阅读说明：本技术 兼具抗菌、促成骨分化及矿化的载碘钛合金植入物及其制备方法 (Iodine-carrying titanium alloy implant with antibacterial, osteogenic differentiation promoting and mineralization functions and preparation method thereof ) 是由 叶招明 刘安 滕王锶源 王翊凯 于 2020-06-19 设计创作，主要内容包括：本发明提供了一种兼具抗菌、促成骨分化及矿化的载碘钛合金植入物及其制备方法,本发明通过共价接枝及氧化还原反应的方法将碘涂层固定到钛合金上,制得的碘涂层钛片表现出抗菌性能,同时能够促进骨髓间充质干细胞成骨分化,并在模拟体液中促进钙磷矿化层生成；本发明制备工艺简单易行,具有高效、低成本、重复性佳的优势,并可有效改善目前钛合金植入物应用于骨科、口腔颌面外科以及神经外科临床的不足,降低其植入体内后的术后早期感染的发生率及因过度的炎症反应引发植入物松动等相关并发症。(The invention provides an iodine-carrying titanium alloy implant with antibacterial, osteogenic differentiation and mineralization promoting functions and a preparation method thereof, wherein an iodine coating is fixed on a titanium alloy by a covalent grafting and redox reaction method, and a prepared iodine coating titanium sheet shows antibacterial performance, can promote osteogenic differentiation of mesenchymal stem cells and promote generation of a calcium phosphate mineralization layer in simulated body fluid; the preparation process is simple and easy to implement, has the advantages of high efficiency, low cost and good repeatability, can effectively overcome the clinical defects of the prior titanium alloy implant applied to orthopedics, oral and maxillofacial surgery and neurosurgery, and reduces the incidence rate of postoperative early infection after the titanium alloy implant is implanted into a body and related complications such as implant loosening caused by excessive inflammatory reaction.)

1. An iodine-carrying titanium alloy implant with antibacterial, osteogenic differentiation promoting and mineralization functions is characterized in that the implant takes a titanium alloy as a matrix, a polydopamine coating is introduced to the surface of the titanium alloy matrix, and iodine elements are covalently bonded on the polydopamine coating; the form of the iodine element is as follows: povidone iodine, iodide ions, iodate ions, and an iodine simple substance formed by oxidation-reduction reaction of the iodide ions and the iodate ions;

the preparation method of the iodine-carrying titanium alloy implant comprises the following steps:

(a) immersing the titanium alloy matrix into an alkali solution, reacting for 10-18h at 60-80 ℃, taking out, washing and drying for later use;

(b) immersing the titanium alloy substrate treated in the step (a) in a dopamine Tris-HCl solution, reacting at 25-37 ℃ for 6-12h under the pH value of 8-9, taking out, washing and drying to obtain the titanium alloy implant coated with the polydopamine;

(c) immersing the titanium alloy implant coated with the polydopamine in the step (b) into a potassium iodide solution of povidone iodine, reacting for 6-12h at 25-37 ℃, taking out, washing and drying for later use;

(d) and (c) immersing the titanium alloy implant prepared in the step (c) in a potassium iodate aqueous solution, reacting for 3-12h at 25-37 ℃ and with the pH value of 3-5, and then washing and drying to obtain the iodine-loaded titanium alloy implant.

2. The titanium alloy implant as claimed in claim 1, wherein the alkali solution is obtained by dissolving an alkaline substance in water at a concentration of 5-10M, and the alkaline substance is sodium hydroxide or potassium hydroxide in step (a).

3. The titanium alloy implant with antibacterial, osteogenic differentiation and mineralization effects of claim 1, wherein in step (b), the dopamine concentration in the dopamine Tris-HCl solution is 1-5 mg/mL.

4. The titanium alloy implant with antibacterial, osteogenic differentiation and mineralization effects as claimed in claim 1, wherein the preparation method in step (c) is characterized in that the potassium iodide solution of povidone iodine is obtained by dissolving povidone iodine in 0.1-0.2M potassium iodide solution, wherein the mass fraction of povidone iodine is 3-5%.

5. The titanium iodide-loaded alloy implant as claimed in claim 1, wherein the concentration of the aqueous solution of potassium iodate in step (d) is 0.1-0.2M.

6. The use of the titanium alloy implant with antibacterial, osteogenic differentiation promoting and mineralization effects of claim 1 as an orthopedic, oromaxillofacial and neurosurgical implant.

