阅读说明：本技术 一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备 (Degradable magnesium-based bone repair material calcium-phosphorus strontium-doped functional coating and preparation thereof ) 是由 裴佳 于梦娇 张健 张磊 袁广银 阎作勤 于 2019-09-23 设计创作，主要内容包括：本发明公开了一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备；所述涂层包括设于所述可降解镁及镁合金材料表层的氟化膜和掺锶生物活性钙磷涂层；制备时,将镁及镁合金材料恒温浸没于氢氟酸中,形成氟转化膜；然后将氟化处理过的镁及镁合金材料恒温浸没于磷酸盐混合液,在氟转化膜表面沉积一层掺锶生物活性钙磷涂层。本发明制备的涂层,操作工艺简便、易行,制备的涂层与基体结合力强,既提高了基体的耐蚀性和生物相容性,又为基体镁及镁合金材料提供了优异的抗骨质疏松性能,促成骨抑制破骨。(The invention discloses a calcium-phosphorus strontium-doped functional coating of a degradable magnesium-based bone repair material and a preparation method thereof; the coating comprises a fluorinated film and a strontium-doped bioactive calcium-phosphorus coating which are arranged on the surface layer of the degradable magnesium and magnesium alloy material; during preparation, magnesium and magnesium alloy materials are immersed in hydrofluoric acid at constant temperature to form a fluorine conversion film; then immersing the magnesium and magnesium alloy material after the fluorination treatment in the phosphate mixed solution at constant temperature, and depositing a strontium-doped bioactive calcium-phosphorus coating on the surface of the fluorine conversion film. The coating prepared by the invention has simple and easy operation process, the prepared coating has strong binding force with a matrix, the corrosion resistance and the biocompatibility of the matrix are improved, excellent osteoporosis resistance is provided for the matrix magnesium and magnesium alloy materials, and bone inhibition is promoted.)

1. The degradable magnesium-based calcium-phosphorus strontium-doped functional coating for bone repair is characterized by comprising a fluorinated film and a strontium-doped bioactive calcium-phosphorus coating, wherein the fluorinated film is arranged on the surface layers of degradable magnesium and magnesium alloy.

2. The degradable magnesium-based calcium-phosphorus strontium-doped functional coating for bone repair according to claim 1, wherein the thickness of the fluoride film is 140nm to 3 μm; the thickness of the strontium-doped bioactive calcium-phosphorus coating is 120 nm-200 mu m, and the component of the strontium-doped bioactive calcium-phosphorus coating is Ca_xSr_yHPO₄(x+y＝1)。

3. A method for preparing a degradable magnesium-based calcium-phosphorus strontium-doped functional coating for bone repair according to claim 1 or 2, wherein the method comprises the following steps:

A. soaking degradable magnesium and magnesium alloy endosteal plants in hydrofluoric acid at constant temperature;

B. preparing a phosphate mixed solution containing strontium/calcium, and adding inorganic base to adjust the pH value to a preset pH value;

C. and D, placing the degradable magnesium and magnesium alloy endosteal plant treated in the step A into the strontium/calcium-containing phosphate mixed solution obtained in the step B for soaking at constant temperature, taking out and drying, and depositing a strontium-doped bioactive calcium-phosphorus coating on the surface.

4. The preparation method according to claim 3, wherein in the step A, the constant-temperature soaking is carried out at 5-45 ℃ in 15-40 wt.% hydrofluoric acid for 4-48 h.

5. The preparation method according to claim 3, wherein in the step B, the strontium/calcium-containing phosphate mixed solution is a mixed aqueous solution of 1 to 5 parts by weight of phosphate and 3 to 9 parts by weight of strontium/calcium salt; the addition amount of the inorganic base is 1-2 parts by weight.

6. The method of claim 5, wherein the phosphate is NH₄H₂PO₄、Ca(H₂PO₄)₂、Ca(H₂PO₄)₂·H₂One or a combination of O; the strontium/calcium salt is Sr (NO)₃)₂And Ca (NO)₃)₂(ii) a The inorganic base is NaOH, KOH or NH₃·H₂And O is one of the compounds.

7. The method of claim 6, wherein the strontium/calcium salt contains Sr (NO)₃)₂And Ca (NO)₃)₂Is one of 1:9, 2:8, 4:6, 6:4 and 8: 2.

8. The method according to claim 3, wherein in the step B, the predetermined pH is 3.5 to 5.5.

9. The preparation method according to claim 3, wherein in the step C, the soaking temperature of the constant-temperature soaking is 10-40 ℃, and the soaking time is 6-48 h.

