Methods of making polymer-coated localization labels and polymer-coated localization labels

Abstract

The application discloses a method for preparing a positioning marker with a polymer coating and the positioning marker with the polymer coating. The method for preparing the positioning marker with the polymer coating comprises the following steps: raw material pretreatment, batching, melt blending, coating solution preparation, substrate pretreatment, coating and post-treatment, realizes optimized preparation of the polymer coating layer, and has the advantages of enhancing the bonding strength of the coating and the substrate, accurately controlling the degradation rate to match the diagnosis and treatment time window, improving medical imaging visibility, and improving process reproducibility and batch consistency. The positioning marker with the polymer coating is designed as a multi-layer composite structure, realizes firm bonding between the polymer coating and the magnesium alloy substrate, effectively improves the interface stability in a physiological environment, adopts a biocompatible polymer material with a controllable degradation rate, matches a clinical diagnosis and treatment cycle, and takes into account the developing performance and tissue compatibility.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and more particularly to a method for preparing a positioning marker with polymer coating and the positioning marker with polymer coating. Background Technology

[0002] Early-stage breast lesions are difficult to identify directly through clinical examination due to their small size. To ensure the accuracy of diagnosis and treatment, it is necessary to accurately locate the lesion during biopsy sampling, surgery, and postoperatively in order to preserve normal tissue to the greatest extent and reduce damage to the body.

[0003] Currently, commonly used clinical localization markers mainly include protein markers (such as CEA and CA19-9) and gene markers. However, these traditional markers have problems such as limited sensitivity, low specificity, and difficulty in dynamic monitoring during treatment. Therefore, researchers have begun to explore marker materials with higher stability and detection sensitivity, and metallic materials have gradually attracted attention due to their unique physicochemical properties. Currently commonly used metallic localization marker materials include stainless steel, titanium, and their alloys, which have been widely used in preoperative localization and post-biopsy marking of breast cancer. Nevertheless, they still have certain inherent defects and clinical limitations. Especially for patients who do not require secondary surgery, these non-degradable metallic markers will remain in the body for a long time, which may cause foreign body sensation, psychological burden, and even affect the accuracy of postoperative follow-up due to displacement. In some cases, a second surgery may be required to remove them, increasing the patient's health risks and psychological stress.

[0004] Among biodegradable metallic materials, magnesium alloys are considered highly promising candidates for in vivo temporary biomarkers due to their good biocompatibility, biodegradability, degradation rate matching the treatment process, ideal medical imaging visibility, and suitable mechanical properties. However, in practical applications, magnesium alloys still face challenges such as poor corrosion resistance, excessively rapid degradation, accompanying hydrogen release, and reduced visibility due to degradation in the later stages of diagnosis and treatment, which limit their clinical translation. To improve the corrosion resistance and biostability of magnesium alloys, common strategies include surface modification and protective coating technologies, among which polymer coating has been widely studied as an effective barrier protection method.

[0005] However, existing polymer coating solutions still have several shortcomings: First, the bonding strength between the polymer coating and the magnesium alloy substrate is often insufficient, making it prone to peeling or localized damage in the complex mechanical environment of the body, leading to accelerated localized corrosion; second, existing polymer materials lack precision in controlling the degradation rate, making it difficult to achieve precise matching with the entire treatment time window, resulting in premature failure or long-term retention; in addition, some polymer coatings may hinder the visibility of medical imaging or cause inflammatory reactions in surrounding tissues during degradation; the reproducibility and stability of the coating preparation process are also current technical challenges, affecting the batch consistency and clinical reliability of the products. Summary of the Invention

[0006] In view of this, the present invention provides a method for preparing a positioning marker having a polymer coating and a positioning marker having a polymer coating.

[0007] The method for preparing a polymer-coated positioning marker provided by the present invention includes the following steps: S1. Raw material pretreatment: The raw materials containing polylactic acid, polycaprolactone and polyethylene glycol are dried under vacuum conditions; S2. Ingredients and Premixing: Weigh each component of the pretreated raw material according to the proportions and premix to obtain a premixed material; wherein the mass percentages of polylactic acid, polycaprolactone, and polyethylene glycol are as follows: polylactic acid: 70% ~ 80%, polycaprolactone: 10% ~ 20%, polyethylene glycol: 10% ~ 20%; S3. Melt blending, extrusion and granulation: The premixed materials are fed into a twin-screw extruder for melt blending, extrusion and granulation to obtain composite polymer particles; S4. Preparation of coating solution: Dissolve the composite polymer particles in an organic solvent to form a homogeneous coating solution; S5. Substrate pretreatment: Cleaning and activating the surface of the substrate for the positioning markers; S6. Coating and molding by dip coating: The pretreated substrate is immersed in the coating solution, and a uniform wet film is formed on its surface by dip coating. S7. Post-treatment: The wet film is dried and heat-annealed to form a dense polymer composite coating layer.

[0008] Preferably, in step S2, the mass percentages of polylactic acid, polycaprolactone, and polyethylene glycol are as follows: polylactic acid: 65% - 85%, polycaprolactone: 10% - 25%, and polyethylene glycol: 5% - 15%.

[0009] Preferably, in step S2, the polylactic acid is composed of L-polylactic acid and D-polylactic acid, and the molar ratio of L-polylactic acid to D-polylactic acid is 1:1.

[0010] Preferably, the ingredients in step S2 further include the following components in percentage of the total mass of the premix: antioxidant: 0.2-0.5 wt.%, initiator: 0.05-0.2 wt.%, plasticizer: 5-10 wt.%, coupling agent: 0.5-1.5 wt.%, and / or reinforcing agent: 2-5 wt.%; wherein the antioxidant is ascorbyl palmitate, the initiator is benzoyl peroxide, the plasticizer is tributyl citrate, the coupling agent is 3-(trimethoxysilyl)propyl methacrylate, and the reinforcing agent is hydroxyapatite.

