Method for the production of metal-polyphenol polymer coatings for metal-based biomaterials, metal-based biomaterials and uses

Abstract

The application discloses a preparation method of a metal-polyphenol polymer coating for a metal-based biomaterial, a degradable medical metal-based biomaterial composite and application. The preparation method is characterized in that the degradable medical metal-based biomaterial is immersed into a reaction solution containing a transition metal salt, a polyphenol monomer, an alkaline catalyst and an organic solvent, and a metal-polyphenol polymer coating is formed on the surface of the metal substrate by using the transition metal ion to catalyze the in-situ polymerization and self-assembly of the polyphenol monomer under an alkaline condition. The application is prepared by a full organic phase synthesis method and by adding suitable transition metal ions, so that the metal substrate is prevented from being corroded in advance by an aqueous solution, and a supramolecular polymer coating is prepared. The coating is dense and complete, the thickness of the coating is adjustable, the coating is combined closely with the substrate, compared with an existing self-assembled small molecule coating, the coating can provide a longer period, stable and excellent protection effect for the metal substrate, and can be widely applied to various degradable medical metal-based biomaterials and devices, and has high conversion value.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a method for preparing a metal-polyphenol polymer coating for metal-based biomaterials, a metal-based biocomposite material and its applications, and particularly to a method for preparing a metal-polyphenol polymer coating for degradable medical metal-based biomaterials, a degradable medical metal-based biocomposite material and its applications. Background Technology

[0002] Biodegradable medical metal materials are a class of biomedical materials that can gradually corrode and degrade in the body and eventually be absorbed or excreted by the body. They mainly include magnesium, zinc, iron, molybdenum and their alloys. Compared with traditional non-degradable metal materials (stainless steel, nickel-titanium alloy, cobalt-chromium alloy, etc.), biodegradable medical metal materials have the following advantages: (1) After fulfilling their function in the body, they can be completely absorbed and degraded, reducing inflammatory reactions and eliminating foreign body reactions while avoiding secondary surgery for removal, significantly reducing patient pain and medical costs; (2) Magnesium, zinc, iron and molybdenum are all essential elements for the human body and have good biosafety; (3) Degradation products usually have biological activity, such as magnesium and zinc ions having the effect of promoting cell differentiation and growth within a certain concentration range.

[0003] However, biodegradable medical metals also face a series of challenges in in vivo implantation: (1) Uncontrollable degradation makes it difficult to achieve precise matching with tissue combination cycles. The rapid degradation of magnesium-based alloys leads to premature loss of implant function, while the corrosion rate of iron-based alloys is much lower than the time required for tissue healing, resulting in long-term implant retention; (2) Insufficient interfacial biocompatibility. The products of rapid magnesium degradation and the sharp increase in local pH may induce hemolysis and inflammatory reactions. Excessive zinc ion concentration directly induces cell apoptosis, and iron overload can induce macrophages to polarize towards the pro-inflammatory (M1) type; (3) Difficulty in adapting and coordinating implantation functions. For example, magnesium-based alloys have the highest degradation rate in the early stage of implantation, which may lead to premature loss of mechanical properties, which is the critical period when fracture healing or vascular remodeling requires the most mechanical support. The high elastic modulus of iron-based alloys may also cause stress shielding effects. Simple alloying only mainly improves mechanical properties, and it is difficult to achieve both the controllability of degradation and the requirements of biological function required for implantation applications at the same time.

[0004] To address these issues, researchers have developed various surface modification techniques to regulate the degradation behavior of biodegradable metals and improve their biological properties. However, the existing technology still has the following limitations: (1) Insufficient bonding between coating and substrate: coatings prepared by micro-arc oxidation, spraying, spin coating, etc. are mostly physically bonded, which are easy to peel off when degradable metals are corroded, reducing the protective effect of the coating and the peeling particles may cause inflammation or thrombosis; (2) Limited anti-corrosion effect of coating and single anti-corrosion mechanism: for magnesium and zinc alloys, whether it is inorganic ceramic coating or polymer coating, most of them can only provide physical barrier protection in the initial stage to delay corrosion, and it is difficult to achieve long-term regulation and multi-mechanism regulation of degradation rate; (3) Poor compatibility between coating thickness and preparation process: in order to ensure the biocompatibility of the implant interface, especially for small-sized implants with complex geometric structures such as vascular stents and porous bone stents, the coating thickness needs to be controlled at the submicron level or even the nanometer level, and uniform coverage is required. However, most of the existing coating preparation processes are direct physical deposition, which makes it difficult to achieve continuous and uniform coating on the surface of these implants, and problems such as discontinuous coating and uneven thickness are easy to occur, affecting the overall performance of the coating.

[0005] Polyphenol coatings are widely used on various material surfaces due to their unique adhesion properties and excellent biocompatibility. Compared with traditional biodegradable pharmaceutical metal surface coatings, polyphenol coatings have at least the following significant advantages: (1) Excellent interfacial bonding performance: Polyphenol molecules are rich in catechol groups, which can form coordination bonds with hydroxyl groups on many substrate surfaces, thereby enhancing the bonding force between the coating and the substrate; (2) Good biocompatibility and bioactivity: Many polyphenol monomers are derived from plant polyphenols and have good biosafety; (3) Strong molecular designability: Polyphenols and their derivatives have chemically active functional groups (such as phenolic hydroxyl and amino groups), which can be further chemically modified to achieve secondary functionalization and multifunctionalization of materials.

