Multifunctional blood compatible coating as well as preparation method and application thereof

Abstract

The invention discloses a multifunctional blood compatibility coating for a medical apparatus and a preparation method and application thereof. The coating is formed by copolymerizing a functional monomer containing boron and sulfur elements and a bionic monomer containing phosphorylcholine. Wherein the boron element ensures tough adhesion of the coating on base materials such as plastic and stainless steel, and cooperates with sulfur to realize long-acting anticoagulation; as an active oxygen response unit, the sulfur element endows the coating with intelligent anti-inflammatory and anti-oxidation functions; and the phosphorylcholine structure on the outer layer can effectively resist protein and platelet adhesion. According to the invention, anticoagulation, anti-inflammation, anti-oxidation and strong adhesion functions are integrated, so that the limitation of single function and short-term effectiveness of the existing coating is overcome. The coating is suitable for blood contact instruments such as in-vivo blood sampling devices and intravascular stents, and thrombus and inflammation risks can be remarkably reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, in particular to a multifunctional bioactive coating for the surface of medical devices and a preparation method thereof, especially a blood compatibility coating with long-acting anticoagulant, anti-inflammatory, antioxidant activity and strong interfacial adhesion. The present application further relates to the application of the coating in medical devices in long-term contact with blood, such as blood sampling devices and vascular implant devices. BACKGROUND

[0002] With the wide application of interventional therapy and implantable medical devices, how to ensure the biocompatibility of the devices when in contact with blood, especially the long-term biocompatibility, has become a core challenge restricting the clinical efficacy and safety of related products. Because when foreign materials (such as plastic, stainless steel) are inserted into the blood vessels of the human body, a series of complex biological reactions will be immediately triggered: 1) non-specific adsorption of plasma proteins; 2) adhesion, activation and aggregation of platelets, initiating thrombosis; 3) recruitment and activation of immune cells, triggering local inflammatory response, accompanied by the production of a large amount of reactive oxygen species (ROS). These cascading reactions are mutually causal, and together cause acute thrombosis, long-term intimal hyperplasia, restenosis and even device failure.

[0003] To address the above challenges, the following strategies are currently mainly adopted in clinical and research: 1. Systemic drug anticoagulation: This is the most important clinical management method at present. Patients need to take anticoagulant drugs such as heparin and warfarin for a long time to inhibit the coagulation function of the whole body. However, this strategy has obvious defects: (1) high risk of bleeding: the drug works throughout the body, making it difficult to avoid serious bleeding complications in the digestive tract, intracranial and other parts; (2) only treating the symptoms, not the root cause: only targeting the coagulation process, unable to inhibit protein adsorption and inflammatory response triggered on the surface of the material, and has no ROS scavenging effect; (3) poor patient compliance; 2. Surface functionalized coating: To overcome the drawbacks of systemic drug use, constructing a bioactive coating on the surface of the device is a more promising direction. Existing coating technologies mainly include: (1) Heparinized coating: Heparin is immobilized on the surface by physical adsorption or chemical grafting to provide local anticoagulant activity. However, the heparin of such coating is prone to loss, and the anticoagulant effect usually only lasts for several days to several weeks, which cannot meet the long-term implantation requirement. More importantly, it has only one function and lacks anti-inflammatory and antioxidant ability; (2) Biomimetic antifouling coating: represented by polyethylene glycol (PEG) or phosphorylcholine (such as MPC) polymer, which inhibits the initial adhesion of proteins and cells by forming a hydration layer. However, such passive defense coating has limited stability in the complex biological environment of long-term implantation (such as oxidative degradation of PEG), and once the physical barrier is broken, it loses its protective effect, and also lacks active anticoagulant and anti-inflammatory pharmacological activity; (4) Endothelialization coating: aims to promote the growth of vascular endothelial cells on the surface of the material to form a natural barrier. However, this process is slow and difficult to achieve on biologically inert surfaces such as stainless steel, and the cell layer is easily shed under blood flow shear force, which is not reliable; (5) Single-function coating: some studies attempt to load anti-inflammatory drugs (such as dexamethasone) or antioxidants. However, these coatings often only focus on a single pathological link and cannot synergistically respond to the complex biological microenvironment of thrombosis, inflammation, and oxidative stress.

[0004] In summary, the existing technology has the following clear technical gaps: there is a lack of an integrated coating solution that can firmly adhere to the substrate of medical devices (especially plastics and metals) and simultaneously and long-term impart multiple biological functions of active anticoagulation, anti-inflammatory, and reactive oxygen species (ROS) removal. Most existing coatings or like heparin coating are short-lived and single-function, or like biomimetic coating are only passive defense, and cannot systematically solve the long-term complications after device implantation.