10. The preparation method of claim 3, wherein the binding force between the strontium-doped bioactive calcium-phosphorus coating and the substrate is more than or equal to 10 MPa.

Technical Field

The invention belongs to the technical field of preparation of biomedical materials, and particularly relates to a calcium-phosphorus strontium-doped functional coating of a degradable magnesium-based bone repair material and a preparation method thereof.

Background

In the field of bone repair materials, magnesium and magnesium alloys are considered as revolutionary medical implant materials, and compared with traditional implant materials such as stainless steel, titanium and titanium alloys, the magnesium and magnesium alloys have the advantages of unique biodegradability, biocompatibility, biomechanical compatibility and the like. However, magnesium and magnesium alloy as bone implant materials have the problem of too fast degradation rate in vivo, and the biocompatibility needs to be further improved.

Osteoporosis, one of the problems affecting public health, is manifested by decreased bone mass and deterioration of the microstructure, making the skeleton brittle and prone to fracture. In the case of osteoporotic fractures, there is a need for a bone repair material that can promote bone healing while treating osteoporosis. Strontium, one of the essential trace elements of the human body, is considered to be closely related to the formation of bones. Strontium preparations are considered to be an effective way of preventing and treating osteoporosis because of its dual effects of inhibiting bone resorption and enhancing osteogenesis. The main pharmacological actions of strontium in preventing and treating osteoporosis are as follows: 1. inhibit osteoclast function, and reduce osteoclast precursor differentiation to osteoclast by inhibiting osteoclast differentiation activation and shortening survival cycle, so as to inhibit bone resorption; 2. promoting osteoblast function, and promoting osteogenesis by promoting osteoblast differentiation, enhancing alkaline phosphatase activity and the like; 3. regulating and controlling the differentiation of the mesenchymal stem cells and the bone marrow mesenchymal cells, promoting the differentiation of the mesenchymal stem cells to osteoblasts and the differentiation of tissues to adipocytes and the like, promoting osteogenesis and increasing bone mass.

The bioactive calcium-phosphorus coating is constructed on the surface of the magnesium and magnesium alloy, so that the biocompatibility of the magnesium alloy can be improved, bone tissue deposition on the surface of the magnesium and magnesium alloy is guided, bone growth is promoted, the degradation rate of a magnesium matrix in body fluid is slowed down, and the method is an important direction for modifying the surface of the magnesium and magnesium alloy. The magnesium and magnesium alloy has mechanical properties similar to human bones and a proper degradation rate regulated and controlled by surface modification of the calcium-phosphorus coating, is matched with a bone healing process, and has good biocompatibility and bone performance, but the magnesium and magnesium alloy and the calcium-phosphorus coating do not inhibit osteoclasts, so the osteoporosis fracture cannot be treated sufficiently, and strontium is doped in the calcium-phosphorus coating, so that the bone resorption can be inhibited while the osteogenesis is promoted, and the bone defect caused by osteoporosis can be effectively cured. Therefore, the development of a preparation method of the calcium-phosphorus strontium-doped functional coating on magnesium and magnesium alloy has important significance for the clinical application of the magnesium and magnesium alloy bone repair material in curing osteoporotic fracture.

At present, the relevant methods for doping strontium elements into the calcium-phosphorus coating on the surface of magnesium and magnesium alloy are less. The patent with the publication number of CN 104888271A discloses a preparation method of a strontium-incorporated hydroxyapatite coating on the surface of a biodegradable magnesium alloy, the method is to prepare the strontium-incorporated hydroxyapatite coating through hydrothermal reaction, the corrosion resistance of the coating is mainly emphasized, and no consideration is given to biocompatibility, whether osteoclast inhibition is performed or not and other properties. The degradable magnesium-based calcium-phosphorus strontium-doped functional coating prepared by the chemical solution deposition method has simpler preparation method and preparation conditions, and can effectively improve the corrosion resistance and biocompatibility of a magnesium matrix and inhibit osteoclasts.

