An implant, its production and use

Abstract

The application discloses a kind of implant and its preparation method and application, the implant includes material body, metal oxide layer and mixed crystal layer, the mixed crystal layer is located the surface of the metal oxide layer;The metal oxide layer includes metal oxide nanorod array;The metal oxide is selected from zinc oxide, silver oxide or its combination;The mixed crystal layer includes CaP crystal and metal oxide crystal.The implant of the application is sterilized by the bacteriostatic metal ion generated by physical puncture and degradation of metal oxide nanorod, has good antibacterial effect to gram-positive bacteria and gram-negative bacteria, prevents infection;It can also relieve post-implantation inflammatory response, reduce immune response under post-implantation infection, shorten wound healing time.In addition, due to the coating effect of mixed crystal layer on metal oxide layer, the bacteriostatic metal ion is slowly released, the release time is long, and long-lasting antibacterial effect can be achieved, and post-implantation inflammatory response can be reduced.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to an implant, its preparation method, and its application. Background Technology

[0002] Superhydrophilic implants are those where the water contact angle of a water droplet on the implant surface is less than 10°, making the surface extremely easy to wet. This type of implant has seen rapid development in recent years. Using titanium as the implant body, various surface functionalization methods are employed to achieve a superhydrophilic interface. Compared to traditional hydrophobic titanium implants, superhydrophilicity provides the implant with faster blood absorption, thereby promoting osteogenic differentiation of stem cells around the implant, shortening bone healing time, and enhancing osseointegration. This makes them particularly suitable for patients with poor bone health.

[0003] Existing methods for preparing superhydrophilic implants mainly include: ① Large-particle sandblasting and acid etching: Corundum particles of approximately 0.25-0.5 mm are used to impact the implant surface under high pressure with a high-speed airflow, forming pores equivalent to bone lacunae. The implant is then immersed in a high-temperature hydrochloric acid and sulfuric acid mixture for acid etching, which etches the oxide film on the metal surface to increase hydrophilicity. The combined action of large-particle sandblasting and acid etching produces a multidimensional structure suitable for the attachment of osteoblasts and fibrinogen. ② Anodizing technology: The implant is placed in an electrolyte as the anode. Through electrochemical means, the thickness of the oxide layer on the implant surface is increased from an average of 17-200 nm to an average of 600-1000 nm, while simultaneously forming a microscopic multidimensional structure, which together promotes the osteogenic properties of the implant surface. ③ Plasma spraying technology: This technology generally uses osteo-like chemicals such as hydroxyapatite (HAP) or β-tricalcium phosphate (β-TCP) to be plasma-sprayed onto the surface of titanium implants. Leveraging the excellent biocompatibility, low immunogenicity, and corrosion resistance of HAP, the hydrophilicity and bone integration ability of pure titanium implants are improved. ④ Ultraviolet activation: In an air environment, pure titanium can form a TiO2 layer on its surface. Ultraviolet irradiation can trigger a photocatalytic redox reaction on the TiO2 surface, forming active groups such as hydroxyl and oxygen free radicals with strong oxidizing capabilities, and decomposing surface organic matter to produce a superhydrophilic surface. ⑤ Laser surface treatment technology: Femtosecond lasers can be used to prepare multi-level roughness morphologies on the surface of pure titanium implants, which are conducive to cell adhesion and growth, improving the biocompatibility of the implant and promoting osteoblast adhesion and growth on the implant surface. During the treatment process, the hydrophilicity of the titanium implant surface can be adjusted by controlling the laser energy density. However, the surfaces of superhydrophilic implants prepared using existing technologies are easily contaminated by carbon and nitrogen compounds in the air, causing them to quickly lose their superhydrophilic properties. They require storage in special environments, such as immersion in a 0.9% sodium hydroxide solution; or chairside restoration (using sodium hydroxide solution treatment or a specialized ultraviolet light activation instrument) to activate their superhydrophilicity before use. Furthermore, existing superhydrophilic implants lack antibacterial properties, making post-implantation wounds susceptible to infection and hindering post-implantation oral care. Summary of the Invention

[0004] In order to overcome the problems existing in the prior art, one of the objectives of the present invention is to provide an implant.

[0005] The second objective of this invention is to provide a method for preparing the above-mentioned implant.

[0006] The third objective of this invention is to provide a dental implant.

[0007] The fourth objective of this invention is to provide an application of an implant in the preparation of medical implant materials.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] A first aspect of the present invention provides an implant comprising, from the inside out, a material body, a metal oxide layer, a mixed crystal layer and a CaP crystal layer; the metal oxide layer comprising an array of metal oxide nanorods; the metal oxide being selected from at least one of zinc oxide and silver oxide; the mixed crystal layer comprising CaP crystals and metal oxide crystals.

[0010] In this invention, the metal oxide layer comprises an array structure of metal oxide nanorods. These nanorods have a rough surface and sharp shapes, enabling them to pierce or damage the cell membranes of bacterial strains, thus achieving physical sterilization. Simultaneously, the metal oxide nanorods continuously release antibacterial metal ions during hydrolysis, achieving chemical sterilization. The mixed crystal layer enhances the adhesion of the CaP crystal layer, preventing the CaP crystal layer from detaching from the implant during use. The CaP crystal layer protects the metal oxide layer, preventing rapid degradation during use, and also imparts a superhydrophilic surface to the implant.

[0011] Preferably, the implant is a superhydrophilic material. More preferably, the water contact angle of the implant is ≤5°; even more preferably, the implant is a superhydrophilic material with a water contact angle of 0° to 2°. The implant of the present invention has a water contact angle close to 0°, exhibiting excellent hydrophilicity.

[0012] Preferably, the water contact angle of the implant is <5° after being stored in air for 20 days.

[0013] Preferably, the content of CaP crystals decreases from the surface layer of the mixed crystal layer to the inner layer of the mixed crystal layer.

