A imaging scaffold based on hafnium dioxide nanoparticles and its preparation method

Abstract

This invention discloses a radiopaque scaffold based on hafnium dioxide nanoparticles and its preparation method, belonging to the field of biomedical materials technology. The radiopaque scaffold of this invention includes a scaffold substrate and a radiopaque coating layer and a polymer protective layer sequentially covering the scaffold substrate from the inside out. The radiopaque coating layer is composed of sheet-like hafnium dioxide nanoparticles. This invention prepares sheet-like hafnium dioxide nanoparticles by controlling the temperature, reaction time, and pH of the hydrothermal reaction, and uses them as the radiopaque coating layer of the scaffold. Comparison of radiopaque effects under X-rays shows that the radiopaque coating layer formed by sheet-like hafnium dioxide has a good X-ray shielding effect, and the scaffold can be radiopaque as a whole, which is beneficial for observing the scaffold's status during implantation and for postoperative monitoring.

Description

Technical Field

[0001] This invention relates to a radiographic scaffold based on hafnium dioxide nanoparticles and its preparation method, belonging to the field of biomedical materials technology. Background Technology

[0002] A stent is a prosthesis or implant that can be inserted into a patient's blood vessel or channel and, when deployed, adheres to the blood vessel or channel. In the field of modern medicine, its importance as a key medical device for treating diseases such as vascular stenosis and occlusion is self-evident. Doctors need to have real-time and clear control over the stent's position, shape, and deployment during surgery, and also need to use imaging techniques to track the stent's status in the body long-term after surgery to assess the treatment effect and promptly detect and manage potential complications. Therefore, the stent's radiolucency plays a decisive role in the precise execution of the surgery and effective postoperative monitoring.

[0003] Currently, non-degradable stents are widely used in clinical practice. However, because non-degradable stents remain in the body for extended periods, they may cause thrombosis or rejection reactions, requiring long-term medication. Degradable stents, on the other hand, are designed to gradually degrade and be absorbed by the body after fulfilling their function of supporting blood vessels, avoiding the potential risks of permanent foreign body retention and eliminating the need for long-term medication. This is particularly suitable for younger patients or those sensitive to foreign bodies in their bodies. However, most degradable materials (such as polymers like polylactic acid (PLA) and polycaprolactone (PCL), as well as degradable metals like magnesium, zinc, and iron alloys) have weak absorption or reflection capabilities for imaging techniques like X-rays, resulting in poor imaging effects. This makes it difficult for surgeons to clearly and intuitively determine the stent's position and deployment status using conventional imaging equipment during surgery, unlike with non-degradable stents. This significantly increases the difficulty and risk of the procedure (for example, when implanting a degradable stent in a complex, tortuous blood vessel, inaccurate positioning may lead to stent placement deviation, failure to effectively open narrowed vessels, or even damage to the vessel wall).

[0004] Furthermore, during the long degradation process after stent implantation, radiolucency helps doctors closely monitor the degradation process. Through imaging techniques, doctors can monitor in real time whether the stent degradation rate is as expected and whether there are any local degradation anomalies. If the stent degrades too quickly, it may not provide sufficient support during the critical period of vascular healing, leading to restenosis; conversely, if degradation is too slow, it may affect the recovery of normal vascular physiological function. Through regular imaging examinations, based on the stent's radiolucency, doctors can accurately determine the stent's degradation status, adjust treatment plans in a timely manner, and safeguard the patient's cardiovascular health. Therefore, radiolucency is of paramount importance for biodegradable stents.

[0005] Currently, there are various techniques for achieving stent visualization in clinical practice. Firstly, adding metallic contrast markers is a relatively traditional method. This involves introducing high atomic number metals such as gold, tantalum, and platinum into the stent material, or directly using these metals to construct part of the structure. Because these metals have strong X-ray absorption capabilities, they can produce clear images under X-ray machines and CT scanners, providing accurate information for surgical procedures. Their high mechanical strength also enhances the stent's support performance. However, this method is costly; gold, tantalum, and other metals are expensive, significantly increasing stent manufacturing costs, which are ultimately passed on to patients, increasing their financial burden. More importantly, some metals pose biocompatibility risks; the release of metal ions can easily trigger inflammation and allergic reactions, hindering vascular endothelial repair and increasing the long-term risk of restenosis.

