阅读说明：本技术 一种骨科植入器械表面涂层的制备方法 (Preparation method of surface coating of orthopedic implant instrument ) 是由 鄢江龙 夏丹丹 郑玉峰 成艳 于 2020-06-23 设计创作，主要内容包括：本发明涉及骨科植入器械表面涂层改性技术领域,具体为一种骨科植入器械表面涂层的制备方法,提供了一种通过聚多巴胺在骨科植入器械表面载入并控释铜-柠檬酸盐纳米簇的方法。该涂层的制备方法简单方便,适用范围广,能够应用于各种类型的骨科植入器械。此外,该发明能够通过聚多巴胺响应ph值变化,调控铜离子释放浓度,从而控制植入器械成骨和抗菌功能之间的转换。(The invention relates to the technical field of modification of surface coatings of orthopedic implant instruments, in particular to a preparation method of a surface coating of an orthopedic implant instrument, and provides a method for loading and controlling release of copper-citrate nanoclusters on the surface of an orthopedic implant instrument through polydopamine. The preparation method of the coating is simple and convenient, has wide application range, and can be applied to various orthopedic implantation instruments. In addition, the invention can regulate and control the release concentration of copper ions by the poly-dopamine responding to the change of ph value, thereby controlling the conversion between osteogenesis and antibacterial functions of the implantation instrument.)

1. A preparation method of a surface coating of an orthopedic implant instrument is characterized by comprising the following steps:

1) pretreating the orthopedic implant instrument substrate to obtain a smooth or micro-nano structured surface appearance on the surface;

2) after the orthopedic material is pretreated, adding the prepared copper-citrate composite nano-cluster into the prepared dopamine solution to form a mixed solution, then adding an implantation instrument into the mixed solution to react for a period of time, and fixing the copper-citrate nano-cluster on the surface of the implantation instrument by utilizing the excellent binding property of polydopamine;

3) and (5) rinsing the material by using deionized water, and naturally drying.

2. The method of claim 1, wherein: the pretreatment is to obtain a smooth and flat surface by polishing and cleaning, or to obtain a micro-nano structure by means of surface roughening, acid/alkali etching, anodic oxidation, micro-arc oxidation, electrochemical deposition, plasma spraying and ion implantation.

3. The method of claim 1, wherein: the orthopedic implant instrument is made of a polyether-ether-ketone implant material, and the micro-nano structure can be subjected to sulfonation treatment to obtain a three-dimensional porous structure.

4. The method of claim 1, wherein: the preparation method of the copper-citrate composite nano cluster comprises the following steps: and mixing the copper salt and the citrate to prepare a solution, adding a reducing agent, and reacting under the condition of heating and stirring to obtain the copper-citrate composite nano-cluster.

5. The method of claim 4, wherein: the copper salt is one or more of copper sulfate, copper nitrate and copper chloride.

6. The method of claim 4, wherein: the reducing agent is one or more of ascorbic acid, hydrazine hydrate and sodium borohydride.

7. The method of claim 4, wherein: the size distribution of the composite nanoclusters is 1-10 nm.

8. The method of claim 1, wherein: the dopamine solution was prepared by preparing a 10mM Tris-HCl buffer solution at pH 8.5 and preparing a 2mg/mL dopamine solution using the solution.

9. The method of claim 1, wherein: the matrix material of the orthopedic implant device is metal and alloy thereof, polymer material and inorganic ceramic material.

10. The method of claim 1, wherein: the micro-nano structure comprises a nano tube, a nano hole, a pit with a micron or nano size, a porous, a reticular, a filiform or a lamellar acicular structure.

Technical Field

The invention relates to a surface modification method for an orthopedic implant apparatus, belonging to the field of surface modification of medical apparatuses and slow release of medicines.

Background

The orthopedic implant device is often implanted in human body to cause implant failure, and insufficient osseointegration and bacterial infection of the implant device are main reasons for the implant failure. In order to further improve the success rate of implantation and reduce the harm to human life and health caused by implantation failure, the implantation instrument is required to have excellent osteogenesis promoting and antibacterial properties. However, in most cases, many of the methods that can confer osteoinductive properties to the implant device do not take into account the risk of bacterial infection, even the method that promotes cell adhesion and proliferation while facilitating bacterial adhesion and biofilm formation. Conversely, strategies aimed at inhibiting bacterial colonization may compromise the osteogenic differentiation potential of the cells.

