An amphiphilic silicone coating, and methods of making and using the same

Abstract

The application discloses an amphiphilic organic silicon coating and a preparation method and application thereof. A hydrophobic alkyl or phenyl containing organic silicon source precursor is hydrolyzed to generate silicon hydroxyl, the silicon hydroxyl is partially polymerized, and a chemical bond is formed between the silicon hydroxyl and a base material, so that the amphiphilic organic silicon coating containing hydrophilic hydroxyl and hydrophobic organic groups is prepared. The organic silicon coating prepared by the application has a smooth surface and a unique hydrophilic-hydrophobic amphiphilic structure, has excellent compatibility in blood contact, and can be used for preparing medical materials such as artificial blood vessels and blood catheters.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to an amphiphilic organosilicon coating, its preparation method, and its application. Background Technology

[0002] Blood compatibility refers to the ability of biomaterials to inhibit thrombus formation and maintain normal blood function after contact with host blood. This includes reducing erythrocyte hemolysis, decreasing platelet and erythrocyte adhesion, and prolonging clotting time. Medical polymer materials that come into contact with blood are an important component of biomedical polymer materials and are widely used in implantable and interventional devices such as artificial blood vessels and artificial lungs.

[0003] Polydimethylsiloxane (PDMS) is a commonly used biomedical polymeric silicone material that comes into contact with blood. It is formed by the polymerization of silane ((CH3)2-Si-X2) with two active groups, creating a linear structure with Si-O bonds and -CH3 groups. PDMS exhibits advantages such as hydrophobicity, oxidation resistance, minimal reaction to human tissues, no inflammation in surrounding tissues, and good physical and mechanical properties, leading to its widespread application in biomedical fields such as artificial organs, medical devices, and drug delivery. However, the extremely strong hydrophobicity of PDMS surface causes it to irreversibly adsorb large amounts of plasma proteins upon contact with blood, potentially triggering adverse reactions such as coagulation.

[0004] Improving the hydrophilicity of PDMS materials to enhance their blood compatibility has always been a hot topic and a challenge in the field of biomedical materials. CN201710615366.3 describes the modification of PDMS with hydrophilic materials hyaluronic acid and dopamine to promote blood compatibility. However, this type of chemical grafting is difficult to control in terms of grafting amount and can cause chemical residues.

[0005] Therefore, developing a material with excellent blood compatibility is of great scientific significance and practical application value for solving existing problems. Summary of the Invention

[0006] Objective of the Invention: The objective of this invention is to address the shortcomings of existing technologies by providing an amphiphilic organosilicon coating, its preparation method, and its applications. The amphiphilic organosilicon coating of this invention has an amphiphilic structure containing both hydrophilic and hydrophobic components, and simultaneously possesses a three-dimensional network structure. This coating uses an organosiloxane containing three-branched active groups as a precursor, which is hydrolyzed and polymerized to form a polyhydroxyl-containing sol. This sol is then dip-coated onto a substrate material, and calcination is used to allow some hydroxyl groups to self-polymerize and polymerize with the substrate material, forming a stable organosilicon coating.

[0007] To overcome the blood compatibility issues caused by the hydrophobicity and chemical grafting of PDMS, this invention develops a novel PDMS-like organosilicon biomaterial. It is formed by hydrolysis and polymerization of a membrane with three active groups and an organic group, resulting in an amphiphilic structure with both hydrophilic and hydrophobic properties. The cross-linked organosilicon network is an amphiphilic microstructure similar to a phospholipid bilayer, exhibiting excellent blood compatibility.

[0008] Technical solution: The objective of this invention is achieved through the following technical solution:

[0009] This invention provides an amphiphilic organosilicon coating, which is prepared by hydrolyzing an organosilicon precursor containing hydrophobic alkyl or phenyl groups to generate silanol groups. The silanol groups are partially polymerized and partially form chemical bonds with the substrate material, thereby obtaining the amphiphilic organosilicon coating containing both hydrophilic hydroxyl groups and hydrophobic organic groups.

