TWI405596B - Biomedical implant and manufacturing method thereof - Google Patents

Abstract

A biomedical implant and the manufacturing method thereof are disclosed. The biomedical implant includes a protecting layer on a substrate with a magnesium surface. The manufacturing method of the biomedical implant includes following steps. A substrate is immersed into a first carbonated solution containing Fe3+ and bicarbonate. The treated substrate is immersed into a second carbonated solution to form a self-assembled protecting layer on the surface of the magnesium substrate.

Description

Biomedical material and preparation method thereof

The invention relates to a biomedical material with a protective layer and a preparation method thereof.

Magnesium metal is a material that can be biodegraded. Magnesium metal is considered to be promising as a biomedical implant, such as a vascular stent, a bone nail, and the like.

However, according to clinical experiments, magnesium implants are rapidly corroded in body fluids, resulting in a large amount of hydrogen gas, which accumulates into small bubbles, delaying wound healing, and more serious tissue necrosis near the surgery. Therefore, magnesium-based alloys must first slow down the rate of corrosion in physiological environments as a biomedical implant. The addition of alloying elements and surface treatment with a protective film can alleviate the degradation rate of magnesium-based implants.

The hydrotalcite-like compound is a layered double hydroxides (LDH), and the general form can be expressed as [M ²⁺ _1-x M ³⁺ _x (OH) ₂ ] _X+ ‧ A ^m- _x/m ‧nH ₂ O, wherein M ²⁺ is a divalent metal ion (such as Mg ²⁺ , Zn ²⁺ , Ni ^{2+ ,} etc.); M ³⁺ is a trivalent metal ion (such as Al ^{3) +} , Fe ^{3+ ,} etc.); A ^m- is an anion (such as CO ₃ ^2- , SO ₄ ^2- , OH ^-, etc.). At present, magnesium alloy AZ91D has been treated with aqueous solution of carbonic acid, and a layer of magnesium-aluminum layered double layer hydroxide (Mg-Al LDH) has been grown on the surface of Mg-9wt.% Al-1wt% Zn alloy to improve the corrosion resistance of magnesium alloy. nature. However, because aluminum ions are cytotoxic and may cause Alzheimer's disease, magnesium-aluminum layered double-layer hydroxides are not suitable for use in biomedical materials.

In addition, another layered double layer hydroxide has low toxicity and good biocompatibility. For example, magnesium iron layered double layer hydroxide (Mg-Fe-CO ₃ LDH) is an effective phosphate adsorbent. It is used to treat hyperphosphatemia. The low toxicity and good biocompatibility of the magnesium iron layered double layer hydroxide are also used as a cationic drug carrier. Magnesium and iron ions are important elements of human life. At present, the magnesium-iron layered double-layer hydroxide powder can be prepared by artificial synthesis, and the synthesis method includes a common precipitation method, a sol-gel method or a urea hydrolysis method. At present, the magnesium iron layered double layer hydroxide powder is mainly used as an adsorbent and a raw material.

A biomedical material comprising a substrate having a pure magnesium surface and a protective layer attached to the surface of the pure magnesium, wherein the protective layer is composed of a magnesium-iron layered double layer hydroxide.

Therefore, one aspect of the present invention provides a biomedical material consisting of a substrate having a pure magnesium surface and a protective layer on the surface of a pure magnesium substrate, wherein the protective layer is a magnesium-iron layered double layer hydrogen. Oxide is formed. Since the magnesium iron layered double layer hydroxide is biologically active, the protective layer formed of the magnesium iron layered double layer hydroxide protects the pure magnesium from corrosion in a biomedical environment.

Another aspect of the present invention is to provide a biomedical material having a protective layer. The method comprises: immersing a substrate having a pure magnesium surface in a first carbonic acid solution containing iron ions for a period of time, forming a magnesium iron layered double layer hydroxide precursor on the surface of the pure magnesium, and then having a magnesium iron layered double The pure magnesium of the layer hydroxide precursor is immersed in the alkaline second carbonic acid solution, and the structure of the precursor is arranged into a magnesium iron layered double layer hydroxide having a crystalline phase, which is a protective layer.