The bacterial self-response osteogenic antibacterial coating can enable the orthopedic implant instrument to have osteogenic and antibacterial properties at the same time. This strategy is based on the ability of bacterial metabolism to produce acidic species such as acetic acid, lactic acid and formic acid, which acidify the environment, resulting in a decrease in pH. Therefore, when bacteria appear, the pH value of the environment is reduced, the coating with the pH response characteristic is triggered to release the antibacterial agent, and the aim of killing the bacteria and inhibiting infection is achieved; and when bacteria do not appear, the bone-promoting elements on the surface of the material act to promote the generation of new bone. The strategy enables effective local sterilization of lower concentrations of antimicrobial agents at the site of infection, reducing the likelihood of emergence of bacterial resistance. To achieve this strategy, the choice of the drug release controlling material becomes critical.

The polydopamine has certain pH response characteristics due to the existence of amino groups in the structure, and in addition, the polydopamine can adhere to the surfaces of almost all inorganic and organic materials and has strong binding force. Therefore, the poly-dopamine can be used as a controlled release coating of the drug. This is because a substance for controlled drug release requires a dynamic response to changes in environmental pH by protonation/deprotonation, and thus needs to have a weak or weak basic group to accept or release protons, an amino group being one of weak basic groups. Meanwhile, considering that the surface of a part of orthopedic implant apparatus substrate materials has inertia, in order to improve the binding force of the film layer and the substrate, the substance for drug controlled release preferably has excellent binding performance with different substrate materials. The poly-dopamine can meet all the requirements, so that it can be used as a drug controlled release film layer.

Copper ions have excellent antibacterial, osteogenic and angiogenetic functions and are widely used on the surfaces of orthopedic implant instruments. More importantly, the antibacterial agent has the performances of promoting bone formation at low concentration and resisting bacteria at high concentration. With the goal of achieving a transition between osteogenic and antimicrobial functions in the implant device pH response, it is desirable that the antimicrobial agent be present in the implant device for a long period of time and be capable of converting its biological function to osteogenic after the antimicrobial is completed. The traditional strategy is to load osteogenic factors and antibacterial agents on the surface of an implant device respectively and control the release of the osteogenic factors and the antibacterial agents through pH response, so as to realize osteogenesis and antibacterial. However, in this method, the pH-responsive controlled-release coating cannot completely block the release of the antibacterial agent under non-infectious conditions, and thus, certain toxicity is caused and even low concentrations of the antibacterial agent can cause the occurrence of bacterial resistance. The low-concentration bone formation promoting and high-concentration antibacterial properties of the copper ions can solve the problems, and the release concentration of the copper ions can be well controlled through pH change so as to realize biological function conversion. However, there was a large difference between the concentration required for the antibacterial activity of copper and the concentration required for osteogenesis and angiogenesis, 256. mu.g/mL and 6.4. mu.g/mL, respectively. Considering that the pH response controlled release performance of the polydopamine film layer is limited, and the required concentration difference between the copper ion antibacterial function and the osteogenesis function is large, the polydopamine film layer is difficult to enable the material to simultaneously meet the antibacterial function and the osteogenesis function. Therefore, it is necessary to find a substance which can synergistically act against copper ions to reduce the concentration required for the antimicrobial action of copper ions, thereby reducing the concentration difference between the antimicrobial action of copper ions and osteogenesis. Research reports that organic acid can promote metal ions to enter bacteria, so that the antibacterial efficiency is increased. Wherein the citrate can penetrate through a bacterial film layer to cause bacterial death, so that the copper and the citrate are selected to be used together to achieve the effect of synergistic antibiosis. In addition, citrate also has excellent osteogenic activity and can promote new bone formation.

The polydopamine controlled-release copper-citrate composite nanocluster coating on the surface of the orthopedic implant instrument controls the biological function of the implant instrument by regulating and controlling the concentration of copper-citrate in a solution. Under the physiological environment condition that the pH value is 7.4, the polydopamine film layer can control the slow release of copper ions, thereby being beneficial to osteogenic differentiation and angioblast differentiation of cells; when the bacteria generate an acidification environment to reduce the pH value, the release rate and the release amount of copper ions are greatly increased, so that an effective sterilization effect is generated. More importantly, the preparation method of the coating is simple and easy to implement, and can be applied to the surfaces of orthopedic implantation instruments with various shapes and various matrixes.

