Method for forming an antibacterial silicone tube by one-step dipping of an aluminum corrosion inhibitor and a copper ammonia solution

Abstract

The application discloses a method for forming an antibacterial silica gel catheter by one-step impregnation of an aluminum corrosion inhibitor and a copper ammonia solution, and the method comprises the following steps: impregnating the silica gel catheter into an impregnation solution composed of an aluminum corrosion inhibitor siloxane ketone solution, a copper ammonia solution and APTES at room temperature, taking out the silica gel catheter after sufficient stirring, and drying the silica gel catheter to obtain the antibacterial silica gel catheter. The process flow of the method is simple, the reaction condition is mild, the operation is convenient, the production cost is low, the method is suitable for industrial production, and the surface of the obtained silica gel catheter can realize long-lasting, excellent and broad-spectrum antibacterial effect.

Description

Technical Field

[0001] This invention belongs to the field of medical device manufacturing technology, specifically relating to a method for forming antibacterial silicone catheters by one-step impregnation with aluminum corrosion inhibitor and copper ammonia solution. Background Technology

[0002] In hospitals, various acute and chronic critically ill patients require invasive catheters for monitoring and treatment due to their conditions. Examples include urinary catheters for microcirculation assessment, central venous catheters for volume assessment and cardiac function monitoring, dialysis catheters for hemodialysis, and thoracic and abdominal catheters for drainage of infected foci. Inevitably, nosocomial cross-infection and drug-resistant bacterial infections can occur during catheter placement, leading to the risk of catheter-related infections and inflammatory reactions in surrounding tissues. Measures to address these side effects include the use of antibacterial catheters and systemic antibiotics. However, there is no effective solution for the surrounding tissue damage and inflammation that occur during catheter placement. Research indicates that copper nanomaterials possess excellent antibacterial capabilities, while also exhibiting anti-inflammatory, angiogenesis-promoting, and tissue repair-promoting functions. Copper nanomaterials have been extensively studied for their antibacterial properties. Swedish scientist Christofer Leygraf revealed, through high-resolution microscopy, the mechanism of early contact antibacterial action on the surface of copper nanomaterials as three main bactericidal mechanisms: cell membrane damage, formation of copper-containing particles within bacteria, and intracellular copper redox reactions (T. Chang, R.P. Babu, W. Zhao, C.M. Johnson, P. I. Odnevall, C. Leygraf, High-Resolution Microscopical Studies of Contact Killing Mechanisms on Copper-Based Surfaces, ACS applied materials&interfaces 13(41)(2021)49402-49413.).

[0003] A team led by Professor Reza Shahbazian-Yassar at the University of Illinois contacted E. coli with copper-containing nanomaterials and used electron microscopy to show that the bacteria lost their integrity and leaked cytoplasm, demonstrating the bactericidal effect of copper (AHPhakatkar, V.Yurkiv, P.Ghildiyal, Y.Wang, A.Amiri, L.V.Sorokina, MR.Zachariah, T.Shokuhfar, R.Shahbazian-Yassar, In Situ Microscopic Studies on the Interaction of Multi-Principal Element Nanoparticles and Bacteria, ACSnano 17(6)(2023)5880-5893.). Copper nanomaterials not only have broad-spectrum and excellent antibacterial effects, but also possess anti-inflammatory capabilities. Research by Professor Suk Ho Bhang's team in South Korea has shown that copper-deposited cerium dioxide nanoparticles (CuCe NPs) exhibit stronger antioxidant activity than pristine cerium dioxide nanoparticles. The released copper buffers glutathione consumption and provides bioavailable copper as a cofactor for the antioxidant enzyme superoxide dismutase 1 (SOD1), synergistically scavenging reactive oxygen species with cerium dioxide nanoparticles. Furthermore, it promotes anti-inflammatory activity and M2 polarization in macrophages by regulating signal transducer and activator of transcription 1 (STAT1) and STAT6. (G.-B.Im, YGKim, TYYoo, YHKim, K.Kim, J.Hyun, M.Soh, T.Hyeon, SHBhang, Ceria Nanoparticles as Copper Chaperones that Activate SOD1 for Synergistic Antioxidant Therapy to Treat Ischemic Vascular Disease) Diseases, 35(16)(2023)2208989.). Professor JunDeng's team at the Third Military Medical University developed ultra-small Cu... 5.4 O nanoparticles (Cu) 5.4 OUSNPs), these nanoparticles possess multiple enzymatic properties, including catalase, superoxide dismutase, and glutathione peroxidase, and Cu 2+It participates in the synthesis of various reducible metal complex enzymes such as ceruloplasmin, lysyl oxidase, and superoxide dismutase to scavenge intracellular reactive oxygen species (ROS), and can be used to improve acute kidney injury, acute liver injury, and wound healing (T. Liu, B. Xiao, F. Xiang, J. Tan, Z. Chen, X. Zhang, C. Wu, Z. Mao, G. Luo, X. Chen, J. Deng, Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases, Nature Communications 11(1)(2020)2788.). At the same time, its ultra-small size allows the nanomaterial to be rapidly cleared by the kidneys, ensuring biocompatibility. In terms of implant applications, Professor Xuanyong Liu of the Chinese Academy of Sciences developed titanium plate modified orthopedic implants. Studies have shown that copper bound to the surface of titanium plates has anti-inflammatory effects, promotes angiogenesis, and aids in tissue repair, further demonstrating that copper, as an implant, possesses in vivo tissue repair capabilities (L.Chen,D.Wang,J.Qiu,X.Zhang,X.Liu,Y.Qiao,X.Liu,Synergistic effects of immunoregulation and osteoinduction of ds-block elements on titanium surface,Bioactive Materials 6(1)(2021)191-207.). These results indicate that copper nanomaterials can produce good anti-inflammatory effects through multiple pathways.