[0011] Preferably, in step S3, the process parameters of the twin-screw extruder satisfy the following: the screw configuration along the material conveying direction includes a conveying section, a melt mixing section composed of a combination of forward kneading blocks and reverse kneading blocks, and a homogenization section composed of toothed discs; wherein the temperature is controlled at 170-190℃, the screw speed is 50-100 rpm, and a high vacuum of 0.01-0.03MPa is activated before the homogenization section.

[0012] Preferably, in step S4, the organic solvent is a volatile organic solvent, preferably dichloromethane, trichloromethane, acetone, tetrahydrofuran, or a mixture thereof; the concentration of the coating solution is 1% to 15% g / mL, preferably 3% to 8% (w / v); the specific process parameters are: immersion time 30-120 seconds, lifting speed 1-10 mm / s, lifting times 1-5 times, ambient temperature 20-30℃, and relative humidity 30%-50%.

[0013] Preferably, in step S5, the substrate pretreatment includes: mechanically polishing the substrate of the positioning marker, followed by oxygen plasma cleaning and activation.

[0014] Preferably, in step S6, the lifting coating method uses a program-controlled lifting device, and the lifting speed is controlled between 0.1 mm / s and 10 mm / s. The thickness of the coating layer is adjusted by controlling the lifting speed and / or the solution concentration.

[0015] Preferably, in step S7, the heat annealing is carried out under vacuum or inert atmosphere protection, the treatment temperature is above the glass transition temperature and below the melting point of the crystalline component in the blend, and the treatment time is 2-4 hours.

[0016] The positioning markers with polymer coating prepared by the method are also within the scope of protection of this invention.

[0017] The method for preparing polymer-coated positioning markers provided by this invention, through steps including raw material pretreatment, ingredient mixing, melt blending, coating solution preparation, matrix pretreatment, coating, and post-treatment, achieves optimized preparation of the polymer coating layer. This method offers advantages such as enhanced interfacial bonding strength between the coating and the matrix, precise control of degradation rate to match the diagnostic and treatment time window, improved medical imaging visibility, and enhanced process reproducibility and batch consistency. The polymer-coated positioning markers provided by this invention, through the design of a multi-layer composite structure, achieve a strong bond between the polymer coating and the magnesium alloy matrix, effectively improving interfacial stability under physiological conditions. The use of biocompatible polymer materials with controllable degradation rates matches the clinical treatment cycle, balancing imaging performance and tissue compatibility. The combination of surface functionalization treatment and precision coating processes ensures coating uniformity, integrity, and batch-to-batch consistency, thereby overcoming the problems of weak bonding, uncontrollable degradation, and insufficient biosafety in existing technologies. Detailed Implementation

[0018] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0019] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0020] For ease of understanding, some key terms in this invention are explained below: Polymer-coated localization markers refer to medical devices used in vivo, particularly for localizing breast lesions, whose surface is covered by one or more layers of polymer material. This polymer coating is designed to regulate the biocompatibility, degradation behavior, and mechanical properties of the marker.

[0021] Polylactic acid (PLA) is a biodegradable polymer with good biocompatibility and mechanical strength, and is often used as a main component of biomedical materials. Its degradation product is lactic acid, which can be metabolized by the body.

[0022] Polycaprolactone (PCL) is a semi-crystalline biodegradable polymer with excellent flexibility and biocompatibility. Its degradation rate is generally slower than that of polylactic acid, and it can be used to regulate the overall degradation cycle of composite materials.

[0023] Polyethylene glycol (PEG) is a water-soluble polymer with good biocompatibility and hydrophilicity. In polymer blends, PEG can act as a plasticizer or compatibilizer, and can adjust the hydrophilicity and degradation rate of the material.

[0024] A twin-screw extruder is a commonly used polymer processing equipment. It uses two meshing screws rotating inside a barrel to transport, melt, mix, plasticize, and extrude polymers. It possesses excellent mixing and dispersing capabilities and is suitable for blending and modifying multi-component polymers.

[0025] The dip-coating method is a solution coating technique that involves immersing a substrate in a coating solution at a controlled speed and then pulling it out of the solution at a controlled speed, thereby forming a uniform wet film on the substrate surface. This method allows for precise control of the coating thickness and is suitable for substrates of various shapes.

[0026] Thermal annealing is a heat treatment process that involves heating a material to a specific temperature and holding it for a period of time, followed by slow cooling, to eliminate internal stress, promote grain growth, and improve the density and stability of the material. In polymer coatings, thermal annealing helps improve the structural integrity of the coating and its adhesion to the substrate.

[0027] Experimental materials: Core material: Polylactic acid (PLA); purchased from Sigma-Aldrich, catalog number: 76504.

[0028] Modified materials (for blending control): Polyethylene glycol (PEG), purchased from Sigma-Aldrich, catalog number: 81240: a plasticizer that effectively lowers the glass transition temperature of PLA, significantly improving the material's flexibility and hydrophilicity. Polycaprolactone (PCL), purchased from Sigma-Aldrich, catalog number: 440744: a toughening agent, also a biodegradable polyester with excellent flexibility and ductility. Blending it with PLA can produce materials with better toughness, and the degradation rate is between that of the two.

[0029] By designing single and composite coatings with different proportions, the effects of these coatings on the degradation rate, biocompatibility, and ultrasonic imaging performance of composite materials were systematically evaluated, and the optimal coating ratio was determined.

[0030] 1. Single material coating (control group) This group is used to establish a performance baseline.

[0031] Comparative Example 1-1: PLA coating layer (thickness ~10μm).

[0032] Comparative Examples 1-2: PEG coating layer (thickness ~10μm).

[0033] Comparative Examples 1-3: PCL coating (thickness ~10μm).

[0034] 2. Binary composite coating This study investigated the synergistic effect between two polymers, focusing on modulating degradation rates and biocompatibility. The total polymer concentration was kept constant (10 mg / mL), with only the proportions adjusted.

[0035] Experimental group 2-1: PLA / PEG (mass ratio: 90 / 10) Design concept: Using PLA as a continuous phase to ensure structural integrity. Introducing 10% (by mass) of hydrophilic PEG to form hydrophilic microchannels within the PLA aims to moderately accelerate PLA degradation and enhance surface hydrophilicity to facilitate cell adhesion.