[0010] The structural formula of the organosilicon source precursor is as follows:

[0011]

[0012] in,

[0013] X is selected from -OCH3, -OCH2CH3, -OPr, and Cl;

[0014] R is selected from -CH2-, -CH2-CH2-, -(CH2)8-, -Ph-;

[0015] The substrate material is an organic polymer matrix or an inorganic matrix that reacts with -OH.

[0016] Preferably, the organosilicon source precursor is one of 1,2-bis(triethoxysilyl)ethane (BTESE), bis(triethoxysilyl)methane (BTESM), 1,8-bis(triethoxysilyl)octane (BTESO), or 1,2-bis(triethoxysilyl)benzene (BTESB).

[0017] Preferably, the organic polymer matrix is ​​an organic polymer matrix such as cellulose, polyvinyl alcohol, or polyether; and the inorganic matrix is ​​an inorganic matrix such as quartz glass, activated ceramic, or hydroxyapatite.

[0018] The present invention also provides a method for preparing the amphiphilic organosilicon coating, comprising the following steps:

[0019] (1) Chemically treat the substrate material to activate the surface;

[0020] (2) The organosilicon source precursor was added to a solvent, water and a catalyst, and the organosilicon sol was prepared by hydrolysis polymerization.

[0021] (3) The surface of the substrate material activated in step (1) is fixed with the organosilicon sol obtained in step (2) by dip-coating method to obtain the amphiphilic organosilicon coating.

[0022] The reaction structure is as follows:

[0023]

[0024] Preferably, in step (1), the chemical treatment method is: immersing the substrate material in a freshly prepared piranha solution for activation; the piranha solution is prepared by mixing 98% concentrated sulfuric acid and 30% hydrogen peroxide in a volume ratio of 7:3.

[0025] Further, the substrate material is immersed in a piranha solution for 1-60 minutes, then removed, cleaned with pure water and sonicated, then cleaned with anhydrous ethanol and sonicated, and finally dried.

[0026] Preferably, in step (2), the solvent is anhydrous ethanol or isopropanol; the catalyst is any one of hydrochloric acid, nitric acid or sulfuric acid; the molar ratio of the organosilicon source precursor, water and catalyst is 1:120-400:0.1-0.5; and the mass fraction of the organosilicon source precursor in the solution is maintained at 0.5-5.0 wt%.

[0027] Preferably, in step (3), the organosilicon sol obtained in step (2) is coated onto the activated substrate material by dip-coating for 1-120 min, and then calcined in air at 100-500°C for 30-60 min. This coating and calcination process is repeated 1-10 times to form the amphiphilic organosilicon coating.

[0028] A preferred preparation method of the present invention includes the following steps:

[0029] (1) Immerse the quartz glass plate used as the substrate in a freshly prepared piranha solution for 1-30 minutes. Take it out, clean it with pure water and sonicate it, then clean it with anhydrous ethanol and sonicate it again, and then put it in an oven to dry.

[0030] (2) Preparation of organosilicon sol: Add the organosilicon source precursor to anhydrous ethanol, and add water and hydrochloric acid to start the reaction under continuous water bath stirring to obtain organosilicon sol; organosilicon source precursor: H2O:HCl=1:240-360:0.1-0.5 (molar ratio), the mass fraction of organosilicon source precursor in the solution is maintained at 0.5-3.0wt%, and the solution is stirred at a constant temperature of 1-100℃ for 10-500min.

[0031] (3) Prepare an organosilicon coating by coating the activated substrate surface with organosilicon sol by dip-coating and calcining at 100-300℃ for 30-60 minutes. Repeat the coating and calcination process 1-5 times to obtain a uniform organosilicon coating.

[0032] The present invention also provides the application of the aforementioned amphiphilic organosilicon coating in the preparation of blood-related biomedical materials.

