Method for detecting stability and homogeneity of key parameters of high concentration gadolinium ct contrast agents

Abstract

The application relates to a stability and uniformity detection method of key parameters of a high-concentration gadolinium CT contrast agent, relates to medical image quality control, rare earth standard substance metering value, and CT equipment performance calibration. The application relates to a modular, expandable and full-density covering gadolinium-doped high polymer composite CT multi-density phantom, which is prepared by using medical-grade polymer materials and five-component compounding of gadolinium oxide and nano silicon dioxide, has a CT value long-term stability better than plus or minus 1.8 HU, realizes full-density coverage of-950 HU to +1100 HU, establishes a high-concentration gadolinium solution precise value method, adopts a differential weight method for tracing, carries out main measurement by using a matrix matching ICP-OES, carries out verification by EDTA complexing titration, only slightly dilutes, and has a value relative expanded uncertainty of less than or equal to 0.45% (k=2); integrates sample pretreatment, CT scanning calibration, image quality evaluation, enhanced quantitative tracing, and detection conclusion output, and forms a phantom preparation-gadolinium value-CT quality control integrated closed-loop detection system.

Description

Technical Field

[0001] This invention relates to a method for detecting the stability and uniformity of key parameters of high-concentration gadolinium CT contrast agents. This method falls under the technical fields of medical imaging equipment quality control, rare earth standard material metrology, clinical enhanced CT quantitative calibration, and CT equipment performance testing. Specifically, it involves a gadolinium-doped polymer composite CT multi-density phantom, a method for determining the value of high-concentration gadolinium solution standard materials, and an integrated testing method for CT equipment. This method is applicable to daily CT quality control, enhanced scanning quantification, low-dose screening, CTA, gadolinium contrast dose value traceability, and rare earth metallurgy and related industrial material testing in medical institutions at all levels. Background Technology

[0002] CT equipment has become the core imaging equipment for clinical disease screening, diagnosis, and interventional guidance. Its density linearity, CT value stability, spatial resolution, noise, homogeneity, and quantitative accuracy of enhancement directly determine the quality of diagnosis and the reliability of treatment decisions.

[0003] Existing technologies have three major shortcomings: 1. CT phantoms have obvious defects: traditional water phantoms can only simulate 0HU and cannot cover the lungs, fat, muscles, liver, bones and enhanced lesions; imported phantoms are expensive, have high maintenance costs, are prone to aging and cracking, and have poor long-term stability; domestic phantoms generally have narrow density coverage, poor tissue equivalence, and lack gadolinium enhancement quantitative modules, making it difficult to meet the needs of enhanced CT, low-dose lung screening, angiography and other scenarios.

[0004] The accuracy of high-concentration gadolinium solution determination is insufficient: the concentration of gadolinium solution used in clinical and standard substances is 5~100 g / L, and traditional methods require dilution by thousands of times, resulting in large dilution errors; matrix effects, self-absorption, and rare earth spectral interference are serious, the reliability of single methods is low, the traceability chain is long, and the uncertainty is poor; it cannot meet the requirements of quantitative traceability of enhanced CT, contrast agent quality control, and standard substance grading.

[0005] The testing process is fragmented and data is not linked: phantom preparation, gadolinium determination, and CT detection are independent of each other, and the data cannot be directly traced or verified in a closed loop; there is a lack of an integrated solution for "phantom-determination-quality control", resulting in low quality control efficiency, poor repeatability, and weak traceability.

[0006] In summary, there is an urgent need to develop a novel CT phantom with full-density coverage, high stability, low cost, and gadolinium enhancement modules, along with a gadolinium determination method that features slight dilution, matrix matching, dual-method verification, and high-precision traceability. This would allow for the construction of an integrated, closed-loop, and traceable CT quality control solution to meet the requirements of accurate clinical diagnosis and metrological traceability. Summary of the Invention

[0007] This invention aims to overcome the shortcomings of existing CT phantoms, such as incomplete density coverage, poor stability, and lack of gadolinium enhancement modules, and provides a gadolinium-doped polymer composite CT multi-density phantom.

[0008] Another objective of this invention is to provide a method for accurately determining the concentration of high-concentration gadolinium solutions, overcoming the shortcomings of large dilution errors, strong matrix interference, and poor traceability in determining the concentration of high-concentration gadolinium.

[0009] Another objective of this invention is to provide an integrated detection method for CT equipment, overcoming the shortcomings of fragmented detection processes and lack of data linkage.

[0010] A method for detecting the stability and homogeneity of key parameters of a high-concentration gadolinium CT contrast agent, comprising the following implementation scheme: 1. Establish a novel gadolinium-doped polymer composite CT phantom: full density coverage from -950 HU to +1100 HU, CT value stability ≤ ±1.8 HU, low cost, good tissue equivalence, and containing a gradient gadolinium-enhanced quantitative module; 2. High-precision determination of high-concentration gadolinium solutions: slight dilution, matrix matching, dual-method verification, short traceability chain, and controllable uncertainty; 3. Integrated closed-loop detection: sample pretreatment - gadolinium determination - CT scan - image evaluation - conclusion output, with data linkage, clear traceability, and efficient quality control; 4. Wide range of applications: compatible with plain scan, enhanced scan, low-dose scan, CTA, contrast agent traceability, and standard substance determination.

[0011] The overall technical route of this invention is divided into three parts: (i) preparation of gadolinium-doped polymer composite CT multi-density phantom; (ii) method for precise determination of high-concentration gadolinium solution; and (iii) integrated detection method for CT equipment.

[0012] (I) Preparation of Gadolinium-Doped Polymer Composite CT Multi-Density Phantom It adopts an integrated structural design with a modular nested elliptical cylinder body, a detachable multi-density tissue equivalent disk, an embedded gradient gadolinium-enhanced calibration core, and expandable functional modules. This design achieves full density coverage, high stability, detachability, replaceability, expandability, and easy calibration, meeting the quality control needs of different clinical scenarios and equipment models.

[0013] Overall Structure and Modular Design of Gadolinium-Doped Polymer Composite CT Multi-Density Phantom 1.1 Main reference phantom 1. Material: Medical-grade PEEK (polyetheretherketone), with good biocompatibility, anti-aging properties, radiation resistance, and high dimensional stability; 2. Structure: 4-layer concentric nested elliptical cylinder structure, outer diameter 280mm, total height 200mm; 3. Internal cavity design: The internal cavity volume is infinitely adjustable from 0.4 to 0.65 L. The internal cavity volume can be changed by rotating the inner elliptical cylinder to adapt to CT equipment of different sizes. 4. Accuracy indicators: Ellipticity error < 0.08 mm, coaxiality error < 0.05 mm, surface roughness Ra < 0.8 μm; 5. Temperature Compensation System: The top is equipped with a medical silicone temperature compensation airbag that is connected to the inner cavity. The airbag has a volume of 50mL and can automatically compensate for volume expansion / contraction caused by temperature changes, eliminating the influence of temperature fluctuations on CT values ​​(temperature compensation range: 15~35℃). 6. Positioning system: Three positioning pin holes are set at the bottom, which cooperate with the special fixture of the scanning bed to ensure that the installation position is consistent every time, with a positioning error of <0.3mm.

[0014] Detachable tissue equivalent density module 1. Structure: Independent detachable disc (or density disc), 250mm in diameter and 20mm in thickness, with a snap-on design for quick installation / removal; 2. Mounting Holes: The disc surface has 8 standard mounting holes (30mm in diameter and 20mm in depth), which can be used to embed equivalent density blocks of different tissues; 3. Identification System: Each well is laser-marked with the corresponding tissue name and target CT value for easy identification and installation; 4. Scalability: Two expansion holes are reserved, which can be used to add low contrast modules, high resolution modules, radiation dose modules, etc. as needed.

[0015] Embedded gradient gadolinium enhancement calibration module 1. Structure: A cylindrical core with a diameter of 50mm and a thickness of 30mm is embedded in the center of the density disk; 2. Gradient design: It contains 5 concentric ring regions, each corresponding to different gadolinium concentrations, with CT values ​​ranging from +200HU to +1100HU, simulating lesions with different degrees of enhancement; 3. Uniformity: The uniformity of CT values ​​within each annular region is ≤1.5HU, with no obvious gradient changes; 4. Traceability: Each gadolinium enhancement module comes with a unique traceability QR code, which is linked to the corresponding high-concentration gadolinium solution value report and calibration certificate.

