanent foreign body retention in the body and patients do not need to take medicine for a long time, especially suitable for young patients or people sensitive to foreign bodies in the body. However, most degradable materials (such as polymers such as polylactic acid (PLA), polycaprolactone (PCL), etc. and degradable metals such as magnesium alloys, zinc alloys and iron alloys) have weak absorption or reflection ability for imaging means such as X-rays, and the imaging effect is poor. This makes it difficult for doctors to clearly and intuitively determine the position and deployment state of the stent through conventional imaging equipment during the operation, greatly increasing the difficulty and risk of the operation (for example, when implanting a degradable stent in a complex curved blood vessel, if the precise positioning cannot be achieved, it may lead to deviation of the stent placement, unable to effectively expand the stenosed blood vessel, and even damage the blood vessel wall).

[0004] In addition, during the long degradation process after stent implantation, the developability can help doctors closely observe the degradation process. Through imaging techniques, doctors can understand in real time whether the degradation rate of the stent meets the expectations and whether there are local degradation abnormalities. If the stent degrades too fast, it may not provide sufficient support during the critical period of blood vessel healing, resulting in restenosis of the blood vessel; on the contrary, if the degradation is too slow, it may affect the recovery of the normal physiological function of the blood vessel. Through regular imaging examinations and based on the imaging of the stent, doctors can accurately judge the degradation state of the stent and timely adjust the treatment plan to ensure the cardiovascular health of patients. It can be seen that for degradable stents, the developability is of even more important significance that cannot be ignored.

[0005] At present, there are many technical means to achieve stent development in clinical practice. First of all, adding metal development markers is a more traditional method. Development is achieved by introducing metal elements such as gold, tantalum, and platinum with high atomic numbers into the stent material, or directly constructing part of the structure with these metals. Due to the strong absorption capacity of the above-mentioned metal elements for X-rays, they can present clear images under equipment such as X-ray machines and CT scanners, providing accurate information for surgical operations. At the same time, their high mechanical strength also enhances the support performance of the stent. However, this method is costly, and metals such as gold and tantalum are expensive, resulting in a significant increase in the cost of stent manufacturing, which is ultimately passed on to patients, increasing the economic burden; more importantly, some metals have biocompatibility risks, and the release of metal ions can easily cause inflammation and allergic reactions, hindering endothelial repair, and increasing the risk of vascular restenosis in the long run.

[0006] Second, using radioactive particles to mark stents, with the help of low-energy gamma rays continuously emitted by radioactive particles such as iodine-125, high-precision imaging can be achieved through nuclear medicine imaging equipment such as SPECT or PET. In surgeries at special locations such as intracranial blood vessels, it can provide doctors with precise location information, significantly improving the success rate of surgery, and some particles can also inhibit the growth of diseased tissue around tumor-related blood vessels. However, this technology has high radiation risks, and the particle dose must be strictly controlled and well protected to avoid harm to doctors and patients; and the half-life of radioactive particles is limited, and the imaging effect weakens over time. For patients who need long-term monitoring, stents need to be replaced frequently or auxiliary imaging methods need to be supplemented; at the same time, its preparation, transportation, storage and use involve radioactive substances, and the management and operation requirements are strict, which greatly increases the difficulty and cost of clinical application.

[0007] Third, nanomaterial development coatings are used to coat the surface of the stent with nanogold, quantum dots, inorganic nanoparticles, etc., and the sharp contrast between the nanomaterials and the surrounding tissues during imaging is used for development. This type of method has high sensitivity and specificity, and can assist doctors in accurately observing fine structures and lesions in the body. Some nanomaterials can regulate the growth of vascular cells after modification, reducing the risk of vascular restenosis, and most nanomaterials have high chemical stability, good biocompatibility, and good metabolic safety. However, this method also faces the problems of complex preparation process, high requirements for technical equipment, and increased production costs. The long-term safety and stability of some nanomaterials need further research, and quality control is difficult during large-scale production.