Disclosure of Invention

The invention aims to provide a preparation method of a surface coating of an orthopedic implant instrument, which can improve the bone binding force and reduce the incidence rate of bacterial infection. The invention can realize the intelligent conversion between the osteogenesis and antibacterial functions of the implanted instrument, and the improved coating preparation method has simple process, convenience and effectiveness, and can be applied to the surfaces of various orthopedic implanted instruments with different matrixes and different shapes.

Specifically, the technical scheme of the invention is as follows:

1) pretreating an orthopedic implant instrument: the method comprises the following steps of grinding and cleaning to obtain a smooth and flat surface, or carrying out surface roughening, acid/alkali etching, anodic oxidation, micro-arc oxidation, electrochemical deposition, plasma spraying, ion implantation and other means on the micro-nano structure;

2) preparing the copper-citrate composite nano-cluster: mixing copper salt and citrate to prepare a solution, adding a reducing agent, and reacting under the condition of heating and stirring until the color of the solution becomes dark. Centrifuging the reacted solution to obtain the copper-citrate composite nano-cluster;

3) a2 mg/mL dopamine solution was prepared using 10mM Tris-HCl buffer at pH 8.5 as the solvent, to which was added an appropriate amount of copper-citrate complex nanoclusters. The mixture was then added to the surface of the material and reacted away from light. Completing the preparation of the surface film layer of the implantation instrument;

4) and (5) rinsing the material by using deionized water, and naturally drying.

Preferably, in the step 1), the orthopedic implant device may be a Polyetheretherketone (PEEK) implant material, an alloy, a polymer material, and an inorganic ceramic material.

Preferably, in the step 1), the micro-nano structure can be sulfonated to obtain a three-dimensional porous structure, wherein the micro-nano structure comprises a nanotube, a nanopore, a micron-sized or nanometer-sized pit, a porous structure, a mesh structure, a filamentous structure or a lamellar needle-like structure.

Preferably, in the step 2), the copper-citrate complex nanoclusters may be prepared by dissolving 1.2g of sodium citrate in 40mL of deionized water, and adding 50mM CuSO in a volume of 40mL₄·5H₂And heating the O solution to 80 ℃, then dropwise adding 10% (w/v) ascorbic acid with the volume of 4mL, and reacting for 6 h.

It is preferred. In the step 2), the centrifugation parameter is 8500rpm, and the centrifugation time is 20 min.

Preferably, in the step 3), the concentration of the copper-citrate complex nanoclusters is 20 mM.

Preferably, in the step 3), the dopamine solution is reacted and polymerized on the surface of the material for 12 hours.

Preferably, the pretreatment is to obtain a smooth and flat surface by polishing and cleaning, or to obtain a micro-nano structure by surface roughening, acid/alkali etching, anodic oxidation, micro-arc oxidation, electrochemical deposition, plasma spraying and ion implantation.

Preferably, the orthopedic implant instrument is made of a polyetheretherketone implant material, and the micro-nano structure can be subjected to sulfonation treatment to obtain a three-dimensional porous structure.

Preferably, the copper salt is derived from one or more of copper sulfate, copper nitrate and copper chloride, and the reducing agent is one or more of ascorbic acid, hydrazine hydrate and sodium borohydride.

The invention has the following beneficial effects:

the preparation method of the coating is simple and convenient and is not influenced by the type, shape and appearance of the base material. Meanwhile, the citrate in the coating can promote copper ions to enter cells, so that a better osteogenesis promoting effect and an antibacterial effect can be displayed. More importantly, the polydopamine film layer in the coating can respond to the change of pH value and control the release concentration of copper ions, thereby controlling the conversion of the antibacterial osteogenesis biological function of the implantation instrument.

Drawings

FIG. 1 is a flow chart of preparation of a surface coating of porous polyetheretherketone material.

FIG. 2 is an SEM morphology of a polydopamine coating loaded with copper-citrate composite nanoclusters on the surface of a porous polyetheretherketone material.

Figure 3 is a TEM image of copper-citrate composite nanoclusters.

FIG. 4 is an XPS spectrum of a porous PEEK material with a polydopamine coating loaded with copper-citrate composite nanoclusters deposited on the surface.

Fig. 5 is a release curve chart of the modified implant surface copper ions under different pH conditions.

Detailed Description

The purpose of the embodiments of the present invention is to aid in further understanding the invention, but those skilled in the art will appreciate that: various substitutions and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the invention should not be limited to the embodiments disclosed, but the scope of the invention is defined by the appended claims.