[0016] Auxiliary function module Also known as an extensible functional module, it includes one or more of the following modules: 1. Water model calibration module: Detachable water model, 200mL capacity, used for daily water model calibration and CT value zero-point calibration; 2. Spatial resolution module: Embedded wire pair card, resolution coverage 2~20 lp / cm, used for spatial resolution testing; 3. Low contrast module: Contains 6 cylindrical holes with different contrast ratios (0.5%~5%), used for low contrast resolution testing; 4. Radiation dose module: Built-in ionization chamber slot, which can be inserted into the ionization chamber for radiation dose measurement.

[0017] The temperature compensation airbag is made of medical-grade silicone and has a volume of 50mL. It can automatically compensate for volume changes caused by temperature variations of 15~35℃.

[0018] Precision formulation of multi-tissue equivalent density blocks By precisely adjusting the proportions of each component in a five-element compound system of PEEK, EVA, PC, Gd2O3, and nano-SiO2, full-density coverage from lung tissue to bone tissue is achieved. The equivalent blocks for each tissue include one or more of the following tissues by mass percentage (%): Achieve full-density coverage from -950HU to +1100HU, with CT value stability ≤ ±1.8HU.

[0019] Quality control throughout the entire preparation process 3.1 Raw material pretreatment and quality control 1. Raw material selection: All raw materials are medical grade or food grade, with Gd2O3 purity ≥99.95%, nano SiO2 particle size 20~50nm, and specific surface area 150~200m² / g; 2. Sieving process: All solid raw materials are sieved through a 650-mesh standard sieve to remove large particles and ensure uniform particle size; 3. Sterilization treatment: UV sterilization for 30 minutes to kill microorganisms in the raw materials and prevent bacterial growth in the mold during use; 4. Drying treatment: Dry in a vacuum oven at 80℃ for 2 hours, with the moisture content controlled at <3% to prevent air bubbles from forming in the mold during the molding process; 5. Raw material testing: Each batch of raw materials is tested for density, purity, and moisture content, and can only be used after passing the tests.

[0020] Ingredients and mixing process 1. Precise weighing: Each component is precisely weighed according to the formula using an analytical balance with a weight of 1 / 100,000, and the weighing error is ≤0.01g; 2. Coupling agent addition: Add 0.2~0.5% silane coupling agent KH-550 to improve the interfacial bonding force between the inorganic filler and the polymer matrix; 3. High-speed mixing: Mix at 50℃ and 1500r / min for 15 minutes using a high-speed mixer to ensure uniform dispersion of all components; 4. Mixing uniformity test: Randomly select 3 mixed samples and observe the dispersion of the filler using a scanning electron microscope. No obvious agglomeration is acceptable.

[0021] Twin-screw eutectic extrusion process 1. Temperature control: Segmented temperature control is adopted, with zone 1 at 160℃, zone 2 at 180℃, zone 3 at 195℃, zone 4 at 205℃, and the head at 200℃; 2. Speed ​​control: Screw speed 180 r / min, feeding speed 50 kg / h; 3. Water-cooled pelletizing: The extruder strip is cooled by 20℃ circulating water and pelletized into composite masterbatch with a diameter of 3mm and a length of 4mm by a pelletizer; 4. Masterbatch testing: Each batch of masterbatch is tested for melt index, density, and moisture content. Only after passing the tests can it be molded.

[0022] Vacuum molding process 1. Mold preheating: Heat the mold to 120℃ and hold for 30 minutes to ensure uniform mold temperature; 2. Masterbatch preheating: The composite masterbatch is preheated at 100℃ for 30 minutes to remove residual moisture; 3. Vacuum molding: The mold is evacuated to -0.09MPa, pressurized to 1.8MPa, and held at that temperature for 150 minutes; 4. Gradient cooling: Cool the mold to 40℃ at a rate of 2℃ / h, then demold to avoid internal stress caused by sudden temperature changes. 5. Molding quality inspection: The surface of the mold body should be smooth, free of bubbles, cracks, and delamination, and the dimensional error should be ≤0.1mm.

[0023] Post-processing and finishing 1. Deburring: Use sandpaper to remove burrs and flash from the edges of the mold body; 2. Surface treatment: The surface is sprayed with medical-grade transparent protective varnish to improve wear resistance and anti-aging properties; 3. Dimensional calibration: A coordinate measuring machine is used to measure the dimensional accuracy of the mold to ensure it meets design requirements; 4. Cleaning and disinfection: Wipe the surface of the mold with anhydrous ethanol to remove oil and impurities, and disinfect with ultraviolet light for 30 minutes.

[0024] phantom calibration and traceability system 4.1 CT value calibration 1. Equipment: Calibration was performed using standard CT equipment calibrated by the National Institute of Metrology. 2. Calibration conditions: Scanning parameters 120kVp, 80mAs, slice thickness 1mm, standard algorithm; 3. Calibration method: Scan equivalent blocks of each tissue, measure the CT value of the ROI (20mm in diameter), and fine-tune the formula to make the CT value fall within the target range; 4. Calibration standard: The deviation of the CT value of each module from the target value is ≤ ±2HU, and the uniformity is ≤ 1.5HU.

[0025] Establishment of traceability chain 1. Primary traceability: The CT value of the gadolinium enhancement module is traced back to a high-concentration gadolinium solution standard substance; 2. Secondary traceability: The high-concentration gadolinium solution standard material is traceable to the 5N high-purity metallic gadolinium standard; 3. Three-level traceability: 5N high-purity gadolinium metal is traceable to national reference materials; 4. Traceability Certificate: Each phantom comes with a complete traceability certificate, which includes information such as the CT value, uncertainty, calibration date, and validity period of each module.

[0026] Calibration cycle and maintenance 1. Routine calibration: Perform water model calibration and zero-point calibration before each use; 2. Regular calibration: A full calibration shall be performed every 6 months, including all tissue equivalent blocks and gadolinium-enhanced modules; 3. Maintenance: The mold should be stored in a dry, cool, and dark environment, avoiding high temperature, humidity and direct sunlight; clean the surface of the mold regularly to avoid scratches and contamination.

[0027] Long-term stability and durability testing 5.1 Accelerated aging test 1. Test conditions: Temperature 60℃, relative humidity 90%, stored for 3 months; 2. Test indicators: CT value change, appearance change, dimensional change, and mechanical property change; 3. Acceptance criteria: CT value variation ≤ ±3HU, no cracking, deformation, or delamination, and dimensional variation ≤ 0.2mm.

[0028] High and low temperature cycling test 1. Test conditions: High and low temperature cycling from -20℃ to 50℃, 24 hours per cycle, for a total of 50 cycles; 2. Test indicators: CT value change, appearance change, and size change; 3. Acceptance criteria: CT value variation ≤ ±2HU, no cracking, deformation, or delamination, and dimensional variation ≤ 0.1mm.

[0029] Long-term use test 1. Test conditions: 10,000 continuous cyclic scans, scan parameters 120kVp, 80mAs; 2. Test indicators: CT value change, appearance change, abrasion resistance; 3. Acceptance criteria: CT value variation ≤ ±1.8HU, no obvious scratches or wear on the surface.

[0030] (II) Precise Value Determination Method for High-Concentration Gadolinium Solutions For high-concentration gadolinium solutions of 5~100g / L and 5~15% nitric acid medium, a technical approach is adopted, which includes differential gravimetric traceability, matrix matching gradient calibration, ICP-OES (inductively coupled plasma optical emission spectrometry) main measurement, EDTA (ethylenediaminetetraacetic acid titration) verification, and full-process quality control. This approach requires only 10~200 times slight dilution (while traditional methods require 1000~10000 times), effectively eliminating dilution errors, matrix effects, and spectral interference. The relative expanded uncertainty of the assigned value is ≤0.45% (k=2), meeting the national first-class standard material classification requirements.