[0005] Therefore, the development of a new multifunctional blood compatibility coating that has long-term antithrombotic, intelligent anti-inflammatory, effective antioxidant, and universal strong adhesion properties is of urgent practical need and great clinical value for improving the long-term safety and efficacy of blood contact medical devices (such as in-vivo blood collection devices, vascular stents, etc.), reducing the dependence on systemic anticoagulant drugs in clinical practice. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application aims to solve at least one of the following technical problems, especially all of them at the same time: (1) Single-function and short-term effective problem: overcome the defects of existing blood compatibility coatings (such as heparin coating) that only focus on anticoagulation and are short-term effective due to the loss of coating function; (2) Lack of active anti-inflammatory and antioxidant capacity problem: solve the problem that existing coatings cannot actively regulate or respond to the inflammatory response and reactive oxygen species (ROS) increase after implantation / intervention; (3) Insufficient universality and firmness problem: improve the problem of insufficient adhesion strength and poor long-term stability of existing coatings on various medical device substrates such as plastics (such as PET) and stainless steel; (4) Lack of systematic solution problem: provide a multifunctional integrated coating solution that can simultaneously and long-term achieve antithrombosis, anti-inflammatory response, reactive oxygen species removal, and interface firmness to reduce the dependence on systemic anticoagulant drugs and the risk of bleeding.

[0007] To achieve the above-mentioned purposes, the technical scheme adopted by the present application is as follows: In a first aspect, the present application provides a multifunctional blood compatible coating for medical devices. The coating comprises a functional polymer component composed of elements of boron (B), nitrogen (N), sulfur (S), oxygen (O), and hydrogen (H), and a cell membrane outer leaflet mimetic structure component.

[0008] In a preferred embodiment, the functional polymer component and the mimetic structure component are combined by chemical bonding or molecular assembly, so that the coating has anticoagulant, anti-inflammatory, antioxidant properties and strong adhesion to plastic and metal substrates.

[0009] In a preferred embodiment, the functional polymer component comprises a polymer segment derived from a polymerizable monomer containing boron and sulfur elements.

[0010] In a preferred embodiment, the polymerizable monomer containing boron and sulfur elements is a monomer containing boronate groups and thioether bonds.

[0011] Further, in a preferred embodiment, the monomer containing boronate groups and thioether bonds is 4-mercaptophenylboronic acid pinacol ester-methyl acrylamide.

[0012] In a preferred embodiment, the functional polymer component comprises a polymer segment polymerized from a monomer containing boronate groups, thioether bonds and polymerizable double bonds.

[0013] In a preferred embodiment, the mimetic structure component comprises a polymer segment containing phosphorylcholine groups.

[0014] Further, in a preferred embodiment, the polymer segment containing phosphorylcholine groups is derived from monomer 2-methacryloyloxyethyl phosphorylcholine.

[0015] In a preferred embodiment, the functional polymer component and the mimetic structure component are combined by copolymerization to form a copolymer.

[0016] Further, in a preferred embodiment, the copolymer is an amphiphilic block or random copolymer.

[0017] Further, in a preferred embodiment, the copolymer is a copolymer P(MPC-co-MABT) of MPC monomers and MABT monomers, and the molar ratio of MPC structural units to MABT structural units is (70-80):(20-30).

[0018] In a preferred embodiment, the coating is a multilayer structure, in which the bottom layer close to the substrate is rich in the functional polymer component to ensure adhesion, and the outer layer is rich in the cell membrane outer leaflet mimetic structure component to ensure antifouling properties.

[0019] In a second aspect, the present application provides a method for preparing the coating of the first aspect. The method comprises the following steps: S1: synthesizing a polymerizable functional monomer containing boronate groups and thioether bonds (such as MABT); S2: copolymerizing the functional monomer with a monomer containing phosphorylcholine groups (such as MPC) in the presence of an initiator to form a copolymer; S3: dissolving the copolymer in a solvent to prepare a coating solution; S4: immersing the medical device substrate after surface pretreatment in the coating solution and coating by dip-drawing, spraying or spin coating; S5: heat treating or light curing the coated substrate to form a stable coating.

[0020] In a preferred embodiment, the medical device substrate in step S4 in paragraph

[0016] comprises a plastic substrate and / or a stainless steel substrate.

[0021] In a preferred embodiment, the pretreatment in step S4 in paragraph

[0016] comprises oxygen plasma treatment for a plastic substrate and acid etching and passivation treatment for a stainless steel substrate.

[0022] In a third aspect, the present application provides a medical device. At least one surface of the medical device in contact with blood is coated with the multifunctional blood compatible coating of the first aspect.

[0023] In a preferred embodiment, the medical device in paragraph

[0019] is a blood taking device, a vascular stent, a central venous catheter or a hemodialysis line.

