阅读说明：本技术 一种具有二氧化钛金属卟啉涂层的医用植入材料制备方法 (Preparation method of medical implant material with titanium dioxide metalloporphyrin coating ) 是由 鲁雄 罗刚 姜亚楠 周杰 于 2020-06-03 设计创作，主要内容包括：本发明公开了一种具有二氧化钛金属卟啉涂层的医用植入材料制备方法,包括以下步骤：在预处理后的医用钛或钛合金样品表面通过微弧氧化技术制备Ti0<Sub>2</Sub>纳米涂层,然后将样本材料在多巴胺溶液中聚合一层聚多巴胺,再将样本置于金属卟啉有机框架合成的前驱体溶液中,在多孔的表面上通过PDA的诱导原位生长金属卟啉有机框架涂层,最后将所获得的样品材料浸泡于骨活性因子材料溶液中进行负载。本发明具有与基地结合牢固,生物相容性好,良好的光动力抗菌作用以及与骨诱导再生的效果,可操作性强,作为医疗器械植入材料具有良好的临床应用前景。(The invention discloses a preparation method of a medical implant material with a titanium dioxide metalloporphyrin coating, which comprises the following stepsThe method comprises the following steps: preparing Ti0 on the surface of the pretreated medical titanium or titanium alloy sample by a micro-arc oxidation technology 2 And (2) nano coating, namely polymerizing a layer of polydopamine in dopamine solution on a sample material, then placing the sample in precursor solution synthesized by a metalloporphyrin organic framework, growing the metalloporphyrin organic framework coating on the porous surface in situ through the induction of PDA, and finally soaking the obtained sample material in bone active factor material solution for loading. The invention has the advantages of firm combination with a base, good biocompatibility, good photodynamic antibacterial action, bone induction regeneration effect and strong operability, and has good clinical application prospect when being used as an implantation material of medical instruments.)

1. A preparation method of a medical implant material with a titanium dioxide metalloporphyrin coating is characterized by comprising the following steps:

step 1: preparing Ti0 on the surface of the pretreated medical titanium or titanium alloy sample by a micro-arc oxidation technology₂A nano-coating;

step 2: ti0₂The nano coating is subjected to surface in-situ polymerization in a dopamine solution to form a layer of poly-dopamine;

and step 3: by hydrothermal reaction on dopamine-treated Ti0₂Growing a metalloporphyrin organic framework in situ on the material;

and 4, step 4: and (3) soaking the sample material obtained in the step (3) in a bone active factor material solution for loading.

2. The method for preparing the medical implant material with the titanium dioxide metalloporphyrin coating according to the claim 1, wherein the pretreatment of the medical titanium or titanium alloy sample in the step 1 is as follows:

cutting titanium or titanium alloy into a required shape, then polishing by using sand paper until the surface is smooth, then ultrasonically cleaning by using acetone, ethanol and deionized water, finally carrying out mixed acid treatment, carrying out deionized water ultrasonic treatment again, and finally drying for later use; the mixed acid comprises 4% of HF and 44% of HNO₃；

The step 1 is to prepare Ti0 by a micro-arc oxidation technology₂The nano coating specifically comprises the following components:

in a programmable high-precision constant-voltage DC power supply, graphite is used as a cathode, a Ti sheet is used as an anode, the smooth surface of the Ti sheet is polished to be compared with the graphite, the microarc oxidation time is 0.5-5 min under the conditions that the voltage is 100-300V, the current is 1.0-9.0A, sulfuric acid is used as an electrolyte and the concentration is 0.8-5 mM, and ultrasonic cleaning and drying are carried out in deionized water after the completion for later use;

the step 2 specifically comprises the following steps:

putting the sample prepared in the step 1 into a DA solution with the concentration of 0.5-5 mg/ml, regulating the pH value to 8.5-13, and carrying out surface in-situ polymerization to form a dopamine layer; keeping the materials out of the sun, taking out the materials after 1-12 hours, slightly washing the materials with deionized water, and drying the materials for later use;

the metal of the metalloporphyrin organic framework in the step 3 is ferric chloride hexahydrate, the ligand is benzoic acid, and meso-tetra (4-carboxyphenyl) porphin, and the metal ions comprise any one of iron, copper, zinc, cobalt, manganese and zirconium;

the bone active factor in the step 4 is any one of BMP-2, BMP-4, BMP-6, BMP-7 and BMP-9 which are bone morphogenetic proteins.