[0031] A method for accurately determining the concentration of high-concentration gadolinium solution includes the following steps: 1) Sample pretreatment: Take 5~100g / L gadolinium nitric acid medium solution, accurately weigh 0.25~0.9g of sample by differential gravimetric method, and slightly dilute with nitric acid of the same acidity to 50~480mg / L; 2) Preparation of matrix-matched standard solutions: Using 5N high-purity gadolinium metal as the primary reference, prepare gradient standard working solutions that match the acidity and rare earth impurity content of the sample to be tested. 3) ICP-OES main determination: Gd 342.246nm was selected as the main analytical spectral line. The instrument parameters were optimized, and the adjacent background subtraction method and coexisting element interference correction model were used to eliminate interference and determine the sample concentration. 4) EDTA complexometric titration verification: Adjust the pH to 5.8~6.2, use xylenol orange as an indicator, and titrate with EDTA standard solution standardized with zinc oxide as the reference standard to verify the main determination results; 5) Homogeneity and stability tests: One-way ANOVA was used to evaluate homogeneity, and linear regression model was used to evaluate stability; 6) Uncertainty assessment: The system assesses the six major uncertainty components of weighing, preparation, instrumentation, uniformity, stability, and titration, and combines the expanded uncertainty.

[0032] Specific methods for accurately determining the concentration of high-concentration gadolinium solutions include: 1. Sample Receiving and Preprocessing 1.1 Sample Acceptance and Labelling 1. When receiving gadolinium solutions with undetermined values, verify the sample number, nominal concentration, medium acidity, production date, expiration date, and production unit, etc. 2. Inspect the appearance of the sample: It should be a clear and transparent liquid, without sediment, crystals, suspended matter, or discoloration; 3. Uniquely identify each sample and record the date of receipt, environmental conditions, and operator. 4. If the sample is cloudy, precipitated or crystallized, it must be dissolved by ultrasonication (40℃, 10min) before the value can be determined.

[0033] Container pretreatment 1. All glass containers (volume flasks, beakers, pipettes, burettes) must be soaked in 10% nitric acid for 24 hours, then rinsed three times with ultrapure water and dried for later use. 2. Polytetrafluoroethylene (PTFE) containers are used for weighing and transferring samples to avoid the adsorption of gadolinium by glass containers; 3. The analytical balance with a strength of 0.0001 g needs to be preheated for 30 minutes and calibrated using standard weights. The calibration error should be ≤0.02 mg.

[0034] Differential gravimetric sampling 1. Invert the sample vial and shake for 1 minute to ensure the solution is homogeneous; 2. Use a polytetrafluoroethylene pipette to draw about 1 mL of sample and place it into a pre-weighed polytetrafluoroethylene weighing bottle, then tighten the cap. 3. Weigh accurately using a balance with a mass of 1 / 100,000 and record the total mass m1; 4. Carefully transfer the sample from the weighing bottle to a 50mL Grade A volumetric flask, wash the inner wall of the weighing bottle three times with a small amount of nitric acid of the same acidity, and transfer all the washing solution into the volumetric flask. 5. Weigh the empty weighing bottle again, mass m2, and calculate the sample mass m. s =m1-m2, accurate to 0.0001g; 6. Take 6 parallel samples for ICP-OES determination; take another 6 samples for EDTA titration verification. 7. Sampling volume control: Adjust the sampling volume according to the nominal concentration to ensure that the gadolinium concentration in the injection solution after volume adjustment is 100~400 mg / L, as detailed below: Nominal concentration 5~20g / L: Sample size 0.5~0.8g For nominal concentrations of 20-50 g / L: take a sample of 0.3-0.5 g. For nominal concentrations of 50~100 g / L: sample size 0.25~0.3 g 1.4 Slight dilution and volume adjustment 1. Add pure nitric acid of the same acidity to the volumetric flask until it is 1 cm below the mark. Let it stand for 5 minutes until the solution temperature is the same as the room temperature. Then, add it dropwise to the mark using a dropper. 2. Tighten the stopper, invert and shake 10 times, holding the invert for 3 seconds each time to ensure the solution is thoroughly mixed; 3. Prepare blank matrix solution with the same acidity simultaneously: Take a 50 mL Grade A volumetric flask, add the same volume of nitric acid with the same acidity as the sample, dilute to the mark, and shake well for later use; 4. All dilution operations were performed in a constant temperature laboratory at 20±2℃ to avoid the influence of temperature changes on volume.

[0035] High-concentration gadolinium CT contrast agents and standard solutions must be diluted with nitric acid. The core purpose of this is to prevent gadolinium ion hydrolysis and precipitation, ensure long-term stability and homogeneity of the solution, adapt to ICP-OES and EDTA titration detection, and meet metrological traceability requirements.

[0036] The main reason for using a nitric acid-medium gadolinium solution for the sample is: First, it prevents gadolinium from hydrolyzing and forming precipitates, ensuring stable concentration. Gadolinium ions (Gd³⁺) readily hydrolyze in neutral or acidic water, forming gadolinium hydroxide colloids or white precipitates, leading to inaccurate concentrations, turbid solutions, and CT value drift. Nitric acid (HNO₃) provides a strongly acidic environment, inhibiting hydrolysis and allowing gadolinium to exist in a stable ionic state, preventing precipitation and stratification during long-term storage.

[0037] Secondly, it is to adapt to ICP-OES instrument measurements and reduce matrix interference. Nitric acid is the inorganic acid with the simplest matrix and the least spectral interference. It does not introduce metallic impurities, does not contaminate the instrument, and nitrate ions are easily decomposed in plasma, producing no background interference and ensuring accurate gadolinium detection. In contrast, hydrochloric acid or sulfuric acid easily produces chloride ions and sulfate ions, which can corrode instrument components and are not suitable for high-concentration rare earth element determination.

[0038] Third, it is compatible with EDTA complexometric titration and does not affect endpoint determination. Nitric acid is a strong acid and inert medium, and does not react with EDTA or the indicator xylenol orange, nor does it change the titration pH system, thus ensuring a clear endpoint color change and reliable titration results.

[0039] In addition, from the perspective of the standard reference usage specifications, the National General Specification for Rare Earth Standard References Domestic and international gadolinium standard reference materials all use 5%~15% nitric acid medium, which better ensures consistency in the traceability chain and comparability of values. (Nitric acid medium has moderate volatility and strong stability, is suitable for long-term storage at 4°C, and can fully meet the requirements for standard reference material grading.) Finally, from the perspective of practical clinical medical applications, clinical gadolinium contrast agent stock solutions that are compatible with CT contrast agent production and quality control systems all utilize acidic systems for transition during synthesis, purification, and quality control. Nitric acid media can be directly integrated into the production process, avoiding errors and contamination caused by media conversion.

[0040] The samples were gadolinium solutions with a high concentration of nitric acid medium of 5~100g / L, and all used 5%~15% (v / v) nitric acid as the medium.

[0041] Preparation of matrix-matched standard solutions (key to eliminating matrix effects) 2.1 Primary reference material treatment 1. High-purity 5N gadolinium metal (≥99.999%) is used as the primary standard, and its purity must be certified by the National Center for Standard Materials Research. 2. Wipe the surface of the high-purity gadolinium sheet with anhydrous ethanol to remove the oxide layer, then rinse it three times with ultrapure water, dry it in a vacuum oven at 80°C for 2 hours, and cool it to room temperature before use. 3. Accurately weigh 0.5000g of high-purity gadolinium using the differential gravimetric method and place it in a 100mL polytetrafluoroethylene beaker.

[0042] Preparation of Standard Stock Solution 1. Slowly add 20 mL of analytical grade nitric acid (1+1) to a beaker, cover with a watch glass, and place on a hot plate at a low temperature of 65~75℃ to dissolve; 2. Avoid boiling the solution during heating to prevent splashing; after the gadolinium is completely dissolved, continue heating until the solution volume is approximately 5 mL to remove nitrogen oxides; 3. After cooling to room temperature, transfer the solution to a 100mL Grade A volumetric flask, wash the beaker and watch glass three times with ultrapure water, and transfer all the washing solution into the volumetric flask. 4. Add analytical grade nitric acid to adjust the acidity to match the sample (5~15%), bring the volume to the mark, shake well, and obtain a 5 g / L gadolinium matrix matching stock solution; 5. The mother liquor should be stored at 4°C away from light, and its shelf life is 6 months.

[0043] Preparation of gradient standard working solutions 1. Take a certain volume of 5 g / L gadolinium matrix stock solution and put it into five 50 mL Grade A volumetric flasks; 2. Add a nitric acid solution to each volumetric flask with the same acidity as the sample to be tested and matching the content of rare earth impurities such as lanthanum / cerium / neodymium. 3. Impurity matching method: The contents of lanthanum, cerium, and neodymium in the sample to be tested are determined in advance by ICP-MS. Then, the corresponding amount of high-purity rare earth oxides are added to the standard solution to ensure that the relative deviation of the impurity content in the standard solution from that in the sample is ≤4%. 4. Add to volume to the mark, shake well, and prepare standard working solutions with five concentration gradients of 50, 100, 200, 300, and 400 mg / L; 5. Standard working solutions should be prepared and used immediately to avoid concentration changes due to prolonged storage.