[0036] Experimental group 2-2: PLA / PEG (mass ratio: 70 / 30) Design rationale: Increasing the PEG ratio is expected to significantly accelerate the degradation rate and greatly improve hydrophilicity. However, this may sacrifice some barrier performance.

[0037] Experimental groups 2-3: PCL / PEG (mass ratio: 90 / 10) Design concept: Using PCL, which has good toughness and slow degradation, as the matrix, PEG is introduced to overcome the strong hydrophobicity of PCL. The goal is to moderately improve cell compatibility while maintaining the good barrier function of PCL.

[0038] Experimental groups 2-4: PCL / PEG (mass ratio: 70 / 30) Design rationale: Faster degradation rate and better hydrophilicity, but the density of the coating layer may decrease.

[0039] Experimental groups 2-5: PLA / PCL (50 / 50) Design concept: Combining the rigidity of PLA and the toughness of PCL, a coating layer with balanced mechanical properties is expected to be obtained. Both have relatively slow degradation rates, and this proportional degradation behavior falls between the two.

[0040] 3. Ternary composite coating This group is designed to enable more complex functional integration.

[0041] Experimental group 3-1: PLA / PCL / PEG (80 / 10 / 10) Design concept: PLA is used as the main framework, PCL as the toughening phase, and 10% PEG as a hydrophilicity regulator and pore-forming agent. The goal is to obtain a "smart" coating layer with controllable degradation, good mechanical properties, and a certain degree of hydrophilicity.

[0042] Experimental group 3-2: PLA / PCL / PEG (70 / 20 / 10) Design concept: Increasing the PCL ratio is expected to further improve the toughness (elasticity) of the coating layer, making it more suitable for applications that need to withstand dynamic mechanical loads (such as cardiovascular stents).

[0043] Experimental group 3-3: PLA / PCL / PEG (70 / 10 / 20) Design rationale: Increasing the PEG ratio to 20% will make hydrophilicity and degradation rate the dominant performance characteristics. This coating may be more suitable for applications requiring rapid initiation of tissue integration.

[0044] The comparison results of single and composite coatings with different proportions are shown in Table 1.

[0045] Table 1 Comparison results of single and composite coatings with different proportions System review revealed that: (1) Degradation rate regulation: PEG is a key accelerating factor for degradation rate, and its content is positively correlated with the hydrophilicity and hydrolysis rate of the material. PLA, as the matrix material, determines the basic degradation framework, while the introduction of hydrophobic PCL can effectively delay the overall penetration of water molecules. Therefore, by adjusting the mass ratio of the three, a wide range of fine-tuning of the degradation curve of the composite material can be achieved to meet the needs of different clinical cycles.

[0046] (2) Biocompatibility optimization: The introduction of appropriate amounts of PEG (10%-30%) can significantly improve the cell affinity of PLA or PCL. Among them, experimental group 3-1 (PLA / PCL / PEG=80 / 10 / 10) achieved the best balance between improved hydrophilicity and material stability, and had the best cell adhesion and proliferation performance.

[0047] (3) Ultrasonic imaging performance: PLA provides good initial contrast, and PCL helps maintain imaging durability. An excessively high PEG ratio will reduce the stability of the acoustic interface. Experimental groups 2-5 (PLA / PCL=50 / 50) and 3-1 showed outstanding performance in imaging clarity and durability.

[0048] (4) Optimal overall performance: Experimental group 3-1 (PLA / PCL / PEG=80 / 10 / 10) achieved the best balance in three aspects: controllable degradation (50% weight loss in about 7 months), biocompatibility (cell adhesion rate increased by more than 30%) and ultrasonic imaging performance (high contrast and slow decay), and was determined to be the optimal coating ratio.

[0049] Through the above systematic design and comparison, this invention clarifies the influence of the proportion of each component on the core performance, providing clear guidance for the customization of coatings for specific clinical application scenarios.

[0050] The key ratio adjustments are as follows: PLLA : PDLA = 1:1. L-polylactic acid (PLLA) and D-polylactic acid (PDLA) are mirror isomers of polylactic acid. A PLLA : PDLA ratio of 1:1 can form a high-melting-point stereocomposite crystal with more compact molecular chain packing, slowing down water molecule penetration and hydrolysis, resulting in the slowest degradation rate; it can be used to mitigate degradation rates.

[0051] A PLA : PCL (mass ratio) of 80 : 20 to 70 : 30 allows PCL to act as "elastic islands" dispersed within the PLA matrix, absorbing impact energy and significantly improving elongation at break and toughness. An excessively high ratio may lead to phase separation; however, it can be used to improve toughness.

[0052] PLA : PEG (mass ratio) = 95 : 5 to 85 : 15. PEG acts as an internal plasticizer, lowering the glass transition temperature and increasing chain segment mobility; its hydrophilicity accelerates water absorption and hydrolysis. Adding more than 20% can easily lead to PEG precipitation. It can be used to accelerate degradation and increase hydrophilicity (regulating the degradation rate).

[0053] PLA : HA (mass ratio) = 95 : 5 to 90 : 10. HA, as an inorganic filler, can alter the hydrolysis microenvironment, typically slightly delaying degradation. It also increases the material's compressive modulus and hardness. It can be used to fine-tune the degradation rate and modulus.

[0054] Based on comprehensive evaluation, the optimal ratio range for the ternary system is: PLA / PCL / PEG = (65~85): (10~25): (5~15). This invention provides a method for preparing positioning markers with polymer coatings, which integrates optimized melt blending extrusion and dip-coating (coating deposition) processes, including the following steps: S1. Raw material pretreatment: All polymers and additives are thoroughly vacuum dried to prevent hydrolysis and degradation during processing.

[0055] S2. Ingredients and Premixing: Weigh each component precisely according to the designed proportions. For trace additives, the "masterbatch method" can be used to ensure uniform dispersion. That is, the additive and a small amount of PLA carrier are first melt-blended to form a high-concentration masterbatch, and then physically premixed with the main material.