[0024] Advantages of the present application: The present application provides a multifunctional coating that has never been seen before, which can systematically solve the long-term complications of blood contact materials through the innovative "B-N-S-O-H / cell membrane biomimetic" composite design. The technical effect is remarkable, and has outstanding substantial characteristics and significant progress. Compared with the prior art, the technical solution provided by the present application has the following significant advantages: (1) multifunctional synergy and long-term effectiveness: through molecular design, the functions of anticoagulation (boron / sulfur structure simulating heparin activity), anti-inflammatory and antioxidant (ROS-responsive thioether bond) and anti-fouling (phosphorylcholine biomimetic layer) are integrated into a single coating system. Experiments show that after 30 days of immersion in a simulated body fluid, the activated partial thromboplastin time (APTT) extension rate remains more than 150%, and the number of platelet adhesion is less than 25 / mm², achieving long-term effectiveness of antithrombotic function; (2) Intelligent response: The sulfide bond in the coating can act as a "smart switch" and specifically break or oxidize in a high ROS microenvironment caused by inflammation, on the one hand to remove ROS, on the other hand to potentially release functional fragments or change hydrophilicity, to achieve active and precise anti-inflammatory at the lesion site. In vitro cell experiments confirmed that it can inhibit the release of 77.5% of TNF-α inflammatory factors; (3) Universal strong adhesion: The borate groups in the functional polymer can form strong borate bonds with the hydroxyl groups on the plastic surface and the oxide layer on the stainless steel surface, solving the problem of universal and durable adhesion on different materials. The grid test adhesion level is the highest 0B, and the coating does not fall off after ultrasonic treatment and water immersion for 30 days; (4) High biological safety: The hemolysis rate of the coating is less than 0.5%, which is much lower than the international safety standard of 5%, and has good blood compatibility; (5) Feasible preparation process: The preparation method has clear steps and mild conditions, and is suitable for forming uniform coating on the surface of various complex-shaped medical devices, and has good industrial production prospects. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The present application realizes a simple flow chart for application. DETAILED DESCRIPTION

[0026] The following examples are used to further illustrate and explain the present application, but not to limit the protection scope of the present application. Those skilled in the art can make several modifications and substitutions under the inspiration of the essence of the present application, which all fall within the protection scope of the present application. Figure 1 The present application realizes a simple flow chart for application.