[0006] Secondly, using radiolabeled scaffolds, which utilize the low-energy gamma rays continuously emitted by radioactive particles such as iodine-125, allows for high-precision imaging using nuclear medicine imaging equipment such as SPECT or PET. In surgeries at specific locations, such as intracranial blood vessels, this provides surgeons with precise location information, significantly improving surgical success rates. Furthermore, some particles can inhibit the growth of lesions around tumor-related blood vessels. However, this technology carries a high radiation risk, requiring strict control of particle dosage and proper protective measures to avoid harm to both patients and medical staff. Additionally, the limited half-life of radioactive particles means the imaging effect weakens over time, necessitating frequent scaffold replacements or supplementary imaging methods for patients requiring long-term monitoring. Moreover, the preparation, transportation, storage, and use of these scaffolds involve radioactive materials, demanding stringent management and operational requirements, significantly increasing the difficulty and cost of clinical application.

[0007] Third, a nanomaterial imaging coating is used, where nanomaterials such as gold nanoparticles, quantum dots, and inorganic nanoparticles are coated on the scaffold surface. The strong contrast between the nanomaterials and surrounding tissues during imaging allows for visualization. This method offers high sensitivity and specificity, assisting doctors in accurately observing subtle structures and lesions within the body. Some modified nanomaterials can regulate vascular cell growth, reducing the risk of restenosis. Furthermore, most nanomaterials exhibit high chemical stability, good biocompatibility, and good metabolic safety. However, this method also faces challenges such as complex preparation processes, high requirements for technical equipment, and increased production costs. Additionally, the long-term safety and stability of some nanomaterials require further research, and quality control during large-scale production is challenging.

[0008] Fourth, non-metallic developing agents can be added, such as barium sulfate or bismuth compounds, to the scaffold material. Barium sulfate's high density and high atomic number block X-rays, thus revealing the scaffold outline. This method is relatively low-cost, and some non-metallic developing agents have good biocompatibility, even synergistically enhancing development and degradation performance in biodegradable scaffolds. However, its development efficiency is lower than that of metallic developing markers and some nanomaterial developing coatings, often requiring high addition amounts to achieve ideal results. This can affect the mechanical properties of the scaffold material, leading to reduced strength. Furthermore, poor compatibility between the developing agent and the scaffold substrate can cause developer detachment during degradation, impacting both development effectiveness and scaffold safety. Summary of the Invention

[0009] The first objective of this invention is to provide a developing scaffold based on hafnium dioxide nanoparticles, which provides a novel scaffold with good developing effect.

[0010] The second objective of this invention is to provide a method for preparing a developing scaffold based on hafnium dioxide nanoparticles, and to provide a method for preparing a novel scaffold with good developing effect.

[0011] To achieve the above objectives, the technical solution adopted in this invention for a imaging scaffold based on hafnium dioxide nanoparticles is as follows:

[0012] A developing scaffold based on hafnium dioxide nanoparticles includes a scaffold substrate and a developing coating and a polymer material protective layer sequentially covering the scaffold substrate from the inside out. The developing coating is composed of sheet-like hafnium dioxide nanoparticles.

[0013] The beneficial effects of the above technical solution are as follows: This invention, a radiopaque scaffold based on hafnium dioxide nanoparticles, is a pioneering invention. This invention prepares sheet-like hafnium dioxide nanoparticles by controlling the temperature, reaction time, and pH of the hydrothermal reaction, and uses these nanoparticles as a radiopaque coating for the scaffold. Comparison of radiopaque effects under X-rays shows that the radiopaque coating formed by sheet-like hafnium dioxide has a good X-ray shielding effect, allowing the scaffold to be radiopaque as a whole. Compared to existing methods using a mixture of radiopaque materials and polymer compounds as a radiopaque coating, this method has the advantage of achieving good radiopaque effect with a thinner coating thickness (e.g., 3 μm), and better compatibility with the scaffold's metal substrate, which is beneficial for observing the scaffold's status during implantation and for postoperative monitoring. Furthermore, the surface functionalization of hafnium dioxide nanoparticles can be controlled, making them compatible with various scaffold substrates (metals, polymers).

[0014] Furthermore, hafnium dioxide (HfO2) is almost insoluble in physiological environments (solution product Ksp≈10). -64After degradation, it is excreted through the kidneys in the form of nanoparticles (approximately 10 nm in diameter), exhibiting high biocompatibility. Furthermore, the hafnium dioxide nanoparticles have good biocompatibility with the scaffold matrix. Additionally, a polymer protective layer is provided on the outer layer of the radiopaque coating, ensuring the radiopaque coating is more stably fixed to the scaffold surface and less prone to detachment.