[0056] S3. Melt Blending, Extrusion, and Granulation: The premixed materials are fed into a twin-screw extruder for melt blending, extrusion, and granulation to obtain microscopically uniformly dispersed composite polymer particles. This is the core step, and its optimization points include: a) Screw configuration optimization: The screw is configured with a conveying section, a high-intensity mixing section, and a homogenization and venting section sequentially from the feed port to the die head. The high-intensity mixing section uses a combination of forward and reverse kneading blocks to provide high shear to refine the dispersed phase (e.g., dispersing PCL into micron-sized "island phases"); the homogenization section uses toothed disks for gentle distribution mixing; and a high-vacuum venting port is opened after the mixing section to remove small molecule volatiles.

[0057] b) Process parameter control: A "hump-shaped" temperature profile is adopted, meaning the temperature in the feeding zone is relatively low (150-160℃), the temperature in the melting and mixing zone is the lowest (165-175℃ to inhibit degradation and utilize high viscosity to promote dispersion), and the temperature in the homogenization and die head zones is slightly higher (175-185℃ to facilitate devolatilization and discharge). The screw speed is set at 200-300 rpm, combined with the "starvation feeding" mode, to control torque while ensuring high shear mixing.

[0058] S4. Preparation of coating solution: Dissolve the composite polymer particles obtained in step S3 in a suitable organic solvent (such as dichloromethane or chloroform) to prepare a coating solution with uniform and stable concentration. This is a key step connecting melt blending and coating molding.

[0059] S5. Substrate pretreatment: The magnesium alloy substrate is subjected to step-by-step grinding, cleaning and O2 plasma activation treatment to improve surface roughness, cleanliness and chemical activity, laying the foundation for strong adhesion.

[0060] S6. Dip-Pull Coating: Using a programmable dip-pull equipment, the pretreated substrate is immersed in the coating solution. After a set immersion time, it is pulled up at a controllable speed (typically 0.1-10 mm / s) to form a uniform wet film on its surface. By calibrating the relationship between "pulling speed - solution concentration - dry film thickness," the coating layer thickness can be precisely controlled. Gradient or multilayer structures can also be constructed by sequentially immersing solutions of different components.

[0061] S7. Post-treatment: After the wet film is dried in a stepped manner, a critical heat annealing treatment is performed (the temperature is above the Tg and below the Tm of the polymer component, such as 50-55℃ for PCL-containing systems). This process can eliminate internal stress, promote polymer chain rearrangement and crystallization, heal micro-defects, and remove residual solvents, thereby significantly improving the density, crystallinity, barrier properties, and adhesion to the substrate of the coating layer.

[0062] In some embodiments of the present invention, the process flow for melt blending extrusion (suitable for mass production) is as follows: Raw material drying → precise weighing → premixing → melt blending and extrusion → granulation → drying → injection molding / extrusion molding → post-treatment (annealing) Raw material drying: PLA, PEG, PCL, and ethyl acetate are dried in a vacuum oven at 50-60℃ for at least 12 hours to prevent hydrolysis and degradation during high-temperature processing. Accurate weighing: Each component is accurately weighed according to the designed proportions. Premixing: The powdered components are physically mixed uniformly using a high-speed mixer (manufacturer: Seidel, Germany, model: GM5). Melt blending extrusion: A twin-screw extruder (Coperon, Germany, model: ZSK 18 MEGAlab) is used. Process parameters: Temperature range: 170℃-190℃ (adjusted according to the specific PLA molecular weight and proportions), screw speed: 50~100 rpm, feed rate: matched to the speed to ensure uniform material residence time. Through melt shearing, the components achieve uniform microscopic dispersion. Granulation and drying: The extruded strips are water-cooled and then granulated. The resulting composite particles are dried again for subsequent processing. Molding: The particles are processed into the final desired coating shell or coating layer using a micro-injection molding machine or extruder. This coating layer needs to have the following characteristics: (1) Conformal, complete and uniform film / shell: Form: It must tightly wrap around the surface of the positioning marker, perfectly replicating its complex geometry (including the spiral hollow part and the anchoring structures at both ends), forming a "conformal coating".

[0063] Thickness: The thickness should be in the micrometer range (e.g., 5-50 μm) and uniformly distributed along the entire length and circumference of the label. Thickness is a key parameter for regulating degradation rate and drug release kinetics.

[0064] (2) Clear multifunctionality: Controllable degradation barrier: As a controllable physical barrier, it actively blocks the direct and rapid contact between body fluids and the magnesium alloy matrix, turning the degradation of magnesium from "out of control" to "controllable".

[0065] Drug carrier: As a drug reservoir, it loads and releases therapeutic drugs (such as anticancer drugs and antibiotics) in a controlled manner. Its release profile should match the release of magnesium ions and the course of disease treatment.

[0066] Mechanical property modifiers: improve the biocompatibility of marker surfaces, provide a more compliant surface, and reduce mechanical irritation to surrounding tissues.

[0067] (3) Strong bonding with the substrate: The covering layer must have sufficient adhesion to the underlying marker to prevent peeling or damage during implantation or due to blood flow impact or tissue peristalsis.

[0068] In some embodiments of the present invention, the polymer coating layer is prepared by melt blending extrusion, comprising the following steps: Step 1: Raw material pretreatment and drying PLA: A "step-by-step heating and drying method" is used. First, it is dried at 60-80℃ for 2-4 hours to remove most of the surface moisture; then, it is vacuum dried at 100-105℃ for 4-6 hours to completely remove bound water. Vacuum drying is superior to forced-air drying and can prevent PLA from oxidizing and yellowing at high temperatures.

[0069] Additives: Adjust the drying temperature according to the heat sensitivity of the additives. For example, adjust the set temperature according to the glass transition temperature of the polymer or additive being prepared. For solvents, the temperature should be controlled at around 50°C.

[0070] Technical benefits: It fundamentally avoids hydrolysis and degradation caused by moisture, ensuring that the final product is bubble-free, has minimal molecular weight loss, and stable appearance and mechanical properties.

[0071] Step 2: Ingredients and Mixing Masterbatch method: For additives that are added in small amounts but are crucial (such as antioxidants and initiators), they are first prepared into high-concentration masterbatches with a small amount of PLA carrier. This ensures that they are evenly distributed in the final blend.