[0006] However, on the one hand, the self-assembly polymerization process of polyphenol monomers is uncontrollable; on the other hand, most existing reports involve preparing polyphenol coatings in aqueous solutions, which is not suitable for biodegradable metal substrates. This is because biodegradable metal-based biomaterials are easily corroded by the solution during aqueous preparation, preventing the coating from completely covering the sample surface and providing effective protection. In fact, it may even promote localized corrosion of the biodegradable metal surface. For example, invention patent CN108796491B discloses a magnesium-based metal conversion coating with high corrosion resistance and surface functionalization, and its preparation method. This method involves reacting a pretreated magnesium alloy in a polycationic electrolyte solution, removing it, and washing it with deionized water; then reacting the resulting product in a mixed solution of polyphenol compounds and polyanionic electrolytes, removing it, and washing it with deionized water; repeating the above reaction steps alternately, and finally drying with nitrogen to obtain a polyphenol-based conversion coating with high corrosion resistance and surface functionalization. This patent does not consider the corrosion of the magnesium alloy by the aqueous reaction solution during the preparation process.

[0007] Furthermore, most of the currently disclosed patents regarding polyphenol coatings only involve self-assembled small molecules rather than polymers. Compared to coatings containing self-assembled small molecules, polyphenol coatings containing polymers can provide more stable protection for biodegradable medical metals. For example, patent CN 117531045B discloses a method for preparing a composite coating on a magnesium alloy surface and a biomedical implantable magnesium alloy. This invention uses a magnesium alloy as a substrate, prepares a magnesium fluoride coating through a fluorination reaction, and after plasma treatment, prepares a polydopamine coating on its surface through a self-polymerization reaction. The composite coating not only slows down the degradation rate of the magnesium alloy substrate and has a bioactive loading function, but also can continuously degrade in vivo, exhibiting good biocompatibility. For example, the applicant's earlier invention patent CN105126168B disclosed a biomimetic multifunctional coating for magnesium-based medical materials and devices, its preparation, and its uses. This patent not only improved the reaction solvent from an aqueous phase to an organic phase, effectively solving the problem that magnesium-based materials are easily corroded in aqueous solutions, resulting in incomplete coatings and significantly reduced material corrosion resistance, but also obtained a polydopamine film layer through in-situ growth via self-polymerization, improving the coating's strength and durability. However, subsequent long-term animal implantation experiments revealed that the low molecular weight of the polydopamine film layer in the aforementioned literature was a significant drawback. The excessively short molecular chains could not construct a physically entangled network capable of bearing stress, and the weak intermolecular forces led to low cohesive strength and insufficient deformation stability. Furthermore, it was difficult to form a strong and tough aggregated structure, making it more sensitive to environmental degradation conditions. Consequently, the long-term protective effect of this patented coating remained relatively limited.

[0008] Based on this, how to obtain a supramolecular polymer coating suitable for biodegradable medical metal-based biomaterials under all-organic phase synthesis conditions, and satisfy excellent long-term degradation regulation performance and outstanding biofunctionality, is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0009] To address the shortcomings of the existing technologies, this invention provides a method for preparing a metal-polyphenol polymer coating for metal-based biomaterials, a biodegradable medical metal-based biocomposite material, and its applications. This invention directly impregnates biodegradable medical metal-based biomaterials in an organic solution containing transition metal salts, polyphenol monomers, and an alkaline catalyst. This not only avoids the corrosion of the biodegradable medical metal by the aqueous solution during preparation but also achieves a one-step in-situ growth method using a transition metal-catalyzed polyphenol self-polymerization reaction, resulting in a supermolecular polymer coating with long-term degradation regulation performance and excellent biofunctionality.

[0010] In a first aspect, the present invention provides a method for preparing a metal-polyphenol polymer coating for metal-based biomaterials, comprising the following steps: Step 1: Dissolve the transition metal salt and polyphenol monomer in an organic solvent to obtain a transition metal salt solution and a polyphenol solution, respectively; Step 2: Mix the transition metal salt solution and polyphenol solution evenly, add an alkaline catalyst to dissolve, and obtain the reaction solution; Step 3: The metal-based biomaterial is immersed in the reaction solution. The transition metal ions catalyze the oxidation and polymerization of polyphenol monomers and undergo supramolecular assembly with the polymerized polyphenols through coordination, thereby coating the surface of the biodegradable medical metal-based biomaterial with a metal-polyphenol polymer coating. The weight-average molecular weight (Mw) of the polyphenol polymer is higher than 800 Da.

[0011] Furthermore, the weight-average molecular weight (Mw) of the polyphenol polymer is between 1000 and 15000 Da.

[0012] Furthermore, the metal-based biomaterial also includes surface treatments such as grinding and optional polishing before cleaning.

[0013] Furthermore, the drying of the metal-based biomaterial includes at least one of inert gas drying, nitrogen drying, and vacuum drying.

[0014] This invention systematically studies and develops a metal-polyphenol polymer coating applicable to the surface of biodegradable medical metal-based biomaterials. This coating is formed through in-situ polymerization and self-assembly of polyphenol monomers. The polyphenol polymer has a weight-average molecular weight higher than 800 Da, preferably 1000-15000 Da. The coating is complete, uniform, and dense, with a relatively tight bond to the matrix. It is thin (5 nm~5 μm) and its thickness can be controlled by reaction time and transition metal ions, which is beneficial for adapting to the needs of cell growth and migration. The use of transition metal ions and corresponding polyphenol monomers enables the polymer to form a network structure cross-linked by strong coordination bonds, thereby combining multiple anti-corrosion mechanisms to regulate the coating's anti-corrosion performance over the long term, allowing the material to fully perform its service function under various conditions. It synergistically leverages the biosafety and bioactivity of polyphenols and the biofunctionality of metal ions.