[0044] Instrument optimization and measurement 3.1 Instrument Parameter Optimization 1. An inductively coupled plasma optical emission spectrometer (ICP-OES) is used. The instrument needs to be preheated for 30 minutes and the optical path needs to be purged with argon gas for 15 minutes. 2. Optimize instrument parameters using the single-factor variable method to obtain the highest sensitivity and lowest background noise: RF power: 1200~1280W (1250W optimal) Atomizer flow rate: 0.70~0.78L / min (optimal 0.75L / min) Observation height: 13~14mm (optimal 13.5mm) Cooling air flow rate: 12~15L / min (optimal 14L / min) Auxiliary gas flow rate: 0.5~1.0L / min (optimal 0.8L / min) Integration time: 5s (shortwave), 10s (longwave) 3.2 Spectral line screening and interference correction 1. Taking into account spectral line intensity, interference, and linear range, the following spectral lines are selected: Main analytical spectral line: Gd 342.246nm (minimum rare earth overlap interference, weakest self-absorption effect) Auxiliary verification spectral lines: Gd 364.619 nm, Gd 409.879 nm 2. Correct background interference using the adjacent background subtraction method: Select one background point on each side of the analyzed spectral line, calculate the average background intensity, and subtract it from the total intensity; 3. Establish a coexisting element interference correction model to correct the spectral overlap interference of lanthanum (La 342.252nm), cerium (Ce 342.238nm), and neodymium (Nd 342.26nm) on Gd 342.246nm; 4. For every 8 samples measured, insert one set of intermediate concentration standard solution (200 mg / L) for drift correction. If the drift exceeds 2%, the calibration curve needs to be re-established.

[0045] Sample Measurement and Data Processing 1. Determine the blank matrix solution, 5 gradient standard working solutions, and 6 parallel sample solutions in sequence; 2. Each sample was measured in triplicate, and the average value was taken. 3. Establish a calibration curve with the standard solution concentration as the x-axis and the emission intensity as the y-axis, requiring a linear correlation coefficient R ≥ 0.99995; 4. Calculate the gadolinium concentration ρ (mg / L) in the injection solution based on the calibration curve; 5. Calculate the gadolinium mass concentration C (g / L) in the original high-concentration gadolinium solution using the following formula: In the formula: C: Mass concentration of the original gadolinium solution (g / L) ρ: Mass concentration of gadolinium in the injection solution (mg / L) V: Sample final volume (L) m s : Sample mass (g) obtained by differential weighing method 6. Calculate the mean and relative standard deviation (RSD) of 6 parallel samples, requiring RSD ≤ 0.2%; 7. If the deviation of a sample's measured value from the average value exceeds 3 times the standard deviation, it is considered an outlier, discarded, and remeasured.

[0046] Complexometric titration verification (co-validation method) 4.1 Reagent Preparation and Standardization 1. EDTA standard titration solution (0.05 mol / L): Weigh 18.6 g of disodium ethylenediaminetetraacetate, dissolve it in 1000 mL of ultrapure water, and shake well; 2. Reference zinc oxide: ignited at 800℃ to constant weight, cooled to room temperature and used for later use; 3. Hexamethylenetetramine buffer solution (pH=5.8~6.2): ​​Weigh 40g of hexamethylenetetramine, dissolve it in 100mL of water, add 10mL of concentrated hydrochloric acid, and adjust the pH to 6.0; 4. Xylenol orange indicator (2g / L): Weigh 0.2g of xylenol orange, dissolve it in 100mL of water, and shake well; 5. EDTA solution standardization: Weigh 0.1250 g of standard zinc oxide using the differential method, moisten with a small amount of water, dissolve in 2 mL of hydrochloric acid (1+1), transfer to a 250 mL volumetric flask, and dilute to the mark; pipette 25.00 mL of this solution into an Erlenmeyer flask, add 50 mL of water, adjust the pH to 5-6 with ammonia (1+1), add 10 mL of hexamethylenetetramine buffer solution and 3 drops of xylenol orange indicator, titrate with EDTA standard titration solution until the solution changes from purple-red to bright yellow, and record the volume of EDTA consumed; perform 6 parallel standardizations, calculate the concentration of the EDTA solution, and ensure that RSD ≤ 0.1%.

[0047] Sample titration 1. Weigh 0.5~1.0g of the gadolinium solution to be tested into a 250mL Erlenmeyer flask using the differential method, and add 50mL of water; 2. Adjust the pH of the solution to 5.8-6.2 with ammonia (1+1), and add 10 mL of hexamethylenetetramine buffer solution and 3 drops of xylenol orange indicator; 3. Titrate slowly with the standardized EDTA standard solution, adding it dropwise near the endpoint until the solution changes abruptly from purple-red to bright yellow and remains stable for 30 seconds without fading. Record the volume of EDTA consumed, V1. 4. Simultaneously perform a blank test and record the volume of EDTA consumed, V0; 5. Perform six parallel titrations, calculate the average value and RSD, and ensure that RSD ≤ 0.2%; 6. Calculate the mass concentration C (g / L) of the gadolinium solution using the following formula: In the formula: c: Concentration of the EDTA standard titration solution (mol / L) V1: Volume of EDTA consumed in the titration of the sample (mL) V0: Volume of EDTA consumed in the blank test (mL) 157.25: Molar mass of gadolinium (g / mol) m s Sample mass (g) 4.3 Result Verification 1. Compare the determination results of the ICP-OES master method and the EDTA titration method, requiring that the relative deviation between the two methods be ≤0.25%; 2. If the relative deviation exceeds 0.25%, the sample pretreatment, standard solution preparation, instrument parameters, and other aspects need to be checked to find the cause and repeat the measurement. 3. The determination result of the master method can only be confirmed as valid when the results of the two methods are consistent, that is, when the relative deviation between the results of the ICP-OES master method and the EDTA titration method is ≤0.25%.

[0048] Homogeneity and stability testing of standard substances 5.1 Uniformity test 1. Samples were drawn using random sampling in accordance with the "General Principles and Statistical Principles for the Determination of Standard Reference Materials" (JJF 1343-2022); 2. Randomly select 15 bottles from the entire batch of samples, and take one sample from the top, middle and bottom of each bottle, for a total of 45 samples; 3. The gadolinium concentration of each sample was determined by ICP-OES, with each sample measured in triplicate; 4. One-way ANOVA (F-test) was used to evaluate the homogeneity between and within bottles, and the uncertainty component introduced by homogeneity was calculated; 5. The value of F must be less than the critical value F. 0.05 (14, 30) indicates that the sample has good homogeneity, and the uncertainty component introduced by homogeneity is ≤0.18%.

[0049] Stability test 1. Short-term stability test: Samples were placed at 4℃, room temperature (25℃), and 37℃ respectively, and samples were taken and measured on days 0, 7, 14, 21, and 30. 2. Long-term stability test: The samples were placed at 4℃ in the dark and measured at 0, 1, 2, 3 and 6 months. 3. Take 3 samples at each time point, and perform 3 parallel measurements on each sample. Calculate the average value. 4. The stability was evaluated using a linear regression model. If the absolute value of the slope was less than twice the standard deviation, it indicated that the sample was stable during the observation period. 5. Calculate the uncertainty component introduced by stability, which should be ≤0.15%.

[0050] Uncertainty System Evaluation and Final Determination 6.1 Identification and Evaluation of Uncertainty Components 1. Weighing uncertainty (u_rel, m): Introduced by the maximum permissible error and repeatability of the analytical balance, and evaluated using Type B. 2. Uncertainty of volumetric instruments (u_rel, fitting): Introduced by the volumetric error of volumetric flasks and pipettes and the effect of temperature, and evaluated using Type B. 3. Instrument measurement uncertainty (u_rel, instrument): Introduced by the repeatability and calibration curve uncertainty of the ICP-OES instrument, and evaluated using Type A. 4. Homogeneity uncertainty (u_rel, homogeneity): Introduced by sample homogeneity, assessed using Type A criteria; 5. Stability uncertainty (u_rel, stability): Introduced from sample stability, assessed using Type A criteria; 6. Titration uncertainty (u_rel, drops): Introduced by EDTA calibration, titration volume and endpoint determination, and evaluated using a combination of Type A and Type B methods.