3. The preparation method of the medical implant material with the titanium dioxide metalloporphyrin coating according to claim 1, wherein the step 3 specifically comprises the following steps:

putting the sample material prepared in the step 2 into a synthesis precursor system of metalloporphyrin MOF nanoparticles, and carrying out hydrothermal reaction in a polytetrafluoroethylene inner container of a high-pressure reaction kettle for a period of time to finally obtain a final product;

the preparation method of the precursor system for synthesizing the metalloporphyrin MOF nanoparticles comprises the following steps: weighing 5-45 ml of N, N-dimethylformamide, weighing 0.5-2 g of benzoic acid, adding the benzoic acid into a container, performing magnetic stirring uniformly, then weighing 40-400 mg of ferric chloride hexahydrate, adding the ferric chloride hexahydrate, performing vigorous stirring for 5-50 min, uniformly mixing, performing heat preservation at 80-150 ℃ for 1-4 h, cooling to room temperature, adding 30-100 mg of meso-tetra (4-carboxyphenyl) porphin, stirring for 5-30 min, performing ultrasound for 5-30 min, finally stirring for 5-30 min, transferring the solution into a polytetrafluoroethylene inner container of a high-pressure reaction kettle, and performing heat preservation at 80-150 ℃ for 16-36 h;

the step 4 specifically comprises the following steps:

preparing 0.5-5 mg/mL BMP-2, putting the product obtained in the step (3) into the BMP-2, soaking for 2-24 hours, and taking out for later use.

Technical Field

The invention belongs to the technical field of biological materials, and particularly relates to a preparation method of a medical implant material with a titanium dioxide metalloporphyrin coating.

Background

Among biomedical metal materials, Ti and Ti alloys thereof are gradually the first choice for human hard tissue substitutes and restorations such as dental implants, bone gouge products, artificial joints and the like due to excellent biocompatibility and corrosion resistance, but implanted medical devices are infected by bacteria, which causes many health problems and death seriously, and also require good bone regeneration capability after being implanted into the devices, so that there is a great need to manufacture an implant device which can effectively sterilize and has good osteogenesis biocompatibility. The emergence of antibiotic drugs rescues a plurality of patients with bacterial infection, but the long-term use of both natural antibiotics and artificially synthesized antibiotic drugs can cause the problem of bacterial resistance, and 'super bacteria' appears. Photodynamic therapy (PDT) has been developed as a minimally invasive treatment modality to overcome multidrug resistant bacteria. Under irradiation of light, photosensitizers can generate reactive (MOF) oxygen Radicals (ROS) to destroy bacteria. Ti0₂The compound can be used as a photosensitizer, can be excited by ultraviolet light and the following light for antibiosis due to inherent defects, and photogenerated electron hole pairs are easy to recombine, so that the visible light utilization efficiency is low and the photocatalysis effect is not ideal. The metalloporphyrin organic framework has good biodegradability, photosensitivity and wide light source, and can be used as a candidate for deep photodynamic antibacterial, although Ti0 is used₂The coating and the metalloporphyrin organic framework are compounded to improve the photocatalysis effect, but the combination is not firm enough, and dopa can occurAmine (DA) has superior adhesion and biocompatibility, and can be used as Ti0₂The metal organic framework heterojunction coating can firmly bridge and further improve the biocompatibility of the material. Dopamine (DA) also has super-strong adhesion performance, and micropores of a metalloporphyrin organic framework can also be loaded with some active factors, so that the problems of bacterial infection and osteoinduction of medical device implantation can be solved. At present, most coatings can simultaneously have the defects of few coating materials for antibiosis and bone repair, loose coating combination, poor biocompatibility, high preparation cost, complex process and the like.

Disclosure of Invention

The invention aims to provide a preparation method of a medical implant material with a titanium dioxide metalloporphyrin coating. Aims to use medical titanium or titanium alloy as a substrate, and a layer of Ti0 with light-operated sterilization and osteogenesis activity is covered on the substrate₂The metalloporphyrin organic framework coating not only has firm combination with a base and good biocompatibility, but also has good photodynamic antibacterial effect and bone induction regeneration effect. So as to overcome the defects of bacterial infection and bone growth of Ti and Ti alloy medical instruments implanted.

The invention relates to a preparation method of a medical implant material with a titanium dioxide metalloporphyrin coating, which comprises the following steps:

step 1: preparing Ti0 on the surface of the pretreated medical titanium or titanium alloy sample by a micro-arc oxidation technology₂A nano-coating;

step 2: ti0₂The nano coating is subjected to surface in-situ polymerization in a dopamine solution to form a layer of poly-dopamine;

and step 3: by hydrothermal reaction on dopamine-treated Ti0₂Growing a metalloporphyrin organic framework in situ on the material;

and 4, step 4: and (3) soaking the sample material obtained in the step (3) in a bone active factor material solution for loading.