[0015] Furthermore, the polyphenol monomers include at least one of catechin, catechin, pyrogallol, phlorogallol, resorcinol, tannic acid, gallic acid, amino and / or alkyl substituted derivatives on their corresponding benzene ring structures, and hydrochloride / bromate salts of the above monomers or substituted derivatives.

[0016] Furthermore, the transition metal salt is selected from one or more of the hydrochloride, nitrate, sulfate, phosphate, oxalate, acetate, citrate, and complex salts corresponding to scandium, titanium, vanadium, manganese, iron, copper, zinc, zirconium, niobium, molybdenum, silver, hafnium, tantalum, lanthanum, cerium, praseodymium, neodymium, samarium, and gadolinium.

[0017] Furthermore, the transition metal ions include ions corresponding to at least one of the elements selected from manganese, iron, copper, molybdenum, cerium, praseodymium, and gadolinium; The concentration of polyphenol monomers in the reaction solution is 0.5~50mM, and the concentration of transition metal salts in the reaction solution is 0.1~50mM.

[0018] This invention screened and optimized the types of polyphenol monomers and transition metal ions through a large number of experiments, giving full play to the synergistic effect of transition metal ions and polyphenols. The resulting metal-polyphenol polymer coating has excellent long-term degradation regulation performance and outstanding biofunctionality, with "degradation-function" coupling characteristics. Its effect far exceeds that of existing self-assembled small molecule coatings and is also superior to the protective effect of low molecular weight polymer coatings.

[0019] Furthermore, the reaction solution satisfies at least one of the following: (1) The organic solvent of the reaction solution is selected from methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, acetone, and tetrahydrofuran; (2) The alkaline catalyst is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, sodium methoxide, sodium ethoxide, potassium ethoxide, tris(hydroxymethyl)aminomethane, diethylamine, triethylamine, and aniline; (3) The mass ratio of alkaline catalyst to organic solvent is 0.001:1~0.2:1.

[0020] The reaction solution of this invention is an organic solvent containing transition metal salts, polyphenol monomers, and an alkaline catalyst. The anhydrous reaction environment does not cause significant corrosion to biodegradable medical metal-based biomaterials (including those that have undergone pretreatment). The prepared metal-polyphenol polymer coating is complete, dense, and uniform.

[0021] Furthermore, in step S4, the impregnation process includes constant temperature impregnation at 10~40°C for 1~60 hours in an air or oxygen atmosphere to form a metal-polyphenol polymer coating containing nanoparticles through in-situ polymerization self-assembly, with a coating thickness of 5nm~5μm.

[0022] The impregnation process includes multiple impregnations or a single impregnation, until a metal-polyphenol polymer coating of a predetermined thickness is obtained. In practice, using a multiple impregnation method is beneficial for precise control of the coating thickness.

[0023] Furthermore, by selecting different concentrations of polyphenol monomers, transition metal salts, and reaction times, the coating thickness and polymer molecular weight can be controlled. For example, metal-based biomaterials can be successively immersed in reaction solutions with different concentrations of polyphenol monomers and transition metal salts to obtain a gradient distribution of polymer molecular weight in the coating.

[0024] Furthermore, the metal-based biomaterial satisfies at least one of the following: (1) Metal-based biomaterials include at least one of magnesium, zinc, iron, molybdenum and their alloys; (2) Metal-based biomaterials include oxide micro / nano particles of at least one of magnesium, zinc, iron, molybdenum and their alloys; (3) Before step one, the metal-based biomaterial is cleaned, dried, and optionally pretreated, including at least one of fluorination, alkaline heat treatment, phosphorylation, micro-arc oxidation or anodizing.

[0025] Secondly, the present invention also provides a biodegradable medical metal-based biocomposite material, comprising a biodegradable medical metal-based biomaterial and a metal-polyphenol polymer coating coating the metal-based biomaterial, wherein the metal-polyphenol polymer coating is prepared by the aforementioned preparation method.

[0026] Thirdly, the present invention also provides the use of the aforementioned biodegradable medical metal-based biocomposite material in the manufacture of cardiovascular stents, medical catheters, nerve conduits, tissue engineering scaffolds, and orthopedic implants.

[0027] Furthermore, cardiovascular stents include at least one of magnesium, zinc, iron, molybdenum, and their alloys.

[0028] Furthermore, orthopedic implants include, but are not limited to, bone screws and bone plates.

[0029] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention systematically studies and develops a method for preparing a metal-polyphenol polymer coating for biodegradable medical metal-based biomaterials, and prepares a biodegradable medical metal-based biocomposite material. First, by using an organic solvent, the corrosion of the biodegradable medical metal-based biomaterial by the aqueous environment during the preparation process is avoided, providing a basic guarantee for obtaining a complete and dense coating. Second, appropriate transition metal ions are added during the preparation of the polyphenol polymer coating. The transition metal ions can catalyze the oxidative self-polymerization process of polyphenols, thereby flexibly controlling the film-forming kinetics of the polyphenol polymer coating. The transition metal ions can also crosslink with polyphenol polymer molecules through strong coordination bonds, improve the stability of the coating, assist the supramolecular assembly of polyphenol molecules, and obtain a supramolecular polymer coating (Mw higher than 800 Da, preferably 1000-15000 Da). The overall thickness of the coating can be controlled, and the bonding with the matrix is ​​strong. Its technical effect is beyond that of existing self-assembled small molecule coatings or low molecular weight polymers.