[0008] Fourth, add non-metallic developers, such as adding barium sulfate, bismuth compounds, etc. to the stent material. Relying on the high density and high atomic number of barium sulfate, it blocks the rays under X-ray irradiation, thereby showing the stent contour. This method has a relatively low cost, and some non-metallic developers have good biocompatibility. In degradable stents, they can also synergistically develop and degrade to a certain extent. However, its development efficiency is lower than that of metal development markers and some nano-material development coatings. Often, a high addition amount is required to achieve an ideal effect, which will in turn affect the mechanical properties of the stent material, resulting in a decrease in strength. Moreover, the compatibility between the developer and the stent substrate is poor, and the developer is prone to falling off during the degradation process, affecting the development effect and the safety of the stent. Summary of the Invention

[0009] The first object of the present invention is to provide a developing stent based on hafnium dioxide nanoparticles, providing a novel stent with good imaging effect.

[0010] The second object of the present invention is to provide a preparation method of a developing stent based on hafnium dioxide nanoparticles, providing a preparation method of a novel stent with good imaging effect.

[0011] In order to achieve the above object, the technical solution adopted in a developing stent based on hafnium dioxide nanoparticles in the present invention is:

[0012] A developing stent based on hafnium dioxide nanoparticles, comprising a stent matrix, a developing coating and a polymer material protective layer which are sequentially covered on the stent matrix from the inside to the outside, and the developing coating is composed of flaky hafnium dioxide nanoparticles.

[0013] The beneficial effects of the above technical solution are as follows: The developing stent based on hafnium dioxide nanoparticles of the present invention is an exploratory invention. The present invention prepares flaky hafnium dioxide nanoparticles by controlling the temperature, reaction time and pH of the hydrothermal reaction, and uses them as the developing coating of the stent. Through the comparison of the imaging effects under X-rays, it can be seen that the developing coating formed by flaky hafnium dioxide has a good X-ray shielding effect, and the stent can be imaged as a whole. Compared with the existing developing coating using a mixture of a developing material and a polymer compound, it has the advantages of achieving good imaging with a relatively thin coating thickness (such as 3 μm), and better compatibility with the metal matrix of the stent, which is beneficial to observing the state of the stent during implantation and postoperative monitoring. Moreover, the surface functionalization of hafnium dioxide nanoparticles can be regulated to adapt to a variety of stent substrates (metals, polymers).

[0014] Furthermore, hafnium dioxide (HfO2) is almost insoluble in the physiological environment (solubility product Ksp≈10 -64) After degradation, it is excreted through the kidneys in the form of nanoparticles (particle size about 10 nm), and has relatively high biosafety. At the same time, hafnium dioxide nanoparticles have good compatibility with the matrix of the stent. Meanwhile, a polymer material protective layer is provided on the outer layer of the imaging coating, and the imaging coating is more stably fixed on the surface of the stent and is not easy to fall off.

[0015] As a further improvement, the thickness of the imaging coating is 2 - 3 μm.

[0016] As a further improvement, the stent matrix is a degradable stent matrix, and the polymer material is a degradable polymer material; the degradable polymer material is one of polytrimethylene carbonate, polycaprolactone, and racemic polylactic acid.

[0017] Specifically, the stent matrix can be a degradable stent matrix (such as: a degradable metal stent matrix or a degradable polymer stent matrix), or a non - degradable stent matrix.

[0018] As a further improvement, the thickness of the polymer material protective layer is 1 - 5 μm.

[0019] Preferably, the thickness of the polymer material protective layer is 2 - 3 μm.

[0020] In order to achieve the above - mentioned purpose, the technical solution adopted by a preparation method of an imaging stent based on hafnium dioxide nanoparticles in the present invention is:

[0021] A preparation method of an imaging stent based on hafnium dioxide nanoparticles, in which a suspension of sheet - like hafnium dioxide nanoparticles and water is ultrasonically sprayed on the surface of the stent matrix, and then a polymer material is coated and dried to obtain the product.

[0022] The beneficial effects of the above - mentioned technical solution are as follows: The preparation method of the imaging stent of the present invention is simple, does not require complex instrument equipment, and has a low cost. During the preparation process, the solvent is water, and there is no risk of toxic reagents.

[0023] As a further improvement, the sheet - like hafnium dioxide nanoparticles are prepared by the following method: Hafnium tetrachloride and water are mixed at 65 - 75 °C to form an acidic hydrolysis solution with a pH of 0.5 - 1, an alkali solution is added until the pH is 5 - 5.5, and then a hydrothermal reaction is carried out at 160 - 180 °C.

[0024] Preferably, the sheet - like hafnium dioxide nanoparticles are prepared by the following method: Hafnium tetrachloride and water are mixed at 65 - 70 °C to form an acidic hydrolysis solution with a pH of 0.5 - 1, an alkali solution is added until the pH is 5 - 5.5, and then a hydrothermal reaction is carried out at 160 - 170 °C.