[0051] Combined standard uncertainty and expanded uncertainty 1. Combine the relative standard uncertainty according to the following formula: 2. Taking a coverage factor k=2 (confidence level approximately 95%), calculate the relative expanded uncertainty: 3. The relative expanded uncertainty of the final value result is required to be ≤0.45% (k=2).

[0052] Final value result 1. The final determination result is based on the ICP-OES master method, with the EDTA titration result serving as supporting evidence; 2. The results are expressed as: C±U (k=2), where C is the average concentration and U is the expanded uncertainty; 3. Issue a standard reference value determination report, including: determination method, traceability, homogeneity, stability, uncertainty assessment, etc.

[0053] Method validation and quality control 1. Linear range: 50~480 mg / L, linear correlation coefficient R≥0.99995; 2. Limit of detection: 0.05 mg / L; 3. Limit of quantitation: 0.15 mg / L; 4. Precision: RSD ≤ 0.2% for 6 parallel determinations; 5. Accuracy: Spike recovery rate is 99.8%~100.2%; 6. When testing each batch of samples, national standard reference materials must be measured simultaneously for quality control, and the deviation between the measured value and the standard value should be ≤0.3%.

[0054] (III) Integrated Testing Method for CT Equipment This section integrates seven key steps: gadolinium standard substance pretreatment, high-concentration gadolinium value determination and traceability, CT scan quality control, multi-dimensional image quality evaluation, enhanced quantitative calibration, data closed-loop verification, and automatic conclusion output. It realizes a complete, integrated, traceable, and repeatable testing process from standard solution to clinical CT image, and from value traceability to equipment qualification determination. It forms a standardized operating procedure (SOP) that can be directly used by medical institutions for daily quality control, annual inspection, clinical enhanced CT quantitative calibration, gadolinium contrast agent clinical dosage traceability, and equipment acceptance.

[0055] An integrated detection method for CT equipment includes the following steps: 1) Pre-test preparation: Confirm environmental conditions, prepare standard materials and consumables, and complete the pre-test of CT equipment; 2) Gadolinium standard reference value determination: The high-concentration gadolinium standard solution was determined using the aforementioned method for accurate determination of high-concentration gadolinium solution; 3) Phantom installation and scanning: Fix the phantom on the CT scanning bed, perform laser positioning and calibration, set multi-sequence scanning parameters, and acquire image data; 4) Image quality evaluation: Quantitative measurement of CT value, noise, homogeneity, spatial resolution, density linearity, accuracy of quantitative enhancement, and radiation dose; 5) Data closed-loop verification: Establish a two-way traceability chain between gadolinium fixed value and CT value to identify and handle outliers; 6) Conclusion Output: Determine the performance of CT equipment according to national standards and generate a standardized test report.

[0056] An integrated detection method for CT equipment, comprising the following steps: 1. Preparations before integrated testing 1.1 Environmental Condition Confirmation 1. Computer room temperature: 20~26℃, fluctuation ≤±1℃; 2. Relative humidity: 40%~60%; 3. 220V±5%, well grounded, no strong electromagnetic interference; 4. Scanning bed levelness: Level instrument calibration, tilt ≤0.2°; 5. Environmental cleanliness: Free from dust and volatile organic solvents, avoiding surface contamination and electrostatic adsorption of the mold.

[0057] Preparation of standard materials and consumables 1. High-concentration gadolinium standard solution: nominal 30~60g / L, nitric acid medium 5~15%, determined value, U≤0.45% (k=2), clear appearance, no precipitate, no crystallization; 2. Blank matrix solution: Superior purity nitric acid with the same acidity as the standard substance, free of gadolinium and rare earth impurities; 3. Volumetric instruments: 25mL, 50mL, and 100mL Class A volumetric flasks, pipettes (100~1000μL), and analytical balance with an accuracy of 0.01mg. 4. CT-specific consumables: laser positioning ruler, positioning tape, radiation protection pad, phantom fixing fixture, temperature and humidity recorder.

[0058] Equipment Pre-inspection 1. Power-on preheating: The equipment is powered on and preheated for 30 minutes to complete system self-test, X-ray tube preheating, and detector calibration; 2. Detector calibration: Perform air calibration, water model calibration, and uniformity calibration; no errors / no detector defects reported. 3. X-ray tube status: tube voltage and tube current output are stable, exposure counting and heat dissipation are normal; 4. Software check: The reconstruction algorithm, layer thickness, field of view, matrix, window width and window level parameters are normal, and there are no error logs; 5. Safety check: Collision prevention, emergency stop, radiation protection door, and dose monitoring are all normal.

[0059] Gadolinium Standard Reference Material Pretreatment and Value Determination Traceability 2.1 Sample differential weighing 1. Take a high-concentration gadolinium standard solution, invert and shake well for 1 minute; 2. Using a 1 / 100,000 balance after tareing, accurately weigh 0.3~0.8g using the difference method, and record the mass m. s Two parallel copies; 3. Weighing process: no splashing, no evaporation, no residue on the outer wall of the container, and no vibration or airflow in the weighing environment.

[0060] Slight dilution and volume adjustment 1. Carefully transfer the weighed sample into a 50 mL Grade A volumetric flask; 2. Wash the weighing container and glass rod multiple times with blank matrix solution of the same acidity, and transfer all the washing solution into the volumetric flask; 3. Bring to the mark, invert and shake 10 times, then let stand for 10 minutes; 4. Control the gadolinium concentration in the injection solution to 100~400mg / L, and only perform slight dilution to avoid large-fold dilution errors.

[0061] Establishment of matrix matching standard curve 1. Prepare matrix-matched gradient standard solutions using 5N high-purity gadolinium as a reference: 50, 100, 200, 300, and 400 mg / L, with acidity and rare earth impurities completely matched to the sample; 2. Inject blank, standard solution, and sample sequentially into ICP-OES to establish a calibration curve, with R ≥ 0.99995; 3. Measure the sample concentration ρ and calculate the initial gadolinium solution concentration C; 4. EDTA titration parallel verification, relative deviation ≤0.25%, the determination results are valid and traceable to the national standard.

[0062] Phantom installation, positioning and scanning sequence planning 3.1 Mold Installation and Fixing 1. Place the prepared gadolinium-doped multi-density phantom horizontally in the center of the CT scanning bed; 2. Use specialized clamps to secure the mold body, ensuring it does not slide, tilt, or wobble; 3. The upper surface of the phantom is parallel to the scanning bed, centered in height, with an error ≤1mm; 4. Surface cleanliness: Free from water stains, fingerprints, and dust to avoid affecting CT values ​​and uniformity measurements.

[0063] Laser positioning and scanning center calibration 1. Activate the CT laser positioning line and align it with the crosshair mark in the center of the phantom; 2. Make fine adjustments in the front-back, left-right, and up-down directions to ensure that the center of the phantom coincides with the center of the scanning field, with a positioning error ≤0.5mm; 3. Scan field (FOV): 250~300mm, matrix 512×512, layer thickness 1.0mm; 4. Scan range: Covers the entire height of the phantom (200mm), extending 10mm above and below to avoid truncation artifacts.

[0064] Multi-sequence scan parameters (coverage plain scan / contrast / low dose) 1. Standard quality control sequence (mandatory scan): 120kVp, 80mAs, 1mm layer thickness, standard algorithm, helical scan, pitch 1.0; 2. Low-dose screening sequence: 120kVp, 40~50mAs, 1mm slice thickness, iterative reconstruction, low-noise mode; 3. Enhanced calibration sequence: 120kVp, 100mAs, 1mm slice thickness, soft tissue algorithm, gadolinium enhancement module focused scanning; 4. High-resolution sequence: 120kVp, 150mAs, layer thickness 0.625mm, bone algorithm, spatial resolution test.

[0065] Image data acquisition, reconstruction and quality control 4.1 Scanning, Acquisition, and Data Storage 1. Scan sequentially according to the planned sequence: master reference phantom → tissue equivalent density module → gadolinium enhancement calibration module → low-dose sequence → high-resolution sequence; 2. Scan each sequence once, then repeat the scan twice to ensure data repeatability; 3. All raw data, reconstructed images (DICOM), scan logs, and parameter records are stored, and unique serial numbers and traceability QR codes are established. 4. The image is free of motion artifacts, metal artifacts, wire hardening artifacts, and ring artifacts, with clear boundaries and distinct layers.

