An anticoagulant hydrogel composite coating for the surface of a hemoperfusion adsorbent and a method of making

Abstract

The application belongs to the technical field of biomedical materials and blood purification, and discloses a blood perfusion adsorbent surface anticoagulation hydrogel composite coating and a preparation method. In view of the problems of protein adsorption, platelet adhesion and thrombosis easily induced by polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) in clinical application of blood perfusion, a multilayer plating composite coating construction method based on APTES / BP synergistic bottom layer and heparin / MPC anticoagulation hydrogel surface layer is provided. By first introducing a silanization photosensitive bottom layer on the surface of PS-DVB, and then in-situ grafting methacrylated heparin and MPC on the surface, the application realizes chemical anchoring and thin layer construction of the coating on the surface of inert porous resin, and has high adhesion, no hole blocking and long-term anticoagulation performance.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and blood purification technology, specifically relating to an anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent and its preparation method. In particular, it relates to a long-term stable anticoagulant surface modification technology for porous adsorbent materials such as polystyrene-divinylbenzene copolymer macroporous adsorbent resin (PS-DVB) constructed by a silanized photosensitive underlayer and an anticoagulant hydrogel surface layer. Background Technology

[0002] Hemoperfusion is an important extracorporeal blood purification method used clinically for diseases such as drug poisoning, elevated inflammatory factors, liver failure, and hyperbilirubinemia. The adsorbent material is the core of the hemoperfusion device, and its performance directly affects bilirubin removal efficiency, adsorption kinetics, and blood compatibility. As a metabolic byproduct of hemoglobin, excessive accumulation of bilirubin can cause severe tissue damage and even lead to acute liver failure. Compared with methods such as phototherapy, hemodialysis, and plasma exchange, hemoperfusion is considered one of the most effective ways to remove bilirubin from the blood.

[0003] Polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) is widely used in bilirubin adsorption research due to its high specific surface area, adjustable pore size, and good chemical stability. However, PS-DVB is inherently a hydrophobic polymer material, and its surface is prone to rapid protein adsorption and platelet adhesion, which in turn triggers a coagulation cascade reaction, leading to problems such as thrombosis, pore blockage, and decreased adsorption efficiency, seriously affecting the safety and sustainability of the hemoperfusion process.

[0004] To improve the blood compatibility of porous adsorbents, studies have attempted to construct hydrophilic or anticoagulant coatings on the resin surface, such as heparinization modification, PEG / PVP-based hydrophilic coatings, and zwitterionic coatings. However, traditional coatings still face the following key technical bottlenecks:

[0005] (1) The coating is difficult to achieve high stability adhesion on the inert PS-DVB surface.

[0006] Because PS-DVB lacks reactive groups, traditional coating methods rely on weak physical adsorption or non-selective chemical fixation, which makes the coating easy to detach or break under high shear blood flow conditions, and the anticoagulant performance decreases significantly over time.

[0007] (2) Traditional coatings are prone to "pore blockage" problems, which affect adsorption performance.

[0008] PS-DVB adsorbents have a hierarchical porous structure. Common methods such as coating with hydrogels and impregnation crosslinking can easily form excessively thick or uneven polymer layers inside the pores, obscuring the effective pore volume and increasing the resistance to bilirubin diffusion. Since the diffusion of bilirubin inside the adsorbent is itself one of the control steps, this leads to a decrease in adsorption capacity, a slower adsorption rate, and affects the overall perfusion efficiency.

[0009] In summary, there is an urgent need for a technical solution that can achieve a robust, thin-layer, non-clogging anticoagulant surface coating on porous adsorbents such as PS-DVB. On the one hand, a stable, anchored coating can improve the blood compatibility of the adsorbent, inhibiting protein adsorption and platelet adhesion; on the other hand, by constructing a superhydrophilic polymer hydrogel surface, it can be made to have superlubricating properties, reducing the frictional resistance of blood during the flow between particles, improving the microscopic hemodynamic environment, and helping to reduce local shear damage and further reduce the risk of coagulation. However, there is still a lack of a hydrogel coating system that can simultaneously achieve: (1) high-firm adhesion to the PS-DVB surface; (2) non-clogging thin-layer coating (preserving the original pore structure and adsorption performance); and (3) long-term anticoagulant and superlubricating properties.

[0010] Therefore, developing a composite coating technology that is highly adhesive, highly stable, non-clogging, and has both anticoagulant and lubricating functions suitable for blood perfusion adsorbents has significant application value and clinical significance. Summary of the Invention

[0011] In view of this, and addressing the problems of existing technologies such as the strong hydrophobicity of polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) for hemoperfusion, which easily induces protein adsorption and coagulation, and the low adhesion of traditional hydrophilic / anticoagulant coatings on inert surfaces and their tendency to cause "pore blockage" in porous structures, affecting bilirubin diffusion and adsorption performance, this invention provides an anticoagulant hydrogel composite coating for the surface of a hemoperfusion adsorbent and its preparation method. This invention can be widely applied in blood purification devices such as hemoperfusion, hemodialysis, plasma separation, and extracorporeal circulation to improve the anticoagulant performance and biocompatibility of adsorbent materials during extracorporeal blood processing.

[0012] It should be noted that this invention employs a polymer multilayer coating strategy of "silanization-photosensitive synergy" bottom layer and "heparin / MPC anticoagulant superhydrophilic hydrogel surface layer" to achieve chemical anchoring and thin-layer construction of the coating on the surface of PS-DVB adsorbent, thereby obtaining a surface hydrogel composite coating with high adhesion, non-clogging, strong anticoagulation and super-lubricating properties, which significantly improves the blood compatibility and safety of use of the blood perfusion adsorbent.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] The first technical objective of this invention is to provide an anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent. This anticoagulant hydrogel composite coating comprises a base layer and an anticoagulant hydrogel surface layer formed by photo-initiated graft polymerization covering the surface of the base layer.

[0015] The bottom layer is composed of 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP). The triethoxysilane end group in the APTES molecule can undergo a condensation reaction with active groups such as hydroxyl, amino, or siloxy groups on the surface of the PS-DVB adsorbent to form a stable siloxane bond network, thereby firmly anchoring the APTES / BP synergistic bottom layer to the surface of the PS-DVB porous adsorbent. The aromatic ketone structure in the BP molecule exhibits photoreactivity under ultraviolet light irradiation and can covalently link with the hydrogel chains formed by subsequent polymerization through processes such as free radical hydrogen extraction, achieving chemical bonding between the bottom layer and the surface layer.