[0030] (2) The coating prepared by the present invention exerts both electrochemical and chemical corrosion protection by coordinating and crosslinking the selected transition metal ions with polyphenol monomers, and simultaneously inhibits hydrogen evolution and oxygen absorption corrosion. Thus, it can regulate the corrosion resistance of the material in the long term through a variety of anti-corrosion mechanisms. For example, the coating prepared on magnesium-based biomaterials can provide the substrate with long-term effective degradation regulation for more than 2 months to 2 years at a thickness of nanometers, reducing the degradation rate of the material by 99%, and providing good protection in the pH range of 4-10.

[0031] (3) The coating prepared by the present invention has good biocompatibility and bioactivity. The optimized screened metal ions and polyphenol monomers can play their respective biological functions, and the synergy between the two can produce a "1+1>2" synergistic effect. (4) The coating preparation method proposed in this invention is simple, easy to implement, and low in cost, and can be widely applied to various biodegradable medical metal-based biomaterials and devices. In terms of materials, metal-based biomaterials include at least one of magnesium, zinc, iron, molybdenum and their alloys, or their oxide micro / nano particles; in terms of specific applications, they also include, but are not limited to, the manufacture of magnesium, zinc, iron, and molybdenum-based cardiovascular stents, medical catheters, nerve conduits, tissue engineering scaffolds, and orthopedic implants such as bone nails and bone plates, which have broad application prospects and high transformation value. Attached Figure Description

[0032] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings: Figure 1 shows the water contact angle of an unmodified pure zinc surface (a) and the water contact angle of the surface after coating with a manganese-catechin polymer in Example 1 (b). Figure 2 Fluorescence micrographs of EA.hy926 endothelial cells adhered to a copper-phloroglucinol polymer coating on a pure magnesium surface after alkali heat treatment; wherein, (a) shows the adhesion of endothelial cells on the surface of the well plate; (b) shows the adhesion of endothelial cells on the pure magnesium surface of Example 2 after being coated with a copper-phloroglucinol polymer coating. Figure 3 The image shows the AFM morphology of the Fe-Mn alloy surface after coating with an iron-pyrogallol polymer coating in Example 3. Figure 4 The magnesium ion content in the extracts of the bare Mg-Re alloy, the composite material sample with cerium coating and praseodymium-pyrogallol polymer coating on the surface of the Mg-Re alloy in Example 4, the alloy fluorinated sample, the alloy polylactic acid treated sample, and the alloy organosilane treated sample were all immersed in DMEM for 6 months. The data were then analyzed by ICP-AES. Figure 5 Tafel polarization curves in HBSS solution for the unmodified bare Mg-Re alloy sample and the composite sample of the Mg-Re alloy of Example 4 with cerium-praseodymium-pyrogallol polymer coating. Figure 6 SEM images of the corroded surface and cross-section of the unmodified bare Mg-Re alloy sample and the composite sample of the Mg-Re alloy of Example 4 coated with cerium, praseodymium-pyrogallol polymer coating after immersion in DMEM for 1 year. Figure 7 This is a TEM image of the surface of pure magnesium nanoparticles after being coated with a gadolinium-zinc-gallic acid polymer coating, as shown in Example 6. Detailed Implementation

[0033] To better understand the above technical solutions, a detailed description of the solutions will be provided below in conjunction with the accompanying drawings and specific embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0034] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” as used in the embodiments of this invention and the appended claims are also intended to include the plural forms, and “multiple” generally includes at least two unless the context clearly indicates otherwise.

[0035] It should also be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a product comprising a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a product. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in a product that includes said element.

[0036] A biodegradable medical metal-based biocomposite material includes a biodegradable medical metal-based biomaterial and a metal-polyphenol polymer coating coating the biomaterial. The metal-polyphenol polymer coating is prepared by the following method, which includes the following steps: S1. The biodegradable medical metal-based biomaterial can be cleaned and dried for later use; wherein, the metal-based biomaterial includes at least one of magnesium, zinc, iron, molybdenum and their alloys, or oxide micro / nano particles of the aforementioned metals or alloys. In a preferred embodiment, after step S1, the metal-based biomaterial undergoes pretreatment, which includes at least one of fluorination, alkaline heat treatment, phosphorylation, micro-arc oxidation, or anodizing.

[0037] S2. Dissolve the transition metal salt and polyphenol monomer separately in an organic solvent to obtain a transition metal salt solution and a polyphenol solution; wherein: Organic solvents selected from methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, acetone, and tetrahydroquinone; Transition metal salts are selected from one or more of the hydrochlorides, nitrates, sulfates, phosphates, oxalates, acetates, citrates, and complex salts of the corresponding anions of scandium, titanium, vanadium, manganese, iron, copper, zinc, zirconium, niobium, molybdenum, silver, hafnium, tantalum, lanthanum, cerium, praseodymium, neodymium, samarium, and gadolinium.

[0038] The complex salts include, but are not limited to, cerium ammonium nitrate, ferrous ammonium sulfate, ferric ammonium citrate, copper ammonium sulfate, manganese ammonium sulfate, vanadium ammonium sulfate, zinc ammonium sulfate, and titanium ammonium sulfate.