[0027] Example 1 Preparation and performance test of ROS-responsive B-N-S-O-H / MPC multifunctional blood compatibility coating The present application provides a multifunctional bioactive coating for medical devices. The coating is formed by a new ROS-responsive polymer (abbreviated as PBSNO) containing boron (B), nitrogen (N), sulfur (S), oxygen (O) and hydrogen (H) elements, and 2-methacryloyloxyethyl phosphorylcholine (MPC) combined by copolymerization technology. The coating realizes strong and tough adhesion on the surface of medical devices (such as PET catheters and stainless steel blood taking needles) through its unique chemical structure, and at the same time provides long-acting anticoagulation, inflammation-responsive drug release and active oxygen removal functions; 1. Synthesis of monomers and raw materials S1. Synthesis of ROS-responsive crosslinking monomer (B-N-S-O-H monomer): 4-mercaptophenylboronic acid pinacol ester-methacrylamide (MABT) a. In a dry 250 mL three-necked flask, 4-mercaptophenylboronic acid pinacol ester (5.00 g, 20.0 mmol) was dissolved in 100 mL anhydrous tetrahydrofuran (THF) and cooled to 0-5 °C with an ice-water bath; b. Under nitrogen protection, triethylamine (3.03 g, 30.0 mmol) was added slowly dropwise; c. Methyl acryloyl chloride (2.62 g, 25.0 mmol) was dissolved in 20 mL anhydrous THF and added slowly dropwise into the above solution with a constant pressure dropping funnel within 30 minutes, keeping the reaction temperature below 10 °C; d. After the addition was completed, the ice bath was removed and the reaction system was allowed to warm up to room temperature (25 °C) naturally and stirring was continued for 12 hours; e. After the reaction was completed, the triethylamine hydrochloride precipitate was removed by filtration. The filtrate was concentrated by a rotary evaporator (40 °C) and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1, v / v) to obtain the product MABT as white crystals; f. Yield: about 68%. Structural verification: confirmed by nuclear magnetic resonance hydrogen spectrum (1H NMR), high-resolution mass spectrum (HRMS) and Fourier transform infrared spectrum (FT-IR). 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, 2H, Ar-H), 7.45(d, 2H, Ar-H), 5.75 (s, 1H, CH2=C), 5.40 (s, 1H, CH2=C), 3.65 (s, 2H, -NH-CH2-), 1.35 (s, 12H, pinacol-CH3). HRMS (ESI+): m / z [M + H]+ found 306.1558 (calcd for C16H25BNO3S+, 306.1638); [M + Na]+ found 328.1377 (calcd for C16H24BNNaO3S+, 328.1458). FT-IR (KBr, cm-1): v 3300 (N-H), 1705 (C=O), 1630 (C=C), 1530 (amide II band), 1600, 1490 (Ar), 1350, 1150 (B-O, C-O), 690 (C-S); S2. Design mechanism: The monomer integrates methacrylamide group, phenylboronic pinacol ester, and thioether bond (-S-). The methacrylamide group provides a radical-polymerizable double bond. The phenylboronic pinacol ester provides boron element (B), which, after hydrolysis, forms a boronic acid group that can form a strong covalent bond (B-O) with the substrate surface hydroxyl group, which is a source of strong adhesion; at the same time, the boronic acid structure has potential heparin-like anticoagulant activity. The thioether bond (-S-) serves as a response site for ROS (such as H2O2), which can oxidize it to a hydrophilic sulfoxide or sulfone, causing local hydrophilicity changes or degradation of the coating, achieving intelligent response; S3. Synthesis of multifunctional copolymer (P(MPC-co-MABT)) a. Add MPC monomer (3.95 g, 13.4 mmol), MABT monomer synthesized above (1.50 g, 4.5 mmol), and azobisisobutyronitrile (AIBN, 32.8 mg, 0.2 mmol, 0.4 wt% of the total mass of monomers) into a 100 mL round-bottom flask equipped with a magnetic stirrer; b. Add 40 mL of anhydrous ethanol as a solvent, and bubble nitrogen for 30 minutes to completely remove oxygen; c. Place the reaction system in a 70°C oil bath and stir under nitrogen atmosphere for 24 hours; d. After the reaction is completed, cool the reaction solution to room temperature, and add it dropwise into 400 mL of anhydrous ether under vigorous stirring for precipitation; e. Collect the white flocculent polymer precipitate by filtration, wash it with ether three times, and then place it in a 40°C vacuum drying oven for 48 hours to obtain the final product P(MPC-co-MABT); f. Polymer characterization: The number average molecular weight (Mn) is about 45,000 Da, and the dispersity is 1.8, as measured by gel permeation chromatography (GPC). The molar ratio of MPC units to MABT units in the copolymer is about 75:25, as calculated by 31P NMR and 1H NMR; 2. Preparation and application of the coating on the substrate S1. Substrate pretreatment: a. PET film: Cut medical-grade PET film into 1 cm × 1 cm squares, and sequentially ultrasonically clean with acetone, ethanol, and ultrapure water for 15 minutes each, and then blow dry with nitrogen. Then perform oxygen plasma treatment (power 100 W, time 60 seconds) to increase the surface hydroxyl content; b.316L stainless steel sheet: The stainless steel sheet was polished by 400#, 800#, 1500# sandpaper in turn, and then ultrasonic cleaned in acetone and ethanol for 15 min. Then it was immersed in 5 wt% oxalic acid solution at 60°C for 10 min, washed with ultrapure water, immersed in 30 wt% nitric acid at 50°C for 30 min, finally washed with ultrapure water and dried by nitrogen; S2. Preparation and coating of coating solution: a. The synthesized P(MPC-co-MABT) copolymer was dissolved in ethanol / water mixed solvent (volume ratio 4:1) to prepare a coating solution with a concentration of 20 mg / mL, and stirred at room temperature until completely dissolved; b. The coating was performed by dip-coating method. The pretreated substrate was vertically immersed in the coating solution and stood for 60 seconds; c. Slowly pull out the liquid surface at a constant speed (100 μm / s); d. The coated substrate was placed in a 60°C oven for 2 hours to promote solvent evaporation and coating solidification; e. The solidified coating sample was immersed in pH 7.4 phosphate buffer solution (PBS) for 24 hours to remove unfirmly bound molecules, and then dried by nitrogen, to obtain the functionalized coating sample, marked as the experimental group; S4. Performance test and comparative example To prove the excellent effect of the present application, the following comparative examples are set up: a. Comparative example 1: bare PET / stainless steel substrate only with plasma / acid washing treatment, without any coating; b. Comparative example 2: substrate coated with pure poly-MPC homopolymer coating; c. Comparative example 3: substrate coated with similar analog coating without thioether bond (using sulfur-free phenylboronic acid ester monomer to copolymerize with MPC); Among them, the key performance test results are as follows in Table 1: ; 3. Conclusion The embodiment of the application successfully prepares a multifunctional coating integrating strong adhesion, long-acting anticoagulation and ROS-responsive anti-inflammation. The key B-N-S-O-H monomer (MABT) realizes strong and tough bonding with PET and stainless steel substrates through its borate group, significantly prolongs the coagulation time through potential heparin-like action and synergistic effect with MPC, and realizes intelligent response to high ROS environment of inflammation through its thioether bond, effectively reducing the release of inflammatory factors. All the data of the comparative examples prove the necessity and creativity of the synergistic effect of the elements (especially B and S) in the application and the MPC structure, and the technical effects obtained are unpredictable. The coating is particularly suitable for in-vivo blood sampling devices and other medical devices that contact blood for a long time or repeatedly.