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

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

[0017] Specifically, the scaffold matrix can be a biodegradable scaffold matrix (e.g., a biodegradable metal scaffold matrix or a biodegradable polymer scaffold matrix) or a non-biodegradable scaffold 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] To achieve the above objectives, the technical solution adopted in the preparation method of a imaging scaffold based on hafnium dioxide nanoparticles in this invention is as follows:

[0021] A method for preparing a radiographic scaffold based on hafnium dioxide nanoparticles involves ultrasonically spraying a suspension of sheet-like hafnium dioxide nanoparticles and water onto the surface of a scaffold substrate, followed by coating with a polymer material and drying.

[0022] The advantages of the above technical solution are as follows: the preparation method of the developing scaffold of the present invention is simple, requires no complex instruments or equipment, and has low cost. During the preparation process, water is used as the solvent, eliminating the 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 hydrolysate with a pH of 0.5-1, an alkaline solution is added to bring the pH to 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 hydrolysate with a pH of 0.5-1, an alkaline solution is added to bring the pH to 5-5.5, and then a hydrothermal reaction is carried out at 160-170°C.

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

[0026] As a further improvement, the mass ratio of hafnium tetrachloride to water is (0.1 to 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 8–12 hours.

[0029] Preferably, the hydrothermal reaction takes 10 to 12 hours.

[0030] As a further improvement, the hafnium dioxide nanoparticles account for 2.5 to 10% of the mass fraction of the suspension.

[0031] Preferably, the hafnium dioxide nanoparticles account for 5 to 5.5% of the mass fraction of the suspension. Attached Figure Description

[0032] Figure 1 This is a cross-sectional schematic diagram of the imaging scaffold based on hafnium dioxide nanoparticles in Embodiment 1 of the present invention;

[0033] Figure 2 The hafnium dioxide suspension in Example 2 of this invention uses water as the solvent;

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

[0035] Figure 4 The image shows the XRD pattern of hafnium dioxide nanoparticles in Example 2 of this invention.

[0036] Figure 5 The zeta potential of hafnium dioxide nanoparticles in Example 2 of this invention;

[0037] Figure 6 The particle size distribution of hafnium dioxide nanoparticles in Example 2 of this invention;

[0038] Figure 7 The X-ray imaging properties of the stents in Example 2, Comparative Example 2 and Comparative Example 3 in Experimental Example 1 of the present invention (wherein, the stents on the left, middle and right sides are the stents of Example 2, Comparative Example 2 and Comparative Example 3, respectively).

[0039] Figure 8 The X-ray imaging properties of the stents in Comparative Example 1 and Comparative Example 3 in Experimental Example 1 of the present invention (wherein, the upper and lower stents are the stents of Comparative Example 1 and Comparative Example 3, respectively).

[0040] Figure 9 This is a schematic diagram of the imaging scaffold based on hafnium dioxide nanoparticles implanted into a rabbit in Experimental Example 2 of the present invention.

[0041] Wherein, 1 is the cross-section of the scaffold substrate, 2 is the developing coating, and 3 is the polymer material protective layer. Detailed Implementation

[0042] Existing imaging methods for stents suffer from the following drawbacks: ① Traditional metallic imaging materials (such as gold and tantalum) are costly and have complex processing techniques; ② Non-metallic imaging materials (such as carbon-based materials) have low imaging efficiency, making it difficult to meet clinical needs; ③ Some coatings pose long-term biocompatibility risks (such as metal ion release and inflammatory reactions); ④ Metallic imaging coatings: The thermal expansion coefficients of materials such as gold and tantalum do not match those of biodegradable stents (such as magnesium alloys and polylactic acid), leading to interfacial stress concentration and coating peeling; ⑤ Imaging-degradation contradiction: Traditional biodegradable coatings (such as barium sulfate / PLGA) require high amounts of contrast agent (>30wt%), sacrificing mechanical properties and controllable degradation. This invention utilizes a sheet-like hafnium dioxide nanoparticle coating as the imaging layer of the stent. The resulting imaging coating has a higher X-ray shielding effect. Compared to existing methods using a mixture of imaging materials and polymer compounds as the imaging coating, it has the advantage of achieving good imaging with a thinner coating thickness (e.g., 3μm) and better compatibility with the metal substrate of the stent.

[0043] The present invention will be further described in detail below with reference to specific embodiments. Unless otherwise specified, the equipment and reagents used in the embodiments, experimental examples and comparative examples are all commercially available.