[0039] Based on the preferred transition metal salt, the corresponding transition metal ions include ions corresponding to at least one of the elements selected from manganese, iron, copper, molybdenum, cerium, praseodymium, and gadolinium.

[0040] Polyphenol monomers include at least one of catechins, catechins, pyrogallol, phlorogallol, resorcinol, tannic acid, gallic acid, amino and / or alkyl substituted derivatives on their corresponding benzene ring structures, and hydrochloride / bromate salts of the above monomers or substituted derivatives.

[0041] S3. Mix the transition metal salt solution and the polyphenol solution thoroughly, add an alkaline catalyst to dissolve, and obtain the reaction solution; wherein: Alkaline catalyst, selected from sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, sodium methoxide, sodium ethoxide, potassium ethoxide, tris(hydroxymethyl)aminomethane, diethylamine, triethylamine, and aniline; The mass ratio of alkaline catalyst to organic solvent is 0.001:1 to 0.2:1; The concentration of polyphenol monomers in the reaction solution is 0.5~50mM; The concentration of transition metal salts in the reaction solution is 0.1~50mM.

[0042] S4. The metal-based biomaterial is immersed in the reaction solution, where transition metal ions catalyze the oxidation and polymerization of polyphenol monomers and undergo supramolecular assembly with the polymerized polyphenols through coordination, thereby coating the surface of the biodegradable medical metal-based biomaterial with a metal-polyphenol polymer coating. The weight-average molecular weight (Mw) of the polyphenol polymer is higher than 800 Da, preferably between 1000-15000 Da.

[0043] In a preferred embodiment, the impregnation process includes immersing the material at a constant temperature of 10-40°C for 1-60 hours in an air or oxygen atmosphere to form a metal-polyphenol polymer coating containing nanoparticles through in-situ polymerization and self-assembly, with a coating thickness of 5 nm-5 μm.

[0044] After the reaction is complete, the mixture is washed sequentially with ultrapure water and organic solvent, and then dried with inert gas or nitrogen. Optionally, ultrasonic treatment can be applied during the organic solvent cleaning process.

[0045] The biodegradable medical metal-based biocomposite materials prepared by the above method can be used to manufacture cardiovascular stents, medical catheters, nerve conduits, tissue engineering scaffolds, orthopedic implants, etc., and have broad application prospects and high transformation value.

[0046] Example 1 This embodiment describes the preparation of a metal-polyphenol polymer coating on a pure zinc surface. The specific preparation steps are as follows: S1. Polish the pure zinc with 320#, 1200#, and 3000# wet sandpaper in sequence, then sonicate it with anhydrous ethanol solution and dry it with nitrogen gas.

[0047] S2. Dissolve manganese nitrate (15 mM) and catechin (10 mM) in methanol to prepare transition metal salt solutions and polyphenol solutions, respectively.

[0048] S3. Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add ammonia (mass ratio of ammonia to the organic solvent methanol is 0.2:1) to obtain the reaction solution.

[0049] S4. Immerse pure zinc in the reaction solution and soak at 30°C for 12 hours. After soaking, remove the sample and wash it with ultrapure water and anhydrous ethanol in sequence. After sonication, dry it with nitrogen gas to obtain a composite material sample with a Mn-catechin polymer coating on the surface of pure zinc.

[0050] After preparation, the water contact angle of the Mn-catechin polymer coating on the sample was tested. The test results are shown in the appendix. Figure 1 The figure shows that a moderately hydrophilic pure zinc surface (water contact angle of about 65°) becomes very hydrophilic after coating is prepared, with a water contact angle of about 27°, which means that the coating is successfully prepared.

[0051] XPS analysis also showed that the elemental composition of the pure zinc surface was mainly C, N, O, and Mn, while the Zn signal in the substrate was almost completely absent. Furthermore, elliptic polarization analysis revealed that the thickness of this manganese-catechin coating was approximately 25 nm after 12 hours of reaction, indicating that the thickness could be adjusted by controlling the reaction time. Mechanical property tests showed that the polymer coating had strong adhesion to the substrate, exceeding 10 MPa. Maldi-ToF analysis revealed numerous ion peaks exceeding 3000 m / z, indicating that the coating is a polymer, not a small molecule.

[0052] Example 2 This embodiment describes the preparation of a metal-polyphenol polymer coating on a pure magnesium surface. The specific preparation steps are as follows: S1. Polish the pure magnesium with 320#, 1200#, and 3000# wet sandpaper in sequence, then sonicate it with anhydrous ethanol solution and dry it with nitrogen gas.

[0053] Pretreatment: The sample was placed in a 2.5 mol / L sodium hydroxide solution and then subjected to alkaline heat treatment by shaking at 120 °C for 12 h. After that, the sample was removed and dried with nitrogen gas.

[0054] S2. Dissolve copper nitrate (5mM) and phloroglucinol (10mM) separately in anhydrous ethanol to obtain a mixture of transition metal salt solution and polyphenol solution; S3. Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add sodium hydroxide (mass ratio of 0.1:1 to the organic solvent) to obtain the reaction solution.

[0055] S4. Immerse the pure magnesium sample that has undergone alkali heat treatment in the reaction solution and soak it at 25°C for 18 hours. After soaking, take it out and wash it with ultrapure water and anhydrous ethanol in sequence. After sonication, blow it dry with nitrogen to obtain a composite material sample with a copper-phloroglucinol polymer coating on the surface of pure magnesium.