[0014] Preferably, the content of the metal oxide crystals increases from the surface layer of the mixed crystal layer to the inner layer of the mixed crystal layer.

[0015] Preferably, the molar ratio of calcium to phosphorus in the mixed crystal layer is 10:(4-8); more preferably, the molar ratio of calcium to phosphorus in the mixed crystal layer is 10:(5-7).

[0016] Preferably, the thickness of the mixed crystal layer is 0.1–10 nm; more preferably, the thickness of the mixed crystal layer is 1–8 nm; and even more preferably, the thickness of the mixed crystal layer is 2–5 nm.

[0017] Preferably, the thickness of the metal oxide layer is 200–2000 nm; more preferably, the thickness of the metal oxide layer is 500–1000 nm.

[0018] Preferably, the thickness of the CaP crystal layer is 3-100 nm; more preferably, the thickness of the CaP crystal layer is 5-50 nm; and even more preferably, the thickness of the CaP crystal layer is 10-20 nm.

[0019] Preferably, the diameter of the metal oxide nanorod is 50-200 nm; more preferably, the diameter of the metal oxide nanorod is 80-150 nm; and even more preferably, the diameter of the metal oxide nanorod is 80-120 nm.

[0020] Preferably, the material body is titanium; more preferably, the material body is pure titanium or a titanium alloy.

[0021] Preferably, the material of the material body is selected from at least one of TA3 titanium, TA4 titanium, TA5 titanium, titanium aluminum vanadium alloy, titanium aluminum zirconium alloy, titanium niobium alloy, and nickel titanium alloy.

[0022] The second aspect of the present invention provides a method for preparing the implant provided in the first aspect of the present invention, comprising the following steps:

[0023] S1: Pre-treat the surface of the material body, then mix the metal source and stabilizer and coat them onto the pre-treated surface of the material body, and then anneal it to obtain the treated material body;

[0024] S2: The treated material body, cyclohexamethylenetetramine / triamine citrate, and metal source are subjected to a hydrothermal reaction, followed by heat treatment to obtain a metal oxide layer;

[0025] S3: A mixture of calcium and phosphorus sources is coated onto the surface of the metal oxide layer and then annealed to obtain the implant.

[0026] Preferably, the annealing temperature in step S1 is 450℃~550℃; more preferably, the annealing temperature in step S1 is 480℃~540℃; even more preferably, the annealing temperature in step S1 is 480℃~520℃; more preferably, the annealing temperature in step S1 is 490℃~510℃.

[0027] Preferably, the annealing time in step S1 is 20 to 40 minutes; more preferably, the annealing time in step S1 is 25 to 35 minutes.

[0028] Preferably, step S1 is as follows: the surface of the material body is ground and polished, then washed with detergent, the metal source and stabilizer are mixed and coated on the pretreated material body surface, then dried, the coating and drying steps are repeated 0 to 5 times, and then annealed to obtain the treated material body.

[0029] Preferably, the drying temperature is 100–140°C; more preferably, the drying temperature is 110–130°C.

[0030] Preferably, in step S1, the concentration of the metal source is 0.02 to 0.1 mol / L.

[0031] Preferably, in step S1, the mass ratio of the metal source to the stabilizer is 1:(5-8).

[0032] Preferably, the concentration of the metal source in step S2 is 0.01 to 0.05 mol / L.

[0033] The concentration of the metal source in steps S1 and S2 needs to be within the above range in order to obtain excellent mixed crystal layer and CaP crystal layer during preparation.

[0034] Preferably, in step S2, the mass ratio of the metal source to cyclohexamethylenetetramine is 1:(0.8-1.2); more preferably, in step S2, the mass ratio of the metal source to cyclohexamethylenetetramine is 1:(0.9-1.1).

[0035] Preferably, in step S2, the mass ratio of the metal source to triamine citrate is 1:(0.8-1.2); more preferably, in step S2, the mass ratio of the metal source to triamine citrate is 1:(0.9-1.1).

[0036] Preferably, the pretreatment step is: grinding and polishing the surface of the material body, and then cleaning; more preferably, the pretreatment step is: grinding and polishing the surface of the material body, and then washing with detergent; the detergent includes at least one of acetone, ethanol, and deionized water; even more preferably, the pretreatment step is: grinding and polishing the surface of the material body to a grit of 2000 or higher, and then washing with acetone, ethanol, and deionized water in sequence.

[0037] Preferably, the hydrothermal reaction temperature in step S2 is 90℃~100℃; more preferably, the hydrothermal reaction temperature in step S2 is 92℃~98℃; and even more preferably, the hydrothermal reaction temperature in step S2 is 94℃~96℃.

[0038] Preferably, the hydrothermal reaction time in step S2 is 1h to 10h; more preferably, the hydrothermal reaction time in step S2 is 2h to 8h; and even more preferably, the hydrothermal reaction time in step S2 is 3h to 7h.

[0039] Preferably, the heat treatment temperature in step S2 is 300℃~400℃; more preferably, the heat treatment temperature in step S2 is 320℃~380℃; even more preferably, the heat treatment temperature in step S2 is 340℃~360℃. The purpose of the heat treatment step is to remove residual organic contaminants from the surface.

[0040] Preferably, the heat treatment time in step S2 is 1 to 3 hours; more preferably, the heat treatment time in step S2 is 1.5 to 2.5 hours.

[0041] Preferably, the annealing temperature in step S3 is 500℃~700℃; more preferably, the annealing temperature in step S3 is 550℃~650℃; and even more preferably, the annealing temperature in step S3 is 580℃~620℃.

[0042] Preferably, the annealing time in step S3 is 30 min to 120 min; more preferably, the annealing time in step S3 is 40 min to 100 min; and even more preferably, the annealing time in step S3 is 40 min to 80 min.