Disclosure of Invention

The invention aims to provide a novel calcium-phosphorus strontium-doped functional coating of a degradable magnesium-based bone repair material and a preparation method thereof, aiming at the problem that a calcium-phosphorus coating of magnesium and magnesium alloy cannot inhibit osteoclasts. The preparation method of the calcium-phosphorus strontium-doped functional coating prepared by the invention specifically comprises the steps of preparing a fluorinated film on the surface of the degradable magnesium-based bone repair material, and then depositing a strontium-doped bioactive calcium-phosphorus coating on the material with the fluorinated film in a reaction manner. The invention solves the problem that the calcium-phosphorus coating on the surface of magnesium and magnesium alloy can not inhibit osteoclasts, and the strontium-doped bioactive calcium-phosphorus coating prepared on the surface of magnesium and magnesium alloy can play the dual roles of promoting osteogenesis and inhibiting osteoclasts while meeting the requirements of improving the biocompatibility of a matrix and delaying the corrosion rate of the matrix. The preparation process is simple and easy, the prepared calcium-phosphorus strontium-doped coating has strong binding force with a matrix, and the strontium/calcium ratio is controllable.

The purpose of the invention is realized by the following technical scheme:

in a first aspect, the invention relates to a degradable magnesium-based calcium-phosphorus strontium-doped functional coating for bone repair, which comprises a fluorinated film and a strontium-doped bioactive calcium-phosphorus coating, wherein the fluorinated film is arranged on the surface layer of degradable magnesium and magnesium alloy.

As a preferred technical scheme, the thickness of the fluorinated film is 140 nm-3 μm; the thickness of the strontium-doped bioactive calcium-phosphorus coating is 120 nm-200 mu m.

As the optimized technical proposal, the binding force of the strontium-doped bioactive calcium-phosphorus coating and the fluoridated film is more than or equal to 10MPa, and the component of the strontium-doped bioactive calcium-phosphorus coating is Ca_xSr_yHPO₄(x + y ═ 1). The osteoblastic toxicity of the strontium-doped bioactive calcium-phosphorus coating is grade 0.

In a second aspect, the invention relates to a preparation method of a degradable magnesium-based calcium-phosphorus strontium-doped functional coating for bone repair, which comprises the following steps:

A. soaking degradable magnesium and magnesium alloy endosteal plants in hydrofluoric acid at constant temperature;

B. preparing a phosphate mixed aqueous solution containing strontium/calcium, and adding inorganic base to adjust the pH value to a proper value;

C. and D, placing the degradable magnesium and magnesium alloy endosteal plant treated in the step A into the strontium/calcium-containing phosphate mixed solution obtained in the step B for soaking at constant temperature, taking out and drying, and depositing a strontium-doped bioactive calcium-phosphorus coating on the surface.

Preferably, the magnesium is pure magnesium, and the magnesium alloy is a bare metal magnesium alloy series without any treatment, such as Mg-Al series, Mg-Zn series, Mg-Ca series, Mg-Mn series or Mg-RE series.

In the step a, the soaking temperature of the constant-temperature soaking is 5-45 ℃, more preferably 20 ℃, the hydrofluoric acid concentration is 15-40 wt%, and the soaking time is 4-48 h. The oxide film generated after the fluorination treatment can be used as a surface protective film of magnesium and magnesium alloy matrixes to prevent the matrixes from being corroded.

According to a preferable technical scheme, the strontium/calcium-containing phosphate mixed solution is a mixed aqueous solution of 1-5 parts by weight of phosphate and 3-9 parts by weight of strontium/calcium salt; the addition amount of the inorganic base is 1-2 parts by weight.

As a preferred technical scheme, in the step B, the phosphate is NH₄H₂PO₄、Ca(H₂PO₄)₂、Ca(H₂PO₄)₂·H₂One or a combination of O; the strontium/calcium salt is Sr (NO)₃)₂And Ca (NO)₃)₂(ii) a The inorganic base is NaOH, KOH or NH₃·H₂One of O, more preferably the inorganic base is NaOH.

As a preferable technical scheme, in the step B, the pH is adjusted to 3.5-5.5 by adding inorganic base. The magnesium alloy coating is prepared by reacting calcium hydrogen phosphate and strontium hydrogen phosphate under an acidic condition, the pH of the solution is about 3.3-3.4 before inorganic base adjustment, the inorganic base is added for adjustment, the purpose of the inorganic base adjustment is to improve the pH of a phosphate mixed solution so as to promote the reaction, but when the pH is too high, strontium salt and calcium salt in a supersaturated solution are separated out to form turbid liquid, and then nucleation and deposition can not be carried out on the surface of the magnesium alloy, so that a coating can not be obtained.