[0044] I. A specific embodiment of the present invention of a imaging scaffold based on hafnium dioxide nanoparticles and its preparation method:

[0045] This invention uses a hafnium dioxide nanoparticle coating as a developing layer to prepare a developing scaffold based on hafnium dioxide nanoparticles. The specific implementation is as follows:

[0046] Example 1: A imaging scaffold based on hafnium dioxide nanoparticles

[0047] The hafnium dioxide nanoparticle-based developing scaffold of this embodiment consists of a scaffold substrate and a developing coating and a polymer protective layer sequentially covering the scaffold substrate. The scaffold substrate is a biodegradable substrate, specifically a magnesium alloy scaffold. The developing coating is a sheet-like hafnium dioxide nanoparticle coating with a thickness of approximately 3 μm. The polymer protective layer is a biodegradable polytrimethylene carbonate (PTMC) polymer coating with a thickness of approximately 2 μm. The cross-sectional structure of the scaffold is shown below. Figure 1 As shown, it includes a scaffold substrate 1 and a developing coating 2 and a polymer material protective layer 3 that are sequentially covered on the scaffold substrate from the inside out.

[0048] In other implementation scenarios, the stent matrix can be selected from biodegradable metal stents such as iron alloy stents or zinc alloy stents, biodegradable polymer stents made of PDLLA or PCL materials, or non-biodegradable metal stents such as nickel-titanium alloy stents.

[0049] Example 2: A method for preparing a radiographic scaffold based on hafnium dioxide nanoparticles

[0050] This embodiment prepares the imaging scaffold based on hafnium dioxide nanoparticles as in Example 1. The specific implementation steps are as follows:

[0051] 1. Hydrothermal synthesis of hafnium dioxide nanoparticles

[0052] (1) Precursor hydrolysis and pH regulation:

[0053] Take 100 mL of ultrapure water and place it in a 200 mL Erlenmeyer flask. Heat the flask in a 70°C water bath until the solution temperature stabilizes. Slowly add 1 g of hafnium tetrachloride powder (HfCl4) while stirring magnetically (800 rpm) to form an acidic hydrolysis system with an initial pH of approximately 0.5. Adjust the pH to 5.0 dropwise using 1 M NaOH solution, maintaining magnetic stirring throughout this stage to avoid localized supersaturation that could lead to particle aggregation.

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

[0055] The mixed solution obtained in step (1) was transferred to a 150 mL polytetrafluoroethylene-lined high-pressure reactor and subjected to a hydrothermal reaction at 160 °C for 10 hours. After the reaction was completed, the mixture was allowed to cool naturally to room temperature, forming a milky white colloidal suspension.

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

[0057] The milky white colloidal suspension obtained in step (2) was centrifuged at 8000 rpm for 15 minutes. After discarding the supernatant, it was washed three times with ultrapure water to remove residual Cl- ions. The resulting white precipitate (i.e., hafnium dioxide (HfO2) nanoparticles) was vacuum dried (60℃, 12h) and then mixed with ultrapure water to prepare a 5wt% HfO2 nanoparticle suspension (e.g., Figure 2 As shown), ultrasonic treatment (40kHz, 30min) is performed to ensure uniform dispersion during spraying.

[0058] Morphology and structural characterization of hafnium dioxide (HfO2) nanoparticles, as follows: Figures 3-6 As shown in the figure, the obtained XRD results of hafnium dioxide are consistent with the characteristics of hafnium dioxide. It has a spindle shape, a particle size of about 10-15 nm (referring to the longest side of the particle), and is electrically neutral when dispersed in aqueous solution.

[0059] 2. Spraying of developing coating

[0060] The HfO2 nanoparticle suspension obtained in step 1 was added to an ultrasonic spraying device to perform ultrasonic spraying on the scaffold substrate, forming a developing coating with a thickness of about 3 μm on the scaffold substrate.

[0061] 3. Spraying of polymer material protective layer

[0062] Polytrimethylene carbonate (molecular weight 10,000-50,000 Mw) was dissolved in dichloromethane to prepare a 0.5 wt% polymer solution. This solution was then added to an ultrasonic spraying device and ultrasonically sprayed onto the scaffold obtained in step 2, forming a polymer material layer with a thickness of approximately 2 μm on top of the developing coating. After spraying, the scaffold was placed in a vacuum oven and dried at room temperature for one week to allow the solvent in the coating to completely evaporate.

[0063] II. Comparative Example

[0064] Comparative Example 1

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

[0066] A 1 wt% polytrimethylene carbonate (PTMC) solution was prepared using dichloromethane (DCM) as solvent. An HfO2-PTMC composite system was constructed with a solid mass ratio of HfO2 nanoparticles to PTMC of 20:80 (total solid content 20%). The mixture was ultrasonically dispersed for 10 minutes to obtain a uniform dispersion.