[0043] Preferably, in step S1, the coating step is performed by spin coating; the number of spin coatings is 1 to 20. More preferably, in step S1, the coating step is performed by spin coating; the number of spin coatings is 2 to 15. Even more preferably, in step S1, the coating step is performed by spin coating; the number of spin coatings is 3 to 10.

[0044] Preferably, in step S3, the coating step is performed by spin coating; the number of spin coatings is 1 to 20. More preferably, in step S3, the coating step is performed by spin coating; the number of spin coatings is 2 to 15. Even more preferably, in step S3, the coating step is performed by spin coating; the number of spin coatings is 3 to 10. This invention employs a method of multiple spin coatings of a mixture of calcium and phosphorus sources. The mixture of calcium and phosphorus sources is coated onto the surface of a metal oxide layer and penetrates into the interior of the metal oxide layer. During annealing, CaP crystals and metal oxide crystals are formed, and the content of CaP crystals decreases from the surface layer to the inner layer of the mixed crystal layer, while the content of metal oxide crystals increases from the surface layer to the inner layer of the mixed crystal layer.

[0045] Preferably, the calcium source is selected from at least one of calcium nitrate, calcium chloride, calcium chlorate, and calcium gluconate.

[0046] Preferably, the phosphorus source is selected from at least one of phosphorus pentoxide and phosphorus trioxide.

[0047] Preferably, the metal source is selected from at least one of zinc source and silver source.

[0048] Preferably, the zinc source is selected from at least one of zinc chloride, zinc acetate, and zinc nitrate.

[0049] Preferably, the silver source is selected from at least one of silver nitrate and silver acetate.

[0050] Preferably, the stabilizer is selected from at least one of ethanolamine, diethanolamine, and triethanolamine.

[0051] A third aspect of the present invention provides a dental implant, including the implant provided in the first aspect of the present invention.

[0052] The dental implant of the present invention has all the features and effects of the implant provided in the first aspect of the present invention.

[0053] The fourth aspect of the present invention provides the use of the implant provided in the first aspect of the present invention in the preparation of medical implant materials.

[0054] Preferably, the medical implant material includes medical implant materials for human bodies or medical implant materials for animals.

[0055] The beneficial effects of this invention are as follows: The implant of this invention utilizes antibacterial metal ions generated from the degradation of metal oxide nanorods for chemical sterilization, while simultaneously employing physical sterilization through the piercing effect of the rough and sharp surface morphology of the metal oxide nanorods on the cell membranes of bacterial strains. This achieves good antibacterial effects against both Gram-positive and Gram-negative bacteria, alleviating post-implantation inflammatory responses, reducing immune responses in post-implantation infection situations, preventing infection, and shortening wound healing time. Furthermore, due to the coating effect of the mixed crystal layer on the metal oxide layer, the antibacterial metal ions are released slowly and over a long period, achieving sustained antibacterial effects while simultaneously reducing post-implantation inflammatory responses. In addition, the mixed crystal layer can impart long-lasting superhydrophilic properties to the implant surface, promoting blood adsorption and coagulation on the implant surface. The mixed crystal layer can also release calcium and phosphorus ions, promoting osteogenic differentiation of stem cells around the implant and shortening the recovery time after implantation. On the other hand, it can reduce the degradation rate of metal oxide nanorods and improve storage stability, so that the implant still has excellent antibacterial, long-lasting anti-inflammatory and osteogenic effects after being stored in the air for 20 days. It is especially suitable for patients with high risk of infection and poor osteogenic development after implantation. Attached Figure Description

[0056] Figure 1 This is a flowchart illustrating the preparation process of the titanium implant containing ZnO nanorods in Example 1.

[0057] Figure 2 These are scanning electron microscope (SEM) images of the Ti material bulk and Ti-ZnO from Example 1.

[0058] Figure 3 These are scanning electron microscope images of the superhydrophilic implants in Examples 1-3.

[0059] Figure 4 This is a surface contact angle test diagram of the superhydrophilic implant in Example 3.

[0060] Figure 5 This is a transmission electron microscope image of the superhydrophilic implant in Example 3.

[0061] Figure 6 These are scanning electron microscope (SEM) images of the degradation process of Ti-ZnO in Example 1 and Ti-ZnO@CaP5 in Example 3.

[0062] Figure 7 These are test graphs showing the antibacterial properties of the Ti material bulk and Ti-ZnO in Example 1, and Ti-ZnO@CaP5 in Example 3.

[0063] Figure 8 These are test graphs showing the anti-inflammatory properties of the Ti material bulk and Ti-ZnO in Example 1, and Ti-ZnO@CaP5 in Example 3.

[0064] Figure 9 These are test images of the osteogenic properties of the Ti material bulk and Ti-ZnO in Example 1, and Ti-ZnO@CaP5 in Example 3. Detailed Implementation

[0065] The specific implementation of the present invention will be further described in detail below with reference to the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to the prior art. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.

[0066] In some embodiments of the present invention, the present invention provides an implant comprising, from the inside out, a material body, a metal oxide layer, a mixed crystal layer and a CaP crystal layer; the metal oxide layer comprises an array of metal oxide nanorods; the metal oxide is selected from at least one of zinc oxide and silver oxide; the mixed crystal layer comprises CaP crystals and metal oxide crystals.

[0067] In some embodiments of the present invention, the implant is made of a superhydrophilic material. In some embodiments of the present invention, the water contact angle of the implant is ≤5°. In some embodiments of the present invention, the implant is made of a superhydrophilic material with a water contact angle of 0° to 2°. In some embodiments of the present invention, the water contact angle of the implant is close to 0°, exhibiting excellent hydrophilicity.

[0068] In some embodiments of the present invention, the water contact angle of the implant is <5° after being stored in the air for 20 days.