[0033] The biomedical materials are artificial blood vessels, blood catheters, stents, blood filters, or intravenous catheters.

[0034] The amphiphilic organosilicon coating is used for surface coating of biomedical materials.

[0035] Beneficial effects:

[0036] The organosilicon coating prepared by this invention has, on the one hand, a smooth surface structure, giving it a certain degree of anti-fouling ability. On the other hand, the organosilicon material selected in this invention contains hydrophilic-hydrophobic groups, which have a strong interfacial affinity with blood, greatly reducing the adsorption and interaction of various components in the blood on the material surface, and improving the blood compatibility of the coated material. Attached Figure Description

[0037] Figure 1 The water contact angle diagrams for the amphiphilic silicone coatings in Examples 1-4 are shown.

[0038] Figure 2 Water contact angle diagrams for quartz substrates and PDMS coatings in Comparative Examples 1 and 2;

[0039] Figure 3 Atomic force microscopy (AFM) images of the amphiphilic organosilicon coatings in Examples 1, 2, and 4;

[0040] Figure 4 Atomic force microscopy (AFM) images of the quartz substrates and PDMS coatings in Comparative Examples 1 and 2. Detailed Implementation

[0041] The technical solution of the present invention will be described in detail below through specific embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0042] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0043] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples are commercially available products.

[0044] In the examples, the piranha solution was freshly prepared by mixing 98% concentrated sulfuric acid and 30% hydrogen peroxide in a volume ratio of 7:3.

[0045] The blood compatibility test method is shown below.

[0046] I. Hemolysis rate test

[0047] 1. Place the 1cm round piece of silicone coating in a test tube and add 10mL of physiological saline. Incubate in a 37℃ water bath for 30min.

[0048] 2. Take 4 mL of whole blood (purchased from Wuhan Chundu Biotechnology Co., Ltd., rabbit blood) and dilute it in 5 mL of physiological saline. Take 0.2 mL of the diluted blood and add it to the incubated test tubes, then incubate in a 37℃ water bath for 1 hour.

[0049] 3. Remove the test tube and centrifuge at 1000 r / min. After centrifugation, take the supernatant and measure the absorbance at 540 nm using a spectrophotometer. Set up three parallel samples for each group.

[0050] 4. The negative control group consisted of 10 mL of physiological saline and 0.2 mL of diluted blood, while the positive control group consisted of 10 mL of pure water and 0.2 mL of diluted blood. The mixtures were incubated at 37°C for 1 hour.

[0051] Hemolysis rate (%) = (sample absorbance value - negative control absorbance value) / (positive control absorbance value - negative control absorbance value) × 100%.

[0052] II. Protein Adhesion Experiment

[0053] 1. Dissolve 50 mg bovine serum albumin (BSA) in 50 ml phosphate buffered saline (PBS) to prepare a 1 g / L BSA solution. After preparation, sonicate to disperse evenly.

[0054] 2. Immerse the 1cm disc of silicone coating into PBS buffer and shake at 80 rpm for 20 minutes at room temperature to equilibrate the coating;

[0055] 3. Remove the coated discs and place them into 24-well plates. Add 1 ml of BSA solution to each plate and shake at 80 rpm for 2 hours at room temperature. Then remove the plates and wash them in PBS solution.

[0056] 4. Place the cleaned coated discs into a 24-well plate, add 1 ml of 2wt% sodium dodecyl sulfate (SDS) solution to each well, and sonicate for 10 min.

[0057] 5. Take 100 μl of solution from each well, add 100 μl of BCA working solution (prepared fresh), shake in a 37℃ water bath for 30 min, and measure the absorbance at 562 nm using an ELISA reader.

[0058] 6. Set up a control group of 100 μl of 2 wt% SDS solution, add 100 μl of BCA working solution, and measure its absorbance at 562 nm.