Technical Field

The invention relates to the technical field of implants for orthopedics, oral and maxillofacial surgery and neurosurgery, in particular to an iodine-carrying titanium alloy implant with antibacterial, osteogenic differentiation promoting and mineralization promoting functions and a preparation method thereof.

Background

Because of the excellent biocompatibility and the biomechanical property close to the elastic modulus of bones, the titanium alloy is widely applied to clinical use as a representative bone repair implant. However, an excellent bone repair implant should not only aim at bone repair reconstruction but rather at preventing complicated surgical complications to achieve optimal surgical effects. Bone infection is one of the most serious complications of orthopedic surgery, and the wide infection inflammatory reaction and secondary bone loss and osteonecrosis of local and even whole bodies greatly delay the postoperative rehabilitation of patients, thereby causing a great deal of medical and economic burden. Therefore, the research and development of titanium alloy implant with antibacterial, bone differentiation promoting and mineralization functions for bone repair operation is urgent.

The titanium alloy antibacterial biological coating technology has attracted extensive attention due to the characteristics of various preparation methods, wide material selection, slow release and antibacterial property, adjustable biocompatibility and the like. Metals having antibacterial properties such as silver, zinc, copper; antibacterial organic matters such as quaternary ammonium salts, antibacterial peptides and the like all become the research focus of the titanium alloy antibacterial coating. However, the safety and histocompatibility of the antibacterial substance as an implant coating are questioned due to the lack of a large amount of clinical experimental data and clinical application experience, and the clinical transformation of the titanium alloy coating product is limited.

Povidone iodine is an iodine-containing complex with antibacterial activity, and has potent killing activity against bacteria, spores, viruses and fungi. The advantages of wide antibacterial spectrum, high safety, small irritation and the like make the surgical operation disinfection and debridement the first choice, and have a long clinical practice history. Therefore, the production of the titanium alloy orthopedic implant by taking the povidone iodine as the antibacterial coating material has great transformation prospect.

Previous Japanese scientists use povidone iodine as electrolyte, and coat an iodine coating on the surface of titanium alloy through an electroplating process, and prepare orthopedic implants such as external fixation bone nails, spinal nail rod systems and the like by the method. Relevant clinical experiments show that the titanium alloy implant with the iodine coating has better antibacterial effect and osteogenesis effect. This undoubtedly lays the foundation for further research of iodine-carrying coating titanium alloy. However, the electroplating process has high equipment cost, strict electrolyte preparation conditions and various electroplating condition influence factors, so that the expansion of production and application in areas with different economic development is limited to a certain extent.

Therefore, the invention is inspired by mussel adhesive protein, and polydopamine with simple preparation conditions is introduced into the titanium alloy coating for preparation as a surface modification substance. The polydopamine is adhered on the surface of the titanium alloy to form a stable coating and then is combined with povidone iodine in a povidone iodine aqueous solution or a potassium iodide solution to prepare the implant with adjustable surface iodine density, and the biological characteristics of bone repair of antibiosis, bone differentiation promotion and mineralization are represented.

Disclosure of Invention

The invention aims to provide an iodine-carrying titanium alloy implant with antibacterial, osteogenesis promoting and mineralizing functions and a preparation method thereof, aiming at the clinical defects of the titanium alloy implant in orthopedics, oral and maxillofacial surgery and neurosurgery.

The technical scheme of the invention is as follows:

an iodine-carrying titanium alloy implant with antibacterial, osteogenic differentiation promoting and mineralization functions, which takes titanium alloy as a substrate, a polydopamine coating is introduced on the surface of the titanium alloy substrate, and iodine elements are covalently bonded on the polydopamine coating; the form of the iodine element comprises: povidone iodine, iodide ions, iodate ions, and an iodine simple substance formed by oxidation-reduction reaction of the iodide ions and the iodate ions;

the preparation method of the iodine-carrying titanium alloy implant comprises the following steps:

(a) immersing the titanium alloy matrix into an alkali solution, reacting for 10-18h at 60-80 ℃, taking out, washing and drying for later use;

the alkali solution is obtained by dissolving an alkaline substance in water, the concentration of the alkaline substance is 5-10M, and the alkaline substance is sodium hydroxide or potassium hydroxide;

(b) immersing the titanium alloy substrate treated in the step (a) in a dopamine Tris-HCl solution, reacting at 25-37 ℃ for 6-12h under the pH value of 8-9, taking out, washing and drying to obtain the titanium alloy implant coated with the polydopamine;

the concentration of the dopamine in the dopamine Tris-HCl solution is 1-5 mg/mL;