[0016] The anticoagulant hydrogel surface layer is composed of methacrylated heparin and 2-methacryloxyethyl phosphoric acid choline (MPC), which are formed by in-situ polymerization on the surface of the aforementioned APTES / BP underlayer via UV-initiated graft polymerization. Heparin endows the coating with excellent anticoagulant activity, while MPC provides superhydrophilicity and antiprotein adsorption functions by constructing a cell membrane-like phosphoric acid choline structure. The two work synergistically to achieve long-term stable blood compatibility and anticoagulant properties.

[0017] Preferably, the overall thickness of the composite coating of the present invention is 3 μm to 10 μm, wherein the thickness of the bottom layer is 1 μm to 2 μm and the thickness of the anticoagulant hydrogel surface layer is 2 μm to 8 μm, so as to ensure that while providing effective anticoagulation and lubrication functions, the PS-DVB porous structure is not significantly blocked, and the original pore volume and bilirubin diffusion performance of the adsorbent are maintained.

[0018] The second technical objective of this invention is to provide a method for preparing an anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent as described above, comprising the following steps:

[0019] Deposition and Construction of the Substratum: Polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) is immersed in an organic solvent solution containing 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP) and treated at 40 ℃ to 80 ℃ for 1 to 48 hours. After solvent washing and drying, a photosensitive silanized substratum is formed on the adsorbent surface. The organic solvent is preferably at least one of anhydrous ethanol, anhydrous toluene, and anhydrous xylene. The mass ratio of APTES to BP in the organic solvent is preferably (1:0.01) to (1:5), and the total mass fraction of APTES and BP in the organic solvent is 0.1 wt% to 10 wt%, to obtain a substratum structure that has both sufficient photosensitive group content and good film-forming properties.

[0020] Graft polymerization of the anticoagulant hydrogel surface layer: PS-DVB adsorbent with an APTES / BP substrate is placed in an aqueous prepolymer solution containing heparin methacrylamide and MPC, and graft polymerization is carried out under ultraviolet light irradiation in the presence of a photoinitiator to form an anticoagulant hydrogel surface layer in situ on the substrate surface. Preferably, the mass concentration of heparin methacrylamide in the aqueous prepolymer solution is 1 wt% to 30 wt%, the mass concentration of MPC in the aqueous prepolymer solution is 2 wt% to 60 wt%, and the prepolymer solution is composed of heparin methacrylamide, MPC, photoinitiator Irgacure 2959, and water. The mass concentration of Irgacure 2959 in the water is 0.5 wt% to 2 wt%, and it does not contain any additional chemical crosslinking agents. A stable hydrogel network is formed through chain growth and covalent linkage with the active sites of BP to reduce the risk of potential crosslinking agent residue.

[0021] Through the above steps, an anticoagulant hydrogel composite coating with a well-defined structure, a strong interface, controllable thickness, and no pore blockage can be constructed on the surface of the PS-DVB porous adsorbent.

[0022] In summary, the method of this invention employs a polymer multilayer plating strategy to sequentially form a chemically anchored underlayer and an anticoagulant hydrogel surface layer on the adsorbent surface. First, a synergistic underlayer is formed by 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP). This underlayer, on the one hand, undergoes a condensation reaction between the triethoxysilane end groups and the active groups on the surface of the polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB), constructing a stable siloxane bond network; on the other hand, the aromatic ketone groups of BP possess photoreactive properties, activating under light and undergoing a free radical hydrogen extraction reaction with the subsequent polymer chains, thereby achieving covalent bonding between the surface hydrogel and the underlayer. Subsequently, heparin methacrylamide and 2-methacryloyloxyethylphosphocholine (MPC) are polymerized in situ on the surface of this underlayer to form a dense and uniform hydrogel anticoagulant surface layer. Due to the continuous and stable chemical bonding structure formed between the bottom and surface layers, this coating exhibits excellent interfacial strength and long-term stability. It can maintain its integrity in high-shear blood flow environments, significantly reducing the risk of protein adsorption and thrombosis. It is particularly suitable for long-term anticoagulant surface modification of hemoperfusion materials.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] (i) The coating is firmly bonded and adapted to the surface of inert porous adsorbent: The present invention uses a silanized photosensitive substrate constructed by APTES and BP. Through the dual mechanism of silane condensation and photo-initiated free radical hydrogen extraction, it forms multi-point covalent bond connection with the PS-DVB adsorbent surface, realizing the high adhesion of the coating to the surface of inert porous resin, overcoming the problems of easy detachment and insufficient stability of traditional physical adsorption coatings in high shear blood flow environment.

[0025] (ii) Non-clogging thin-layer design to maintain adsorption performance and diffusion kinetics: By controlling the total thickness of the composite coating within the micron range, especially controlling the hydrogel surface layer to 2-8 μm, this invention provides anti-coagulation and lubrication functions while avoiding significant clogging of the PS-DVB multi-level channels, maximizing the preservation of the original pore structure and specific surface area, avoiding increasing the diffusion resistance of bilirubin inside the particles, and helping to maintain or improve the bilirubin adsorption capacity and adsorption rate.

[0026] (iii) Synergistic effect of heparin and MPC to achieve strong anticoagulant and superhydrophilic / superlubricating properties: Methacrylamide heparin endows the coating with direct anticoagulant function, inhibiting the coagulation cascade reaction; MPC significantly inhibits protein and platelet adhesion by forming a stable hydration layer, providing excellent antifouling and blood compatibility. The synergistic effect of the two enables the coating to maintain low protein adsorption and low thrombosis tendency under long-term blood contact conditions. At the same time, the superhydrophilic hydrogel surface enriched with MPC has superlubricating properties, which can reduce the frictional resistance of blood flowing between adsorbent particles, improve the microscopic hemodynamic environment, and further reduce the risk of local shear damage and induced coagulation.

[0027] (iiii) Simple process, mild conditions, suitable for large-scale production: The preparation process of this invention only includes two steps: "APTES / BP bottom layer deposition" and "heparin / MPC hydrogel surface photoinitiation grafting". The required equipment is simple and the process conditions are mild. It is compatible with the existing blood perfusion adsorbent production process, which is convenient for promotion and application in industrial preparation process and has good prospects for scale-up application.