[0059] Substitute the absorbance of each group into the BSA concentration standard curve to measure the remaining BSA concentration in each group of solutions.

[0060] BSA adsorption capacity = (concentration of experimental group - concentration of control group) / effective membrane area.

[0061] Example 1

[0062] (1) Activation of substrate: Immerse the quartz glass slide in freshly prepared piranha solution for 15 minutes, take it out and wash it twice with pure water and sonicate for 10 minutes, then wash it twice with anhydrous ethanol and sonicate for 10 minutes, and then put it in an oven to dry.

[0063] (2) Preparation of organosilicon sol: Dissolve 1.0 g of BTESE in 25.714 g of anhydrous ethanol, add 13 g of water and 0.286 g of HCl with a mass fraction of 3.7 wt% (BTESE:H2O:HCl = 1:256:0.1, molar ratio) to form a 2.5 wt% BTESE solution, and stir in a 40℃ water bath for 2 h to prepare BTESE sol.

[0064] (3) Preparation of silicone coating: The coating is prepared by dip-coating method. The activated substrate is immersed in silicone sol for 30 min, then pulled out and placed in an oven at 100℃ for calcination for 30 min. The coating and calcination process is repeated 3 times to obtain silicone coating.

[0065] Conduct contact angle tests on it, such as Figure 1 As shown, its contact angle is 51.4°, falling between 0 and 90°, which indirectly demonstrates its amphiphilic nature. Its AFM test results are as follows... Figure 3 As shown, its surface roughness is 3.4 nm, which is less than... Figure 4 The very low roughness, approaching the nanometer level, of the substrates and PDMS coatings in Comparative Examples 1 and 2 demonstrates their surface smoothness, which is beneficial for reducing protein adsorption.

[0066] The prepared organosilicon coating was subjected to a blood compatibility test. The test results showed that the hemolysis rate of the BTESE coating was 0.4%, and the BSA adsorption was 7.74 μg / cm³. 2 .

[0067] Example 2

[0068] The preparation and testing steps were the same as in Example 1, except that the organosilicon precursor used was BTESM and the molar ratio used was BTESM:H2O:HCl = 1:256:0.3, resulting in a BTESM coating.

[0069] Conduct contact angle tests on it, such as Figure 1 As shown, its contact angle is 48.6°, falling between 0 and 90°, indirectly indicating its amphiphilic nature; its AFM test results are as follows... Figure 3 As shown, its surface roughness is 6.2 nm, which is less than... Figure 4 Comparing the substrates and PDMS coatings in Examples 1 and 2, the extremely low roughness at the near-nanoscale indicates the smoothness of the BTESM surface, which is beneficial for reducing protein adsorption. In blood compatibility testing, the hemolysis rate of the BTESM coating was 0.2%, and the BSA adsorption capacity was 6.44 μg / cm³. 2 .

[0070] Example 3

[0071] The preparation and testing steps were the same as in Example 1, except that BTESO was used as the organosilicon precursor. The molar ratio used was BTESO:H2O:HCl = 1:230:0.2, resulting in a BTESO coating.

[0072] Conduct contact angle tests on it, such as Figure 1 As shown, its contact angle is 74.4°, falling within the range of 0-90°, indirectly demonstrating its amphiphilic nature. In blood compatibility testing, the hemolysis rate of the BTESO coating was 0.9%, and the BSA adsorption capacity was 7.23 μg / cm³. 2 .

[0073] Example 4

[0074] The preparation and testing steps were the same as in Example 1, except that BTESB was used as the organosilicon precursor. The molar ratio used was BTESB:H2O:HCl = 1:180:0.2, resulting in a BTESB coating.

[0075] Conduct contact angle tests on it, such as Figure 1 As shown, its contact angle is 58.4°, ranging from 0 to 90°, indirectly indicating its amphiphilic nature. Its surface roughness is 70.5 nm, indicating that different structures affect the smoothness of the coating. The hemolysis rate of the BTESB coating was measured to be 0.6%, and the BSA adsorption capacity was 9.27 μg / cm³. 2 .