[0056] Zinc cell compatibility was evaluated using EA.hy926 endothelial cells and A7r5 smooth muscle cells. The experimental results are shown in the appendix. Figure 2 Twenty-four hours after cell seeding, the number of cells adhering to the pure magnesium sample modified with the copper-phloroglucinol polymer coating increased by 128% compared to the control group, and cell spreading was better. The coated sample promoted endothelial cell adhesion while significantly inhibiting smooth muscle cell adhesion and proliferation, effectively achieving selective vascular cell growth.

[0057] Example 3 This embodiment describes the preparation of a metal-polyphenol polymer coating on the surface of an Fe-Mn alloy. The specific preparation steps are as follows: S1. Polish the Fe-Mn alloy sequentially with 320#, 1200#, and 3000# wet sandpaper, then sonicate it with anhydrous ethanol solution and dry it with nitrogen gas.

[0058] S2. Dissolve ferric nitrate (10 mM) and pyrogallol (8 mM) separately in tetrahydrofuran to obtain a mixture of transition metal salt solution and polyphenol solution; S3. Prepare the reaction solution: Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add tris(hydroxymethyl)aminomethane (mass ratio of 0.05:1 to the organic solvent).

[0059] S4. Immerse the Fe-Mn alloy sample in the reaction solution at room temperature for 24 hours, changing the solution every 12 hours. After 24 hours, remove the sample, wash it sequentially with ultrapure water and anhydrous ethanol, sonicate it, and then dry it with nitrogen gas to obtain a composite material sample with an iron-pyrogallol polymer coating on the surface of the Fe-Mn alloy.

[0060] The iron-pyrogallol polymer coating prepared on the Fe-Mn alloy surface using this method was observed under an atomic force microscope, clearly revealing a dense nanoparticle stacking morphology (see attached figure). Figure 3 When coated stents were implanted into the rabbit abdominal aorta, compared with bare Fe-Mn alloy stents, reendothelialization was significantly accelerated (completed within 2 weeks), and there were no thrombosis, significant inflammation, or in-stent restenosis three months after implantation.

[0061] Example 4 This embodiment describes the preparation of a metal-polyphenol polymer coating on the surface of a Mg-Re alloy. The specific preparation steps are as follows: S1. Polish the Mg-Re alloy sequentially with 320#, 1200#, and 3000# wet sandpaper, then sonicate it with anhydrous ethanol solution and dry it with nitrogen gas.

[0062] Pretreatment: The sample was placed in a 40% hydrofluoric acid solution and then subjected to fluorination treatment with shaking at room temperature for 12 hours. After fluorination, the sample was removed and dried with nitrogen.

[0063] S2. Dissolve cerium nitrate (6mM), praseodymium nitrate (6mM), and pyrogallol (7.5mM) in isopropanol to obtain a mixture of transition metal salt solution and polyphenol solution; S3. Prepare the reaction solution: Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add aniline (mass ratio of 0.01:1 to the organic solvent).

[0064] S4. Immerse the fluorinated Mg-Re alloy sample in the reaction solution at 10°C for 48 hours, changing the solution every 12 hours. After immersion, remove the sample and wash it sequentially with ultrapure water and anhydrous ethanol, followed by sonication and nitrogen drying to obtain a composite material sample with a cerium-praseodymium-pyrogallol polymer coating on the surface of the Mg-Re alloy.

[0065] The Mg-Re alloy samples coated with cerium, praseodymium-pyrogallol polymer were subjected to corrosion tests by immersion in DMEM at 37°C and 5% carbon dioxide atmosphere. The magnesium ion release in the leachate of different samples was detected using ICP-AES to characterize the corrosion rate. The results are shown in the attached figure. Figure 4 As shown, after immersion for 6 months, compared with the bare Mg-Re alloy sample without any modification, the corrosion rate of the Mg-Re alloy sample with the praseodymium-pyrogallol polymer coating was reduced by approximately 99%. Furthermore, compared with other common surface modification methods, this coating exhibited significantly better corrosion resistance. Electrochemical experimental results are attached. Figure 5 As shown, the Mg-Re alloy samples modified with a cerium, praseodymium-pyrogallol polymer coating exhibit higher self-corrosion potential and lower self-corrosion current, indicating that the coating not only provides physical protection but also delays substrate degradation through electrochemical principles. SEM images of the sample surface and cross-section after one year of long-term immersion are shown in the attached figure. Figure 6 As shown, the bare Mg-Re alloy sample without any modification developed severe surface cracks after immersion for one year, and a corrosion product layer of approximately 50 μm was observed on the cross-section. In contrast, the Mg-Re alloy sample with the metal-polyphenol polymer coating remained intact, and no obvious corrosion traces were visible on the cross-section, further demonstrating the long-term corrosion resistance of the coating.

[0066] Example 5 This embodiment describes the preparation of a metal-polyphenol polymer coating on the surface of a Zn-1Ca alloy (Zn-Ca based alloy). The specific preparation steps are as follows: S1. Polish the Zn-1Ca alloy with 320#, 1200#, and 3000# wet sandpaper in sequence, then sonicate it with anhydrous ethanol solution and dry it with nitrogen gas.

[0067] S2. Dissolve molybdenum(II) acetate dimer (0.5 mM) and catechol (30 mM) separately in ethylene glycol to obtain a mixture of transition metal salt solution and polyphenol solution; S3. Prepare the reaction solution: Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add triethylamine (mass ratio of triethylamine to organic solvent is 0.005:1).

