Medical-grade ultralow-adsorption cycloolefin copolymer material and preparation method thereof

Abstract

The invention discloses a medical-grade ultralow-adsorption cycloolefin copolymer (COC) material and a preparation method thereof. According to the material, COC serves as matrix resin, surface-modified nano silicon dioxide is loaded through in-situ polymerization, and a perfluoroalkyl siloxane (PFAS) coating is grafted on the surface of the material through a normal-pressure plasma technology. The preparation method comprises the following steps: surface modification of nano-SiO2, in-situ polymerization of COC, loading of nano-SiO2, and continuous grafting of PFAS with normal-pressure plasma. The adsorption rate of the material is as low as 3.2 * 10 <-7 > copy / mu L (annual loss rate); the temperature from-196 DEG C (liquid nitrogen) to 121 DEG C (autoclaved sterilization) can bear 16,000 g centrifugation without rupture; by means of ethylene oxide sterilization or gamma ray irradiation, it is ensured that the product is free of endotoxin (1t, 0.001 EU / mL), free of DNA enzyme / RNA enzyme residues and other excellent performance, the problems of high adsorption rate and low-temperature brittleness of a traditional COC material in biological sample storage are effectively solved, and the method is suitable for large-scale production of high-end medical cryopreservation tubes and other products.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical materials, in particular to a medical-grade ultra-low adsorption cyclic olefin copolymer (COC) material and a preparation method thereof. BACKGROUND

[0002] In the field of medical materials, especially for products such as cryogenic tubes used for biological sample storage, cyclic olefin copolymer (COC) materials have been widely used due to their good transparency, chemical stability and other advantages. However, when traditional COC materials are applied to high-end biological sample storage, especially in deep cryogenic environments, there are several interrelated and urgent technical problems to be solved: First, the adsorption rate of traditional COC materials on biological samples is high. During storage, the material surface will non-specifically adsorb proteins, DNA and other biological macromolecules in the solution. This adsorption will cause the concentration and activity of target molecules in the sample to decrease, which is unacceptable for trace or valuable samples, and will directly affect the accuracy of subsequent detection and analysis results. More seriously, the adsorbed proteins can become a breeding ground for microorganisms, forming a biofilm and then causing cross-contamination of the sample. Therefore, how to significantly reduce the adsorption of biological molecules by the material and ensure the integrity and detection accuracy of the sample is one of the primary technical problems to be solved in this field.

[0003] Secondly, traditional COC materials have a significant low-temperature brittleness problem. When in a deep cryogenic environment, especially in liquid nitrogen storage conditions at -196℃, the molecular chain movement of the material is frozen, and the toughness decreases sharply, showing increased brittleness and deteriorated impact resistance. During the long-term use of cryogenic tubes, the material is subjected to repeated thermal stress caused by temperature reduction, temperature increase and phase change of liquid nitrogen, and the traditional COC cryogenic tube is prone to rupture. This not only causes valuable biological samples to be exposed and ineffective, resulting in irreparable loss, but also greatly limits the use of COC materials in application scenarios with extremely high requirements for low-temperature toughness, such as deep cryogenic biological tissue banks and stem cell banks. Therefore, how to significantly improve the impact toughness of the material at liquid nitrogen temperature and ensure its safety and reliability in extreme low-temperature environments is another key technical bottleneck to be overcome.

[0004] Furthermore, existing technologies lack a comprehensive solution that can effectively address both of the aforementioned problems simultaneously. Most publicly available improvement methods focus only on reducing adsorption through surface coatings or improving low-temperature performance by adding toughening agents, often failing to achieve both simultaneously. For example, simple surface modification may fail at low temperatures due to insufficient adhesion between the coating and the matrix; while simple blending and toughening may sacrifice material transparency or introduce new adsorption sites. In addition, many improvement processes are complex, costly, or difficult to scale up for continuous production, failing to meet the consistent requirements of the medical field for material performance, cost, and large-scale supply. Therefore, there is an urgent need to develop a comprehensive technical solution that can be co-designed from the material bulk to the surface, simultaneously achieving ultra-low adsorption, high and low temperature toughness, high transparency, and suitability for industrial production. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a medical-grade ultra-low adsorption cyclic olefin copolymer (COC) material, comprising: Matrix resin: The main component is a cyclic olefin copolymer (COC).

[0006] Reinforcing component: Contains surface-modified nano-silica (SiO2) supported by in-situ polymerization. The surface is modified with a silane coupling agent (such as KH-570) and contains active functional groups such as carbon-carbon double bonds that can participate in polymerization.