[0076] Example 5

[0077] (1) Activation of substrate: Immerse the active ceramic sheet in freshly prepared piranha solution for 15 minutes, take it out and wash it twice with pure water and sonicate for 10 minutes, then wash it twice with anhydrous ethanol and sonicate for 10 minutes, and then put it in an oven to dry.

[0078] (2) Preparation of organosilicon sol: Dissolve 1.0 g of BTESE in 178.16 g of anhydrous ethanol, add 18.96 g of water and 1.43 g of HCl with a mass fraction of 3.7 wt% (BTESE:H2O:HCl = 1:350:0.5) to form a 0.5 wt% BTESE solution, and stir in a 40℃ water bath for 2 h to prepare BTESE sol.

[0079] (3) Preparation of silicone coating: The coating is prepared by dip-coating method. The activated ceramic sheet is immersed in silicone sol for 30 min, then the ceramic sheet is pulled out and placed in a muffle furnace at 300℃ for 30 min. The coating and calcination process is repeated 5 times to obtain a uniform silicone coating.

[0080] The prepared organosilicon coating was subjected to blood compatibility testing, and the hemolysis rate of the BTESE coating was 0.8%, while the BSA adsorption capacity was 8.23 ​​μg / cm³. 2 .

[0081] Example 6

[0082] (1) Activation of substrate: Cut polyvinyl alcohol into 1cm pieces, then immerse them in freshly prepared piranha solution for 1 minute, take them out and wash them twice with pure water and sonicate for 10 minutes, then wash them twice with anhydrous ethanol and sonicate for 10 minutes, and then put them in an oven to dry.

[0083] (2) Preparation of organosilicon sol: Dissolve 1.0g of BTESM in 80.33g of anhydrous ethanol, add 17.18g of water and 1.49g of HCl with a mass fraction of 3.7wt% (BTESM:H2O:HCl=1:350:0.5) to form a 1wt% BTESM solution, and stir in a 40℃ water bath for 2h to prepare BTESM sol.

[0084] (3) Preparation of silicone coating: The coating is prepared by dip-coating method. Polyvinyl alcohol sheet is immersed in silicone sol for 30 minutes, then pulled out and placed in 100℃ oven for 30 minutes. The coating and drying process is repeated 5 times to obtain a uniform silicone coating.

[0085] The prepared organosilicon coating was subjected to blood compatibility testing, and the hemolysis rate of the BTESM coating was 0.9%, while the BSA adsorption capacity was 7.52 μg / cm³. 2 .

[0086] Comparative Example 1

[0087] Quartz glass slides were used as a reference for contact angle, AFM, hemolysis, and protein adsorption tests.

[0088] Contact angle test, such as Figure 2 As shown, its contact angle is 18.9°, indicating slightly hydrophilic properties; AFM test results are as follows. Figure 4 As shown, its surface roughness is 65 nm. A hemolysis rate test was performed on the substrate quartz glass slide, and the hemolysis rate was determined to be 1.7%, with a BSA adsorption capacity of 10.29 μg / cm³. 2 Its hemolysis rate and BSA adsorption amount are both greater than those of the organosilicon coating, which indicates that both roughness and hydrophilicity / hydrophobicity affect blood compatibility, and organosilicon coatings, which have both low roughness and amphiphilic properties, have a significant advantage in blood compatibility.

[0089] Comparative Example 2

[0090] A polydimethoxysilane (PDMS) coating was used as a control for contact angle, AFM, hemolysis, and protein adsorption tests.