[0004] Currently, methods for synthesizing antibacterial catheters include: coating method, which results in antibacterial materials on the surface of the catheter that are prone to detachment, lack of durability, and easy diffusion to surrounding tissues, and also has significant toxicity; grafting method, which requires complex synthesis steps and high synthesis conditions, making it difficult to mass-produce; and impregnation method, which results in silicone catheters that are simple to operate, but currently involves many impregnation steps. Summary of the Invention

[0005] To avoid the problems existing in the prior art, the present invention provides a method for forming antibacterial silicone conduits by impregnating aluminum corrosion inhibitor and copper ammonia solution in one step, so as to simplify the process flow of antibacterial silicone conduits, make the production of antibacterial silicone conduits simple, effective and low cost, and enable the obtained antibacterial silicone conduits to achieve broad-spectrum antibacterial effects.

[0006] To solve the technical problem, the present invention adopts the following technical solution:

[0007] The present invention provides a method for forming an antibacterial silicone conduit by impregnating an aluminum corrosion inhibitor and a copper ammonia solution in one step: the aluminum corrosion inhibitor siloxane solution, the copper ammonia solution and APTES are mixed evenly to obtain an impregnation solution; the silicone conduit is impregnated in the impregnation solution at room temperature, and after thorough stirring, it is taken out and dried to obtain the antibacterial silicone conduit.

[0008] Preferably, the concentration of siloxane in the siloxane solution is 0.5-2 mmol / 50 mL, and the solvent used in the siloxane solution is deionized water, ethanol or ethylene glycol.

[0009] Preferably, in the impregnation solution, the copper ions in the copper ammonia solution account for 0.01-0.2% of the molar amount of the siloxane ketone.

[0010] Preferably, the volume ratio of copper ammonia solution to APTES in the impregnation solution is 1:1-10.

[0011] Preferably, the drying temperature is 100℃-120℃ and the drying time is 1h-4h.

[0012] Compared with existing technologies, the beneficial effects of this invention are reflected in:

[0013] 1. The method for preparing antibacterial silicone catheters provided by the present invention can be achieved through one-step impregnation. The process is simple, the reaction conditions are mild, the operation is convenient, and the production cost is low, making it suitable for industrial production.

[0014] 2. The silicone catheter surface obtained by the present invention can achieve long-lasting, excellent and broad-spectrum antibacterial effect, and its antibacterial efficacy against Gram-positive bacteria and Gram-negative bacteria is above 99.9%. Attached Figure Description

[0015] Figure 1 Scanning electron microscope images of the surface of the silicone catheters prepared in Examples 1-4;

[0016] Figure 2 This is a schematic diagram showing the external shape of the antibacterial silicone catheter prepared in Example 7 and a regular silicone catheter;

[0017] Figure 3 This is a particle element mapping diagram of the antibacterial silicone catheter surface prepared in Example 7;

[0018] Figure 4 X-ray diffraction pattern of the surface particles of the antibacterial silicone catheter prepared in Example 7;

[0019] Figure 5These are plate images showing the in vitro anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of the catheters prepared in Examples 1-3;

[0020] Figure 6 These are plate images showing the antibacterial silicone catheters prepared in Examples 4-8 against methicillin-resistant Staphylococcus aureus.

[0021] Figure 7 These are swab images showing the antibacterial silicone tubing prepared in Examples 4-8 against Escherichia coli. Detailed Implementation

[0022] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0023] The copper ammonia solution used in the following examples was prepared as follows: 10 mL of 0.2 mol / L copper nitrate solution was added to a beaker, followed by the dropwise addition of 8 mol / L ammonia solution. A light blue precipitate of basic copper sulfate was formed. Ammonia solution was then added until the precipitate was completely dissolved, yielding a dark blue copper ammonia solution. For application, the copper ammonia solution was diluted with deionized water according to the desired copper ion concentration.