[0007] Surface coating: Perfluoroalkylsiloxane (PFAS) is grafted onto the material surface using atmospheric pressure plasma technology to form a fluoropolymer coating with ultra-low surface energy.

[0008] Furthermore, the present invention also provides a method for preparing a medical-grade ultra-low adsorption cyclic olefin copolymer (COC) material. The method includes the following steps: S1: Raw material and equipment preparation: Select high-purity raw materials, including cyclic olefin monomers with a purity of not less than 99%, a catalytic system composed of zirconium dichlorocerocene (Cp2ZrCl2) and methylaluminoxane (MAO) with a purity of ≥99.5%, nano-SiO2 powder with a particle size of <50nm, and surface modifier KH-570 and graft modifier perfluoroalkylsiloxane (PFAS) with a purity of ≥98%; and configure polymerization reactor, centrifugal drying equipment and atmospheric pressure plasma continuous processing system.

[0009] S2: Surface modification of nano-SiO2: KH-570 was hydrolyzed at 60°C for 30 minutes in an ethanol-water mixed solution with a volume ratio of 4:1. Then, nano-SiO2 was added and reacted at 60°C for 4 hours to graft carbon-carbon double bond active functional groups onto its surface through a condensation reaction. After the reaction, the nano-SiO2 was obtained by centrifugation, washing with ethanol, and vacuum drying at 80°C for 12 hours.

[0010] S3: Polymerization of COC and in-situ loading of nano-SiO2: Under an inert atmosphere, cyclic olefin monomers, modified nano-SiO2 obtained in step (2) (with a mass ratio of 1:100 to 5:100 to monomers), and a catalytic system composed of zirconium dichlorocerocene (Cp2ZrCl2, with a molar ratio of 1:10000 to monomers to 1:5000) and methylaluminoxane (MAO, with a molar ratio of 500:1 to 1000:1 to Cp2ZrCl2) were added to a reactor and polymerized at 80-100℃ for 4-6 hours. After the reaction, the COC material was obtained by dissolving, precipitating, filtering, and drying.

[0011] S4: Continuous grafting of PFAS by atmospheric pressure plasma: After the COC material obtained in step (3) is shaped, it is placed on the conveyor belt (speed 1-5 m / min) of the atmospheric pressure plasma equipment. Under the atmosphere of argon (flow rate 50-100 sccm) and high frequency electric field (power 100-300 W), PFAS is sprayed onto the surface of the material in liquid spray form to carry out the grafting reaction. Then, it is heat-treated at 100-120℃ for 1-2 hours to obtain the final product.

[0012] Compared with the prior art, the present invention has the following specific beneficial effects: This invention addresses the bottleneck issues faced by traditional cyclic olefin copolymers (COCs) in the field of medical cryogenic storage through a combination of technologies including "molecular weight distribution regulation (PDI < 1.2), in-situ polymerization with surface-modified nano-SiO2, and continuous grafting of perfluoroalkyl siloxanes (PFAS) using atmospheric pressure plasma." Specifically, this is reflected in the following aspects: 1. The material exhibits excellent overall performance, especially superior low-temperature toughness and optical transparency. The COC material prepared in this invention achieves a breakthrough improvement in key properties. Firstly, by precisely controlling the molecular weight distribution (PDI < 1.2), the molecular chains are arranged in a regular pattern, resulting in uniform internal stress and fundamentally improving the material's intrinsic toughness. Its notched impact strength at -196℃ reaches as high as 8 kJ / m². 2 This completely overcomes the risk of brittleness in traditional COC materials in liquid nitrogen environments, ensuring the absolute safety of biological samples during cryogenic storage. Secondly, while achieving high toughness, the material maintains a light transmittance of over 92%, providing extremely high clarity for sample observation and meeting the stringent visualization requirements in medical testing.

[0013] 2. It achieves ultra-low adsorption of biomolecules, greatly ensuring sample integrity and detection accuracy. This invention constructs a stable ultra-low adsorption interface on the material surface by introducing surface-modified nano-SiO2 and continuously grafting PFAS. Specifically, the atmospheric pressure plasma continuous PFAS grafting technology forms a dense fluorine-containing coating on the material surface, which, due to its extremely low surface energy, reduces the adsorption affinity of the material for proteins and DNA to an extremely low level. Ultimately, the protein adsorption capacity on the inner wall is ≤5 ng / cm³. 2 DNA adsorption rate as low as 2.1 × 10⁻⁶ -4 Copy / μL. This characteristic minimizes the loss and contamination of precious biological samples during storage, providing a crucial guarantee for the reliability of subsequent high-precision detection results.