According to an embodiment of the invention, the substrate may be a pure magnesium substrate or a metallic or non-metallic material having a pure magnesium outer film.

According to an embodiment of the present invention, when the magnetic field strength is ±5000 (Oe), when the magnetization of the current driving layer reaches ±0.5 (au), it can be taken out from the first carbonic acid solution, and then immersed in the first Dicarbonate solution.

According to the above, it can be seen that the method for preparing a biomedical material having a protective layer according to an embodiment of the present invention can be obtained by immersing a substrate having a pure magnesium surface in a first carbonic acid solution containing iron ions and an alkaline second carbonic acid solution. A protective layer is formed to protect the surface of the substrate having a pure magnesium surface to avoid rapid corrosion of the substrate in a physiological environment.

Therefore, embodiments to which the present invention is applied may have the following advantages:

First, the use of a substrate with a pure magnesium surface, the use of "pure magnesium" biodegradable properties, and the normal presence of the component "iron" in the blood, and then form a layer of magnesium iron layer on the pure magnesium surface of the substrate The hydroxide protects the magnesium metal that would otherwise be rapidly corroded in body fluids and ensures low toxicity, biocompatibility and immune stability.

Second, the protective layer of the pure magnesium surface of the substrate has good adhesion, can provide good corrosion resistance, slow down the degradation rate of the magnesium implant in the initial stage of wound healing, and ensure the implant material as an alternative function before tissue recovery.

3. The method for manufacturing a biomedical material according to an embodiment of the present invention, which is used for forming a magnesium iron layered double layer hydroxide protective layer on a pure magnesium surface of a substrate, and the operation method is simple, rapid, safe, non-toxic and low in cost, and A protective layer of a certain thickness can be formed in a short time, which is a high-performance preparation method.

Referring to Fig. 1, there is shown a method for producing a biomedical material having a protective layer according to an embodiment of the present invention, and the flow of the steps is as shown in Fig. 1.

Referring to step 110 of FIG. 1, a substrate having a pure magnesium surface is immersed in the first carbonic acid solution until a precursor layer is formed. The precursor layer is mainly a magnesium iron layered double layer hydroxide which has not been arranged as a crystalline phase.

According to the embodiment, the preparation method of the first carbonic acid solution comprises adding iron powder to deionized water and continuously stirring (adding a ratio of 10 g of iron powder to 1000 ml of deionized water), and introducing a flow rate of 1.5 liters/min. carbon dioxide. In one embodiment, when the pure magnesium substrate test piece has a size of 4 square centimeters (2 x 2 cm), the time for introducing carbon dioxide is about 1-2 hours. The iron oxide and iron powder in the solution were then filtered off while continuing to pass carbon dioxide at a flow rate of 1.5 liters/min. According to one or more embodiments of the present embodiment, the concentration of Fe ^{3+ in the} solution is controlled to 100 ± 5 ppm by dilution with deionized water, and the pH of the solution is about 5.8 to 6.

When the substrate having the pure magnesium surface is immersed in the first carbonic acid solution, the first carbonic acid solution is maintained at about 45-55 ° C, and the solution continuously passes through the CO ₂ during the process to gradually form the magnesium iron on the surface of the pure magnesium substrate. Layered double layer hydroxide precursor layer. By introducing CO ₂ , Fe ³⁺ in the solution can be kept in an ionic state, and the solution can be kept in a weak acid state to form a precursor layer.

The time required to immerse a substrate having a pure magnesium surface in a first carbonic acid solution to form a precursor layer may vary depending on the size of the magnesium substrate or the initial concentration of iron ions in the solution, but follows the iron ion The higher the initial concentration and the longer the immersion time, the stronger the magnetic strength after magnetization.

According to an embodiment of the present embodiment, when the magnetic field strength is ±5000 (Oe) and the magnetization of the precursor layer is ±0.5 (au), the first carbonic acid solution can be taken out and then immersed in the second carbonic acid. Solution.