[0024] The APTES used in the following examples is KH550.

[0025] Example 1

[0026] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0027] Mix 1 mL of 0.01 mmol / L copper ammonia solution with 1 mL of KH550 solution to obtain an impregnation solution; immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After the impregnation, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100℃ for 1 h to obtain an antibacterial silicone tubing (named Group A).

[0028] Example 2

[0029] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0030] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.01 mmol / L copper ammonia solution to obtain an impregnation solution; immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After the impregnation, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named Group B).

[0031] Example 3

[0032] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0033] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of KH550 solution to obtain an impregnation solution; immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After the impregnation, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named Group C).

[0034] Example 4

[0035] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0036] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.01 mmol / L copper ammonia solution, and then add 1 mL of KH550 solution to obtain an impregnation solution. Immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After that, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named 0.01% group).

[0037] Example 5

[0038] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0039] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.05 mmol / L copper ammonia solution, and then add 1 mL of KH550 solution to obtain an impregnation solution. Immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After that, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named 0.05% group).

[0040] Example 6

[0041] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0042] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.10 mmol / L copper ammonia solution, and then add 1 mL of KH550 solution to obtain an impregnation solution. Soak the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After that, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named 0.10% group).

[0043] Example 7

[0044] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0045] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.15 mmol / L copper ammonia solution, and then add 1 mL of KH550 solution to obtain an impregnation solution. Immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After that, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named 0.15% group).

[0046] Example 8

[0047] In this embodiment, the antibacterial silicone catheter is prepared according to the following steps:

[0048] Dissolve 1 mmol of aluminum corrosion inhibitor siloxane in 50 mL of deionized water, add 1 mL of 0.20 mmol / L copper ammonia solution, and then add 1 mL of KH550 solution to obtain an impregnation solution. Immerse the silicone tubing in the impregnation solution at room temperature and stir for 30 min. After that, remove the tubing and clean off any excess residue on the surface. Place it in an oven and dry at 100 °C for 1 h to obtain an antibacterial silicone tubing (named 0.20% group).

[0049] The catheters obtained in the above embodiments were subjected to the following performance tests:

[0050] 1. Appearance

[0051] Figure 1 The images shown are scanning electron microscope (SEM) images of the silicone catheters prepared in Examples 1-4. A comparison reveals that: In Group A, the impregnation solution contained KH550 and copper ammonia solution (without aluminum corrosion inhibitor siloxane), resulting in no product formation on the surface of the silicone catheters; in Group B, the impregnation solution contained aluminum corrosion inhibitor siloxane and copper ammonia solution (without KH550), resulting in no product formation on the surface of the silicone catheters; in Group C, the impregnation solution contained aluminum corrosion inhibitor siloxane and KH550 solution (without copper ammonia solution), resulting in no product formation on the surface of the silicone catheters; and in the 0.01% group, the impregnation solution contained aluminum corrosion inhibitor siloxane, KH550, and copper ammonia solution, resulting in particulate products forming on the surface of the silicone catheters.

[0052] Figure 2 The diagram shows the external appearance of the antibacterial silicone catheter prepared in Example 7 and the ordinary silicone catheter. The antibacterial silicone catheter has a light blue appearance.

[0053] Figure 3 The image shows the elemental mapping of the antibacterial silicone catheter surface particles prepared in Example 7. The particulate products on the surface of the antibacterial silicone catheter contain Cu, N, and C elements, indicating that the copper-containing product was successfully impregnated on the catheter surface.

[0054] Figure 4The image shows an X-ray diffraction pattern of the particles on the surface of the antibacterial silicone catheter prepared in Example 7. It can be seen from the image that the impregnation product on the surface of the catheter is Cu2(NO3)(OH)3.

[0055] 2. Test for resistance to methicillin-resistant Staphylococcus aureus:

[0056] Take 100 μL of a concentration of 1×10 6 CFU mL -1 Methicillin-resistant Staphylococcus aureus (MRSA) bacterial suspensions were injected via syringe into ordinary silicone tubing (as a control group) or antibacterial silicone tubing (including groups A, B, C, 0.01%, 0.05%, 0.10%, 0.15%, and 0.2%) and incubated for 4 hours. Subsequently, 50 μL of the bacterial suspension was plated and placed in a bacterial incubator for 16 hours. Growth was observed and counted. The above experiment was repeated 3 times.

[0057] Figure 5 The images show the stencil images of the catheters prepared in Examples 1-3 against methicillin-resistant Staphylococcus aureus. It can be seen from the images that the final product catheters of the synthesis systems without aluminum corrosion inhibitors, APTES, or copper ammonia solution do not have antibacterial function.