[0069] In some embodiments of the present invention, the content of CaP crystals decreases from the surface layer to the inner layer of the mixed crystal layer. The content of metal oxide crystals increases from the surface layer to the inner layer of the mixed crystal layer.

[0070] In some embodiments of the present invention, the molar ratio of calcium to phosphorus in the mixed crystal layer is 10:(4-8); in some embodiments of the present invention, the molar ratio of calcium to phosphorus in the mixed crystal layer is 10:(5-7).

[0071] In some embodiments of the present invention, the thickness of the mixed crystal layer is 0.1–10 nm; in some embodiments of the present invention, the thickness of the mixed crystal layer is 1–8 nm; in some embodiments of the present invention, the thickness of the mixed crystal layer is 2–5 nm.

[0072] In some embodiments of the present invention, the thickness of the CaP crystal layer is 3-100 nm; in some embodiments of the present invention, the thickness of the CaP crystal layer is 5-50 nm; and in some embodiments of the present invention, the thickness of the CaP crystal layer is 10-20 nm.

[0073] In some embodiments of the present invention, the thickness of the metal oxide layer is 200–2000 nm; in some embodiments, the thickness of the metal oxide layer is 500–1000 nm.

[0074] In some embodiments of the present invention, the diameter of the metal oxide nanorods is 50-200 nm; in some embodiments, the diameter of the metal oxide nanorods is 80-150 nm; and in some embodiments, the diameter of the metal oxide nanorods is 80-120 nm.

[0075] In some embodiments of the present invention, the material body is a titanium material body; in some embodiments of the present invention, the material body is pure titanium or a titanium alloy.

[0076] In some embodiments of the present invention, the material of the material body is selected from at least one of TA3 titanium, TA4 titanium, TA5 titanium, titanium aluminum vanadium alloy, titanium aluminum zirconium alloy, titanium niobium alloy, and nickel titanium alloy.

[0077] In some embodiments of the present invention, the present invention also provides a method for preparing the above-mentioned implant, comprising the following steps:

[0078] S1: Pre-treat the surface of the material body, then mix the zinc source and stabilizer and coat them onto the pre-treated surface of the material body, and then anneal it to obtain the treated material body;

[0079] S2: The treated material body, cyclohexamethylenetetramine / triamine citrate, and metal source are subjected to a hydrothermal reaction, followed by heat treatment to obtain a metal oxide layer;

[0080] S3: A mixture of calcium and phosphorus sources is coated onto the surface of the metal oxide layer and then annealed to obtain the implant.

[0081] In some embodiments of the present invention, the annealing temperature in step S1 is 450°C to 550°C; in some embodiments of the present invention, the annealing temperature in step S1 is 480°C to 540°C; in some embodiments of the present invention, the annealing temperature in step S1 is 480°C to 520°C; in some embodiments of the present invention, the annealing temperature in step S1 is 490°C to 510°C.

[0082] In some embodiments of the present invention, the annealing time in step S1 is 20 to 40 minutes; in some embodiments of the present invention, the annealing time in step S1 is 25 to 35 minutes.

[0083] In some embodiments of the present invention, step S1 is as follows: the surface of the material body is ground and polished, then washed with detergent, the metal source and stabilizer are mixed and coated on the pretreated material body surface, then dried, the coating and drying steps are repeated 0 to 5 times, and then annealed to obtain the treated material body.

[0084] In some embodiments of the present invention, the drying temperature is 100–140°C; in some embodiments of the present invention, the drying temperature is 110–130°C.

[0085] In some embodiments of the present invention, in step S1, the concentration of the metal source is 0.02 to 0.1 mol / L.

[0086] In some embodiments of the present invention, in step S1, the mass ratio of the metal source to the stabilizer is 1:(5-8).

[0087] In some embodiments of the present invention, in step S2, the mass ratio of the metal source to cyclohexamethylenetetramine is 1:(0.8-1.2); in some embodiments, in step S2, the mass ratio of the metal source to cyclohexamethylenetetramine is 1:(0.9-1.1).

[0088] In some embodiments of the present invention, in step S2, the mass ratio of the metal source to triamine citrate is 1:(0.8-1.2); in some embodiments, in step S2, the mass ratio of the metal source to triamine citrate is 1:(0.9-1.1).

[0089] In some embodiments of the present invention, the concentration of the metal source in step S2 is 0.01 to 0.05 mol / L.

[0090] In some embodiments of the present invention, the pretreatment step is: grinding and polishing the surface of the material body, and then cleaning; in some embodiments of the present invention, the pretreatment step is: grinding and polishing the surface of the material body, and then washing with detergent; the detergent includes at least one of acetone, ethanol, and deionized water; in some embodiments of the present invention, the pretreatment step is: grinding and polishing the surface of the material body to a mesh size of 2000 or higher, and then washing with acetone, ethanol, and deionized water in sequence.

[0091] In some embodiments of the present invention, the hydrothermal reaction temperature in step S2 is 90°C to 100°C; in some embodiments of the present invention, the hydrothermal reaction temperature in step S2 is 92°C to 98°C; in some embodiments of the present invention, the hydrothermal reaction temperature in step S2 is 94°C to 96°C.

[0092] In some embodiments of the present invention, the hydrothermal reaction time in step S2 is 1h to 10h; in some embodiments of the present invention, the hydrothermal reaction time in step S2 is 2h to 8h; in some embodiments of the present invention, the hydrothermal reaction time in step S2 is 3h to 7h.

[0093] In some embodiments of the present invention, the heat treatment temperature in step S2 is 300°C to 400°C; in some embodiments of the present invention, the heat treatment temperature in step S2 is 320°C to 380°C; in some embodiments of the present invention, the heat treatment temperature in step S2 is 340°C to 360°C. The purpose of the heat treatment step is to remove residual organic contaminants from the surface.