[0025] As a further improvement, the lye is a 1-1.5M NaOH solution.

[0026] As a further improvement, the mass ratio of hafnium tetrachloride to water is (0.1-1.0):100.

[0027] Preferably, the mass ratio of hafnium tetrachloride to water is (0.9-1.0):100.

[0028] As a further improvement, the hydrothermal reaction time is 8-12h.

[0029] Preferably, the hydrothermal reaction time is 10-12h.

[0030] As a further improvement, the mass fraction of hafnium dioxide nanoparticles in the suspension is 2.5-10%.

[0031] Preferably, the mass fraction of hafnium dioxide nanoparticles in the suspension is 5-5.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a schematic cross-sectional view of the imaging stent based on hafnium dioxide nanoparticles in Example 1 of the present invention;

[0033] Figure 2 It is a hafnium dioxide suspension with water as the solvent in Example 2 of the present invention;

[0034] Figure 3 It is a TEM image of hafnium dioxide nanoparticles in Example 2 of the present invention;

[0035] Figure 4 It is an XRD image of hafnium dioxide nanoparticles in Example 2 of the present invention;

[0036] Figure 5 It is the Zeta potential of hafnium dioxide nanoparticles in Example 2 of the present invention;

[0037] Figure 6 It is the particle size distribution of hafnium dioxide nanoparticles in Example 2 of the present invention;

[0038] Figure 7 It is the imaging property of the stents in Example 2, Comparative Example 2 and Comparative Example 3 in Experimental Example 1 of the present invention under X-ray (wherein, the left, middle and right stents are the stents of Example 2, Comparative Example 2 and Comparative Example 3 respectively);

[0039] Figure 8 It is the imaging property of the stents in Comparative Example 1 and Comparative Example 3 in Experimental Example 1 of the present invention under X-ray (wherein, the upper and lower stents are the stents of Comparative Example 1 and Comparative Example 3 respectively);

[0040] Figure 9 This is the imaging diagram after the imaging stent based on hafnium dioxide nanoparticles was implanted into a rabbit in Experimental Example 2 of the present invention;

[0041] Among them, 1 is the cross-section of the stent matrix, 2 is the imaging coating, and 3 is the polymer material protective layer. Detailed implementation manners

[0042] The existing imaging methods for stents have the following defects: ① The cost of traditional metal imaging materials (such as gold and tantalum) is high, and the processing technology is complex; ② The imaging efficiency of non-metal imaging materials (such as carbon-based materials) is low, and it is difficult to meet the clinical needs; ③ Some coatings have long-term biocompatibility risks (such as metal ion release and inflammatory reactions); ④ Metal imaging coatings: Materials such as gold and tantalum do not match the thermal expansion coefficients of degradable stents (such as magnesium alloys and polylactic acid), resulting in interfacial stress concentration and coating peeling; ⑤ Imaging-degradation contradiction: Traditional degradable coatings (such as barium sulfate / PLGA) require a high addition amount of imaging agent (>30wt%), sacrificing mechanical properties and degradation controllability. The present invention uses a flaky hafnium dioxide nanoparticle coating as the imaging layer of the stent. The formed imaging coating has a higher X-ray shielding effect. Compared with the existing imaging coating using a mixture of an imaging material and a polymer compound, it has the advantage of achieving good imaging with a relatively thin coating thickness (such as 3μm), and has better compatibility with the metal matrix of the stent.

[0043] The following further describes the present invention in detail with specific embodiments. Unless otherwise specified, the equipment and reagents used in each embodiment, experimental example, and comparative example can be obtained commercially.

[0044] I. Specific embodiments of a kind of imaging stent based on hafnium dioxide nanoparticles and its preparation method of the present invention:

[0045] The present invention uses a flaky hafnium dioxide nanoparticle coating as the imaging layer of the stent, and prepares an imaging stent based on hafnium dioxide nanoparticles. The specific implementation operations are as follows:

[0046] Embodiment 1 An imaging stent based on hafnium dioxide nanoparticles

[0047] The imaging stent based on hafnium dioxide nanoparticles in this embodiment is composed of a stent matrix, an imaging coating and a polymer material protective layer that are sequentially covered on the stent matrix. Among them, the stent matrix is a degradable stent matrix, specifically a magnesium alloy stent. The imaging coating is a flaky hafnium dioxide nanoparticle coating with a thickness of about 3μm; the polymer material protective layer is a polytrimethylene carbonate (PTMC) degradable polymer coating with a thickness of about 2μm. The cross-sectional structure of the stent is as Figure 1 shown, including the stent matrix 1, the imaging coating 2 and the polymer material protective layer 3 that are sequentially covered on the stent matrix from the inside to the outside.