[0058] Figure 6 The images show the coating images of the catheters prepared in Examples 4-8 against methicillin-resistant Staphylococcus aureus. As can be seen from the images, the antibacterial performance of the silicone catheters improves with the increase of copper ion concentration in the impregnation solution. When the copper ion accounts for 0.15% or more of the molar amount of siloxane, the antibacterial efficacy reaches the optimum (inhibition rate ≥ 99.9%) and remains unchanged.

[0059] 3. Anti-E. coli performance test:

[0060] Take 100 μL of bacterial culture with a concentration of 1×10 6 CFU mL -1 Escherichia coli bacterial suspension was injected into silicone tubing (groups A, B, and C), ordinary silicone tubing (control group), and antibacterial silicone tubing (including 0.01%, 0.05%, 0.10%, 0.15%, and 0.2%) via syringe and incubated for 4 hours. Then, 50 μL of bacterial suspension was taken out, plated, and placed in a bacterial incubator for 16 hours. The growth was observed and counted. The above experiment was repeated 3 times.

[0061] Figure 7 The images show the antibacterial properties of the silicone catheters prepared in Examples 4-8 against Escherichia coli. As can be seen from the images, the antibacterial performance of the silicone catheters improves with the increase of copper ion concentration in the impregnation solution. When the copper ion accounts for 0.15% or more of the molar amount of siloxane, the antibacterial efficacy reaches the optimum (inhibition rate ≥ 99.9%) and remains unchanged.

[0062] 4. Copper ion sustained-release performance test

[0063] Take 1 cm of the antibacterial silicone tubing prepared in Example 7 and place it in 5 mL of deionized water. After 7, 14, 30, 60 and 120 days, take out 1 mL of deionized water and measure the copper ion concentration.

[0064] Table 1

[0065] 7 days 2.0±0.021 14 days 4.5±0.063 30 days 7.1±0.033 60 days 8.9±0.052 120 days 9.7±0.022

[0066] Table 1 shows the test results of the copper ion release capacity of the antibacterial catheter prepared in Example 7 within 120 days. It can be seen that the catheter releases a small amount of copper ions slowly and has long-term antibacterial ability.

[0067] 5. Long-lasting antibacterial performance test

[0068] The antibacterial silicone catheters prepared in Examples 4-8 were placed in phosphate buffered solution (PBS solution, pH 7.2-7.4) for 120 days, and their antibacterial durability against Escherichia coli and methicillin-resistant Staphylococcus aureus was tested.

[0069] Take 100 μL of bacterial culture with a concentration of 1×10 6 CFU mL -1 Bacterial suspensions of *Escherichia coli* or methicillin-resistant *Staphylococcus aureus* were injected via syringe into ordinary silicone tubing (as a control group) or antibacterial silicone tubing (including 0.01%, 0.05%, 0.10%, 0.15%, and 0.2%) that had been placed in PBS solution for 120 days and incubated for 4 hours. 50 μL of the bacterial suspension was then plated and incubated in a bacterial incubator for 16 hours. Growth was observed and counted. The experiment was repeated three times, and the average value was taken.

[0070] Table 2 shows the inhibition rates of the antibacterial catheters prepared in Examples 4-8 against Escherichia coli and methicillin-resistant Staphylococcus aureus after 120 days (ordinary silicone catheters placed in PBS solution for 120 days were set as the control group). It can be seen that the prepared antibacterial catheters have long-lasting and excellent antibacterial ability.

[0071] Table 2

[0072]

[0073]

[0074] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for forming an antibacterial silicone conduit by one-step impregnation with an aluminum corrosion inhibitor and a copper ammonia solution, characterized in that: Aluminum corrosion inhibitor siloxane solution, copper ammonia solution and APTES are mixed evenly to obtain an impregnation solution; a silicone tubing is immersed in the impregnation solution at room temperature, stirred thoroughly, removed and dried to obtain an antibacterial silicone tubing; The concentration of siloxane in the aluminum corrosion inhibitor siloxane solution is 0.5-2 mmol / 50 mL; in the impregnation solution, the copper ions account for 0.01-0.2% of the molar amount of siloxane in the copper ammonia solution, and the volume ratio of copper ammonia solution to APTES is 1:1-10.

2. The method for forming an antibacterial silicone conduit by one-step impregnation with an aluminum corrosion inhibitor and a copper ammonia solution according to claim 1, characterized in that: The solvent used in the aluminum corrosion inhibitor siloxane solution is deionized water, ethanol, or ethylene glycol.

3. The method for forming an antibacterial silicone conduit by one-step impregnation with an aluminum corrosion inhibitor and a copper ammonia solution according to claim 1, characterized in that: The drying temperature is 100℃-120℃, and the drying time is 1 h-4 h.

4. An antibacterial silicone catheter prepared by the method described in any one of claims 1 to 3.

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