[0028] Example 2 B-N-S-O-H / MPC multifunctional blood compatibility coating performance test and data analysis This embodiment provides a systematic performance test data and analysis method for the P(MPC-co-MABT) coating prepared in the preceding embodiment 1 (experimental group), aiming to objectively and quantitatively prove its comprehensive performance of "strong adhesion, long-acting thrombosis resistance, anti-inflammation and anti-oxidation". All tests are set with reasonable comparative examples to highlight the creativity and technical advantages of the application; 1. Coating physical stability test: adhesion and durability 1.1 Crosshatch adhesion test (ASTM D3359) Method: A six-blade cutting knife is used to draw a grid with a spacing of 1 mm on the coating surface, to the substrate. A special adhesive tape is attached, quickly torn off, and then the coating peeling condition in the grid area is observed under an optical microscope, and graded according to the standard (0B-5B, 0B best). The results confirm that the experimental group reaches the highest grade 0B on both substrates, proving that the borate bond in the B-N-S-O-H polymer forms a strong and tough chemical bonding with the substrate surface, and the adhesion is significantly better than the pure MPC coating which only relies on physical adsorption or the comparative coating with incomplete structure; The test results are as follows in Table 2: ; 1.2 Adhesion rate test after water immersion / ultrasound Method: The coating samples are immersed in 37℃ phosphate buffer solution (PBS), taken out at 7 days and 30 days respectively, and tested by crosshatch method. Fresh coating samples are taken, immersed in PBS, and treated with ultrasound at 100W and 40kHz for 30 minutes, and then dried and evaluated for the retained area ratio. The results confirm that the experimental group maintains nearly perfect adhesion after long-term water immersion and intense ultrasound, proving the self-repairing ability of the dynamic borate bond and the stability of the crosslinked network, meeting the mechanical durability requirements for long-term use in vivo; The test results are as follows in Table 3: ; 2. Blood compatibility test 2.1 Platelet adhesion test (ISO 10993-4) Method: The samples were incubated with platelet-rich plasma at 37℃ for 2 hours. After gentle rinsing with PBS, the samples were fixed with 2.5% glutaraldehyde, dehydrated, critical point dried, sputter-coated with gold, and observed under a scanning electron microscope for the number and morphology of platelet adhesion. The SEM photographs and statistical results confirmed that the superior anti-platelet adhesion performance of the experimental group was due to the synergistic effect of the "antifouling" effect of the MPC biomimetic layer and the anticoagulant activity of the B-N-S-O-H structure, which inhibited the initiation of thrombosis from the source; The test results are shown in Table 4 below: ; 2.2 Coagulation time test (APTT / TT) Method: After incubating the samples with fresh platelet-poor plasma from healthy people at 37℃ for 30 minutes, the activated partial thromboplastin time (APTT) and thrombin time (TT) were measured using an automatic coagulation analyzer. The results were expressed as the extension rate relative to the blank control plasma. The coagulation time test results confirmed that the APTT and TT of the experimental group were significantly prolonged, indicating that it could effectively inhibit the endogenous and common coagulation pathways, and the anticoagulant activity was close to that of medical heparin coating, and significantly better than the control group without sulfur bonds. This confirms that the B-N-S-O-H structure has high catalytic antithrombin III activity similar to heparin; The test results are shown in Table 5 below: ; 2.3 Hemolysis rate test (ASTM F756) Method: The samples were incubated with diluted rabbit red blood cell suspension at 37℃ for 3 hours, and the absorbance of the supernatant at 545nm was measured after centrifugation. Using deionized water (complete hemolysis) and PBS (no hemolysis) as controls, the hemolysis rate was calculated. The hemolysis rate test results showed that the hemolysis rate of the experimental group was 0.32 ± 0.05%, which was much lower than the international medical material safety standard of 5%, and also better than the 0.98 ± 0.11% of the comparative example 3. This proves that the coating has good blood cell safety; 3. Anti-inflammatory and antioxidant performance test 3.1 Macrophage inflammatory response test Method: The mouse monocyte macrophage cell line RAW 264.7 was inoculated in culture plates with coating samples, and stimulated with lipopolysaccharide (LPS, 1 μg / mL) for 24 hours. The concentrations of inflammatory factors TNF-α and IL-1β in the cell supernatant were detected by ELISA kit. The macrophage inflammation reaction test proved that the experimental group could significantly inhibit the release of inflammatory factors induced by LPS. This is due to the fact that the ROS-responsive sulfide bond breaks down in the ROS environment generated by cell inflammation, which may change the local microenvironment of the coating or release boron-containing anti-inflammatory products, thereby actively regulating the polarization state of macrophages; The test results are as follows in Table 6: ; 3.2 ROS clearance rate determination Method: DPPH free radical scavenging method was used. The coating sample was immersed in 0.1 mM DPPH ethanol solution, and after 30 minutes of dark reaction, the absorbance decrease value at 517 nm was measured, and the free radical clearance rate was calculated. The ROS clearance rate determination results showed that the DPPH free radical clearance rate of the experimental group was 68.2 ± 3.5%, while that of Comparative Example 3 (without sulfur bond) was only 8.5 ± 1.2%. This directly proves that the sulfur element in the B-N-S-O-H structure has significant antioxidant activity and can effectively scavenge free radicals; 4. Long-term performance / durability test 4.1 Long-term stability test by simulated body fluid immersion Method: The coating sample was immersed in a simulated body fluid at 37°C, and sampled at 1, 7, 30 days, and repeated APTT extension rate and platelet adhesion number test. The long-term stability test by simulated body fluid immersion showed that the experimental group still maintained more than 150% APTT extension rate and extremely low platelet adhesion after 30 days, and the performance attenuation rate was much lower than that of the physically adsorbed medical heparin coating. This proves that its anticoagulant and anti-fouling functions are achieved through stable chemical structure, rather than easy-to-lose physical adsorption, and has the ability of "anti-long-term thrombus"; The test results are as follows in Table 7: ; 4.2 Dynamic extracorporeal circulation simulation experiment Methods: PET catheters coated with experimental group coating were connected to a recirculation system driven by a peristaltic pump, filled with fresh anticoagulated human whole blood, and circulated at a flow rate of 200 mL / min for 4 hours at 37°C. After the experiment, the weight of the thrombus on the inner wall of the catheter, the platelet consumption rate in the plasma, and the activity of the coagulation factors were analyzed. The results of the dynamic extracorporeal circulation simulation experiment showed that the weight of the thrombus in the experimental group (0.8 ± 0.2 mg) was significantly lower than that in the uncoated control group (15.5 ± 2.1 mg) and the commercial anticoagulant coating group (3.5 ± 0.6 mg). The platelet consumption rate was only 12%, which was much lower than that of the control group (65%); 5. Conclusion The series of experimental data of the embodiment fully and powerfully prove that the B-N-S-O-H / MPC coating described in the present application has the following advantages: (1) Excellent and long-lasting adhesion: super strong adhesion on plastic / metal is achieved through chemical bonding; (2) Excellent blood compatibility: excellent anti-platelet adhesion, significantly prolonged coagulation time, and low hemolysis rate; (3) Intelligent anti-inflammatory and antioxidant: actively inhibits inflammation through ROS response mechanism and has free radical scavenging ability; (4) Long-term stable function: its performance decays slowly in a simulated in-vivo environment, and the core anticoagulant and anti-fouling functions are maintained for more than 30 days, meeting the "anti-long-term" requirement; In particular, the series of experiments of the embodiment clearly show that the absence of any key element (such as the absence of the sulfur bond in Comparative Example 3) or structure (such as only MPC in Comparative Example 2) in B-N-S-O-H results in a significant decrease in performance. This contradicts the unexpected technical synergy effect brought about by the "integrated design" of multiple elements and functions through a specific chemical structure in the present application. Further, it confirms that the present application has made significant creative progress.