[0094] In some embodiments of the present invention, the heat treatment time in step S2 is 1 to 3 hours; in some embodiments of the present invention, the heat treatment time in step S2 is 1.5 to 2.5 hours.

[0095] In some embodiments of the present invention, the annealing temperature in step S3 is 500-700°C; in some embodiments, the annealing temperature in step S3 is 550-650°C; in some embodiments, the annealing temperature in step S3 is 580-620°C.

[0096] In some embodiments of the present invention, the annealing time in step S3 is 30 min to 120 min; in some embodiments of the present invention, the annealing time in step S3 is 40 min to 100 min; in some embodiments of the present invention, the annealing time in step S3 is 40 min to 80 min.

[0097] In some embodiments of the present invention, in step S1, the coating step is performed by spin coating; the number of spin coatings is 1 to 20; in some embodiments, the number of spin coatings is 2 to 15; in some embodiments, the number of spin coatings is 3 to 10.

[0098] In some embodiments of the present invention, in step S3, the coating step is performed by spin coating; the number of spin coatings is 1 to 20; in some embodiments, the number of spin coatings is 2 to 15; in some embodiments, the number of spin coatings is 3 to 10.

[0099] In some embodiments of the present invention, the calcium source is selected from at least one of calcium nitrate, calcium chloride, calcium chlorate, and calcium gluconate.

[0100] In some embodiments of the present invention, the phosphorus source is selected from at least one of phosphorus pentoxide and phosphorus trioxide.

[0101] In some embodiments of the present invention, the metal source is selected from at least one of a zinc source and a silver source. In some embodiments, the zinc source is selected from at least one of zinc acetate, zinc nitrate, and zinc chloride. In some embodiments, the silver source is selected from at least one of silver acetate and silver nitrate.

[0102] In some embodiments of the present invention, the stabilizer is selected from at least one of ethanolamine, diethanolamine, and triethanolamine.

[0103] In some embodiments of the present invention, the present invention also provides a dental implant, including the implant provided in the above embodiments.

[0104] In some embodiments of the present invention, the present invention also provides the application of the implants provided in the above embodiments in the preparation of medical implantable human materials.

[0105] In some embodiments of the present invention, the present invention also provides the application of the implants provided in the above embodiments in the preparation of medical implant animal body materials.

[0106] Example 1

[0107] In this example, the superhydrophilic implant consists of a titanium implant body (i.e., the titanium material body), a zinc oxide layer, a mixed crystal layer, and a CaP crystal layer, arranged from the inside out. The zinc oxide layer includes an array of zinc oxide nanorods, and the mixed crystal layer includes CaP crystals and metal oxide crystals.

[0108] Reference Figure 1 The preparation flowchart in the image shows the superhydrophilic implant used in this example, prepared using the following method, with the specific steps as follows:

[0109] (1) After polishing the titanium implant body with 2000 grit sandpaper, it is ultrasonically cleaned with acetone, alcohol and deionized water in sequence, and then dried for later use. The cleaned sample is named Ti material body and denoted as Ti.

[0110] (2) Zinc acetate was used as the zinc source. An ethanol solution with a zinc acetate concentration of 0.05 mol / L was prepared and then mixed with the stabilizer ethanolamine at a mass ratio of 1:5 to obtain a mixture. The mixture was then spin-coated onto the surface of the pretreated Ti material body by spin coating (spin coating rate of 1000 rpm and spin coating time of 30 seconds). The mixture was then dried in an oven at 120°C for 15 minutes. The spin coating and drying process was repeated twice. The mixture was then annealed at 500°C for 30 minutes to serve as the seed layer for the next step of generating zinc oxide nanorods. This layer is referred to as the titanium material body containing the seed layer.

[0111] (3) Prepare a mixed aqueous solution of zinc nitrate (concentration of 0.01 mol / L) and cyclohexamethylenetetramine (referred to as mixed aqueous solution, wherein the concentration ratio of zinc nitrate and cyclohexamethylenetetramine is 1:1). Place the titanium material body with seed layer obtained in step (2) together with the mixed aqueous solution into a reaction vessel and carry out hydrothermal reaction at 95°C for 5 hours. Zinc oxide nanorods (ZnO nanorods) grow on the surface of the titanium material body with seed layer. After ultrasonic cleaning, heat treatment at 350°C for 2 hours is carried out to remove residual organic pollutants on the surface. A titanium implant containing ZnO nanorods is obtained, referred to as Ti-ZnO.

[0112] (4) Calcium nitrate and phosphorus pentoxide were dissolved in ethanol to obtain calcium nitrate stock solution and phosphorus pentoxide stock solution with a concentration of 1 mol / L. Then, ethanol was used as a diluent to adjust the calcium-phosphorus ratio to 10:6 to prepare a mixed reaction solution of calcium nitrate and phosphorus pentoxide as a calcium-phosphorus precursor solution. The prepared calcium-phosphorus precursor solution was spin-coated onto the titanium implant containing ZnO nanorods in Example 1. The number of spin-coating layers was 1. After spin-coating, the implant was annealed at 600°C for 1 h to obtain the superhydrophilic implant containing calcium-phosphorus-zinc mixed crystal layer in this example, denoted as Ti-ZnO@CaP1.

[0113] This invention uses a hydrothermal method to prepare zinc oxide nanorod arrays. The specific reaction principle is as follows:

[0114] Zn(OH)2=Zn 2+ +2OH － (Dissolve)

[0115] Zn 2+ +2OH － =ZnO + H₂O (crystallization)

[0116] 1) In the first step of the reaction, ethanolamine does not directly participate in the reaction; it mainly acts as a surfactant and stabilizer, helping and stabilizing the hydrolysis of zinc acetate and zinc acetic acid to form Zn(OH)2, and releasing Zn. 2+ The formation of ZnO cores on the surface of the titanium material can guide the growth direction of the subsequent nanorods and remove potentially interfering heavy metal ions from the environment. The combined effect of the zinc source and ethanolamine is beneficial to the subsequent growth of zinc oxide nanorods.