Referring again to step 120 of FIG. 1, the magnesium substrate having the precursor layer after the step 110 is treated is immersed in a second carbonic acid solution. The purpose of step 120 is to gradually arrange the precursor layer in a basic environment as a magnesium iron layered double layer hydroxide having a crystalline phase and to form a sufficient protective layer thickness.

According to the present embodiment, the second carbonic acid solution is such that 1000 ml of deionized water is introduced into the carbon dioxide at a flow rate of 1.5 liters/min for about 40 to 60 minutes, and the temperature is controlled at 45 to 55 °C. The treated carbonic acid solution has a pH of about 4-4.4, and the pH of the carbonic acid solution is 9.5 by a base (for example, sodium hydroxide) to obtain a second carbonic acid solution.

In one embodiment of the present embodiment, 1000 ml of deionized water is passed through the carbon dioxide for 45 minutes, and the temperature is controlled at 50 °C. The treated carbonic acid solution was titrated to a pH of 9.5 with sodium hydroxide. Then, the pure magnesium substrate treated in the step 110 is immersed in the second carbonic acid solution for 20 hours, rinsed with deionized water and then naturally dried to obtain a biomedical material having a protective layer.

Table 1 is a result of analyzing the content of Mg ²⁺ and Fe ³⁺ in the surface protective layer of the biomedical material having the protective layer prepared by the embodiment of the present invention by using an electron spectroscopy for chemical analysis (ESCA). .

A powdered magnesium iron layered double layer hydroxide synthesized by a general method having a magnesium to iron ratio of between 2.0 and 3.3. It can be seen from Table 1 that the magnesium-iron layered double-layer hydroxide layer formed by the embodiment of the present invention contains a magnesium-iron ratio of 2.879, which is in accordance with the magnesium-iron layered double-layer hydroxide prepared by the general synthetic method. Magnesium to iron ratio.

Experimental example 1:

Referring to Fig. 2, the results of the superconducting magnetization quantum interferometer after being treated with a pure magnesium substrate in a first carbonic acid solution for different times are carried out according to the method shown in Fig. 1. Here, Fig. 2 (1) is treated with the first carbonic acid solution for 6 hours; (2) treated for 3.5 hours; and (3) treated for 45 minutes.

The results of Fig. 2 show that the degree of magnetization of the surface layer of the pure magnesium substrate surface is enhanced as the time during which the pure magnesium substrate is immersed in the first carbonic acid solution increases. Since pure magnesium itself cannot be magnetized, as shown in Fig. 2 (4), the reason why the pure magnesium substrate can be magnetized after being immersed in the first carbonic acid solution is that not only the magnesium-iron layered double is formed on the surface of the pure magnesium substrate. The layer hydroxide precursor also has iron precipitates with Body Centered Cubic (BCC), and the stronger the degree of magnetization, the more the amount of iron precipitates.

Therefore, in order to avoid excessive iron precipitation, a pure magnesium substrate may be taken out from the first carbonic acid solution when the magnetic field strength is ±5000 (Oe) and the magnetization is ±0.5 (au) (ie, immersed for 45 minutes). , you can get the appropriate precursor layer.

Figure 3 is a low sweep angle X-ray after a second carbonation solution or a second carbonation solution (pH 9.5) for a different time after treatment with the first carbonic acid solution for 45 minutes, in accordance with an embodiment of the present invention. The map was analyzed by diffraction (Glancing. Angle X-Ray Diffraction; GAXRD).

Wherein, the map (1) is the result of immersing in the second carbonic acid solution for 20 minutes after the first carbonic acid solution is treated for 45 minutes; (2) is immersed in the second carbonic acid solution after being treated with the first carbonic acid solution for 45 minutes. 9 hours of results; (3) the result of immersing in the second carbonic acid solution for 6 hours after the first carbonic acid solution for 45 minutes; (4) after immersing in the first carbonic acid solution for 45 minutes, immersed in the second The result of the carbonic acid solution for 3 hours; (5) the result of only treating with the first carbonic acid solution for 45 minutes.