[0048] In other embodiments, the stent matrix can be a degradable metal stent such as an iron alloy stent or a zinc alloy stent, or a degradable polymer stent prepared from PDLLA or PCL materials, or a non-degradable metal stent such as a nitinol stent.

[0049] Example 2 Preparation method of a developing stent based on hafnium dioxide nanoparticles

[0050] In this example, the developing stent based on hafnium dioxide nanoparticles in Example 1 is prepared, and the specific implementation operations are as follows:

[0051] 1. Hydrothermal synthesis of hafnium dioxide nanoparticles

[0052] (1) Hydrolysis of the precursor and pH regulation:

[0053] Take 100 mL of ultrapure water in a 200 mL conical flask and heat it in a 70 °C constant temperature water bath until the solution temperature is stable. Slowly add 1 g of hafnium tetrachloride powder (HfCl4) under magnetic stirring (800 rpm) to form an acidic hydrolysis system with an initial pH of about 0.5. Use 1 M NaOH solution to gradually adjust the pH to 5.0. During this stage, maintain magnetic stirring to avoid particle agglomeration caused by local supersaturation.

[0054] (2) Hydrothermal crystallization and crystal form control:

[0055] Transfer the mixed solution obtained in step (1) to a 150 mL polytetrafluoroethylene-lined high-pressure reaction kettle and carry out a 10-hour hydrothermal reaction at 160 °C. After the reaction, naturally cool to room temperature to form a milky white colloidal suspension.

[0056] (3) Purification and preparation of the dispersion:

[0057] Centrifuge the milky white colloidal suspension obtained in step (2) at 8000 rpm for 15 minutes. After discarding the supernatant, wash it with ultrapure water 3 times in sequence to remove residual Cl- ions. The obtained white precipitate (i.e., hafnium dioxide (HfO2) nanoparticles) is vacuum dried (60 °C, 12 h), and then added to ultrapure water to prepare a 5 wt% HfO2 nanoparticle suspension (as Figure 2 shown), and ultrasonically treated (40 kHz, 30 min) to ensure uniform dispersion during the spraying process.

[0058] The morphology and structure characterization of hafnium dioxide (HfO2) nanoparticles are as Figures 3 to 6 . It can be seen from the figure that the obtained XRD test results of hafnium dioxide conform to the characteristics of hafnium dioxide, the shape is spindle-shaped, the particle size is about 10 - 15 nm (referring to the longest side of the particle), and it is electrically neutral when dispersed in an aqueous solution.

[0059] 2. Spraying of the imaging coating

[0060] Add the HfO2 nanoparticle suspension obtained in Step 1 into an ultrasonic spraying device, and perform ultrasonic spraying on the stent substrate to form an imaging coating with a thickness of about 3 μm on the stent substrate.

[0061] 3. Spraying of the polymer material protective layer

[0062] Dissolve polytrimethylene carbonate (molecular weight 10,000 - 50,000 Mw) in dichloromethane to prepare a 0.5 wt% polymer solution, add it into an ultrasonic spraying device, and perform ultrasonic spraying on the stent obtained in Step 2 to form a polymer material layer with a thickness of about 2 μm outside the imaging coating. After spraying, place it in a vacuum oven and dry it at room temperature for one week to completely volatilize the solvent in the coating.

[0063] II. Comparative examples

[0064] Comparative example 1

[0065] The imaging stent in this comparative example consists of a stent substrate and an HfO2 nanoparticle - PTMC composite coating covering the stent substrate, and the preparation process of the HfO2 nanoparticles is as described in Example 2. The specific preparation process is as follows:

[0066] Prepare a 1 wt% polytrimethylene carbonate (PTMC) solution with dichloromethane (DCM) as the solvent, construct an HfO2 - PTMC composite system according to the solid mass ratio of HfO2 nanoparticles to PTMC of 20:80 (total solid content 20%), and ultrasonically disperse for 10 minutes to obtain a uniformly dispersed liquid.