[0072] Additive 1: Ascorbate palmitate. Function: Antioxidant; it is a vitamin C derivative, non-toxic and biodegradable, effectively inhibiting the thermal oxidative degradation of PLA and other materials during processing. Dosage: 0.2-0.5 wt.% (percentage of the total weight of the final composite material). This dosage is sufficient for stabilization and is well below its biosafety threshold.

[0073] Additive 2: Benzoyl peroxide. Function: Initiator. At controlled low doses, it can be used to induce graft copolymerization of PLA with certain functional monomers to moderately increase melt strength or introduce reaction sites. Dosage: 0.05-0.2 wt.%. The dosage must be extremely low to ensure complete reaction and no residue.

[0074] The method for preparing high-concentration masterbatch is as follows: Preparation of PLA masterbatch with an antioxidant concentration of 5%. Specific steps: 1. Accurate weighing: Weigh 5g of ascorbate palmitate and 95g of PLA resin powder. 2. Premixing: Place both in a high-speed mixer and mix at low speed for 5-10 minutes to achieve preliminary physical mixing. 3. Melt blending: Use a micro twin-screw extruder for melt blending, setting the temperature to the typical processing temperature of PLA (170-180℃). This process ensures uniform dispersion of the antioxidant in the PLA carrier. 4. Granulation: After water cooling, granulate the extruded strips to obtain the 5% antioxidant masterbatch.

[0075] Ordered feeding: During high-speed mixing, feed the materials in the order of "liquid → powder → granules". For example, first add liquid plasticizer or coupling agent to uniformly coat the surface of PLA granules, then add powdered nucleating agent or reinforcing agent, and finally add large elastomer particles. This facilitates preliminary pre-dispersion.

[0076] (1) The liquid components are as follows: Chemical name: Tributyl citrate, used as a liquid plasticizer. Dosage: 5-10 wt.%, which can be adjusted within this range according to specific flexibility requirements.

[0077] Chemical name: 3-(trimethoxysilyl)propyl methacrylate, used as a coupling agent. One end of its molecule can bind to inorganic fillers (such as hydroxyapatite, if added), while the methacrylate group at the other end can interact with the polymer matrix, improving interfacial compatibility. Dosage: 0.5-1.5 wt.% (relative to the weight of the inorganic filler).

[0078] (2) The powdered components are as follows: Chemical name: Hydroxyapatite, used as a bioactivity enhancer / nucleating agent. Dosage: 2-5 wt.%. Excessive addition will cause material embrittlement.

[0079] (3) Large-particle elastomers are as follows: Chemical name: Polycaprolactone (PCL), used as an elastomer toughening agent. As mentioned earlier, PCL possesses excellent flexibility and biodegradability. Blending with PLA can effectively improve the impact toughness and elongation at break of composite materials. Form and dosage: Added in granular form (approximately 2-4 mm in diameter), at a dosage of 10-20 wt.%.

[0080] Technical effect: It achieves uniform distribution of additives at both the macro and micro scales, providing a stable feed for subsequent extrusion and avoiding local agglomeration or uneven performance.

[0081] Step 3: Melt blending extrusion (core step) This is the most important aspect of optimization, mainly focusing on the process parameter settings of the twin-screw extruder.

[0082] a. Temperature profile optimization PLA is sensitive to heat; it is easily degraded at excessively high temperatures, while it will not melt sufficiently at excessively low temperatures, resulting in poor mixing and high torque.

[0083] Optimization strategy: Adopt a camel-hump-shaped temperature curve with "high at both ends and low in the middle".

[0084] Feeding zones (zone 1 and zone 2): The temperature is relatively low (approximately 150-160℃) to prevent materials from melting and adhering prematurely, ensuring stable feeding.

[0085] Melting and mixing zone (middle zones): Set to the lowest temperature (approximately 165-175℃), where PLA is completely melted. Shear mixing is performed at this lower temperature to minimize thermal degradation.

[0086] Homogenization and discharge zone (die head): The temperature is slightly higher (about 175-185℃), which reduces the melt viscosity and facilitates venting and stable extrusion.

[0087] b. Screw speed and torque Optimization strategy: Within the safe range of ensuring the main torque (usually <70%), appropriately increase the screw speed (e.g., 200-400 rpm).

[0088] Technical benefits: High rotation speed leads to high shear rate, which is beneficial to the refinement of dispersed phase particles (polymer particles), forming a more uniform "island structure", promoting the chemical reaction between interfacial compatibilizers (such as PLA-g-MAH, where g represents grafting in polymer, PLA and MAH grafting) and PLA and dispersed phase, and improving production efficiency.

[0089] "Island structure" is a classic microscopic morphological model in polymer blends. In blends, the "sea phase" refers to the polymer component that forms a continuous phase. It is usually the matrix resin that constitutes the majority (or, although not dominant, has better compatibility with other components). In this system, PLA acts as the sea phase. The island phase refers to the polymer component that is distributed as a dispersed phase, in the form of tiny particles or droplets, within the continuous sea phase. It is often used to improve certain properties of the matrix, such as toughening. In this system, the goal of the PCL elastomer particles is to become uniform, fine "islands."

[0090] c. Screw configuration optimization This is the key to achieving high-performance blending. The combination of screw elements is designed according to the blending purpose.

[0091] Conveying elements: responsible for material conveying.

[0092] Kneading Blocks: Provide strong shear for dispersive mixing (such as breaking up agglomerated particles) and distribution mixing. Forward kneading blocks at an angle (e.g., 45°) are primarily used for mixing, while reverse kneading blocks can establish back pressure, prolong residence time, and enhance mixing effects.

[0093] Toothed disks (Mixing Disks): Primarily used for distribution mixing, they have weak shear resistance and are suitable for materials that are sensitive to shear.

[0094] Example of optimized configuration (taking PLA / PBAT toughening as an example): Downstream of the feed inlet: A set of forward kneading blocks is set up for initial melting and mixing; Middle section (reaction zone): After the compatibilizer is added, a combination of reverse kneading blocks and forward kneading blocks is set up to create high shear and long residence time, promoting interfacial reaction; Upstream of the vent: A conveying element is set up to seal and establish a melt seal; Homogenization section: A toothed disc is used for gentle final mixing to avoid excessive shearing that leads to degradation.