[0028] In summary, this invention, through a multi-layer coating strategy of a specific APTES / BP bottom layer and a heparin / MPC anticoagulant hydrogel surface layer, fundamentally improves the anticoagulant performance and blood compatibility of blood perfusion adsorbents such as PS-DVB without sacrificing adsorption performance, demonstrating significant technological innovation and clinical application value. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0030] Figure 1 SEM images of the PS-DVB adsorbent surface before and after modification with the composite coating prepared in Example 1.

[0031] Figure 2 The graph shows the anti-BSA protein adhesion properties of the PS-DVB adsorbent surface before and after modification with the composite coating prepared in Example 1.

[0032] Figure 3 The graph shows the antiplatelet activation performance of the PS-DVB adsorbent before and after the composite coating prepared in Example 1 was modified.

[0033] Figure 4 The graph shows the hemolysis rate test results of the PS-DVB adsorbent before and after coating modification in Example 1.

[0034] Figure 5 The graph shows the plasma recalcification time test results of the PS-DVB adsorbent before and after coating modification in Example 1.

[0035] Figure 6 The graph shows the specific surface area test results of the PS-DVB adsorbent before and after coating modification in Example 1.

[0036] Figure 7 The image shows the wettability test results of the PS-DVB adsorbent before and after coating modification in Example 1. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0038] This invention discloses an anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent, which consists of a bottom layer and an anticoagulant hydrogel surface layer formed by photo-initiated graft polymerization covering the surface of the bottom layer. The bottom layer is composed of 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP), and the thickness of the bottom layer ranges from 1 μm to 2 μm. The anticoagulant hydrogel surface layer is composed of heparin methacrylamide and 2-methacryloyloxyethylphosphocholine (MPC), and is formed by in-situ polymerization on the surface of the APTES / BP bottom layer by ultraviolet light-initiated graft polymerization. The thickness of the grafted anticoagulant hydrogel surface layer ranges from 2 μm to 8 μm, and the overall thickness of the composite coating ranges from 3 μm to 10 μm.

[0039] Furthermore, the preparation method of the photosensitive silanized substrate is as follows: Polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) is immersed in an organic solvent solution containing 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP), and treated at 40℃~80℃ for 1~48 hours. Subsequently, it is washed with solvent and dried to form a photosensitive silanized substrate on the adsorbent surface. The organic solvent is preferably at least one of anhydrous ethanol, anhydrous toluene, and anhydrous xylene. The mass ratio of APTES to BP in the organic solvent is preferably (1∶0.01)~(1∶5), and the total mass fraction of APTES and BP in the organic solvent is 0.1wt%~10wt%, to obtain a substrate structure that has both sufficient photosensitive group content and good film-forming properties.

[0040] Further, the graft polymerization of the anticoagulant hydrogel surface layer: The PS-DVB adsorbent with the deposited APTES / BP underlayer was placed at 60 °C and immersed in an aqueous prepolymer solution containing heparin methacrylamide, MPC, and photoinitiator Irgacure 2959. The reaction was gently stirred for 3–20 min to uniformly wet the adsorbent surface with the prepolymer solution. After removal, the material was filtered through a 200-mesh stainless steel sieve to remove excess prepolymer solution. Then, it was placed under 365 nm ultraviolet light irradiation for 5–30 min to achieve surface graft polymerization, forming an anticoagulant hydrogel surface layer in situ on the underlayer surface. After photocuring, the obtained material was washed three times with deionized water for 5 min each time. Then, it was immersed in deionized water for 1–12 h to fully diffuse and remove unreacted monomers. After washing, it was vacuum dried at 60 °C for 4–12 h.

[0041] Preferably, the mass concentration of heparin in water in the prepolymer solution is 1 wt% to 30 wt%, and the mass concentration of MPC in water is 2 wt% to 60 wt%. The prepolymer solution is composed of heparin, MPC, photoinitiator Irgacure2959 and water, and does not contain any additional chemical crosslinking agents. It forms a stable hydrogel network through chain growth and covalent connection with BP active sites to reduce the risk of potential crosslinking agent residue.

[0042] To better understand this invention, specific embodiments are described in detail below. Although preferred embodiments are described below, it should be understood that this invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Those skilled in the art can make various modifications and improvements without departing from the concept of this invention. These all fall within the scope of protection of this invention. Reagents or instruments used in this invention, unless otherwise specified, are all commercially available conventional products. All animal experiments were conducted strictly in accordance with protocols approved by the Animal Experiment Ethics Committee of the Chinese Academy of Medical Sciences.

[0043] Example 1

[0044] The preparation steps of the anticoagulant hydrogel composite coating on the surface of the PS-DVB adsorbent are as follows:

[0045] Step 1: Pretreatment of PS-DVB Adsorbent: Take 10 g of dried PS-DVB adsorbent, place it in a beaker, add 100 mL of anhydrous ethanol, and stir magnetically for 30 min at room temperature to remove dust and soluble impurities from the particle surface. After settling, discard the supernatant and repeat the ethanol washing process twice. Then, place the resin in a 60 ℃ vacuum drying oven for 8 h for later use.

[0046] Step 2: Construction of the APTES / BP photosensitive silanized substrate:

[0047] (1) Preparation of bottom treatment solution: Dissolve APTES and BP in anhydrous ethanol so that the mass ratio of APTES to BP is 1:0.1 and the total mass fraction of APTES and BP in the solution is 5 wt%.

[0048] (2) Silane photosensitive substrate deposition: 10 g of pretreated and dried PS-DVB adsorbent was added to the above APTES / BP ethanol solution to completely immerse the resin particles. The solution was then magnetically stirred in an oil bath or constant temperature water bath at 60 ℃ for 12 h to allow APTES and BP to undergo silane condensation and physical adsorption on the surface of the PS-DVB adsorbent.

[0049] (3) Washing and drying: After the reaction, the resin was filtered through a filter membrane or a glass frit funnel. It was first washed three times with anhydrous ethanol to remove unreacted or unbound APTES / BP molecules, and then quickly rinsed once with a small amount of deionized water. Subsequently, the resin was dried in a vacuum drying oven at 60 ℃ for 8 h to obtain PS-DVB adsorbent particles with an APTES / BP photosensitive silanized underlayer on the surface. This sample can be designated as PS-DVB@APTES / BP.