[0117] 2) In the second step of the reaction, zinc nitrate serves as the zinc source for the continued growth of the nanorods, while cyclohexamethylenetetramine provides an alkaline environment and OH- for the reaction. － This provides a source and also helps maintain the growth of zinc oxide nanorods.

[0118] Example 2

[0119] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the number of spin coatings in step (4) of this example is 3, denoted as Ti-ZnO@CaP3.

[0120] Example 3

[0121] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the number of spin coatings in step (4) of this example is 5, denoted as Ti-ZnO@CaP5.

[0122] Example 4

[0123] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the number of spin coatings in step (4) of this example is 10, denoted as Ti-ZnO@CaP10.

[0124] Example 5

[0125] The only difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that triamine citrate is used instead of cyclohexamethylenetetramine in Example 1.

[0126] Example 6

[0127] The only difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the hydrothermal temperature in step (3) is 100°C and the hydrothermal reaction time is 1 hour.

[0128] Example 7

[0129] The only difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the hydrothermal temperature in step (3) is 90°C and the hydrothermal reaction time is 10h.

[0130] Example 8

[0131] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the annealing time in step (4) of this example is 30 min.

[0132] Example 9

[0133] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that the annealing time in step (4) of this example is 2 hours.

[0134] The properties of the superhydrophilic implants prepared in Examples 5-9 are consistent with those of the superhydrophilic implant in Example 1.

[0135] Example 10

[0136] The difference between the preparation method of the superhydrophilic implant in this example and that in Example 1 is that silver nitrate is used instead of zinc acetate in step (2) and silver nitrate is used instead of zinc nitrate in step (3).

[0137] Performance testing:

[0138] (1) Surface morphology test

[0139] The surface morphology of the Ti implant body and Ti-ZnO in Example 1 was tested using scanning electron microscopy. The specific test results are as follows: Figure 2 As shown, where, Figure 2 a and Figure 2 b represents the SEM images of the Ti bulk material and Ti-ZnO, respectively. (From...) Figure 2 It can be seen that zinc oxide nanorod arrays were successfully prepared on the surface of Ti material, and the diameter of the zinc oxide nanorods was 50-70 nm.

[0140] The surface morphology of the superhydrophilic implants in Examples 1-3 was tested using scanning electron microscopy. The specific test results are as follows: Figure 3 As shown, where, Figure 3 a, Figure 3 b and Figure 3 c represents the SEM images of Ti-ZnO@CaP1 in Example 1, Ti-ZnO@CaP3 in Example 2, and Ti-ZnO@CaP5 in Example 3. By comparison... Figure 2 and Figure 3It can be seen that a calcium-phosphorus bone crystal layer is deposited on the surface of the zinc oxide nanorod array, and the thickness of the calcium-phosphorus-zinc bone crystal layer deposited on the surface of the zinc oxide nanorod array increases with the increase of the number of spin-coating layers.

[0141] (2) Hydrophilicity test

[0142] The water contact angle of the superhydrophilic implant surfaces in Examples 1-9 was measured using a contact angle meter. The specific testing method was as follows: 4 μL of ultrapure water was added to the sample surface using a syringe, and the static water contact angle (i.e., the initial contact angle) was measured. The initial contact angle test results for the superhydrophilic implants in Examples 3-9 are shown in Table 1. The surface contact angle test results for Ti-ZnO@CaP5 in Example 3 are shown in Table 1. Figure 4 As shown. By Figure 4 It can be seen that the surface contact angle of Ti-ZnO@CaP5 in Example 3 is close to 0°. Testing showed that the surface contact angle of the superhydrophilic implants in Examples 1-9 of this invention is all <10°, further demonstrating that the superhydrophilic implants of this invention have a superhydrophilic surface.

[0143] The superhydrophilic implants from Examples 3 to 9 were placed in an air environment for 20 days, and then the water contact angle of the samples was tested according to the above test method. The test results are recorded in Table 1 below.

[0144] Table 1. Contact angles of the superhydrophilic implants in Examples 3-9 of the present invention

[0145] Example Initial contact angle Contact angle after 20 days of air exposure 3 0° 4～5° 4 0° 2～3° 5 0° 4～5° 6 0° 4～5° 7 0° 4～5° 8 0° 4～5° 9 0° 4～5°

[0146] According to the test results in Table 1, the initial contact angle of the superhydrophilic implants in Examples 3-9 was close to 0° at day 0, and the water contact angle was less than 5° after 20 days. This further indicates that the superhydrophilic implants of the present invention can maintain superhydrophilic performance (water contact angle less than 5°) in an air environment for a relatively long time (more than 20 days). The hydrophilic properties of the superhydrophilic implants in Examples 1-2 are comparable to those in Examples 3-9.

[0147] (3) Transmission electron microscopy test

[0148] The superhydrophilic Ti-ZnO@CaP5 in Example 3 was subjected to TEM detection, and the specific test results are as follows: Figure 5 As shown, where Figure 5 a is a TEM image of Ti-ZnO@CaP5. Figure 5 b is Figure 5 a. The magnified TEM image within the yellow box. Figure 5 c is correct. Figure 5 b. Further magnification of the test image showing the mutual dissolution of crystal lattices in the mixed crystal layer. Figure 5Image d shows the SAED detection result of Ti-ZnO@CaP5. (Source: [Insert image here]) Figure 5 It can be seen that the diameter of the ZnO nanorods containing the calcium-phosphorus-zinc mixed crystal layer in Ti-ZnO@CaP5 is approximately 100 nm (see details). Figure 5 a) The thickness of the calcium-phosphorus-zinc mixed crystal layer is approximately 3 nm (see details). Figure 5 b and Figure 5 c), and gradually transitions from CaP to ZnO from the outside to the inside; the outermost crystal is mainly hydroxyapatite crystal, with a typical (211) crystal plane and a plane spacing of 0.27 nm; inside the interface, there is a typical ZnO crystal structure, with a plane gradient spacing of 0.232-0.24 nm (see details). Figure 5 c); The lattice compression near the interface originates from defects introduced when calcium and phosphorus atoms diffuse into the ZnO lattice, a conclusion confirmed by SAED analysis (see details). Figure 5 d).