[0068] S4. Immerse the Zn-1Ca alloy sample in the reaction solution and soak at room temperature for 10 hours. After soaking, remove the sample and wash it with ultrapure water and anhydrous ethanol in sequence. After sonication, dry it with nitrogen gas to obtain a composite material sample with a molybdenum-catechol polymer coating on the surface of the Zn-1Ca alloy.

[0069] The Zn-1Ca alloy sample with the molybdenum-catechol polymer coating prepared above was immersed in a heparin solution with a concentration of 5 mg / mL (pH=8) and reacted at room temperature for 12 hours. After 12 hours, it was removed, ultrasonically cleaned with anhydrous ethanol, and dried with nitrogen gas to obtain the heparin-functionalized surface. Platelet adhesion experiments showed that compared with the unmodified heparin-coated Zn-1Ca alloy sample, the number of platelets adhering was reduced by about 50%, and the platelets exhibited an inactive spherical morphology. This demonstrates that the blood compatibility of the sample after functionalization with heparin was significantly improved.

[0070] Furthermore, the Zn-1Ca alloy sample with the prepared molybdenum-catechol polymer coating was immersed in an 80 mM silver nitrate aqueous solution and reacted at room temperature for 20 hours. Afterward, it was removed, ultrasonically cleaned with anhydrous ethanol, and dried with nitrogen gas, thus obtaining a composite material sample with a functionalized silver nanoparticle coating. S. aureus bacterial adhesion experiments showed that compared with the composite material sample without the silver nanoparticle coating, the number of adhering S. aureus bacteria was reduced by approximately 25%, and more than 99% of these were dead bacteria. This demonstrates that the antibacterial properties of the composite material sample after functionalization with silver nanoparticles were significantly improved.

[0071] The above two experimental results demonstrate that the metal-polyphenol polymer coating of this invention, due to its chemically active functional groups (such as phenolic hydroxyl and amino groups), can be further chemically modified to achieve secondary functionalization of the sample. Animal implantation experiments showed that this coated vascular stent effectively accelerates the re-endothelialization process, inhibits smooth muscle intimal hyperplasia, and reduces the matrix degradation rate by up to 90%, maintaining effective support for at least 6 months. This also indicates that the metal-polyphenol supramolecular polymer coating of this invention can significantly regulate the corrosion of metal-based biomaterials in high-speed fluid environments.

[0072] Example 6 This embodiment prepares a metal-polyphenol polymer coating on the surface of pure magnesium nanoparticles (average particle size approximately 100 nm). The specific preparation steps are as follows: S1. Dissolve gadolinium nitrate (5 mM), zinc sulfate (2.5 mM), and gallic acid (10 mM) in anhydrous ethanol to obtain a mixture of transition metal salt solution and polyphenol solution; S2. Prepare the reaction solution: Mix the transition metal salt solution and the polyphenol solution, sonicate, and then add ammonia (mass ratio of ammonia to organic solvent is 0.05:1).

[0073] S2. Immerse the pure magnesium nanoparticle sample in the reaction solution and soak at room temperature for 12 hours. Stir with a magnetic stirrer, then ultrasonically clean with anhydrous ethanol, centrifuge and dry to obtain a composite particle sample with a gadolinium-zinc-gallic acid polymer coating on the surface of magnesium nanoparticles.

[0074] TEM images are shown in the attached image. Figure 7 As shown, pure magnesium nanoparticles can be uniformly coated with a zinc-gallic acid polymer in an organic solvent, and the pure magnesium nanoparticles are not corroded by the solvent during the preparation process. This further demonstrates the universality of the metal-polyphenol polymer coating preparation method of the present invention.

[0075] Comparative Example 1 This comparative example prepares a polyphenol polymer coating on a pure zinc surface, and the preparation steps are basically the same as in Example 1, except that Comparative Example 1 does not use transition metal salts: Preparation of reaction solution: Dissolve catechin (10mM) in methanol, sonicate, and then add ammonia (mass ratio of ammonia to organic solvent is 0.2:1).

[0076] The obtained catechin polyphenol coating was analyzed by Maldi-ToF. It was found that the ion peaks mainly appeared in the range of less than 300 m / z, and there were very few ion peaks above 500 m / z. In contrast, the Maldi-ToF test results of Example 1 showed a large number of ion peaks above 3000 m / z. This indicates that the molecular weight of the coating obtained in Comparative Example 1 is much lower than that in Example 1. This clearly demonstrates that transition metal ions play a decisive role in the catalysis and assistance of polyphenol molecules in assembling into a more stable supramolecular polymer.

[0077] Comparative Example 2 This comparative example prepared a polyphenol coating on the surface of a Mg-Re alloy. The preparation steps were basically the same as in Example 4, except that Comparative Example 2 did not use transition metal salts. Preparation of reaction solution: Dissolve pyrogallol (7.5 mM) in isopropanol, sonicate, and then add aniline (mass ratio of 0.01:1 to organic solvent).

[0078] Corrosion tests were conducted on Mg-Re alloy samples coated with pyrogallol in DMEM. It was found that although magnesium ion release decreased by 60% within two weeks, meaning the corrosion rate of the coated samples decreased by 60% after two weeks of immersion, after one month, magnesium ion release in the coated samples became increasingly faster, and the corrosion rate was only 20% lower than that of the unmodified Mg-Re alloy matrix. This indicates that the metal-polyphenol polymer coating in Example 4, which involves supramolecular assembly with transition metal ions, provides longer-term (months to years) corrosion regulation compared to the lower molecular weight polyphenol coating obtained in Comparative Example 2, further demonstrating the decisive role of transition metal ions in catalyzing and assisting the assembly of polyphenol molecules into more stable supramolecular polymers.