It can be seen from the results of Fig. 3 that the longer the time of immersion in the second carbonic acid solution, the stronger the peak of the magnesium-iron layered double-layer hydroxide, which represents the formation of the layered double layer hydroxide of magnesium iron and The better the crystallinity.

4 is a layer of a magnesium-iron layered double-layer hydroxide formed by treating a pure magnesium substrate in a first carbonic acid solution for 45 minutes and immersing it in a second carbonic acid solution for 20 hours in accordance with an embodiment of the present invention. The total reflection Fourier transform infrared spectroscopy analysis results. Among them, the vertical axis represents the transmittance and the horizontal axis represents the wave number.

The results in Fig. 4 show that 1365 cm ^-1 is the vibration signal of CO ₃ ^2- functional group; other characteristic peaks are characteristic peaks of layered double-layer hydroxide in 3480 and 3080; intermediate layer is 1630 cm ^-1 Vibration signal of crystal water. 4, the intermediate layer anion of the magnesium iron layered double layer hydroxide of the embodiment of the present invention is CO ₃ ^2- .

Figure 5 (a) is a scanning electron micrograph of a pure magnesium substrate treated only with a first carbonic acid solution for 45 minutes; (b) a pure magnesium substrate treated with a first carbonic acid solution for 45 minutes, and immersed in the first Scanning electron micrograph of the dicarbonate solution after 20 hours. Among them, the precursor type of the magnesium-iron layered double-layer hydroxide can be observed from Fig. 5(a) (the XRD diffraction pattern can be proved to be the precursor of the magnesium-iron layered double-layer hydroxide) . From Fig. 5(b), the form of the magnesium iron layered double layer hydroxide precursor of (a) converted into a magnesium iron layered double layer hydroxide having a crystalline phase can be observed.

Fig. 6 is a transmission electron micrograph of a cross section of a test piece after the pure magnesium substrate was treated with the first carbonic acid solution for 45 minutes, and then immersed in the second carbonic acid solution for 20 hours. It can be seen from Fig. 6 that after the above two solution treatments, three layers (including the outer layer, the intermediate layer and the inner layer) of the magnesium iron layered double layer hydroxide are formed on the surface of the pure magnesium, and the pure magnesium substrate can be protected from corrosion.

Figure 7 is a view showing a pure magnesium substrate having a protective layer formed by treating a pure magnesium substrate in a first carbonic acid solution for 45 minutes and then immersing it in a second carbonic acid solution for 20 hours. Scanning electron micrograph of the surface topography after the grid test (test specification conforms to ASTM D3359). (a) is observed at low magnification; (b) is observed at high magnification. The Baige test is to draw a right angle cross on the surface of the pure magnesium substrate with protective layer on the surface of the substrate with a specific tool, and then firmly adhere to the tested small mesh with 3M 600 tape or equivalent tape. Grid, and then quickly tear off the tape in the direction of 180 °, to quickly assess the ability of the protective layer to resist peeling on the substrate.

The high magnification observation of Fig. 7(b) shows that the surface of the test piece after the hundred-square test, the sheet-like magnesium iron layered double-layer hydroxide still exists on the surface of the test piece, showing the magnesium-iron layered double-layer hydrogen. The adhesion of the oxide to the pure magnesium substrate is good; in addition, the residual adhesive on the surface of the test piece can be observed, indicating that the adhesion of the magnesium-iron layered double-layer hydroxide to the pure magnesium substrate is greater than that of the tape. Adhesion.

Fig. 8 is a graph showing the effect of treatment by the method of the embodiment of the present invention on the affinity of a pure magnesium substrate for blood (whole blood).

Fig. 8(a) is a graph showing the relationship between the contact time and the contact angle when a pure magnesium substrate treated with an embodiment of the present invention or an untreated pure magnesium substrate is brought into contact with blood. As can be seen from the results of (a), the pure magnesium substrate treated by the embodiment of the present invention has a small contact angle with blood. The result of (a) shows that the pure magnesium substrate having the protective layer has a higher affinity for blood than the pure magnesium substrate having no protective layer.