[0050] Step 3: Graft polymerization of the surface layer of the heparin / MPC anticoagulant gel:

[0051] (1) Preparation of hydrogel prepolymer solution: Take an appropriate amount of deionized water and prepare an aqueous prepolymer solution with the following mass concentrations: heparin methacrylamide: 5 wt%; MPC: 20 wt%; photoinitiator Irgacure 2959: 1 wt%. The specific operation is as follows: add 2.5 g of heparin methacrylamide and 10 g of MPC to about 50 g of deionized water, stir magnetically until completely dissolved, then add 0.5 g of Irgacure 2959, continue stirring and dissolve in the dark to obtain a uniform and transparent prepolymer solution. The prepolymer solution should be stored in the dark for later use.

[0052] (2) Take 5 g of the PS-DVB@APTES / BP adsorbent obtained in the second step and place it in 50 mL of prepolymer solution. Stir gently with magnetic force for 10 min at 60 °C to ensure that the prepolymer solution fully contacts and wets the particle surface and penetrates into its pore inlet.

[0053] (3) Remove excess prepolymer solution: filter the impregnated particles through a 200-mesh stainless steel screen, and gently vibrate or roll the screen to fully remove excess and unadsorbed prepolymer solution from the surface, so as to obtain PS-DVB@APTES / BP particles with a thin layer of prepolymer solution uniformly coated on the surface.

[0054] (4) UV-induced graft polymerization: The above-mentioned moistened particles are spread evenly in a glass or quartz dish, with a thickness of a single layer or a thin layer, and irradiated under a UV light source with a wavelength of 365 nm, a light intensity of about 10 mW / cm², and an irradiation time of 15 min. Under these conditions, Irgacure 2959 generates free radicals, which initiate the polymerization of heparin methacrylate and MPC. At the same time, the aromatic ketone groups of BP undergo free radical hydrogen extraction under light irradiation and form covalent bonds with the polymer chain segments, thereby forming a dense anticoagulant hydrogel surface layer in situ on the surface of the APTES / BP bottom layer.

[0055] (5) Cleaning and Drying: After photocuring, the obtained coated resin was transferred to a beaker, and sufficient deionized water was added. The mixture was magnetically stirred for 5 min at room temperature, filtered, and the supernatant was discarded. The cleaning process was repeated 3 times, with the water changed each time. Subsequently, the resin was soaked in fresh deionized water for 4 h, with the water changed every 1 h to ensure sufficient diffusion and removal of unreacted monomers and soluble oligomers. After cleaning, the resin was filtered and dehydrated, spread thinly, and dried in a vacuum drying oven at 60 ℃ for 8 h to obtain PS-DVB adsorbent particles with an anticoagulant hydrogel composite coating on the surface. This sample can be designated as PS-DVB@APTES / BP@HM.

[0056] The coating prepared under the conditions of this embodiment has a thickness of both the bottom layer and the surface layer within the aforementioned preferred range (bottom layer approximately 1–2 μm, hydrogel surface layer approximately 2–8 μm, overall thickness approximately 3–10 μm). While maintaining the original porous structure and specific surface area of ​​PS-DVB, it achieves excellent anti-protein adhesion and anti-platelet activation properties. The corresponding test results for surface morphology, wettability, protein adsorption, platelet adhesion / activation, hemolysis rate, plasma recalcification time, and specific surface area are shown in [the table below]. Figures 1 to 7 .

[0057] Comparative Example 1

[0058] This comparative example uses PS-DVB adsorbent without any surface coating modification as the comparison sample. Only routine pretreatment is performed; the APTES / BP photosensitive silanized substrate and the methacryloylheparin / MPC anticoagulant hydrogel surface are not constructed. The specific steps are as follows:

[0059] Step 1: Pretreatment of PS-DVB Adsorbent

[0060] Take 10 g of dried PS-DVB adsorbent, place it in a beaker, add 100 mL of anhydrous ethanol, and stir magnetically for 30 min at room temperature to remove dust and soluble impurities from the particle surface. After settling, discard the supernatant and repeat the ethanol washing process twice. Then, place the resin in a vacuum drying oven at 60 ℃ and dry for 8 h to obtain pretreated PS-DVB adsorbent particles, denoted as PS-DVB (Comparative Example 1).

[0061] Step 2: Performance Testing

[0062] The pretreated PS-DVB adsorbent was subjected to surface morphology observation, protein adsorption experiment, platelet adhesion / activation experiment, hemolysis rate test, plasma recalcification time test, and specific surface area test under the same conditions as in Example 1. The test methods and conditions were consistent with those in Example 1. The relevant results are also listed below. Figures 1 to 7 The middle is used as a comparison.

[0063] The comparative example and the structure and properties of the prepared PS-DVB@APTES / BP@HM surface coating are as follows: Figures 1-6 , and as shown in Table 1.

[0064] Table 1. Performance analysis of coatings prepared in Example 1 and Comparative Example 1

[0065]

[0066] T APTES / BP Thickness of the photosensitive silanized APTES / BP substrate; T tol Total coating thickness; Ad pro Protein adsorption capacity; Ad pla Platelet adhesion amount; HR: hemolysis rate; PRT: plasma recalcification time; SSA: specific surface area.

[0067] As can be seen from Table 1, compared with Comparative Example 1, the anticoagulant hydrogel composite coating prepared in Example 1 of this invention showed significant changes in all performance indicators. First, while maintaining a total coating thickness of approximately 8 μm and a bottom layer thickness of approximately 1.7 μm, the original porous structure of the PS-DVB adsorbent was not significantly blocked, and the specific surface area actually increased from 630 m² / g to 750 m² / g. This is because the porous structure of the surface hydrogel coating forms a highly wetted hydrophilic interface on the adsorbent surface, allowing the particles to be more fully wetted and penetrated by the gas or liquid probe during the specific surface area test. The previously unexposed micropores were effectively included in the measurement, resulting in an apparent increase in specific surface area.

[0068] Secondly, the protein adsorption capacity in Example 1 decreased significantly from 0.92 μg / cm² in Comparative Example 1 to 0.021 μg / cm², indicating that the composite coating of the present invention can effectively inhibit the initial adsorption of plasma proteins on the adsorbent surface. The platelet adhesion number Adpla decreased from 1.1 × 10⁻⁶. 4 The platelet count / mm² dropped to 0, and platelet adhesion was basically not observed, indicating that the coating has a good inhibitory effect on platelet adhesion and its subsequent activation process.