[0014] 3. The preparation method is efficient and controllable, possessing significant advantages for industrial application. The preparation process of this invention is scientifically designed, with mild and synergistic conditions in each step, making it easy to control and scale up industrially. In particular, the atmospheric pressure plasma continuous grafting PFAS process, using a conveyor belt (speed 1-5 m / min) for continuous production, significantly improves production efficiency and effectively reduces production costs compared to traditional intermittent surface treatment. This method provides a reliable technical path for the large-scale and stable production of high-performance medical-grade ultra-low adsorption COC materials, strongly promoting their widespread application in high-end biological sample cryopreservation tubes and other products. Attached Figure Description

[0015] Figure 1 is a schematic diagram of surface modification with nano-SiO2; Figure 2 is a schematic diagram of the microstructure of COC polymerization and in-situ supported nano-SiO2; Figure 3 is a schematic diagram of the continuous grafting of PFAS by atmospheric pressure plasma; Figure 4 shows the results of the material performance test. Detailed Implementation

[0016] A method for preparing a medical-grade ultra-low adsorption cyclic olefin copolymer material includes the following steps: S1: Prepare raw materials and equipment This step aims to identify all the materials and equipment required for the preparation process, laying the foundation for subsequent experiments and production.

[0017] S11. Selection of key raw materials Norbornene or its derivatives were selected as the cyclic olefin monomers, ensuring a purity of not less than 99%. High-purity zirconium dichloroethylene (Cp₂ZrCl₂, ≥99.5%) and methylaluminoxane (MAO) were prepared to form the catalyst system. Particles with a particle size <50 nm and a specific surface area >200 m² were purchased. 2 / g of nano-SiO2 powder. It is prepared with surface modifier KH-570 and graft modifier perfluoroalkylsiloxane (PFAS), both with a purity ≥98%. Analytical grade solvents such as ethanol, toluene, and methanol are also available.

[0018] S12. Configure the required equipment A polymerization reactor equipped with stirring, temperature control, and inert gas interfaces is used. A high-speed centrifuge and vacuum drying oven are prepared for post-processing. A continuous atmospheric pressure plasma treatment system, including a conveyor belt, liquid spray system, and high-frequency power supply, is employed. Finally, material forming equipment such as injection molding machines or extruders is required.

[0019] S2: Surface modification of nano-SiO2 The core of this step is to graft carbon-carbon double bond active functional groups onto the surface of nano-SiO2 through chemical reactions, thereby improving its compatibility and reactivity in subsequent polymerization.

[0020] S21. Preparation of hydrolysis solution An ethanol-water mixture with a volume ratio of 4:1 is added to a reactor equipped with a stirring and reflux device.

[0021] S22. Complete the hydrolysis of KH-570. Heat the reaction system to 60°C, start stirring, slowly add the measured amount of KH-570, maintain this temperature and continue stirring for 30 minutes to allow the methoxy groups to be fully hydrolyzed to generate silanol groups.

[0022] S23. Perform surface grafting reaction Nano-SiO2 powder was slowly added to the above system and reacted continuously at 60°C for 4 hours, so that the silanol groups of KH-570 and the silanol groups on the surface of nano-SiO2 would undergo a dehydration condensation reaction.

[0023] S24. Complete separation and drying. After the reaction was completed, the modified nano-SiO2 was collected by centrifugation and washed repeatedly with ethanol to remove impurities. Finally, the product was dried in a vacuum drying oven at 80°C for 12 hours and then sealed for later use.

[0024] S3: Implementing COC polymerization and in-situ supported nano-SiO2 This step aims to simultaneously achieve the polymerization of cyclic olefin monomers and the in-situ introduction of modified nano-SiO2 through precisely controlled catalytic polymerization reactions.

[0025] The specific implementation process is as follows: S31. Establishing the polymerization reaction environment First, the polymerization reactor is thoroughly dried and purged with inert gas, and then metered cyclic olefin monomers are added.

[0026] S32. Dispersed modified nano-SiO2 The modified nano-SiO2 prepared by S2 was added to the reactor at a mass ratio of 1:100 to 5:100 (relative to the monomer) and stirred at high speed at 1000 to 1500 rpm for 30 minutes to disperse it evenly.

[0027] S33. Adding a catalyst to initiate polymerization. Under inert gas protection, the metallocene catalyst zirconium dichlorodi ...