[0149] (4) Degradation performance test

[0150] Using Ti implants as a control, the degradation performance of Ti-ZnO in Example 1, Ti-ZnO@CaP1 in Example 1, Ti-ZnO@CaP3 in Example 2, and Ti-ZnO@CaP5 in Example 3 were tested. The specific testing method was as follows: the test samples were immersed in physiologically buffered saline (PBS) solution, and then an electron microscope was used to observe whether the ZnO nanorods on the surface of the superhydrophilic implants, or ZnO nanorods containing a calcium-phosphorus-zinc mixed crystal layer, underwent degradation behavior such as collapse after immersion for 1, 3, and 7 days. The results obtained according to the above testing method are as follows: Figure 6 As shown, where Figure 6 a, Figure 6 b and Figure 6 c represents the SEM images of Ti-ZnO after soaking for 1 day, 3 days, and 7 days; Figure 6 d、 Figure 6 e and Figure 6 f are SEM images of Ti-ZnO@CaP1 after soaking for 1 day, 3 days and 7 days, respectively; Figure 6 g、 Figure 6 h and Figure 6 i represents the SEM images of Ti-ZnO@CaP3 after soaking for 1 day, 3 days, and 7 days; Figure 6 j、 Figure 6 k and Figure 6 Images 1 and 3 are SEM images of Ti-ZnO@CaP5 after soaking for 1, 3, and 7 days, respectively. Figure 6It can be seen that the zinc oxide nanorods in Ti-ZnO without CaP deposition on their surface began to degrade after 1 day of immersion, and the degradation rate was rapid, with most of the nanorod structures collapsing after 3 days. Conversely, ZnO nanorods with CaP deposition not only had a delayed degradation initiation time but also a slower degradation rate. Furthermore, the greater the thickness of the CaP layer, the later the degradation initiation time and the slower the degradation rate. After depositing 5 CaP layers on the Ti-ZnO@CaP5 surface, the degradation time of the ZnO nanorods containing the calcium-phosphorus-zinc mixed crystal layer was delayed compared to the ZnO nanorods in Ti-ZnO, and the degradation rate was also significantly lower than that of Ti-ZnO. They still retained a relatively good nanorod structure on the 7th day.

[0151] (5) Antibacterial performance test

[0152] Using Ti material bulk as a control, the antibacterial properties of Ti-ZnO in Example 1 and Ti-ZnO@CaP5 in Example 3 were tested respectively. The specific testing method was as follows: bacterial suspensions containing *E. coli* and *S. aureus* were co-incubated on the surfaces of different samples, and the antibacterial efficiency was then obtained through an agar plate cloning experiment. Specific test results are shown below. Figure 7 As shown, where, Figure 7 a, Figure 7 b and Figure 7 c represents the antibacterial test results of Ti material bulk, Ti-ZnO, and Ti-ZnO@CaP5 against Staphylococcus aureus. Figure 7 d、 Figure 7 e and Figure 7 f represents the antibacterial test results of Ti bulk material, Ti-ZnO, and Ti-ZnO@CaP5 against Escherichia coli. Figure 7 It can be seen that, compared with Ti-ZnO@CaP5, the Ti-ZnO sample has the highest surface antibacterial rate, with antibacterial rates >99% against both E. coli and S. aureus. Because the ZnO nanorods are coated with a calcium-phosphorus-zinc mixed crystal layer, the release of zinc is affected, thus reducing the antibacterial rate of Ti-ZnO@CaP5. Furthermore, the antibacterial rate of the superhydrophilic implant gradually decreases with the thickness of the calcium-phosphorus-zinc mixed crystal layer. However, overall, the superhydrophilic implants in this invention all possess antibacterial properties, with an antibacterial rate of not less than 90%.

[0153] (6) Anti-inflammatory effect test

[0154] Using the Ti implant itself as a control, the anti-inflammatory effects of Ti-ZnO in Example 1 and Ti-ZnO@CaP5 in Example 3 were tested. The specific testing method was as follows: bacteria were first coated on the surface of the test samples, then implanted into SD rats, with the Ti material itself serving as the control group. Tissue samples were collected 7 days and 14 days after implantation, and the in vivo antibacterial effect and degree of inflammatory stress response were assessed using Giemsa staining. Specific test results are as follows: Figure 8 As shown, where, Figure 8 a, Figure 8 b、 Figure 8 c represents the anti-inflammatory effect test images of Ti material bulk, Ti-ZnO, and Ti-ZnO@CaP5 implanted 7 days after implantation; Figure 8 d、 Figure 8 e Figure 8 f are respectively Figure 8 a, Figure 8 b、 Figure 8 c. Enlarged view of the area inside the box; Figure 8 g、 Figure 8 h、 Figure 8 i represents the anti-inflammatory effect test images of Ti material bulk, Ti-ZnO, and Ti-ZnO@CaP5 implanted 14 days after implantation; Figure 8 j、 Figure 8 k、 Figure 8 l are respectively Figure 8 g、 Figure 8 h、 Figure 8 A magnified view of the area inside the box in section i. (From...) Figure 8 It can be seen that after the Ti material was implanted, the surrounding tissue showed severe inflammation following bacterial infection, which did not subside even 14 days after implantation; while neither the Ti-ZnO nor Ti-ZnO@CaP5 samples showed strong acute or bacterial infection inflammation on their surfaces.