[0069] Furthermore, regarding the hemolysis rate (HR), Example 1 showed a HR of 2.23%, lower than Comparative Example 1's 3.5%, and both were within the 5% safety limit specified in ISO 10993-4. This indicates that the coating of the present invention further reduces the material's damaging effect on erythrocytes, improving blood compatibility. The plasma recalcification time (PRT) increased from 202 s to 240 s, demonstrating that under the same conditions, the composite coating of the present invention can delay the coagulation process and exhibits better anticoagulant properties.

[0070] In summary, the present invention, by constructing an APTES / BP photosensitive silanized underlayer and a methacrylamide heparin / MPC anticoagulant hydrogel surface layer on the PS-DVB adsorbent, significantly reduces protein and platelet adhesion, lowers hemolysis rate, and prolongs plasma recalcification time without significantly reducing or even increasing the specific surface area. This effectively improves the anticoagulant properties and blood compatibility of the adsorbent.

[0071] from Figure 1 As can be seen from the image, the PS-DVB adsorbent treated by the method of this invention forms a continuous and uniformly distributed hydrogel coating on its surface. The magnified image shows that this hydrogel layer exhibits a regular and controllable porous structure, with pore sizes significantly larger than the original internal channel size of the PS-DVB particles, thus not blocking the resin channels. Furthermore, SEM images at different magnifications further confirm that the hydrogel coating only covers the surface of the framework and does not block the internal pore entrances; the adsorbent's interconnected pore structure remains intact, effectively ensuring that its original specific surface area and mass transfer performance are not affected.

[0072] from Figure 2 As can be seen, the comparative sample exhibited significant non-specific protein contamination due to the adsorption of a large amount of BSA protein on the particle surface; while the PS-DVB adsorbent modified with the composite coating of this invention showed a significant decrease in surface protein adhesion, with almost no obvious protein deposition. These results demonstrate that the superhydrophilic anticoagulant hydrogel surface layer constructed in this invention can effectively inhibit protein adsorption on the adsorbent surface, thereby significantly improving the material's anti-protein adhesion performance and blood compatibility.

[0073] from Figure 3 As can be seen, the comparative sample surface exhibits a large number of irregularly shaped, significantly extended platelets, displaying typical activation characteristics such as pseudopodia extension and enlargement, indicating that unmodified PS-DVB easily induces platelet adhesion and triggers the activation reaction. In contrast, the sample surface modified with the composite coating of this invention shows only a small number of round or slightly adhered platelets, without significant pseudopodia extension, maintaining an overall inactive or slightly activated morphology. This result fully demonstrates that the superhydrophilic anticoagulant hydrogel surface layer constructed in this invention can significantly inhibit platelet adhesion and activation processes, thereby effectively improving the material's antiplatelet activation performance and blood compatibility.

[0074] from Figure 4 As can be seen, the hemolysis rate of the comparative sample was 3.5%, while the hemolysis rate of the PS-DVB adsorbent modified with the composite coating in Example 1 was 2.23%. Both hemolysis rates are lower than the evaluation limit of 5% for hemolysis rate in the international standard ISO 10993-4, indicating that the hydrogel composite coating constructed in this invention maintains the blood compatibility of the material without causing additional red blood cell damage, thus meeting the safety requirements for blood contact medical materials.

[0075] from Figure 5 As can be seen, compared with the comparative example, the plasma recalcification time of the PS-DVB adsorbent modified with the composite coating in Example 1 was slightly prolonged, and the PRT of both groups of samples were within the normal reference range. This result indicates that the bio-inert anticoagulant hydrogel composite coating constructed in this invention can, to a certain extent, slow down the initiation process of the intrinsic coagulation pathway without inducing abnormal procoagulant reactions, and has a mild inhibitory effect on the coagulation system, thereby improving the safety and stability of the material in blood contact applications.

[0076] from Figure 6 As can be seen, the specific surface area of ​​the PS-DVB adsorbent after coating modification not only did not decrease, but actually increased compared to the control group. This phenomenon indicates that the hydrogel composite coating constructed in this invention has a certain internal microporous structure, which contributes additionally to the overall specific surface area after being coated on the surface of PS-DVB particles; at the same time, the coating does not block the original through-pores and macropores, and the inherent pore system of PS-DVB is completely preserved. Therefore, the introduction of the hydrogel coating can slightly increase the overall specific surface area of ​​the material without affecting the resin mass transfer performance, which helps to maintain the performance stability of the adsorbent.

[0077] from Figure 7As can be seen, the comparative PS-DVB adsorbent exhibits a large water contact angle, demonstrating significant hydrophobic properties, indicating poor surface wettability and a tendency to induce protein adsorption and blood component adhesion. In contrast, the PS-DVB adsorbent modified with the hydrogel composite coating of this invention shows a significantly reduced water contact angle, exhibiting excellent superhydrophilic properties, indicating that the coating can construct a stable hydration layer on the material surface. The contact angle results demonstrate that the hydrogel surface layer constructed in this invention can effectively improve the wettability and interfacial hydration capacity of the material surface, thereby forming a stable hydration barrier in the blood contact environment, reducing non-specific adhesion between proteins and platelets, and helping to reduce the risk of triggering the coagulation cascade reaction. This superhydrophilic interfacial characteristic is consistent with the aforementioned results on protein anti-adhesion and anti-platelet activation, further proving that the composite coating of this invention has significant advantages in improving the blood compatibility of materials.

[0078] Example 2-Example 3

[0079] The procedure was carried out according to Example 1, and unless otherwise stated, all other steps and conditions were the same as in Example 1. The difference in this example is that different types of organic solvents were used to prepare the APTES and BP undercoat solutions to investigate the effects of different organic solvent systems on the surface morphology, protein adsorption, platelet adhesion / activation behavior, hemolysis rate, plasma recalcification time, and specific surface area of ​​the resulting coatings. The relevant test results are listed in Table 2.

[0080] Table 2. Performance analysis of APTES / BP underlayers prepared with different organic solvents on composite coatings

[0081]

[0082] As shown in Table 2, anhydrous ethanol, anhydrous toluene, and anhydrous xylene all effectively dissolved APTES / BP when used as organic solvents, successfully constructing a uniform and dense APTES / BP synergistic underlayer on the PS-DVB adsorbent surface. Based on this underlayer, a stable anticoagulant hydrogel coating can be further formed on its surface through photo-initiated graft polymerization. This anticoagulant hydrogel coating is composed of cross-linked hydrophilic monomers and anticoagulant components, endowing the adsorbent with excellent antifouling and anticoagulant interfacial properties.