[0095] d. Vacuum exhaust Optimization strategy: After the melting section and before the homogenization section, start a high vacuum of 0.01-0.03 MPa.

[0096] Technical benefits: Effectively extracts small molecules (such as water and lactic acid monomers), residual monomers, and moisture generated during the reaction, further improving material purity and preventing defects and performance degradation in the products.

[0097] Step 4: Cooling, pelletizing and post-processing Optimized operation: Water-cooled strip cutting ensures a constant water temperature in the cooling tank (10-20℃ recommended) to rapidly cool the strips, resulting in low crystallinity and regular pellet shape. Post-drying: The pellets still need to undergo a brief vacuum drying process (e.g., 80℃, 2 hours) to remove surface-adsorbed moisture before packaging or use in the next processing step (e.g., injection molding, blown film).

[0098] In some embodiments of the present invention, the adhesion method has been optimized. The ultimate goal of optimization is to obtain a uniform, dense, strongly adhesive, reproducible, and precisely controllable polymer coating layer in terms of thickness and composition. Optimization is performed step-by-step from the following four key aspects: Optimization of substrate pretreatment (creating an ideal "foundation" for polymer adhesion), optimization of adhesion process (precise control of the "construction" process), and optimization of post-treatment process (performing final "finishing" to stabilize performance).

[0099] (1) Optimization of matrix pretreatment A clean substrate with appropriate roughness and surface chemistry is a prerequisite for strong adhesion.

[0100] Optimization direction 1: Surface roughness and cleanliness Solution: Use stepped sandpaper for polishing (e.g., gradually increasing from 800 grit to 2000 grit or higher) to ensure uniform surface scratches and increase the mechanical interlocking area. Then perform O2 plasma cleaning. Plasma not only thoroughly removes organic contaminants but also activates the surface, introducing hydrophilic groups such as hydroxyl groups, greatly improving the spreadability of polymer solutions.

[0101] (2) Optimization of the adhesion process This is the core step in controlling the uniformity and thickness of the coating layer.

[0102] Optimization Direction 1: Dynamic Impregnation-Lifting Technology Solution: Use a programmed dip-lift system. Optimize the following parameters: Pulling speed: This is the most critical parameter for controlling thickness. According to the Landau-Levich equation, low speed (~0.1 mm / s) yields thinner layers, while high speed (~10 mm / s) yields thicker layers. Experimental calibration is required.

[0103] Impregnation time: Ensure the substrate is in full contact with the solution.

[0104] Lifting acceleration: Smooth acceleration avoids vibration and ensures uniformity.

[0105] Optimization Direction 2: Construction of Gradient or Multi-Layer Structures Solution: Implement sequential impregnation. For example, first impregnate with a layer of pure PCL solution as a dense barrier underlayer, then dry and impregnate with a layer of PLA / PEG mixed solution as a functional top layer. This approach balances the excellent corrosion resistance of the underlayer with the good biocompatibility of the top layer.

[0106] In some embodiments of the present invention, the post-processing technology has been optimized: Post-treatment can significantly improve the crystallinity, adhesion and long-term stability of the coating.

[0107] Optimization direction 1: Thermal annealing Solution: Perform stepped thermal annealing at a temperature above the polymer's glass transition temperature but below its melting point. For example, for PCL (Tm ~60℃), annealing can be performed at 50℃ for 2 hours.

[0108] Functions: It eliminates internal stress, promotes polymer chain rearrangement and crystallization, making the film denser, and can "heal" microscopic defects, significantly improving its barrier performance. Most importantly, it removes residual solvents, ensuring biocompatibility.

[0109] Optimization Direction 2: Crosslinking Treatment Solution: For systems containing PEG or other reactive functional groups, UV photocrosslinking or thermal crosslinking can be used. For example, adding a small amount of photoinitiator to the polymer and irradiating it with UV light of a specific wavelength can cause a covalent network to form between the polymer chains.

[0110] Function: Greatly improves the mechanical strength and stability of the coating in the degradation medium, preventing premature peeling.

[0111] Example 1: Preparation of positioning markers for polymer composite coating (PLA / PCL / PEG=75 / 15 / 10) The method for preparing the positioning marker of the polymer composite coating layer in this embodiment includes the following steps: S1. Raw material pretreatment: Place PLA, PCL, and PEG granules in a vacuum oven and dry at 55°C for 24 hours.

[0112] S2. Ingredients and Premixing: Weigh the dried PLA, PCL, and PEG in a mass ratio of 75:15:10. Add 0.3% ascorbyl palmitate, 0.1% benzoyl peroxide, 8% tributyl citrate, and 3% hydroxyapatite, representing 0.3% of the total premix mass. Mix all materials in a high-speed mixer for 10 minutes to obtain the premix.

[0113] S3. Melt Blending Extrusion Granulation: The premixed material is fed into a twin-screw extruder (Coperion ZSK 18, Germany). The screw configuration is as described in the invention. Temperature settings: Zone 1 170°C, Zone 2 175°C, Zone 3 180°C, Zone 4 185°C, Die head 185°C. Screw speed 80 rpm, with -0.02 MPa vacuum exhaust activated after the melting zone. The melt is water-cooled, pelletized, and then dried again to obtain composite polymer particles.

[0114] S4. Preparation of coating solution: Dissolve the above composite particles in dichloromethane to prepare a 6% (w / v) solution, and stir magnetically for 12 hours until completely clear.

[0115] S5. Substrate Pretreatment: A magnesium alloy cylinder with a diameter of 0.5 mm and a length of 3 mm was selected as the substrate for the positioning marker. Its surface was evenly sanded with 2000-grit sandpaper, and then placed in a plasma cleaner and treated with O2 plasma at a power of 100W for 3 minutes.