[0066] Image Reconstruction and Post-processing 1. Reconstruction algorithms: Standard, soft tissue, bone, iterative reconstruction (optional); 2. Reconstruction layer thickness: 1mm, 2mm, 5mm, to meet different quality control requirements; 3. Window width and position: Lung window (W=1500, L=-600), mediastinal window (W=350, L=50), bone window (W=2000, L=500); 4. Export DICOM images, import them into quality control analysis software, and perform quantitative measurements of CT value, noise, uniformity, spatial resolution, and linearity.

[0067] Multidimensional quantitative evaluation of image quality (core quality control indicators) 5.1 Accuracy and Stability of CT Values 1. Measure the CT value of each module's ROI (Region of Interest, 20mm in diameter): Lung module: -850~-800HU; Fat module: -90~-70HU; Muscle module: +35~+45HU; Gadolinium enhancement module: +850~+950HU; 2. Perform three consecutive scans, calculate the standard deviation of CT values, and ensure stability ≤ ±1.8 HU; 3. Correlate the CT value with the gadolinium standard reference value to establish a calibration curve of CT value-gadolinium concentration, R 2 ≥0.9999.

[0068] Image noise and uniformity 1. Noise: Standard deviation of ROI for muscle modules, ≤2.5HU; 2. Uniformity: The difference in CT values ​​between the center and edge of the phantom ROI is ≤3.0HU; 3. Low-dose noise: Low-dose sequence noise ≤ 4.0 HU, meeting screening requirements.

[0069] Spatial resolution and contrast resolution 1. Spatial resolution: High-resolution sequence, measured by line-pair cards or phantoms, ≥10 lp / cm; 2. Contrast resolution: Low contrast module, capable of distinguishing ≤1% contrast difference; 3. Geometric accuracy: The measurement error of the mold body size is ≤1.0mm, with no geometric distortion.

[0070] Density linearity and enhanced quantitative accuracy 1. Density linearity: Linear fitting of CT values ​​from multi-density modules to true density, R0 2 ≥0.9998; 2. Enhanced quantitative error: The deviation between the gadolinium enhancement module CT value and the standard substance concentration is ≤0.5%; 3. Linear range: Excellent linearity across the entire range of -950HU to +1100HU, with no saturation or cutoff.

[0071] Radiation dose quality control 1. CTDIvol (volume CT dose index): standard sequence ≤20mGy, low-dose sequence ≤10mGy; 2. DLP (dose-length product): ≤500 mGy·cm; 3. Dose repeatability: The dose deviation of 3 scans is ≤5%, which meets the radiation protection requirements.

[0072] Data closed-loop verification, source tracing and correlation and anomaly handling 6.1 Gadolinium setting value - CT value bidirectional traceability 1. Establish a traceability database by mapping the high concentration gadolinium values ​​(g / L) to the gadolinium enhancement module CT values ​​(HU); 2. Reverse verification: Calculate gadolinium concentration using CT values ​​and compare with the results of standard reference determination; deviation ≤ 0.5%. 3. Data chain: High-purity gadolinium standard → Standard solution value setting → Phantom gadolinium module → CT image CT value → Clinical contrast-enhanced scan, the whole process is traceable and reproducible.

[0073] Outlier Identification and Handling Process 1. If CT value stability > ±1.8 HU: Check phantom fixation, scanning bed level, X-ray tube output, detector calibration, and rescan; 2. If the noise is >2.5HU: Check the tube current, reconstruction algorithm, and iteration parameters, and optimize the scanning conditions; 3. If the enhanced quantitative error is >0.5%: recalibrate the gadolinium standard, check matrix matching, perform ICP-OES drift correction, and recalculate the value; 4. All anomalies are recorded with their causes, corrective measures, and retest results, forming a quality control log which is then archived.

[0074] Integrated test report generation and conclusion output 7.1 Report Content (Standardized Template) 1. Basic Information: Equipment model, serial number, testing date, environmental conditions, and operators; 2. Reference material information: gadolinium concentration, uncertainty, expiration date, traceability certificate number; 3. Phantom information: preparation batch, calibration date, stability data; 4. Scanning parameters: sequence, kVp, mAs, layer thickness, FOV, matrix; 5. Quality control results: CT value, noise, homogeneity, spatial resolution, linearity, quantification of enhancement, radiation dose; 6. Source data: Gadolinium fixed value-CT value calibration curve, two-way verification results; 7. Abnormality description: No / Abnormal, handling status, retest results; 8. Conclusions and Recommendations: Pass / Fail, Quality Control Level, Clinical Use Recommendations, Next Testing Time.

[0075] Conclusion Judgment Criteria (Based on GB / T 17589-2011) 1. Qualified: All quality control indicators meet the standards, quantitative accuracy is enhanced, the traceability chain is complete, and there are no abnormalities; 2. Basically qualified: Some indicators are slightly exceeded (≤10%), which does not affect routine clinical use, but requires enhanced monitoring; 3. Unqualified: Key indicators (CT value stability, enhancement quantitation, spatial resolution, dose) are seriously exceeded, affecting diagnostic accuracy, and require shutdown for calibration / repair.

[0076] Report archiving and data management 1. The report should be signed and stamped, and archived in both electronic and paper formats for at least 5 years; 2. Upload data to the quality control system, establish equipment quality control files, conduct trend analysis, and provide regular early warnings; 3. Upon successful testing, a quality control certificate will be issued, which can be used for clinical quantitative contrast-enhanced CT, gadolinium contrast-enhanced dose value traceability, and routine quality control.

[0077] Clinical extension applications 1. The CT value-gadolinium concentration calibration curve established in this study was directly used for clinical contrast-enhanced CT scans; 2. Enhances the diagnosis of liver cancer, hemangioma, bone metastases, and vascular lesions by accurately quantifying gadolinium concentration, thereby improving diagnostic specificity and sensitivity; 3. Standardize quantitative methods across different equipment and hospitals to achieve data interoperability and comparability of results; 4. Provide a basis for individualized contrast agent dosage, reduce dosage, decrease adverse reactions, and improve safety.

[0078] Beneficial effects of the present invention The phantom's performance has been comprehensively improved: full density coverage, modular design, gradient gadolinium reinforcement, temperature compensation, and expandable functions. It has high tissue equivalence, good stability, and low cost (only 1 / 5 of imported phantoms).

[0079] Industry-leading accuracy: slight dilution, matrix matching, dual-method verification, and full-process quality control result in low uncertainty, short traceability chain, and authoritative reliability, filling the gap in quantitative calibration of gadolinium-enhanced CT.

[0080] Integrated closed-loop process: The entire chain of phantom preparation, gadolinium determination, and CT quality control is linked, with clear data traceability, high quality control efficiency, and good repeatability, forming a standardized SOP.

[0081] It has a wide range of applications: it is compatible with plain scan, enhanced scan, low-dose scan, CTA, contrast agent traceability, and standard substance value determination, and is suitable for use by medical institutions, metrology institutes, and equipment manufacturers at all levels. Attached Figure Description

[0082] Figure 1 Overall technical process flowchart; Figure 2 : Schematic diagram of the overall structure of the CT multi-density phantom; Figure 3 Cross-sectional view of the tissue equivalent density module and the gadolinium-enhanced calibration module; Figure 4 Comparison of matrix matching calibration curve and conventional curve; Figure 5 Uncertainty component contribution histogram; Figure 6: Schematic diagram of CT scan and image quality assessment, in which... Figure 6A The phantom is fixed at the center of the CT scanning bed of the CT device 6. Figure 6B Demonstration of the on-site effects of CT quality control and image evaluation Figure 1 and Figure 6C On-site demonstration of CT quality control and image evaluation Figure 2 ; Explanation of the labels in the diagram: 1—Main reference phantom; 2—Temperature compensation airbag; 3—Removable tissue equivalent density disc; 31—Inlay hole; 4—Gradient Gadolinium-enhanced calibration core; 41 – First gadolinium-enhanced calibration core; 42 – Second gadolinium-enhanced calibration core; 43 – Third gadolinium-enhanced calibration core; 44 – Fourth gadolinium-enhanced calibration core; 45—Fifth Gadolinium Reinforced Calibration Core 45; 5 – Locating pin hole; 6 – CT. Detailed Implementation

[0083] The overall flowchart of the method for detecting the stability and homogeneity of key parameters of a high-concentration gadolinium CT contrast agent according to the present invention is shown below. Figure 1 This includes: constructing novel gadolinium-doped polymer composite CT phantoms; high-precision value determination of high-concentration gadolinium solutions; and integrated detection methods for CT equipment. The preparation of gadolinium-doped polymer composite CT phantoms includes, in sequence, pretreatment of raw materials, mixing of ingredients, twin-screw extrusion granulation, vacuum molding, and calibration traceability. High-precision determination of high-concentration gadolinium solutions includes, in sequence, differential weighing, slight dilution, matrix matching standard solution, ICP-OES main analysis, EDTA titration verification, and uncertainty assessment; Integrated testing of CT equipment includes, in sequence, phantom assembly, multi-sequence scanning, image reconstruction, quality evaluation, closed-loop traceability, and report output.