[0083] The thicknesses of the APTES / BP underlayer and the anticoagulant hydrogel coating formed under different organic solvent systems showed only slight experimental fluctuations, indicating that the solvent type does not affect the chemical anchoring efficiency of APTES / BP on the substrate, nor does it affect the surface film quality and structural uniformity of the anticoagulant hydrogel coating. Corresponding performance tests also showed that the coatings obtained under the three solvent systems exhibited consistent anti-protein adsorption, anti-platelet adhesion / activation, and good anticoagulant properties, while maintaining the original specific surface area of ​​the adsorbent without significant impact. These results confirm that the key biointerface properties of the coating are independent of solvent selection.

[0084] Therefore, the multilayer plating construction method described in this invention has good compatibility with organic solvents used to dissolve APTES / BP. Regardless of whether anhydrous ethanol, anhydrous toluene, or anhydrous xylene is used, a structurally complete and stable anticoagulant hydrogel coating can be obtained. In practical applications, organic solvents can be flexibly selected based on factors such as process compatibility, production safety, and cost, without affecting the final coating's anticoagulant properties and overall interfacial characteristics.

[0085] Examples 4-10

[0086] The procedure was the same as in Example 1, except that the soaking time of the PS-DVB adsorbent in the APTES / BP organic solvent solution was adjusted. The relevant properties of the samples obtained under different soaking time conditions were then tested and compared, and the results are shown in Table 3.

[0087] Table 3. Performance comparison of APTES / BP@HM hydrogel composite coatings constructed under different immersion times.

[0088]

[0089] As shown in Table 3, with the extension of the immersion time of PS-DVB adsorbent in APTES / BP organic solvent, the thickness of APTES / BP increased within a certain range, and the total coating thickness also increased. However, when the immersion time exceeded 10 hours, the thickness of the APTES / BP layer and the overall coating remained unchanged with the extension of the immersion time. Furthermore, the coatings prepared with different immersion times in Examples 4-10 showed almost identical comprehensive properties in terms of protein adsorption capacity, platelet adhesion / activation behavior, hemolysis rate, plasma recalcification time, and specific surface area, exhibiting excellent anti-protein adsorption, anti-platelet adhesion / activation, and good anticoagulant properties.

[0090] Examples 11-16

[0091] The procedure was followed according to Example 1, and unless otherwise stated, all other steps and conditions were the same as in Example 1. The difference in this example lies in adjusting the mass ratio of APTES to BP in the organic solvent solution. While ensuring the total mass fraction of APTES and BP in the solution remained constant at 5 wt%, the mass ratio was sequentially set to 1:0.01, 1:0.05, 1:0.1, 1:0.5, 1:1, 1:2, and 1:5. Subsequently, the relevant properties of the APTES / BP substrate and the HM anticoagulant hydrogel composite coating constructed on it under different APTES / BP mass ratio conditions were tested and compared. The tests included: substrate thickness T... APTES / BP Total coating thickness T tol Protein adsorption capacity Ad pro Platelet adhesion amount Ad pla The hemolysis rate (HR), plasma recalcification time (PRT), and specific surface area (SSA) were measured, and the results are listed in Table 4.

[0092] Table 4. Comparison of the performance of APTES / BP@HM anticoagulant hydrogel composite coatings constructed under different APTES / BP mass ratios.

[0093]

[0094] As shown in Table 4, with the change in the mass ratio of APTES to BP, the thickness, anti-fouling and anti-condensation properties, and specific surface area of ​​the APTES / BP underlayer and composite coating exhibit certain regular changes. When the BP content is extremely low (e.g., 1:0.01), T APTES / BP With T tol The slightly lower value indicates insufficient density of photosensitive groups in the underlying layer, resulting in a limited number of active sites that can covalently link with subsequent hydrogel chains. This slightly affects the overall film thickness and integrity of the coating, manifested in a decrease in protein adsorption capacity. pro Slightly higher.

[0095] As the BP content increased from 1:0.05 to 1:0.5, 1:1, and 1:2, T APTES / BP and T tol A slight increase followed by stabilization indicates that a relatively dense, uniform, and moderately photosensitive group content synergistic underlayer can be formed on the PS-DVB surface within this range. Correspondingly, the protein adsorption capacity of the composite coating... pro Maintaining at a low level of 0.020–0.023 μg / cm², platelet adhesion ad... plaThe hemolysis rate (HR) remained close to 0, with a hemolysis rate (HR) of approximately 2.22%–2.26%, and a slightly prolonged plasma recalcification time (PRT). All these characteristics demonstrated excellent and stable anti-protein adsorption, anti-platelet adhesion / activation, and anticoagulant properties. Simultaneously, the specific surface area (SSA) remained at approximately 748–754 m² / g, indicating that the composite coating constructed within this mass ratio range did not clog the porous structure of the PS-DVB and had virtually no adverse effect on the original pore volume and mass transfer performance of the adsorbent.

[0096] When the BP content is further increased to 1:5, the thickness of the base layer and coating increases slightly, but the protein adsorption capacity remains unchanged. pro Compared to the 1:0.5 to 1:2 conditions, the plasma recalcification time (PRT) was slightly reduced, indicating that excessively high BP content does not bring additional improvement to the biointerface performance. On the contrary, it may lead to a higher degree of local cross-linking of the coating structure due to the excessive density of photosensitive groups, affecting the flexibility of hydrophilic segments and the wettability of the interface.

[0097] In summary, the above results show that within the range of APTES to BP mass ratio of (1:0.01) to (1:5), the present invention can construct a hydrogel composite coating with anticoagulant function on the surface of PS-DVB adsorbent. When the mass ratio of APTES to BP is preferably controlled within the range of 1:0.05 to 1:2, especially within the range of approximately 1:0.1 to 1:2, more balanced and stable anti-protein adhesion, anti-platelet adhesion / activation, anticoagulant properties, and specific surface area can be obtained while ensuring a moderate coating thickness and preventing pore blockage. This further verifies the rationality and effectiveness of setting the APTES to BP mass ratio to (1:0.01) to (1:5).

[0098] Examples 17-30

[0099] This embodiment follows the method of Example 1, and all other steps and conditions remain the same unless otherwise stated. The difference in this set of embodiments lies in adjusting the mass concentrations of heparin and 2-methacryloyloxyethyl phosphocholine (MPC) in the water of the anticoagulant hydrogel prepolymer solution to investigate the effect of different heparin to MPC ratios on the structure and properties of the anticoagulant hydrogel composite coating. Specifically, the mass concentration of heparin was set to 1 wt%–30 wt%, and the mass concentration of MPC was set to 2 wt%–60 wt%. The coating thickness, protein adsorption, platelet adhesion / activation, hemolysis rate, plasma recalcification time, and specific surface area of ​​the obtained samples were systematically tested and compared, and the results are listed in Table 5.