[0116] S6. Coating and molding by dip coating method: Using a precision dip coating machine, the treated magnesium alloy substrate is vertically immersed into the coating solution. After immersion for 60 seconds, it is steadily pulled out of the liquid surface at a constant speed of 2 mm / s, so that a uniform wet film is attached to its surface.

[0117] S7. Post-treatment: The coated substrate was allowed to evaporate the solvent at room temperature for 30 minutes, and then dried in a 40°C oven for 4 hours. Finally, it was heat-annealed in a vacuum environment at 55°C (higher than the Tg of PCL, which is conducive to chain segment movement) for 3 hours. After furnace cooling, a positioning marker with a dense and smooth polymer coating layer was obtained, with a coating layer thickness of approximately 20±3 μm.

[0118] Examples 2-4: Preparation of coating layers with different ratios Referring to the steps of Example 1, only the mass ratio of PLA, PCL, and PEG in step S2 was changed, and samples with the following mass ratios were prepared respectively: Example 2: PLA / PCL / PEG = 80 / 10 / 10 Example 3: PLA / PCL / PEG = 70 / 20 / 10 Example 4: PLA / PCL / PEG = 70 / 10 / 20 Comparative Example 1 The steps are the same as in Example 1, but in step S2 only PLA is used, without adding PCL, PEG and other additives.

[0119] Example 5: Preparation of a coating layer with stereocomposite crystals The steps are the same as in Example 1, but in step S2, ordinary PLA is replaced with an equimolar physical mixture of PLLA and PDLA (i.e., PLLA:PDLA molar ratio = 1:1), while the proportions of other components remain unchanged.

[0120] The following performance tests were performed on the polymer composite coating positioning markers prepared in different embodiments and comparative examples: (1) Hydrophilicity (water contact angle) Test method: Static drop contact angle measurement method 1. Instrument: Contact angle measuring instrument.

[0121] 2. Sample preparation: Fix the sample with a flat coating layer horizontally on the sample stage.

[0122] 3. Testing procedure: Use a microsyringe to add a drop of ultrapure water (usually 2-5 μL) to the sample surface, and capture the droplet profile using the instrument's high-speed camera.

[0123] 4. Data Analysis: The software uses the Young-Laplace equation fitting or the tangent method to calculate the tangent angle at the solid-liquid-gas three-phase contact point, which is the water contact angle. Measurements are taken at at least three different locations for each sample, and the average value is calculated. The smaller the contact angle, the stronger the surface hydrophilicity.

[0124] (2) Flexibility (elastic modulus) Test method: Nanoindentation 1. Instrument: Nanomechanical testing system (nanoindenter).

[0125] 2. Principle: A very small diamond indenter (such as a Berkovich indenter) is used to press into the surface of the coating layer in a controlled manner, while the load (P) and indentation depth (h) curves are recorded with high precision.

[0126] 3. Testing process: Select multiple test points, apply preset load or depth control programs, and obtain the Ph curve.

[0127] 4. Data Analysis: By analyzing the initial slope of the unloading curve, the elastic modulus of the material is calculated according to the Oliver-Pharr model. This method is particularly suitable for measuring the local mechanical properties of micron-scale thin films or coatings without the need to peel off the coating. The lower the modulus value, the more flexible the material.

[0128] (3) In vitro degradation rate Test method: In vitro immersion simulation method 1. Degradation medium: Standard simulated body fluid (e.g., SBF, pH 7.4, 37°C) or phosphate-buffered saline (PBS). The pH can be adjusted (e.g., pH 6.5) to simulate specific environments such as tumors.

[0129] 2. Procedure: The sample with a known initial mass (M0) is completely immersed in a certain volume of medium and placed in a constant temperature oscillator at 37°C.

[0130] 3. Monitoring Indicators: - Mass loss: Periodically remove the sample, wash it with deionized water, vacuum dry it to constant weight, and weigh it (Mt). Calculate the residual mass rate (Mt / M0 × 100%) or the mass loss rate.

[0131] - Medium pH: Use a pH meter to periodically measure changes in the pH of the degradation medium to assess the impact of degradation products on the local environment.

[0132] - Surface morphology: The corrosion morphology and crack formation on the sample surface at different time points were observed by scanning electron microscopy (SEM).

[0133] 4. Data comparison: Plot mass loss-time curves and pH-time curves, and compare the slopes of the curves for different formulation samples to qualitatively or semi-quantitatively compare the degradation rate.

[0134] (4) Adhesion of the coating layer Test method: Cross-cut test (ASTM D3359 standard) 1. Tools: Scrap paper cutter (blade spacing 1mm or 2mm), transparent pressure-sensitive tape.

[0135] 2. Process: a. Use a grid cutter to create an intersecting grid on the surface of the coating layer, cutting through the coating to the substrate.

[0136] b. Remove the debris with a soft-bristled brush.

[0137] c. Firmly adhere the special tape to the grid area, flatten it, and then quickly peel it off at a 60° angle.

[0138] 3. Rating: Observe the peeling of the coating in the grid area under a microscope and rate it according to the standard: - Level 0: The cut edges are completely smooth, with no chips falling off (optimal).

[0139] - Level 1: Detachment area ≤ 5%.

[0140] - Level 5: Detachment area > 65% (worst).

[0141] In the table, "Level 0 (No Peeling)" indicates excellent adhesion.

[0142] (5) Continuous ultrasound imaging Test method: Simulated test using a tissue ultrasound model 1. Model construction: Prepare tissue-like ultrasound phantoms (usually made of water, glycerol, agarose or special polymer gel) that are similar to the acoustic properties of human soft tissue.

[0143] 2. Test setup: Implant the marker sample into the phantom at a fixed position, and use a clinical diagnostic-grade ultrasound machine to set fixed imaging parameters (such as frequency, gain, and depth).

[0144] 3. Process and Measurement: a. Initial imaging: Record clear ultrasound images (hyperechoic bright spots) and signal intensity of the implanted sample.

[0145] b. Long-term simulation: The sample is immersed in a degradation medium at 37°C to simulate the in vivo environment. It is periodically removed, cleaned, and then placed in a fresh, identical phantom for ultrasound scanning at the same location.