Sr (NO) in this patent₃)₂And Ca (NO)₃)₂Can be prepared in any molar ratio, wherein Sr (NO) is preferred₃)₂And Ca (NO)₃)₂In a molar ratio of 1:9, 2:8, 4:6, 6:4 and 8:2, but Sr (NO)₃)₂And Ca (NO)₃)₂The molar ratio of (b) is not limited to the above five.

In order to ensure that the inorganic salt coating with the expected calcium-strontium molar ratio is obtained, Sr (NO) in the solution needs to be ensured₃)₂And Ca (NO)₃)₂The molar concentration ratio of the strontium carbonate to the calcium carbonate is consistent with the molar ratio of the strontium carbonate to the calcium carbonate, and meanwhile, Sr (NO) is added₃)₂And Ca (NO)₃)₂The sum of the molar concentrations of (a) and (b) is consistent with the molar concentration of dihydrogen phosphate.

As a preferred technical scheme, the strontium/calcium-containing phosphate mixed liquor is specifically any of the following formulas:

a.NH₄H₂PO₄：Sr(NO₃)₂：Ca(NO₃)₂10:1:9 (molar ratio);

b.Ca(H₂PO₄)₂：Sr(NO₃)₂：Ca(NO₃)₂5:2:8 (molar ratio);

c.NH₄H₂PO₄：Sr(NO₃)₂：Ca(NO₃)₂10:4:6 (molar ratio);

d.Ca(H₂PO₄)₂·H₂O：Sr(NO₃)₂：Ca(NO₃)₂not to scale 5:6:4 (molar ratio)

e.NH₄H₂PO₄：Sr(NO₃)₂：Ca(NO₃)₂10:8:2 (molar ratio).

And C, as a preferred technical scheme, in the step C, the soaking temperature of the constant-temperature soaking is 10-40 ℃, and the soaking time is 6-48 hours. The static corrosion rate of magnesium and magnesium alloys increases with increasing temperature, so that if the soaking temperature is too high, the corrosion of magnesium and magnesium alloys is accelerated; the solubility of calcium salt and strontium salt is reduced along with the reduction of temperature, so the soaking temperature can not be too low to ensure the concentration of the supersaturated solution.

As a preferred technical scheme, the binding force between the strontium-doped bioactive calcium-phosphorus coating and the substrate is more than or equal to 10MPa, and the osteoblast toxicity is 0 grade. The strontium-doped bioactive calcium-phosphorus coating has good biocompatibility, can obviously regulate and control the degradation rate of a magnesium substrate, has the effects of inhibiting osteoclast, inhibiting bone resorption and promoting bone formation, and is beneficial to bone repair.

The magnesium and magnesium alloy material for bone repair is soaked in hydrofluoric acid at constant temperature, so that a layer of compact fluorinated film is generated on the surface; preparing mixed phosphoric acid water solution of strontium/calcium salt, and soaking the magnesium and magnesium alloy after fluorination treatment in mixed phosphate solution at constant temperature to obtain the strontium-doped bioactive calcium-phosphorus coating. Compared with the prior art, the invention has the following beneficial effects:

(1) the invention provides a strontium-doped bioactive calcium-phosphorus coating for degradable magnesium and magnesium alloy endosteal implants and a novel preparation method thereof, wherein the coating comprises a fluorinated film and a strontium-doped bioactive calcium-phosphorus coating, and the fluorinated film is arranged on the surface layers of magnesium and magnesium alloy;

(2) the invention solves the problem that the magnesium, magnesium alloy and calcium-phosphorus coating can not inhibit osteoclast and can not treat osteoporosis fracture, the strontium-doped element in the calcium-phosphorus coating can effectively cure bone defect caused by osteoporosis, promote bone formation and inhibit bone absorption, and can effectively improve osteoporosis;

(3) the invention has simple process, simple and convenient operation and low cost;

(4) the invention is suitable for all the magnesium and magnesium alloys at present and has wide application range.

Drawings

Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:

FIG. 1 is an SEM image of the surface morphology of a strontium-doped bioactive calcium-phosphorus coating of an endosteal plant of magnesium and magnesium alloy;

FIG. 2 is a SEM image of the cross section of a magnesium and magnesium alloy intra-osseous plant strontium-doped bioactive calcium-phosphorus coating sample;

FIG. 3 shows the result of osteoblast 3day adhesion staining on strontium-doped bioactive calcium phosphate coatings of magnesium and magnesium alloy endosteal plants.

Detailed Description

The invention is described in detail below with reference to the figures and the specific embodiments. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.