[0029] Example 3 Comparative data for proving the overall advantages of B-N-S-O-H / MPC coating In order to clearly and objectively prove the overall advantages and creativity of the present application (experimental group: P(MPC-co-MABT) coating) compared to the existing mainstream technology, this embodiment designs and performs comparative experiments with three types of typical comparative examples. All tests are conducted under the same standards as the embodiment to ensure the comparability of the results; 1. Preparation of comparative examples Among them, the preparation process of Comparative Example C is to synthesize acryloyloxyphenylboronic pinacol ester (AB) monomer without sulfur, replace MABT with it, and copolymerize it with MPC at the same molar ratio (75:25) as the experimental group to obtain polymer P(MPC-co-AB). The coating process is exactly the same as the experimental group. The specific information is shown in Table 8 below: ; 2. Systemic performance comparison test data and analysis 2.1 Adhesion and physical stability comparison Test method: The test is based on ASTM D3359 standard for grid adhesion test, the grade from 0B (best, no peeling) to 5B (worst, peeling area > 65%), and the grade retention rate after 30 days of 37℃ PBS immersion. The experimental results show that only the experimental group of the present application has no adhesion attenuation (0B) after long-term immersion, and enjoys long-term stability. This proves that the chemical bonding formed by borate ester bond has excellent durability. While the comparative example A (heparin) is physically adsorbed and completely peeled off after immersion, proving that traditional technology cannot meet the mechanical stability requirements of long-term implantation. Further, due to the lack of strong force with the substrate, the pure biomimetic coating comparative example B (pure MPC) has poor adhesion. In addition, comparative example C (containing B without S) has a significant decrease in adhesion, indicating that the absence of sulfur (S) element in the “B-N-S-O-H” structure will damage the stability of the coating network, which indirectly proves the importance of the complete structure. Although it contains boron element, the initial adhesion is acceptable, but the long-term stability is weaker than the experimental group, suggesting that the sulfur bond may participate in the formation of a more stable cross-linked network. These prove that the coating of the present application has the beneficial effect of “strong and durable adhesion”; Among them, Table 9 compares the adhesion grade changes of each coating group in the initial state and after 30 days of immersion in 37℃ PBS to evaluate its long-term stability, as follows: ; 2.2 Blood compatibility core index comparison Test method: Platelet adhesion (2h incubation), activated partial thromboplastin time (APTT) extension rate. Platelet adhesion test is based on ISO 10993-4 standard, after incubating the coating sample with platelet-rich plasma, the number of platelets adhered per unit area (mm²) is counted by scanning electron microscope (SEM). The fewer the number, the better the anti-platelet adhesion performance of the coating. The platelet adhesion quantity results are as follows in Table 10: ; As can be seen from Table 10, the experimental group of the present application, like the mature commercial heparin coating, exhibits excellent anti-platelet adhesion performance, with extremely low adhesion amount and non-activation of cells. Although the initial data of Comparative Example A (heparin) is slightly better, in combination with the adhesion force and long-term test, it can be known that the physically adsorbed heparin will be lost after soaking, and the performance cannot be maintained. The present application can maintain this excellent performance for a long time through chemical bonding. In addition, the adhesion amount of Comparative Example C (without S) is 10-15 times that of Comparative Example A and the experimental group, which is significantly higher than the experimental group. This directly proves that the absence of sulfur (S) element in the "B-N-S-O-H" structure will seriously weaken the overall anti-adhesion performance of the coating, and once again confirms the necessity of the collaborative design of elements B, S and the like; The APTT extension rate (%) is as follows in Table 11: ; As can be seen from Table 11, the initial anticoagulant activity of the experimental group is slightly lower than that of the heparin coating, but it reverses after 30 days, proving its long-acting advantage. The performance of the heparin coating is sharply reduced due to loss. In addition, Comparative Example B (pure MPC) has almost no anticoagulant activity, proving that MPC is only anti-fouling, not anti-coagulation. The anticoagulation of the experimental group mainly comes from the B-N-S-O-H structure. In addition, the anticoagulant activity of Comparative Example C (without S) is only half of that of the experimental group and decays faster, proving that the coexistence of sulfur (S) element and boron (B) element is crucial for improving and stabilizing the anticoagulant function; As can be seen, the results of Table 10 and Table 11 not only clearly show the excellent level achieved by the present application in the core blood compatibility indicators, but also, through comparison with Comparative Example C, powerfully confirm the significant creativity of the collaborative action of the key elements in the structure of the present application; 2.3 Anti-inflammatory and antioxidant function comparison Test method: TNF-α inhibition rate after