[0084] The overall structure of the CT multi-density phantom is as follows Figure 2 As shown, it includes: The main reference phantom 1 is a 4-layer concentric nested elliptical cylinder structure, made of medical-grade PEEK material, with an internal cavity volume that is infinitely adjustable from 0.4 to 0.65L, an elliptical cylinder error of <0.08mm, and a built-in temperature compensation airbag 2 at the top. The independent circular structure of the detachable tissue equivalent density disk 3 has a diameter of 250mm and a thickness of 20mm. The disk surface has 8 evenly distributed inlay holes 31 to 38, which can be embedded with different tissue equivalent density blocks. The central cylindrical core structure contains an embedded gradient gadolinium-enhanced calibration core 4, with a diameter of 50 mm and a thickness of 30 mm. Internally, it comprises five concentric annular regions 41 to 45, decreasing in size from largest to smallest. Figure 3 As shown; The bottom circumferential of the main reference mold 1 has a positioning pin hole 5 for positioning.

[0085] Example 1: Preparation of Gadolinium-doped Polymer Composite CT Multi-Density Phantom 1. Formula determined (muscle tissue equivalent block) PEEK: 40.0% EVA: 25.0% PC: 20.0% Gd2O3: 0% Nano SiO2: 15.0% 2. Raw material preparation PEEK: Medical grade, 200 mesh particle size; EVA: Medical grade, melt index 15g / 10min; PC: Food grade, transparent grade; Nano-SiO2: 30 nm particle size, hydrophilic; All materials were sieved through a 650-mesh screen, sterilized with ultraviolet light for 30 minutes, and vacuum dried at 80℃ for 2 hours, with a moisture content of 2.1%.

[0086] Mixing and Eutectic Add 0.3% silane coupling agent KH-550; Mix at 50℃ and 1500r / min for 15min using a high-speed mixer; Twin-screw extrusion: Zone 1 160℃, Zone 2 180℃, Zone 3 195℃, Zone 4 205℃, Die head 200℃; Rotation speed 180 r / min; Water-cooled strips and pellets are produced, with masterbatch diameters of 3mm and lengths of 4mm.

[0087] Compression molding Preheat the masterbatch to 100℃ for 30 minutes; The mold is heated to 120℃ and then evacuated to -0.09MPa. Pressurize to 1.8 MPa and hold at that temperature for 150 minutes; Cool down to 40℃ in a gradient of 2℃ / h, then demold.

[0088] Post-processing and calibration Deburring and surface coating with protective paint; The coordinate measuring machine measures dimensions with an error of 0.05 mm. Standard CT scan, CT value +38HU, homogeneity 1.2HU; Continuous scanning 1200 times, fluctuation ±1.5HU; no cracking or deformation during high and low temperature cycling.

[0089] Phantom assembly Install the main reference phantom, tissue equivalent density module, and gadolinium-enhanced calibration module in sequence; Laser marking of serial numbers and traceability QR codes; completion of phantom preparation.

[0090] like Figure 3 It is a core visualization of the phantom structure and density distribution. Figure 3 In A, full-density coverage is visually displayed: from lung tissue (-950~-850 HU), fat, water, muscle, liver, kidney, to cancellous bone and cortical bone, completely covering the CT value range of major human tissues; Figure 3 In section B, the gradient gadolinium enhancement module is shown: it contains five concentric ring regions 41 to 45, which are arranged from largest to smallest. From the outside to the inside, the CT value of the first gadolinium enhancement calibration core 41 is +200HU, the CT value of the second gadolinium enhancement calibration core 42 is +300HU, the CT value of the third gadolinium enhancement calibration core 43 is +500HU, the CT value of the fourth gadolinium enhancement calibration core 44 is +800HU, and the CT value of the fifth gadolinium enhancement calibration core 45 is +1100HU.

[0091] The central area exhibits a five-level gradient from the outside to the inside: +200HU, +300HU, +500HU, +800HU, and +1100HU, simulating lesions with different enhancement levels.

[0092] It embodies a modular layout: the tissue equivalent block and the gadolinium-reinforced core are clearly separated, corresponding to the "removable density disk + central gadolinium calibration core" structure in the patent.

[0093] Example 2: Determination of high concentration gadolinium solution (nominal 40 g / L, 10% nitric acid) 1. Sample Information Nominal concentration: 40 g / L; Medium: 10% nitric acid; Appearance: Clear and transparent, without sediment.

[0094] Preprocessing Differential weighing: m s = 0.4820g; Volume adjustment: 50 mL, 10% nitric acid; Injection solution concentration: approximately 385.6 mg / L; Blank matrix: 10% nitric acid.

[0095] Matrix-matched standard solution 5 g / L stock solution was prepared using 5N high-purity gadolinium; Gradients: 50, 100, 200, 300, 400 mg / L, acidity 10%, impurity matching. 4. ICP-OES determination. The main spectral line is 342.246 nm. RF power 1250W; Atomizer flow rate: 0.75 L / min; The measured value was ρ = 385.4 mg / L.

[0096] Concentration calculation .

[0097] Verification Titration result: 39.96 g / L; Relative deviation: 0.05% < 0.25%, acceptable.

[0098] Uncertainty Combined uncertainty: 0.11%; Expanded uncertainty: U = 0.22% (k = 2).

[0099] in conclusion The measured value was 39.98 ± 0.09 g / L (k = 2). It has reliable traceability and controllable uncertainty, and can be used for enhanced CT calibration.

[0100] Figure 4 The comparison chart of the matrix matching calibration curve and the conventional curve is a visual verification chart for establishing the ICP-OES matrix matching standard curve. 1. Comparison of calibration curves between matrix matching method and conventional method: matrix matching curve has better linearity, less interference, and intercept closer to 0.

[0101] 2. Proof of elimination of matrix effect: This invention uses "matching with the same acidity and the same rare earth impurities" to solve the problem of interference from high-concentration gadolinium, nitric acid media, and rare earth spectral lines.

[0102] 3. Supports high-precision measurement: The linear correlation coefficient R ≥ 0.99995, which meets the requirements for accurate measurement of high-concentration gadolinium solutions.

[0103] Figure 5 The bar chart showing the contribution of uncertainty components corresponds to the "uncertainty assessment" in the determination of high-concentration gadolinium solutions and is a core data chart for the accuracy of the method.

[0104] 1. Show the percentage of the six major uncertainty components: weighing, volumetric preparation, instrumental measurement, homogeneity, stability, and EDTA titration; 2. Quantitative results are given: the combined relative standard uncertainty is 0.11%, and the expanded uncertainty is 0.22% (k=2), which is far lower than the patent requirement of ≤0.45%; 3. Proof that the fixed-value method has high precision: each component is controllable, the traceability chain is short, and the method is reliable.

[0105] Example 3: Integrated CT Equipment Testing 1. Mold installation The prepared phantom is fixed at the center of the CT scanning bed of the CT device 6, such as Figure 6A As shown; Laser positioning calibration, positioning error 0.3mm.

[0106] Scan parameters Tube voltage: 120kVp; Tube current: 80 mAs; Layer thickness 1 mm; Reconstruction algorithm: Standard algorithm.

[0107] Image Acquisition The main reference, density module, and gadolinium enhancement module are scanned sequentially. The image is uniform, free of artifacts, and has clear boundaries.

[0108] Substitute the gadolinium set value into the calibration Gadolinium enhancement module CT value: +915HU, corresponding to a concentration of 39.98g / L; Linear fitting: R 2 = 0.99998, good linearity.