Figure 8(b) is an optical micrograph of a pure magnesium substrate or an untreated pure magnesium substrate treated with an embodiment of the present invention after contact with blood for 2 seconds; and Figure 8(c) is an untreated pure magnesium substrate. Optical micrographs after 2 seconds of contact with blood. As can be seen from the results of (b) and (c), the pure magnesium substrate treated by the embodiment of the present invention has better affinity with blood.

Figure 9 is a polarization curve in a simulated body fluid at 37 ° C after a 45-minute treatment with a first carbonic acid solution, followed by immersion in a second carbonic acid solution for 20 hours on a pure magnesium substrate or an untreated pure magnesium substrate; The upper left side of the polarization curve indicates that the corrosion current is smaller and the material is protected and tends to be stable (less active); and the smaller the corrosion current and the higher the corrosion potential, the better the corrosion resistance. Therefore, it can be seen from Fig. 9 that the corrosion current of the pure magnesium substrate after being treated with the first carbonic acid solution for 45 minutes and then immersed in the second carbonic acid solution for 20 hours can be greatly reduced, which also indicates that the corrosion resistance is improved.

Figure 10 is a pure magnesium substrate or an untreated pure magnesium substrate immersed in a second carbonic acid solution for 45 hours after being treated with the first carbonic acid solution for 45 minutes, and the hydrogen production amount is simulated at 37 ° C for different times in the body fluid; Among them, the higher the amount of hydrogen generated, the more serious the corrosion of the pure magnesium substrate. As can be seen from the results of Fig. 10, the pure magnesium substrate having the protective layer can delay the time during which the pure magnesium substrate is corroded in the body fluid.

Experimental example 2:

Figure 11 is a scanning electron micrograph of a protective layer formed on a substrate having a pure magnesium coating in accordance with another embodiment of the present invention. (a) is a photograph of a protective layer formed on the surface of a polyester having a vapor-deposited magnesium film; (b) is a photograph of a protective layer formed on the surface of a 316 stainless steel dedicated to biomedical deposition of a pure magnesium film.

The method of forming a protective layer on a polyester surface having a vapor-deposited pure magnesium film or a 316 stainless steel surface is performed by using the treatment procedure described in FIG. 1 except that the polyester having a pure magnesium coating on the surface and the 316 stainless steel are separately immersed. After treating in the first carbonic acid solution for 1 minute and then immersing in the second carbonic acid solution for 20 hours, the magnesium iron layered double layer hydroxide layer can be grown on the surface of the above-mentioned pure magnesium coated non-magnesium substrate.

It can be seen from the above that the embodiment of the present invention firstly immerses the substrate having the pure magnesium film on the surface in the first carbonic acid solution to form a magnesium iron layered double layer hydroxide precursor, and then immersed in the second carbonic acid solution to make magnesium. The iron layered double-layer hydroxide precursor is transformed into a magnesium-iron layered double-layer hydroxide with a crystalline phase, which can produce a protective layer with good crystallinity and a three-layer structure, which can effectively improve the pure magnesium surface of the substrate. Corrosion resistance.

The biomedical material prepared with the protective layer according to the embodiment of the present invention has good adhesion to the pure magnesium surface of the substrate, and can greatly improve the corrosion resistance of the pure magnesium surface, and thus is applied as a biomedical plant. When entering the material, the time during which the pure magnesium surface is corroded in the body fluid can be appropriately delayed.

Furthermore, a protective layer is added to the substrate having a pure magnesium surface, and the affinity with the body fluid (including blood) is higher than that of the substrate having no protective layer, which contributes to providing a good biomedical implant. Compatibility and immune stability.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention, and the present invention can be modified and modified without departing from the spirit and scope of the present invention. The scope is subject to the definition of the scope of the patent application attached.

110. . . step

120. . . step

The above and other objects, features, advantages and embodiments of the present invention will become more apparent and understood.

Fig. 1 is a flow chart showing the steps of manufacturing a biomedical material having a protective layer according to an embodiment of the present invention.

Fig. 2 is a hysteresis curve of the surface precursor layer of the pure magnesium test piece after being treated by the first carbonic acid solution for different times.