[0091] Preparation of PDMS coating: PDMS (Dow Corning) from DC184 was dissolved in ethanol to form a 2.5 wt% PDMS solution. A quartz glass slide was immersed in a freshly prepared piranha solution for 15 min, then rinsed twice with pure water and sonicated for 10 min each time. Next, it was rinsed twice with anhydrous ethanol and sonicated for 10 min each time, then dried in an oven. The PDMS solution was then coated onto the activated substrate surface using an dip-coating method and calcined at 100 °C for 30 min. This coating and calcination process was repeated three times to obtain the PDMS coating.

[0092] Contact angle test, such as Figure 2 As shown, its contact angle is 109.4°, indicating slightly hydrophobic properties; AFM test results are as follows. Figure 4 As shown, its surface roughness is 8.3 nm, which is relatively small. Blood compatibility testing was performed on the prepared PDMS coating, and the hemolysis rate was 1%, with a BSA adsorption capacity of 12.15 μg / cm³. 2 This indicates that its hydrophobicity increases protein adsorption, and protein adsorption can trigger a coagulation reaction, leading to thrombosis.

[0093] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. Use of an amphiphilic silicone coating for the preparation of a biomedical material in relation to blood, characterized in that, The biomedical material is an artificial blood vessel, blood catheter, stent, blood filter, or intravenous catheter; The amphiphilic organosilicon coating is prepared by hydrolyzing an organosilicon precursor containing hydrophobic alkyl or phenyl groups to generate silanol groups, and then partially polymerizing the silanol groups on a substrate material to obtain an amphiphilic organosilicon coating containing both hydrophilic hydroxyl groups and hydrophobic organic groups. The substrate material is an organic polymer matrix or an inorganic matrix that reacts with -OH; the organic polymer matrix is ​​polyvinyl alcohol; the inorganic matrix is ​​a quartz glass sheet or an activated ceramic. The organosilicon source precursor is one of 1,2-bis(triethoxysilyl)ethane (BTESE), bis(triethoxysilyl)methane (BTESM), 1,8-bis(triethoxysilyl)octane (BTESO), or 1,2-bis(triethoxysilyl)benzene (BTESB).

2. Use according to claim 1, characterized in that, The amphiphilic organosilicon coating is used for surface coating of biomedical materials.

3. The application according to any one of claims 1-2, characterized in that, The preparation method of the amphiphilic organosilicon coating includes the following steps: (1) Chemically treat the substrate material to activate the surface; (2) Organosilicon sol was prepared by adding solvent, water and catalyst to organosilicon source precursor and using hydrolysis polymerization method; (3) The surface of the substrate material activated in step (1) is fixed with the organosilicon sol obtained in step (2) by dip-coating method to obtain the amphiphilic organosilicon coating.

4. The application according to claim 3, characterized in that, In step (1), the chemical treatment method is as follows: the substrate material is immersed in a freshly prepared piranha solution for activation; the piranha solution is prepared by mixing 98% concentrated sulfuric acid and 30% hydrogen peroxide in a volume ratio of 7:

3.

5. The application according to claim 4, characterized in that, The substrate material is immersed in a piranha solution for 1-60 minutes, then removed and first cleaned with pure water and sonicated, then cleaned with anhydrous ethanol and sonicated, and finally dried.

6. The application according to claim 3, characterized in that, In step (2), the solvent is anhydrous ethanol or isopropanol; the catalyst is any one of hydrochloric acid, nitric acid or sulfuric acid; the molar ratio of the organosilicon source precursor, water and catalyst is 1:120-400:0.1-0.5; and the mass fraction of the organosilicon source precursor in the solution is maintained at 0.5-5.0 wt%.

7. The application according to claim 3, characterized in that, In step (3), the organosilicon sol obtained in step (2) is coated onto the activated substrate material by dip-coating. The dip time is 1-120 min. Then, for organic polymer substrates, it is calcined in air at 100°C for 30-60 min, and for inorganic substrates, it is calcined in air at 100-300°C for 30-60 min. This coating and calcination process is repeated 1-10 times to form the amphiphilic organosilicon coating.

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