[0028] S34. Controlling the polymerization process The reaction system was heated to 80-100℃ and the polymerization reaction was maintained at this temperature for 4-6 hours to ensure that nano-SiO2 participated in copolymerization in situ through surface double bonds.

[0029] S35. Separation and purification of products After the reaction was complete, the product was dissolved in toluene and then poured into excess methanol to precipitate. The mixture was then filtered, and the resulting solid was vacuum dried at 60°C to constant weight to obtain nano-SiO2-reinforced COC material.

[0030] S4: PFAS continuously grafted via atmospheric pressure plasma This step utilizes atmospheric pressure plasma technology to efficiently and continuously construct a perfluoroalkylsiloxane (PFAS) ultra-low adsorption coating on the material surface.

[0031] The specific method is as follows: S41. Processing and placing materials First, the COC material obtained in step three is processed into the target shape (such as a cryopreservation tube blank) and placed on the conveyor belt of the atmospheric pressure plasma processing equipment.

[0032] S42. Set and activate plasma Set the conveyor belt speed to 1-5 m / min. Turn on the equipment, introduce argon gas at a flow rate of 50-100 sccm, and apply a high-frequency electric field with a power of 100-300 W to generate plasma.

[0033] S43. Simultaneous spraying of PFAS for grafting In the plasma treatment zone, PFAS is uniformly sprayed onto the material surface in the form of a liquid spray. Surface free radicals generated by plasma activation initiate the hydrolysis of PFAS and a condensation grafting reaction.

[0034] S44. Implement post-processing to enhance stability. After grafting, the material is heat-treated at 100-120℃ for 1-2 hours to enhance the adhesion between the PFAS coating and the substrate and its own stability.

[0035] Through the above specific implementation methods, the prepared medical-grade ultra-low adsorption cyclic olefin copolymer (COC) material exhibits excellent performance, achieving an adsorption rate as low as 3.2 × 10⁻⁶. -7 Copy / μL (annual loss rate); -196℃ (liquid nitrogen) to 121℃ (autoclave), can withstand 16,000g centrifugation without breakage; sterilized with ethylene oxide or irradiated with gamma rays to ensure that the product is free of endotoxins (<0.001 EU / mL), free of DNase / RNase residues, and compatible with liquid nitrogen phase change environment, meeting the strict material requirements of products such as medical cryopreservation tubes.

[0036] The specific test results are shown in the table below: Table 1 Test Results

[0037] In summary, the materials and preparation methods of this invention are of great significance in improving material performance, meeting medical needs, and realizing industrial production, bringing new breakthroughs and developments to the field of medical materials.

Claims

1. A medical grade ultra-low adsorbing cyclic olefin copolymer material characterized in that, Comprise: a base resin which is a cyclic olefin copolymer; a reinforcing component which is in-situ polymerization loaded surface modified nano-silica, the surface of which is modified with a silane coupling agent with active functional groups that can participate in polymerization; a surface coating which is a fluoropolymer coating formed by grafting perfluoroalkylsiloxane through atmospheric pressure plasma technology.

2. The medical grade ultra-low adsorption cyclic olefin copolymer material of claim 1, wherein, The particle size of the surface modified nano-silica is less than 50 nm, and the silane coupling agent is KH-570.

3. The medical grade ultra-low adsorption cyclic olefin copolymer material of claim 1, wherein, The molecular weight distribution PDI of the cyclic olefin copolymer is less than 1.

2.

4. The medical grade ultra-low adsorption cyclic olefin copolymer material of claim 1, wherein, The material has an adsorption rate as low as 3.2 x 10 -7 Copies / μL (annual loss rate), -196°C (liquid nitrogen) to 121°C (autoclave), withstands 16,000g centrifugation without breakage; sterilized by ethylene oxide or gamma irradiation, ensuring product is endotoxin-free (<0.001 EU / mL), DNase / RNase-free.

5. A method of making a medical grade ultra-low adsorption cyclic olefin copolymer material as claimed in any one of claims 1 to 4, characterised in that, Comprise the following steps: S1: raw material and equipment preparation; S2: surface modification of nano-silica, including surface grafting of KH-570 on the surface of nano-silica in an ethanol-water mixed solution; S3: polymerization of COC and in-situ loading of nano-silica, including polymerization reaction of cyclic olefin monomer, modified nano-silica and catalyst system under inert atmosphere; S4: continuous grafting of perfluoroalkylsiloxane by atmospheric pressure plasma, including grafting reaction by spraying PFAS on the surface of the material under argon atmosphere, and heat treatment.

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