[0155] (7) Osteogenesis test

[0156] Using Ti material as a control, the osteogenic effects of Ti-ZnO in Example 1 and Ti-ZnO@CaP5 in Example 3 were tested. The specific testing method was as follows: bone marrow mesenchymal stem cells (BMSCs) were seeded on the surface of each group of superhydrophilic implants. Then, the expression of alkaline phosphatase (ALP), a key factor in osteogenic differentiation, and the relative content of extracellular matrix mineralization were detected after 3 and 7 days to evaluate the osteogenic performance of different implants. Specific test results are as follows: Figure 9 As shown, where, Figure 9 a represents the activity assay for alkaline phosphatase. Figure 9 b is a test graph showing the relative quantitative results of extracellular matrix osteogenic mineralization. (From...) Figure 9It can be seen that due to the degradation of ZnO nanorods and the release and accumulation of zinc ions on the surface, the osteogenic induction activity of Ti-ZnO is significantly lower than that of Ti-ZnO@CaP5. On the other hand, the CaP layer on the surface of Ti-ZnO@CaP5 reduces the degradation of ZnO nanorods and the release of Zn ions, which has a positive promoting effect on osteogenic differentiation of BMSCs.

[0157] In summary, the implant of this invention utilizes antibacterial metal ions generated from the degradation of metal oxide nanorods for sterilization, exhibiting good antibacterial effects against both Gram-positive and Gram-negative bacteria. This alleviates post-implantation inflammatory responses, reduces immune responses in post-implantation infection situations, prevents infection, and shortens wound healing time. Furthermore, the encapsulation effect of the mixed crystal layer on the metal oxide layer allows for the slow release of antibacterial metal ions over a long period, achieving sustained antibacterial activity. Additionally, the mixed crystal layer imparts long-lasting superhydrophilic properties to the implant surface, promoting blood adsorption and coagulation. It also slowly releases calcium and phosphorus ions, promoting osteogenic differentiation of stem cells around the implant and shortening post-implantation recovery time. Furthermore, it reduces the degradation rate of the metal oxide nanorods, resulting in high storage stability. Even after 20 days of storage in air, the implant retains excellent antibacterial, long-lasting anti-inflammatory, and osteogenic effects, making it suitable for patients with high post-implantation infection risk and poor osteogenic development.

[0158] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. An implant, characterized in that: The material comprises, from the inside out, a material body, a metal oxide layer, a mixed crystal layer, and a CaP crystal layer; the metal oxide layer comprises an array of metal oxide nanorods; the metal oxide is selected from zinc oxide, silver oxide, or a combination thereof; the mixed crystal layer comprises CaP crystals and metal oxide crystals; The implant is made of a superhydrophilic material; the water contact angle of the implant is <10°; The thickness of the mixed crystal layer is 0.1~10nm; The content of CaP crystals decreases from the surface layer to the inner layer of the mixed crystal layer; the content of metal oxide crystals increases from the surface layer to the inner layer of the mixed crystal layer.

2. The implant according to claim 1, characterized in that: The implant has a water contact angle of <5° after being stored in air for 20 days.

3. The implant according to claim 1, characterized in that: The molar ratio of calcium to phosphorus in the mixed crystal layer is 10:(4~8).

4. The implant according to claim 1, characterized in that: The thickness of the metal oxide layer is 200~2000nm.

5. The implant according to claim 1, characterized in that: The diameter of the metal oxide nanorods is 50~200 nm.

6. The implant according to claim 1, characterized in that: The material itself is titanium.

7. The implant according to claim 6, characterized in that: The material body is selected from at least one of TA3 titanium, TA4 titanium, TA5 titanium, titanium aluminum vanadium alloy, titanium aluminum zirconium alloy, titanium niobium alloy, and nickel titanium alloy.

8. The method for preparing the implant according to any one of claims 1 to 7, characterized in that: Includes the following steps: S1: Pre-treat the surface of the material body, then mix the metal source and stabilizer and coat them onto the pre-treated surface of the material body, and then anneal it to obtain the treated material body; S2: The treated material body, cyclohexamethylenetetramine / triamine citrate, and metal source are subjected to a hydrothermal reaction, followed by heat treatment to obtain a metal oxide layer; S3: A mixture of calcium and phosphorus sources is coated onto the surface of the metal oxide layer and then annealed to obtain the implant.

9. The method for preparing an implant according to claim 8, characterized in that: The annealing temperature in step S1 is 450℃~550℃, and the annealing time is 20~40min.

10. The method for preparing an implant according to claim 8, characterized in that: The pretreatment steps are as follows: polishing the surface of the material body and then cleaning it.

11. The method for preparing an implant according to claim 8, characterized in that: The hydrothermal reaction temperature in step S2 is 90℃~100℃, and the hydrothermal reaction time is 1h~10h.

12. The method for preparing an implant according to claim 8, characterized in that: The annealing temperature in step S3 is 500~700℃, and the annealing time is 30min~120min.

13. The method for preparing an implant according to claim 8, characterized in that: In steps S1 / S3, the coating step is performed by spin coating; the number of spin coating cycles is 1 to 20.

14. The method for preparing an implant according to claim 8, characterized in that: The calcium source is selected from at least one of calcium nitrate, calcium chloride, calcium chlorate, and calcium gluconate. And / or, the phosphorus source is selected from at least one of phosphorus pentoxide and phosphorus trioxide.

15. The method for preparing an implant according to claim 8, characterized in that: The metal source is selected from at least one of zinc source and silver source; And / or, the stabilizer is selected from at least one of ethanolamine, diethanolamine, and triethanolamine.

16. A dental implant, characterized in that: Includes the implant as described in any one of claims 1 to 7.

17. The use of the implant according to any one of claims 1 to 7 in the preparation of medical implant materials.

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