[0100] Table 5 Performance analysis of APTES / BP@HM composite coatings constructed under different heparin and MPC concentrations

[0101]

[0102] As shown in Table 5, under the same APTES / BP photosensitive silanization substrate conditions, by systematically controlling the mass concentration of heparin and MPC in the prepolymer solution, APTES / BP@HM composite coatings with controllable thickness, stable structure, and different blood compatibility levels can be obtained. All interface properties show a regular changing trend, further proving the adjustability and universality of the multilayer plating construction strategy of this invention.

[0103] First, heparin concentration significantly affects the coating structure and anticoagulant properties. As the heparin mass fraction increases from 1 wt% to 30 wt%, the total coating thickness and specific surface area (SSA) gradually increase. This is closely related to the higher solids content and increased microporous structure formed by heparin in the hydrogel network. Protein adsorption capacity (Ad...) pro ) and platelet adhesion amount (Ad pla The anticoagulant activity of heparin also increases with increasing heparin concentration. Plasma recalcification time (PRT) increases from 234 s to approximately 240 s in the 1-5 wt% range, indicating a gradual increase in heparin's anticoagulant activity. However, when the heparin concentration exceeds 5 wt%, the PRT essentially remains in a plateau range of 241–243 s. This is because under high chain density conditions, some heparin active sites may be embedded or conformationally restricted, limiting its ability to further enhance anticoagulant effects. Therefore, heparin achieves the optimal balance between anticoagulant performance and antibioadhesion in the 3-10 wt% range.

[0104] Secondly, MPC concentration plays a dominant role in anti-fouling performance and blood compatibility. With heparin fixed at 5 wt%, as the MPC concentration increased from 2 wt% to 60 wt%, protein adsorption and platelet adhesion significantly decreased, indicating that when MPC ≥ 20 wt%, it can effectively block the contact and adhesion between plasma proteins and platelets by constructing a stable hydration layer, thereby forming a superhydrophilic non-adhesive interface close to the cell membrane. Simultaneously, the plasma retardation time (PRT) gradually increased with increasing MPC concentration (232-243 s), indicating that high MPC concentration can further delay the initiation of the coagulation cascade reaction, contributing to improved overall anticoagulant performance. The specific surface area of ​​the coating also showed a moderate increasing trend with increasing MPC, which is related to the homogenization of the hydrogel network and the formation of microporous structures promoted by MPC.

[0105] In summary, heparin and MPC exhibit a significant synergistic regulatory effect in the composite coating of this invention: heparin provides direct anticoagulant activity, while MPC significantly inhibits protein and platelet adhesion through the construction of a hydration layer. Together, they ensure the long-term anti-fouling, anticoagulant, and superhydrophilic properties of the coating. Under preferred conditions (heparin 3-10 wt%, MPC 20-60 wt%), the resulting composite coating has a moderate thickness, stable structure, and maintained or slightly increased specific surface area. It also reduces protein adsorption and platelet adhesion to below 2% and 1% of the control group, respectively, while effectively prolonging the platelet-to-thickness (PRT). These results fully demonstrate that the multilayer coating strategy proposed in this invention, consisting of an APTES / BP synergistic underlayer and a heparin / MPC hydrogel surface layer, has excellent controllability and can significantly improve the stability, safety, and anticoagulant performance of PS-DVB adsorbent in hemoperfusion.

[0106] The characterization methods for the above-mentioned anticoagulant hydrogel composite coating are as follows:

[0107] 1. Scanning electron microscopy (SEM) was used to observe the morphology and thickness of the coating.

[0108] The surface microstructure and cross-sectional morphology of the material were observed using a field emission scanning electron microscope (HITACHI S-4800, Hitachi). Before testing, the sample was subjected to a short-term gold sputtering treatment (approximately 60 s) under an inert atmosphere to enhance its conductivity. During imaging, the accelerating voltage was set to 3 kV, and the working distance was maintained within the range of 10–15 mm. Surface and cross-sectional images were acquired under these conditions, and the continuity, uniformity, and thickness distribution of the coating were analyzed.

[0109] 2. Protein Adsorption Test Method

[0110] The amount of protein adsorbed on the surface of each sample was quantitatively determined using the BCA colorimetric method. Before testing, the samples were equilibrated in PBS solution at 37℃ for 6 h to allow the surface to reach a stable hydration state. Then, a concentration of 2.0 mg / mL was added to the system. - ¹ Bovine serum albumin (BSA) solution was incubated at 37 °C for 2 h. After incubation, the sample was gently washed three times with PBS to remove unbound protein, and then placed in 1 wt% SDS solution and sonicated at room temperature for 20 min to completely desorb the adsorbed protein. The protein content in the SDS solution was determined according to the kit instructions, and the protein adsorption per unit area was calculated accordingly.

[0111] 3. Platelet adhesion test

[0112] Fresh peripheral blood from New Zealand white rabbits was used in the experiment, and platelet-enriched plasma (PRP) was obtained using a dedicated separation kit. The treated samples were immersed in PRP and incubated at 37 °C for 2 h to simulate the initial contact process between platelets and the material interface. After incubation, the samples were gently rinsed with PBS buffer at 37 °C to remove unattached platelets. Subsequently, the samples were fixed with 2.5 wt% glutaraldehyde solution at room temperature for 2 h to maintain the morphology of the attached platelets. The fixed samples were then dehydrated sequentially through a gradient of 50%–100% ethanol solutions, each gradient lasting 30 min. After dehydration, the samples were allowed to air dry, and the number and morphology of the attached platelets were observed and recorded using SEM.

[0113] 4. Hemolysis rate test

[0114] Hemolysis rate testing was conducted according to the blood compatibility evaluation standards in ISO 10993-4. Samples were co-incubated with anticoagulated human (or rabbit) venous blood, with physiological saline and deionized water serving as negative and positive controls, respectively. After incubation, plasma was separated by centrifugation, and the absorbance of the supernatant at 540 nm was measured. The hemolysis rate (HR) was calculated by comparing the results with the negative and positive controls. The calculation formula is as follows:

[0115]

[0116] The obtained HR value is used to evaluate the degree of damage the material causes to red blood cells.