(c) immersing the titanium alloy implant coated with the polydopamine in the step (b) into a potassium iodide solution of povidone iodine, reacting for 6-12h at 25-37 ℃, taking out, washing and drying for later use;

the potassium iodide solution of povidone iodine is obtained by dissolving povidone iodine in 0.1-0.2M potassium iodide aqueous solution, wherein the mass fraction of the povidone iodine is 3-5%;

(d) immersing the titanium alloy implant prepared in the step (c) in a potassium iodate aqueous solution, reacting for 3-12h at 25-37 ℃ and with the pH value of 3-5, and then washing and drying to obtain the iodine-loaded titanium alloy implant;

the concentration of the potassium iodate aqueous solution is 0.1-0.2M.

The iodine-carrying titanium alloy implant can be used for preparing orthopedic, oral and maxillofacial surgery and neurosurgery implants, and specifically comprises the following components: the titanium alloy external fixation frame bone nail, the fracture bone fracture plate, the intramedullary nail, the spine internal fixation device, the artificial joint prosthesis, the tumor prosthesis and the personalized additive manufacturing (3D printing) titanium alloy series joint prosthesis comprise a metal cushion block and a reinforcing mortar cup; titanium alloy implant, implant nail and oral bone fracture plate for oral and maxillofacial surgery; titanium alloy implants such as skull repairing titanium alloy meshes and skull bone fracture plates for neurosurgery.

The iodine-carrying titanium alloy implant has the characteristics of resisting infection and promoting osteogenic differentiation and bone mineralization, and the anti-infection is mainly aimed at common bacteria of orthopedic infection, including gram-positive bacteria and gram-negative bacteria, wherein the gram-positive bacteria comprise staphylococcus aureus, drug-resistant staphylococcus aureus, staphylococcus epidermidis, drug-resistant staphylococcus epidermidis and the like, and the gram-negative bacteria comprise escherichia coli, pseudomonas aeruginosa and the like.

The invention has the advantages that:

1. the iodine-containing titanium alloy implant is modified by the iodine coating, and the obtained iodine-containing titanium alloy implant not only has the function of resisting infection, but also has the functions of promoting osteogenic differentiation of mesenchymal stem cells and promoting generation of a calcium phosphate mineralized layer in simulated body fluid. The invention can effectively overcome the clinical defects of the prior titanium alloy implant applied to orthopedics, oral and maxillofacial surgery and neurosurgery, reduce the incidence rate of postoperative early infection after the titanium alloy implant is implanted into a body and cause the related complications such as implant loosening and the like.

2. The iodine-carrying titanium alloy implant covalently connects iodine and the titanium alloy by utilizing the classical adsorption effect of polydopamine, and simultaneously further increases the iodine-carrying amount of the titanium alloy implant by utilizing the strong oxidizing property of iodate, has the advantages of simple process, proper reaction conditions, high efficiency, low cost and good repeatability, and has very obvious effects of resisting bacteria, promoting bone differentiation and mineralization.

Drawings

FIG. 1: the surface electron microscope characterization and element EDS analysis results of the iodine-carrying titanium sheet Ti-I in example 1.

FIG. 2: the release curve of iodide ions in Tris-HCl buffer solution is soaked in the iodine-carrying titanium plate Ti-I in example 1.

FIG. 3: example 1 antibacterial effect of elution culture after culturing Staphylococcus aureus (ATCC25923) on the surface of titanium albo-lite Ti and titanium iodonium-carrying Ti-I.

FIG. 4: example 1 live and dead staining of human mesenchymal stem cells 1 day after the surface inoculation of hollow titanium sheet Ti and iodine-carrying titanium sheet Ti-I, green indicates viable cells and red indicates dead cells.

FIG. 5: mineralization electron microscopy characterization and elemental EDS analysis of iodine-loaded titanium plates of example 1 after 14 days of immersion in SBF simulated body fluid.

FIG. 6: example 1 expression of osteogenesis related genes Runx2 and Sp7 after inoculating human bone marrow mesenchymal stem cells on the surfaces of a hollow titanium dioxide sheet Ti and an iodine-carrying titanium sheet Ti-I for 3 days, the bone gene composed of the iodine-carrying titanium sheet Ti-I is highly expressed, and P is less than 0.05.

Detailed Description

The invention will be further described by means of specific embodiments with reference to the attached drawings, but the scope of protection of the invention is not limited thereto.