[0146] 4. Data Analysis: Compare the intensity, clarity, and posterior acoustic shadowing characteristics of the marker signal in ultrasound images at different time points. Quantify the echo signal intensity using image analysis software and plot the signal intensity attenuation curve. Slower attenuation indicates better protective effect of the coating layer and stronger imaging persistence.

[0147] The performance test results of the polymer composite coating positioning markers prepared in different embodiments and comparative examples are shown in Table 2.

[0148] Table 2 Performance test results of polymer composite coating positioning markers prepared in different embodiments and comparative examples Results Explanation: 1. Material Proportions: This section shows the core variable for each embodiment, namely the mass ratio of the three polymers PLA, PCL, and PEG. Example 5 uses a PLLA / PDLA mixture capable of forming stereocomposite crystals instead of ordinary PLA.

[0149] 2. Hydrophilicity: This is visually demonstrated by the water contact angle. The smaller the angle, the better the hydrophilicity. All examples containing PEG showed significantly better hydrophilicity than the pure PLA comparative example.

[0150] 3. Flexibility: Evaluated by the range of elastic modulus obtained through nanoindentation testing. The lower the modulus, the more flexible the material. All examples containing PCL showed better flexibility than pure PLA, with Example 3, which had the highest PCL content, performing the best.

[0151] 4. In vitro degradation rate: Qualitative comparison based on mass loss and pH change curves in simulated body fluids. PEG accelerates degradation, while PCL and stereocomplex PLA delay degradation. Example 2 (minimum PEG) and Example 5 (containing stereocomplex crystals) showed the slowest degradation; Example 4 (maximum PEG) showed the fastest degradation.

[0152] 5. Coating adhesion: Using the cross-cut test, all examples with optimized pretreatment and posttreatment showed excellent adhesion (grade 0).

Claims

1. A method for preparing a positioning marker with polymer coating, characterized in that: The method includes the following steps: S1. Raw material pretreatment: The raw materials containing polylactic acid, polycaprolactone and polyethylene glycol are dried under vacuum conditions; S2. Ingredients and Premixing: Weigh each component of the pretreated raw material according to the proportions and premix to obtain a premixed material; wherein the mass percentages of polylactic acid, polycaprolactone, and polyethylene glycol are as follows: polylactic acid: 70% - 80%, polycaprolactone: 10% - 20%, polyethylene glycol: 10% - 20%; S3. Melt blending, extrusion and granulation: The premixed materials are fed into a twin-screw extruder for melt blending, extrusion and granulation to obtain composite polymer particles; S4. Preparation of coating solution: Dissolve the composite polymer particles in an organic solvent to form a homogeneous coating solution; S5. Substrate pretreatment: Cleaning and activating the surface of the substrate for the positioning markers; S6. Coating and molding by dip coating: The pretreated substrate is immersed in the coating solution, and a uniform wet film is formed on its surface by dip coating. S7. Post-treatment: The wet film is dried and heat-annealed to form a dense polymer composite coating layer.

2. The method for preparing a positioning marker with polymer coating according to claim 1, characterized in that: In step S2, the mass percentages of polylactic acid, polycaprolactone, and polyethylene glycol are as follows: polylactic acid: 65% - 85%, polycaprolactone: 10% - 25%, and polyethylene glycol: 5% - 15%.

3. The method for preparing a positioning marker with polymer coating according to claim 1 or 2, characterized in that, In step S2, the polylactic acid is composed of L-polylactic acid and D-polylactic acid, and the molar ratio of L-polylactic acid to D-polylactic acid is 1:

1.

4. The method for preparing a positioning marker with polymer coating according to any one of claims 1-3, characterized in that: The ingredients in step S2 further include the following components in percentage of the total mass of the premix: antioxidant: 0.2-0.5 wt.%, initiator: 0.05-0.2 wt.%, plasticizer: 5-10 wt.%, coupling agent: 0.5-1.5 wt.%, and / or reinforcing agent: 2-5 wt.%; wherein the antioxidant is ascorbyl palmitate, the initiator is benzoyl peroxide, the plasticizer is tributyl citrate, the coupling agent is 3-(trimethoxysilyl)propyl methacrylate, and the reinforcing agent is hydroxyapatite.

5. The method for preparing a positioning marker with polymer coating according to any one of claims 1-4, characterized in that: In step S3, the process parameters of the twin-screw extruder satisfy the following: the screw configuration along the material conveying direction includes a conveying section, a melt mixing section composed of forward kneading blocks and reverse kneading blocks, and a homogenization section composed of toothed discs; wherein the temperature is controlled at 170-190℃, the screw speed is 50-100 rpm, and a high vacuum of 0.01-0.03MPa is turned on before the homogenization section.

6. The method for preparing a positioning marker with polymer coating according to any one of claims 1-5, characterized in that: In step S4, the organic solvent is a volatile organic solvent, preferably dichloromethane, trichloromethane, acetone, tetrahydrofuran, or a mixture thereof; the concentration of the coating solution is 1% - 15% g / mL; the specific process parameters are: immersion time 30-120 seconds, lifting speed 1-10 mm / s, lifting times 1-5 times, ambient temperature 20-30℃, and relative humidity 30%-50%.

7. The method for preparing a positioning marker with polymer coating according to any one of claims 1-6, characterized in that: In step S5, the substrate pretreatment includes: mechanically polishing the substrate of the positioning marker, followed by oxygen plasma cleaning and activation.

8. The method for preparing a positioning marker with polymer coating according to any one of claims 1-7, characterized in that: In step S6, the dip coating method uses a program-controlled dip device, and the dip speed is controlled between 0.1 mm / s and 10 mm / s. The thickness of the coating layer is adjusted by controlling the dip speed and / or the solution concentration.

9. The method for preparing a positioning marker with polymer coating according to any one of claims 1-8, characterized in that: In step S7, the heat annealing is carried out under vacuum or inert atmosphere protection, the treatment temperature is above the glass transition temperature and below the melting point of the crystalline component in the blend, and the treatment time is 2-4 hours.

10. A positioning marker with polymer coating prepared by the method according to any one of claims 1 to 9.

Images