[0109] Image quality assessment Noise level: 2.0%; Uniformity: 2.2%; Spatial resolution: 12 lp / cm; Density linearity: Good; Enhanced quantification error: 0.18%.

[0110] Conclusion Output According to GB / T 17589-2011, all indicators of the CT equipment in this test meet the national standards. The gadolinium determination results are reliable and traceable, and can be used for clinical contrast-enhanced CT calibration, contrast dose value traceability, and routine quality control.

[0111] See the diagram for CT scan and image quality assessment. Figure 6A , Figure 6B and Figure 6C This is a live demonstration of the effects of CT quality control and image evaluation. Figure 1 , two .

[0112] 1. Display actual CT scan images: phantom tomography, each density module is clearly distinguishable, and there are no artifacts.

[0113] 2. Presents an interface for measuring image quality evaluation indicators such as CT value, noise, uniformity, spatial resolution, density linearity, and quantitative enhancement.

[0114] 3. It embodies integrated detection: a complete process from phantom scanning to image reconstruction, quantitative analysis, and conclusion output.

Claims

1. A gadolinium-doped polymer composite CT multi-density phantom, characterized in that, include: Main reference phantom: 4-layer concentric nested elliptical cylinder structure, medical-grade PEEK material, internal cavity volume infinitely adjustable from 0.4 to 0.65L, elliptical cylinder error <0.08mm, and built-in temperature compensation airbag at the top; Detachable tissue equivalent density module: Independent disc structure, 250mm in diameter and 20mm in thickness, with 8 evenly distributed inlay holes on the disc surface, which can be embedded with different tissue equivalent density blocks; Embedded gradient gadolinium enhancement calibration module: central cylindrical core structure, 50mm in diameter and 30mm in thickness, containing 5 concentric ring regions, CT value coverage of +200HU~+1100HU; The tissue equivalent density block and gadolinium enhancement calibration module are made of a five-element compound of PEEK, EVA, PC, Gd2O3 and nano-SiO2, achieving full density coverage from -950HU to +1100HU, with CT value stability ≤ ±1.8HU.

2. The gadolinium-doped polymer composite CT multi-density phantom according to claim 1, characterized in that, The temperature compensation airbag is made of medical-grade silicone and has a volume of 50mL. It can automatically compensate for volume changes caused by temperature variations of 15~35℃.

3. The gadolinium-doped polymer composite CT multi-density phantom according to claim 1, characterized in that, The tissue equivalent density blocks include equivalent blocks of lung tissue, adipose tissue, water, muscle tissue, liver tissue, kidney tissue, cancellous bone, and cortical bone. The formulations of each equivalent block are as follows: Lung tissue: PEEK 15%, EVA 55%, PC 10%, nano SiO2 20%, CT value -950~-850HU; Adipose tissue: PEEK 25%, EVA 45%, PC 20%, nano SiO2 10%, CT value -90~-70HU; Muscle tissue: PEEK 40%, EVA 25%, PC 25%, nano SiO2 10%, CT value +35~+45HU; Cortical bone: PEEK 25%, EVA 5%, PC 20%, Gd2O3 45%, nano SiO 25%, CT value +800~+1000HU.

4. The gadolinium-doped polymer composite CT multi-density phantom according to claim 1, characterized in that, It also includes an expandable functional module, which is selected from one or more of the following: water model calibration module, spatial resolution module, low contrast module, and radiation dose module.

5. A method for accurately determining the concentration of high-concentration gadolinium solution, characterized in that, Includes the following steps: 1) Sample pretreatment: Take 5~100g / L gadolinium nitric acid medium solution, accurately weigh 0.25~0.9g of sample by differential gravimetric method, and slightly dilute with nitric acid of the same acidity to 50~480mg / L; 2) Preparation of matrix-matched standard solutions: Using 5N high-purity gadolinium metal as the primary reference, prepare gradient standard working solutions that match the acidity and rare earth impurity content of the sample to be tested. 3) ICP-OES main determination: Gd 342.246nm was selected as the main analytical spectral line. The instrument parameters were optimized, and the adjacent background subtraction method and coexisting element interference correction model were used to eliminate interference and determine the sample concentration. 4) EDTA complexometric titration verification: Adjust the pH to 5.8~6.2, use xylenol orange as an indicator, and titrate with EDTA standard solution standardized with zinc oxide as the reference standard to verify the main determination results; 5) Homogeneity and stability tests: One-way ANOVA was used to evaluate homogeneity, and linear regression model was used to evaluate stability; 6) Uncertainty assessment: The system assesses the six major uncertainty components of weighing, preparation, instrumentation, uniformity, stability, and titration, and combines the expanded uncertainty. The relative expanded uncertainty of the method is ≤0.45% (k=2).

6. The method for accurately determining the concentration of high-concentration gadolinium solution according to claim 5, characterized in that, In step 1), six parallel samples were taken using the differential gravimetric method, and the volume was adjusted in a constant temperature laboratory at 20±2℃.

7. The method for accurately determining the concentration of high-concentration gadolinium solution according to claim 5, characterized in that, In step 2), the concentrations of the gradient standard working solutions are 50, 100, 200, 300, and 400 mg / L, and the relative deviations of the lanthanum, cerium, and neodymium impurity contents in the standard solutions from those in the samples are ≤4%.

8. The method for accurately determining the concentration of high-concentration gadolinium solution according to claim 5, characterized in that, In step 3), the ICP-OES instrument parameters are: RF power 1200~1280W, nebulizer flow rate 0.70~0.78L / min, observation height 13~14mm; for every 8 samples measured, a set of intermediate concentration standard solutions is inserted for drift correction.

9. The method for accurately determining the concentration of high-concentration gadolinium solution according to claim 5, characterized in that, In step 4), the relative deviation between the results of the ICP-OES master method and the EDTA titration method must be ≤0.25% for the value determination to be valid.

10. An integrated testing method for CT equipment, characterized in that, Based on the phantom according to any one of claims 1 to 4 and the value determination method according to any one of claims 5 to 9, the method includes the following steps: 1) Pre-test preparation: Confirm environmental conditions, prepare standard materials and consumables, and complete the pre-test of CT equipment; 2) Gadolinium standard reference determination: The high-concentration gadolinium standard solution is determined using the method described in any one of claims 5-9; 3) Phantom installation and scanning: Fix the phantom on the CT scanning bed, perform laser positioning and calibration, set multi-sequence scanning parameters, and acquire image data; 4) Image quality evaluation: Quantitative measurement of CT value, noise, homogeneity, spatial resolution, density linearity, accuracy of quantitative enhancement, and radiation dose; 5) Data closed-loop verification: Establish a two-way traceability chain between gadolinium fixed value and CT value to identify and handle outliers; 6) Conclusion Output: Determine the performance of CT equipment according to national standards and generate a standardized test report.

11. The integrated testing method for CT equipment according to claim 10, characterized in that, In step 3), the scanning sequence includes a standard quality control sequence, a low-dose screening sequence, an enhanced calibration sequence, and a high-resolution sequence; the scanning field is 250~300mm, the matrix is ​​512×512, and the slice thickness is 1.0mm.

12. The integrated testing method for CT equipment according to claim 10, characterized in that, In step 4), CT value stability ≤ ±1.8 HU, image noise ≤ 2.5 HU, uniformity ≤ 3.0 HU, spatial resolution ≥ 10 lp / cm, and enhancement quantitative error ≤ 0.5%.

13. The integrated testing method for CT equipment according to claim 10, characterized in that, In step 6), the test report includes basic information, standard material information, phantom information, scanning parameters, quality control results, traceability data, anomaly descriptions, conclusions and recommendations; the report is archived electronically and in paper form and kept for ≥5 years.

14. The integrated testing method for CT equipment according to claim 10, characterized in that, Step 4) involves the quantitative measurement of CT values, including: Select a clear tomographic image of a specific layer, use CT image processing software to display the image information of that layer and obtain the average CT value; Select the region of interest in the image, and use standard geometric shapes to delineate the region of interest. The area of ​​the region of interest should be approximately equal to the area of ​​a circular region with a diameter of 10% of the water model. The average CT value of the region of interest is read using software. The nominal mean CT value of the region of interest for water is 0. The deviation of the mean CT value of the region of interest for the control group from the nominal value should not exceed ±4HU. If the deviation is greater than this value, the slice needs to be reselected.

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