[0117] 5. Plasma recalcification time (PRT) test

[0118] The effect of samples on the plasma coagulation process was determined using standard coagulation analysis methods. First, plasma treated with sodium citrate as an anticoagulant was obtained and incubated with the sample for a certain period. Then, calcium chloride solution was added at 37 °C to restore coagulation activity, and a timer was started simultaneously. Timing was stopped when a visible gel-like structure appeared in the plasma; this time was the plasma recalcification time (PRT). The degree of PRT prolongation reflects the material's inhibitory effect on the intrinsic coagulation pathway.

[0119] 6. Specific Surface Area (SSA) Test

[0120] The specific surface area (SSA) of the samples was determined using the nitrogen adsorption method (BET analysis). Before testing, the samples were thoroughly dried under vacuum to remove adsorbed moisture. Adsorption-desorption isotherms were then recorded at liquid nitrogen temperature, and the SSA was calculated using the BET model. This index reflects the retention of the material's pore structure and the change in the effective surface contact area after coating treatment.

[0121] In summary, this invention addresses the problems of protein adsorption, platelet adhesion, and thrombosis easily induced by polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) for hemoperfusion in clinical applications. It proposes a method for constructing a multilayer composite coating based on an APTES / BP synergistic underlayer and a heparin / MPC anticoagulant hydrogel surface. By first introducing a silanized photosensitive underlayer onto the PS-DVB surface, and then in situ grafting methacrylamide heparin and MPC onto it, this invention achieves chemical anchoring and thin-layer construction of the coating on an inert porous resin surface, while maintaining high adhesion, non-clogging of pores, and long-term anticoagulant properties.

[0122] System test results show that, under the premise of a total coating thickness of only 3–10 μm and controllable bottom / top layer thickness, the composite coating of this invention can significantly reduce protein adsorption and platelet adhesion, significantly prolong plasma recalcification time, and maintain the original hierarchical porous structure and mass transfer performance of PS-DVB without sacrificing, and even to some extent increasing, the specific surface area. By adjusting the mass ratio of APTES to BP and the concentrations of heparin and MPC in the prepolymer solution, a stable anticoagulant and antifouling interface can be obtained within a wide parameter range, achieving fine control of the coating structure and biological properties, and verifying the adjustability and reproducibility of the process of this invention.

[0123] Therefore, the APTES / BP@HM anticoagulant hydrogel composite coating constructed in this invention not only solves the key technical problems of insufficient adhesion, easy coating peeling and serious "pore blockage" in the surface modification of existing PS-DVB adsorbents, but also significantly improves the blood compatibility and safety of the material during blood perfusion. It is suitable for long-term anticoagulant surface modification of various targeted adsorption blood perfusion materials such as bilirubin and toxins, and has good clinical application prospects and industrialization promotion value.

[0124] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent, characterized in that, The composite coating comprises a base layer composed of 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP), and an anticoagulant hydrogel surface layer covering the surface of the base layer and formed by photoinitiated graft polymerization; wherein the anticoagulant hydrogel surface layer is composed of heparin methacrylamide and 2-methacryloyloxyethyl phosphocholine (MPC).

2. The anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 1, characterized in that, The bottom layer is a silanized photosensitive bottom layer formed by 3-aminopropyltriethoxysilane APTES and benzophenone BP on the surface of polystyrene-divinylbenzene copolymer macroporous adsorption resin PS-DVB.

3. The anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 1, characterized in that, The overall thickness of the composite coating is 3 μm to 10 μm, the thickness of the bottom layer is 1 μm to 2 μm, and the thickness of the anticoagulant hydrogel surface layer is 2 μm to 8 μm.

4. A method for preparing an anticoagulant hydrogel composite coating on the surface of a blood perfusion adsorbent as described in any one of claims 1-3, characterized in that, Includes the following steps: Step 1: Deposit 3-aminopropyltriethoxysilane (APTES) and benzophenone (BP) onto the surface of polystyrene-divinylbenzene copolymer macroporous adsorption resin (PS-DVB) to form an underlayer; Step 2: Graft polymerization of heparin methacrylamide and 2-methacryloyloxyethyl phosphocholine (MPC) on the surface of the bottom layer is initiated by ultraviolet light to form an anticoagulant hydrogel surface layer, thereby finally obtaining the anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent.

5. The method for preparing the anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 4, characterized in that, The specific steps for step one are as follows: The polystyrene-divinylbenzene copolymer macroporous adsorption resin PS-DVB is immersed in an organic solvent solution containing 3-aminopropyltriethoxysilane APTES and benzophenone BP, and treated at 40 ℃~80 ℃ for 1~48 hours. After washing and drying, a photosensitive substrate is obtained. The organic solvent is selected from at least one of anhydrous ethanol, anhydrous toluene, and anhydrous xylene.

6. The method for preparing the anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 5, characterized in that, The mass ratio of APTES to BP in the organic solvent solution is (1:0.01) to (1:5), and the total mass fraction of APTES and BP is 0.1 wt% to 10 wt% of the organic solvent.

7. The method for preparing the anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 4, characterized in that, The anticoagulant hydrogel prepolymer used in step two is formed by heparin methacrylamide, MPC, photoinitiator Irgacure 2959 and water. The mass concentration of heparin methacrylamide in water is 1 wt% to 30 wt%, the mass concentration of MPC in water is 2 wt% to 60 wt%, and the mass concentration of Irgacure 2959 in water is 0.5 wt% to 2 wt%.

8. The method for preparing the anticoagulant hydrogel composite coating on the surface of the blood perfusion adsorbent according to claim 7, characterized in that, The grafting polymerization of the anticoagulant hydrogel surface layer: PS-DVB adsorbent with APTES / BP deposited on the bottom layer was placed at 60 °C and immersed in an aqueous prepolymer solution containing heparin methacrylate, MPC and photoinitiator Irgacure 2959. The mixture was stirred for 3–20 min, then filtered through a 200-mesh stainless steel sieve to remove excess prepolymer solution. The mixture was then irradiated with 365 nm ultraviolet light for 5–30 min to achieve surface grafting polymerization, forming an anticoagulant hydrogel surface layer in situ on the bottom layer surface. After photocuring, the obtained material was washed three times with deionized water for 5 min each time, and then immersed in deionized water for 1–12 h. After washing, the material was vacuum dried at 60 °C for 4–12 h.

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