[0067] Coating forming: Adopt the ultrasonic spraying process to construct an imaging coating on the surface of the stent substrate, and finally make the coating thickness 5 ± 0.5 μm.

[0068] Comparative example 2

[0069] The stent in this comparative example is a magnesium alloy bare stent.

[0070] Comparative example 3

[0071] The stent in this comparative example is a nitinol stent, and tantalum metal imaging points are wrapped at both ends of the stent.

[0072] The nitinol stent is a commonly used vascular stent in clinics. Nitinol has low radiopacity, and usually imaging markers are added at both ends of the stent to achieve imaging.

[0073] III. Experimental examples

[0074] Experimental example 1 Comparison of imaging properties under X - ray

[0075] The imaging stent based on hafnium dioxide nanoparticles prepared in Example 2, the magnesium alloy bare stent in Comparative Example 2, and the nitinol stent in Comparative Example 3 were imaged under X-ray, and the results are as Figure 7 shown. It can be seen from the figure that the magnesium alloy bare stent is not visible under X-ray, and the imaging stent with a hafnium dioxide nanoparticle coating is clearly visible under X-ray, showing an imaging effect. Compared with the nitinol stent, which is a commonly used stent in clinical practice, the details of the stent are more clearly imaged.

[0076] The imaging stent prepared in Comparative Example 1 and the nitinol stent in Comparative Example 3 were imaged under X-ray, and the results are as Figure 8 shown. It can be seen from the figure that the stent is only faintly visible and does not achieve the imaging effect of existing clinical stents.

[0077] Experimental Example 2 Imaging property of the imaging stent based on hafnium dioxide nanoparticles after implantation into rabbits

[0078] The imaging stent based on hafnium dioxide nanoparticles prepared in Example 2 was surgically placed in the carotid artery of a rabbit, and X-ray was used to observe its imaging property in the animal body. The results are as Figure 9 shown. It can be seen from the figure that the shape of the vascular stent in the animal body is clearly visible and has imaging property under the tissue.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A development stent based on hafnium dioxide nanoparticles, characterized in that: It includes a stent matrix, a developing coating and a polymer material protective layer that are sequentially coated on the stent matrix from the inside to the outside. The developing coating is composed of flaky hafnium dioxide nanoparticles.

2. The development support based on hafnium dioxide nanoparticles according to claim 1, characterized in that: The thickness of the developing coating is 2-3 μm.

3. The development stent based on hafnium dioxide nanoparticles according to claim 1 or 2, characterized in that: The stent matrix is a degradable stent matrix, and the polymer material is a degradable polymer material; the degradable polymer material is one of polytrimethylene carbonate, polycaprolactone, and racemic polylactic acid.

4. The developing stent based on hafnium dioxide nanoparticles according to claim 3, characterized in that: The thickness of the polymer material protective layer is 1-5 μm.

5. A method for preparing a development stent based on hafnium dioxide nanoparticles according to any one of claims 1 to 4, characterized in that: A suspension of flaky hafnium dioxide nanoparticles and water is ultrasonically sprayed on the surface of the stent matrix, and then the polymer material is coated and dried to obtain the product.

6. The preparation method of the development stent based on hafnium dioxide nanoparticles according to claim 5, characterized in that: The flaky hafnium dioxide nanoparticles are prepared by the following method: hafnium tetrachloride and water are mixed at 65-75 °C to form an acidic hydrolysis solution with a pH of 0.5-1, an alkali solution is added until the pH is 5-5.5, and then a hydrothermal reaction is carried out at 160-180 °C.

7. The preparation method of the development stent based on hafnium dioxide nanoparticles according to claim 6, characterized in that: The alkali solution is a 1-1.5 M NaOH solution.

8. The preparation method of the development stent based on hafnium dioxide nanoparticles according to claim 6 or 7, characterized in that: The mass ratio of hafnium tetrachloride to water is (0.1-1.0):

100.

9. The preparation method of the development stent based on hafnium dioxide nanoparticles according to claim 6, wherein: The time of the hydrothermal reaction is 8-12 h.

10. The preparation method of the development stent based on hafnium dioxide nanoparticles according to claim 5, characterized in that: The mass fraction of the hafnium dioxide nanoparticles in the suspension is 2.5-10%.

Images