[0079] Comparative Example 3 This comparative example prepares a metal-polyphenol polymer coating on the surface of an Fe-Mn alloy. The preparation steps are basically the same as in Example 3, except that the reaction solution in Comparative Example 3 is an aqueous phase. Preparation of reaction solution: Dissolve ferric nitrate (10 mM) and pyrogallol (8 mM) in ultrapure water, sonicate, and then add tris(hydroxymethyl)aminomethane (mass ratio of 0.05:1 to organic solvent).

[0080] SEM images show that the surface of the metal-polyphenol polymer coating prepared in aqueous phase is uneven, with many cracks and pits. This indicates that the aqueous phase preparation method not only easily causes corrosion to the metal substrate, but the resulting coating also fails to provide good protection for the substrate. The organic solvent preparation method can effectively avoid this problem.

[0081] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the protection scope of the technical solution of the present invention, which do not affect the substantive content of the present invention.

Claims

1. A method for preparing a metal-polyphenol polymer coating for metal-based biomaterials, characterized in that, Includes the following steps: Step 1: Dissolve the transition metal salt and polyphenol monomer in an organic solvent to obtain a transition metal salt solution and a polyphenol solution, respectively; Step 2: Mix the transition metal salt solution and polyphenol solution evenly, add an alkaline catalyst to dissolve, and obtain the reaction solution; Step 3: The metal-based biomaterial is immersed in the reaction solution. The transition metal ions catalyze the oxidation and polymerization of polyphenol monomers and undergo supramolecular assembly with the polymerized polyphenols through coordination, thereby coating the surface of the biodegradable medical metal-based biomaterial with a metal-polyphenol polymer coating. The weight-average molecular weight (Mw) of the polyphenol polymer is higher than 800 Da.

2. The method for preparing the metal-polyphenol polymer coating as described in claim 1, characterized in that, The weight-average molecular weight (Mw) of the polyphenol polymer is between 1000 and 15000 Da.

3. The method for preparing the metal-polyphenol polymer coating as described in claim 1 or 2, characterized in that, The polyphenol monomers include at least one of catechin, catechin, pyrogallol, phlorogallol, resorcinol, tannic acid, gallic acid, amino and / or alkyl substituted derivatives on their corresponding benzene ring structures, and hydrochloride / bromate salts of the above monomers or substituted derivatives.

4. The method for preparing the metal-polyphenol polymer coating as described in claim 3, characterized in that, The transition metal salt is selected from one or more of the hydrochloride, nitrate, sulfate, phosphate, oxalate, acetate, citrate, and complex salts of scandium, titanium, vanadium, manganese, iron, copper, zinc, zirconium, niobium, molybdenum, silver, hafnium, tantalum, lanthanum, cerium, praseodymium, neodymium, samarium, and gadolinium corresponding to the aforementioned anions.

5. The method for preparing the metal-polyphenol polymer coating as described in claim 4, characterized in that, The transition metal ions include ions corresponding to at least one of the elements selected from manganese, iron, copper, molybdenum, cerium, praseodymium, and gadolinium; The concentration of polyphenol monomers in the reaction solution is 0.5~50mM, and the concentration of transition metal salts in the reaction solution is 0.1~50mM.

6. The method for preparing the metal-polyphenol polymer coating as described in claim 4 or 5, characterized in that, The reaction solution satisfies at least one of the following: (1) The organic solvent of the reaction solution is selected from methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, acetone, and tetrahydrofuran; (2) The alkaline catalyst is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, sodium methoxide, sodium ethoxide, potassium ethoxide, tris(hydroxymethyl)aminomethane, diethylamine, triethylamine, and aniline; (3) The mass ratio of alkaline catalyst to organic solvent is 0.001:1~0.2:

1.

7. The method for preparing the metal-polyphenol polymer coating as described in claim 6, characterized in that, In step three, the impregnation process includes constant temperature impregnation at 10~40℃ for 1~60 hours in an air or oxygen atmosphere to form a metal-polyphenol polymer coating containing nanoparticles through in-situ polymerization self-assembly, with a coating thickness of 5nm~5μm.

8. The method for preparing the metal-polyphenol polymer coating as described in claim 4 or 5, characterized in that, The metal-based biomaterial satisfies at least one of the following: (1) Metal-based biomaterials include at least one of magnesium, zinc, iron, molybdenum and their alloys; (2) Metal-based biomaterials include oxide micro / nano particles of at least one of magnesium, zinc, iron, molybdenum and their alloys; (3) Before step one, the metal-based biomaterial is cleaned, dried, and optionally pretreated, including at least one of fluorination, alkaline heat treatment, phosphorylation, micro-arc oxidation or anodizing.

9. A biodegradable medical metal-based biocomposite material, characterized in that, The invention includes a biodegradable medical metal-based biomaterial and a metal-polyphenol polymer coating that coats the metal-based biomaterial, wherein the metal-polyphenol polymer coating is prepared by the preparation method according to any one of claims 1-8.

10. The use of the biodegradable medical metal-based biocomposite material according to claim 9 in the manufacture of cardiovascular stents, medical catheters, nerve conduits, tissue engineering scaffolds, and orthopedic implants.

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