The pretreatment of the medical titanium or titanium alloy sample in the step 1 comprises the following steps:

cutting titanium or titanium alloy into desired shape, and grinding with sand paperPolishing until the surface is smooth, ultrasonically cleaning with acetone, ethanol and deionized water, finally performing mixed acid treatment, ultrasonically treating with deionized water again, and finally drying for later use; the mixed acid comprises 4% of HF and 44% of HNO₃。

The Ti0 is prepared by the micro-arc oxidation technology in the step 1₂The nano coating specifically comprises the following components:

in a programmable high-precision constant-voltage DC power supply, graphite is used as a cathode, a Ti sheet is used as an anode, the smooth surface of the Ti sheet is polished to be compared with the graphite, the microarc oxidation time is 0.5-5 min under the conditions that the voltage is 100-300V, the current is 1.0-9.0A, sulfuric acid is used as an electrolyte and the concentration is 0.8-5 mM, and ultrasonic cleaning and drying are carried out in deionized water for later use after the microarc oxidation is finished.

The step 2 is specifically as follows:

putting the sample prepared in the step 1 into a DA solution with the concentration of 0.5-5 mg/ml, regulating the pH value to 8.5-13, and carrying out surface in-situ polymerization to form a dopamine layer; and (4) keeping away from light, taking out the material after 1-12 hours, slightly washing the material with deionized water, and drying the material for later use.

The metal of the metalloporphyrin organic framework in the step 3 is ferric chloride hexahydrate, the ligand is benzoic acid, and meso-tetra (4-carboxyphenyl) porphin, and the metal ion comprises any one of iron, copper, zinc, cobalt, manganese and zirconium.

The bone morphogenetic factor in the step 4 is any one of BMP-2, BMP-4, BMP-6, BMP-7 and BMP-9.

The step 3 is specifically:

and (3) putting the sample material prepared in the step (2) into a precursor synthesis system of the metalloporphyrin MOF nanoparticles, and carrying out hydrothermal reaction in a polytetrafluoroethylene inner container of a high-pressure reaction kettle for a period of time to finally obtain a final product.

The preparation method of the precursor system for synthesizing the metalloporphyrin MOF nanoparticles comprises the following steps: weighing 5-45 ml of N, N-dimethylformamide, weighing 0.5-2 g of benzoic acid, adding the benzoic acid into a container, performing magnetic stirring uniformly, then weighing 40-400 mg of ferric chloride hexahydrate, adding the ferric chloride hexahydrate, performing vigorous stirring for 5-50 min, uniformly mixing, performing heat preservation at 80-150 ℃ for 1-4 h, cooling to room temperature, adding 30-100 mg of meso-tetra (4-carboxyphenyl) porphin, stirring for 5-30 min, performing ultrasound for 5-30 min, finally stirring for 5-30 min, transferring the solution into a polytetrafluoroethylene inner container of a high-pressure reaction kettle, and performing heat preservation at 80-150 ℃ for 16-36 h.

The step 4 is specifically:

preparing 0.5-5 mg/mL BMP-2, putting the product obtained in the step (3) into the BMP-2, soaking for 2-24 hours, and taking out for later use.

Compared with the prior art, the invention has the following beneficial effects:

1. the MOF prepared by the invention is firmly and uniformly combined with a base and has good biocompatibility. The operability is strong. Can provide ideas for medical device implantation materials.

2. The metalloporphyrin (porphin and its derivatives (porphyrin) form coordination compounds with metal ions) organic framework nanoparticles form a similar heterojunction with Ti02, and Ti02 not only can be used as MOF implantation carrier, but also can effectively guide and disperse electrons of the metalloporphyrin organic framework nanoparticles. So that the photodynamic action thereof generates more Reactive Oxygen Species (ROS). Meanwhile, the introduction of the PDA can improve the capture of bacteria, enhance the sterilization effect and effectively overcome various defects or shortcomings of poor effect and the like in the prior art.

3. The main antibacterial source in the antibacterial coating prepared by the method is that the active oxygen (ROS) generated by metal organic framework porphyrin Photosensitizers (PSs) kills bacteria, and the bacteria resistance and local controllability cannot be generated.

4. Due to the excellent porous medicine-carrying property of the metalloporphyrin organic framework and the adhesion of dopamine, the metalloporphyrin organic framework not only has antibacterial property, but also has good cartilage repairing property for carrying bone repairing factors, mof can play a role in protecting and slowly releasing bioactive factors, long-term bone repair is realized, and the purposes of antibacterial property and bone repair can be achieved together with mof photodynamic controllable antibacterial property.

Drawings

FIG. 1 shows micro-arc oxidized Ti0 prepared by the present invention₂Electron microscopeAnd scanning the graph.

FIG. 2 is an electron microscope scanning image of the iron-based metalloporphyrin organic framework prepared by the invention.

FIG. 3 shows Ti0 prepared by the present invention₂/iron-based metalloporphyrin organic framework electron microscope scanning image.

FIG. 4 shows a diagram of Ti0 with dopamine prepared by the present invention₂/iron-based metalloporphyrin organic framework electron microscope scanning image.

Detailed Description