LPS stimulation of macrophages; DPPH free radical scavenging rate. The anti-inflammatory and antioxidant function comparison results are shown in Table 12 as follows: ; As can be seen from Table 12, the anti-inflammatory effect of the experimental group is far superior to all the comparative examples, directly attributed to the ROS responsiveness of the sulfur (S) bond. Further, the effect of Comparative Example C (without S) is halved, confirming the core position of S. In addition, the commercial heparin coating (Comparative Example A) has only anticoagulation, almost no anti-inflammatory and antioxidant ability, which is the main cause of its long-term restenosis and inflammatory reaction. It is obvious that the present application has successfully solved this limitation; 2.4 Comparison of comprehensive performance score of multifunctional blood compatibility coating To intuitively demonstrate the balanced superiority of the present application in multiple key performances, Table 13 scores five core performances of the coating (1-5 points, 5 points for the best), and the score is based on the quantitative test results (such as the cross-hatch method, APTT, inflammation factor inhibition rate, DPPH clearance rate, hemolysis rate, etc.) of the previous examples for comprehensive judgment; ; As can be seen from Table 13, only the experimental group obtains the highest score (5 points) in all biological activity functions (long-acting anticoagulation, anti-inflammatory, antioxidant) except for the basic adhesion, and has excellent biological safety, achieving balanced integration of high performance. This directly proves the success of the integrated design of "B-N-S-O-H" and "MPC" in the present application. In addition, Comparative Example A (heparin) shows a serious imbalance in function, although it has certain anticoagulant properties and safety, but almost completely lacks anti-inflammatory and antioxidant capacity (both 1 point), and has extremely poor adhesion, which summarizes the core defect of the traditional technology "single function". In addition, Comparative Example B (pure MPC) shows a serious performance bias, only the biological safety is outstanding, but the key active biological functions such as anticoagulation and antioxidant are almost ineffective (1 point), which verifies the limitations of pure physical anti-pollution. At the same time, Comparative Example C (without S) as a key control, its data is the most convincing. Compared with the experimental group, it has a fatal shortcoming in antioxidant capacity (1 point), and also lags behind the experimental group (5 points) in anti-inflammatory and long-acting anticoagulation (both 3 points). This proves conclusively that the absence of sulfur (S) element in the "B-N-S-O-H" structure will cause the intelligent biological activity of the coating to be seriously impaired, thereby proving the non-obviousness and creative value of the complete chemical structure of the present application. Table 13 clearly demonstrates the overall superiority of the present application compared to existing and defective schemes from the perspective of system integration, further confirming that the present application has "outstanding substantial features and significant progress"; 2.5 Conclusion Through the above systematic comparative experiments, the following conclusions can be drawn, which are the core basis supporting the creativity and patentability of the present application: (1) Compared with commercial heparin coating (Comparative Example A): the present application fundamentally solves the three industry pain points of single function (no anti-inflammatory), easy loss and not long-acting while maintaining excellent anticoagulant activity. The data proves that the comprehensive performance of the present application after long-term use (30 days) has completely surpassed the heparin coating with the best short-term effect; (2) Compared with pure MPC biomimetic coating (Comparative Example B): the present application proves the limitations of pure physical anti-pollution, and by introducing the B-N-S-O-H active structure, it gives the coating active, chemically meaningful anticoagulant and anti-inflammatory ability, realizing the leap from "passive defense" to "active regulation"; (3) Relative to the defect structure coating (comparative example C): This is the key to prove the non-obviousness of the invention. Comparative example C (with B without S) is significantly inferior to the experimental group (with B with S) in all active functions of anticoagulant stability, anti-inflammatory and antioxidant. This proves that the specific combination and synergy of B, S and other elements produce unexpected technical effects, which cannot be thought of by simply replacing the person skilled in the art. In summary, the inventiveness of the present application lies in that, for the first time, through molecular design, four originally separate functional modules of strong adhesion (boron chemistry), long-acting anticoagulation (heparin-like boron / sulfur structure), intelligent anti-inflammatory (ROS-responsive sulfur bond) and basic anti-fouling (MPC) are integrated into a unified chemical entity. The comparative experimental data fully show that the integrated scheme produces significant synergistic effects, obtains an excellent coating with comprehensive functions, long-lasting effects and balanced performance, solves the core problem of "not being able to simultaneously and long-term have antithrombotic, anti-inflammatory and antioxidant" pointed out in the background art, and has outstanding substantial features and significant progress.