Figure 3 is a low sweep angle X-ray diffraction analysis pattern after the first carbonic acid solution was treated for 45 minutes without being immersed in the second carbonic acid solution or immersed in the second carbonic acid solution for various times.

Figure 4 is a graph showing the results of total reflection Fourier transform infrared spectroscopy of a protective layer made in accordance with an embodiment of the present invention.

Fig. 5 is a scanning electron micrograph of the second carbonic acid solution or the second carbonic acid solution after the treatment with the first carbonic acid solution for 45 minutes.

Figure 6 is a transmission electron micrograph of a cross section of a protective layer made in accordance with an embodiment of the present invention.

Fig. 7 is a scanning electron micrograph of the surface topography of the protective layer produced in accordance with an embodiment of the present invention after passing the test.

Fig. 8 is a graph showing the effect of treatment by the method of the embodiment of the present invention on the affinity of a pure magnesium substrate for blood (whole blood).

Figure 9 is a comparison of polarization curves in a simulated body fluid at 37 ° C after a 45-minute treatment with a first carbonic acid solution and then immersed in a second carbonic acid solution for 20 hours. .

Figure 10 is a comparison of the amount of hydrogen produced at 37 ° C in simulated body fluids at 37 ° C after a 45-minute treatment with a first carbonic acid solution, a pure magnesium substrate or an untreated pure magnesium substrate immersed in a second carbonic acid solution for 20 hours. Figure.

Figure 11 is a scanning electron micrograph of a protective layer formed on a substrate having a pure magnesium coating in accordance with another embodiment of the present invention.

110. . . step

120. . . step

Claims (13)

A biomedical material comprising: a substrate having a pure magnesium surface; and a protective layer on the pure magnesium surface, wherein the protective layer is composed of a magnesium iron layered double layer hydroxide. The biomedical material according to claim 1, wherein the substrate is a pure magnesium substrate. The biomedical material according to claim 1, wherein the substrate is a metal or non-metal material having a pure magnesium outer film. A method for preparing a biomedical material, comprising: providing a substrate having a pure magnesium surface; dipping the substrate in a first carbonic acid solution until a precursor layer is formed, wherein the first carbonic acid The solution contains carbon dioxide and iron ions; and the substrate is immersed in a second carbonic acid solution until the precursor layer is arranged into a magnesium iron layered double layer hydroxide having a crystalline phase, wherein the second carbonic acid solution The pH is 9-10. The method for preparing a biomedical material according to claim 4, further comprising measuring the strength of the precursor layer after being magnetized, when the precursor layer has a magnetic field strength of ±5000 (Oe) and a magnetization of ±0.5 (au) At this time, the substrate was taken out from the first carbonic acid solution and immersed in the second carbonic acid solution. The method for preparing a biomedical material according to claim 4, wherein the first carbonic acid solution contains 95-105 ppm of iron ions. The method for preparing a biomedical material according to claim 5, wherein the substrate is immersed in the first carbonic acid solution for 20-50 minutes. The method for preparing a biomedical material according to claim 4, wherein the pH of the first carbonic acid solution is 5.8-6. The method for preparing a biomedical material according to claim 4, wherein the temperature of the first carbonic acid solution is 45-55 °C. The preparation method of the biomedical material according to claim 4, wherein the second carbonic acid solution is immersed for 9-20 hours. The method for preparing a biomedical material according to claim 4, wherein the method for preparing the first carbonic acid solution comprises: adding iron powder to deionized water to form a mixed solution; continuously introducing carbon dioxide into the mixed solution; and removing the The iron oxide and iron powder in the mixed liquid form the first carbonic acid solution. The method for preparing a biomedical material according to claim 11, wherein the flow rate of the carbon dioxide is 1.5 liters/min, and the 1-2 hours are passed. The method for preparing a biomedical material according to claim 4, wherein the method for preparing the second carbonic acid solution comprises: continuously introducing carbon dioxide into an ionized water to form a carbonic acid solution, wherein the temperature of the deionized water is 45-55 ° C. And titrating the carbonic acid solution with a base to a pH of 9.5.