[0067] Coating formation: An ultrasonic spraying process is used to construct a developing coating on the surface of the scaffold substrate, resulting in a final coating thickness of 5±0.5μm.

[0068] Comparative Example 2

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

[0070] Comparative Example 3

[0071] The support used in this comparative example is a nickel-titanium alloy support, with tantalum metal development points wrapped around both ends of the support.

[0072] Nickel-titanium alloy stents are commonly used vascular stents in clinical practice. Nickel-titanium alloys have low radiation impermeability, and radiopaque markers are usually added to both ends of the stent to achieve radiopaqueness.

[0073] III. Experimental Examples

[0074] Experimental Example 1: Imaging Contrast under X-rays

[0075] The hafnium dioxide nanoparticle-based developmental scaffold prepared in Example 2, along with the magnesium alloy bare scaffold of Comparative Example 2 and the nickel-titanium alloy scaffold of Comparative Example 3, were developed under X-rays. The results are as follows: Figure 7 As shown in the figure, the bare magnesium alloy stent is not visible under X-rays, while the stent coated with hafnium dioxide nanoparticles is clearly visible under X-rays, exhibiting a visible effect. Compared with the commonly used nickel-titanium alloy stents in clinical practice, the details of the stent are more clearly visible.

[0076] The developing scaffold prepared in Comparative Example 1 and the nickel-titanium alloy scaffold prepared in Comparative Example 3 were developed under X-rays, and the results are as follows. Figure 8 As shown in the image, the stent is only vaguely visible and does not achieve the imaging effect of existing clinical stents.

[0077] Experimental Example 2: Immunosorbent Properties of a Hafnium Dioxide Nanoparticle-Based Immunosorbent Scaffold Implanted in Rabbits

[0078] The hafnium dioxide nanoparticle-based radiopaque scaffold prepared in Example 2 was surgically placed in the carotid artery of a rabbit. Its radiopaqueness in vivo was observed using X-rays, and the results are as follows: Figure 9 As shown in the figure, the vascular stent morphology in the animal is clearly visible and exhibits radioactivity under tissue imaging.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions 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 hafnium dioxide nanoparticle-based visualization stent, characterized by: The stent includes a stent base and a developing coating and a polymer material protective layer successively coated on the stent base from inside to outside, wherein the developing coating is composed of flaky hafnium dioxide nanoparticles. The preparation method of the developing stent based on the hafnium dioxide nanoparticles comprises the following steps: spraying a suspension of flaky hafnium dioxide nanoparticles and water on the surface of the stent base by ultrasonic spraying, then coating a polymer material, and drying to obtain the developing stent. The flaky hafnium dioxide nanoparticles are prepared by the following method: mixing hafnium tetrachloride and water at 65-75 ℃ to form an acidic hydrolysis solution with a pH of 0.5-1, adding an alkali solution to a pH of 5-5.5, and then performing a hydrothermal reaction at 160-180 ℃. The hydrothermal reaction is performed for 8-12 h.

2. The Hf02 nanoparticle-based developing scaffold of claim 1, wherein: The thickness of the developing coating is 2-3 μm.

3. The Hf02 nanoparticle-based developing scaffold according to claim 1 or 2, wherein: The stent base is a degradable stent base, 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 Hf02 nanoparticle-based visualization scaffold of claim 3, wherein: The thickness of the polymer material protective layer is 1-5 μm.

5. A method for preparing a Hf02 nanoparticle-based developing scaffold according to any one of claims 1 to 4, characterized in that: The suspension of flaky hafnium dioxide nanoparticles and water is sprayed on the surface of the stent base by ultrasonic spraying, then a polymer material is coated, and drying is performed to obtain the developing stent. The flaky hafnium dioxide nanoparticles are prepared by the following method: mixing hafnium tetrachloride and water at 65-75 ℃ to form an acidic hydrolysis solution with a pH of 0.5-1, adding an alkali solution to a pH of 5-5.5, and then performing a hydrothermal reaction at 160-180 ℃. The hydrothermal reaction is performed for 8-12 h.

6. The method of claim 5, wherein the Hf02 nanoparticle-based developing stent is prepared by the steps of: The alkali solution is a 1-1.5 M NaOH solution.

7. The method for preparing a Hf02 nanoparticle-based developing stent according to claim 5 or 6, characterized in that: The mass ratio of the hafnium tetrachloride to water is (0.1-1.0):

100.

8. The method for preparing a imaging scaffold 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%.

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