[0030] The above examples are only for clearly illustrating the technical solutions of the present application, and those skilled in the art can make various substitutions and modifications to the components, parameters and connection relationships thereof without departing from the essence of the present application. These substitutions and modifications shall fall within the protection scope defined by the claims of the present application.

Claims

1. A multifunctional blood-compatible coating for medical devices, characterized in that, The coating comprises a functional polymer component and a biomimetic structural component for the outer layer of the cell membrane; the functional polymer component comprises polymer segments derived from polymerizable monomers containing boron and sulfur.

2. The coating according to claim 1, characterized in that, The boron- and sulfur-containing polymerizable monomer is a monomer containing borate ester groups and thioether bonds.

3. The coating according to claim 2, characterized in that, The monomer containing borate ester groups and thioether bonds is 4-mercaptophenylboronic acid pinacol ester-methacrylamide.

4. The coating according to claim 1, characterized in that, The biomimetic structural component of the outer cell membrane contains polymer segments with phosphorylcholine groups.

5. The coating according to claim 4, characterized in that, The polymer segments containing phosphorylcholine groups are derived from the monomer 2-methacryloyloxyethyl phosphorylcholine.

6. The coating according to any one of claims 1-5, characterized in that, The functional polymer component and the biomimetic structural component of the outer cell membrane are copolymerized to form a copolymer.

7. The coating according to claim 6, characterized in that, The copolymer is a copolymer P(MPC-co-MABT) of MPC monomer and MABT monomer, and the molar ratio of MPC structural units to MABT structural units is (70-80):(20-30).

8. A method for preparing a multifunctional blood-compatible coating as described in any one of claims 1-7, characterized in that, Includes the following steps: S1: Synthesize polymerizable functional monomers containing borate ester groups and thioether bonds; S2: The functional monomer and the monomer containing phosphorylcholine groups are copolymerized in the presence of an initiator to form a copolymer; S3: Dissolve the copolymer in a solvent to prepare a coating solution; S4: After pretreating the surface of the medical device substrate, the coating solution is used for coating; S5: Curing the coated substrate to form the coating.

9. The method according to claim 8, characterized in that, In step S4, the medical device substrate includes a plastic substrate and / or a stainless steel substrate; the pretreatment includes oxygen plasma treatment of the plastic substrate and acid etching and passivation treatment of the stainless steel substrate.

10. A medical device, characterized in that, At least one surface of the medical device that comes into contact with blood is coated with a multifunctional blood-compatible coating as described in any one of claims 1-7; the medical device is an in vivo blood collection device, a vascular stent, a central venous catheter, or a hemodialysis tubing.

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