WO2022262600A1 - 促细胞生长和抑细菌粘附的医用材料及加工方法 - Google Patents

促细胞生长和抑细菌粘附的医用材料及加工方法 Download PDF

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WO2022262600A1
WO2022262600A1 PCT/CN2022/097080 CN2022097080W WO2022262600A1 WO 2022262600 A1 WO2022262600 A1 WO 2022262600A1 CN 2022097080 W CN2022097080 W CN 2022097080W WO 2022262600 A1 WO2022262600 A1 WO 2022262600A1
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nano
level
micro
coating
medical
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PCT/CN2022/097080
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French (fr)
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梁春永
邹显睿
王洪水
杨泰
周欢
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河北工业大学
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Definitions

  • the invention belongs to the field of medical materials, and relates to material modification technology and laser processing technology, in particular to a surface structure and processing method of medical materials that promote cell growth and inhibit bacterial adhesion.
  • Biomedical materials are materials used to diagnose, treat, repair or replace damaged tissues and organs of living organisms or enhance their functions.
  • Various types of implant-interventional medical devices prepared using biomedical metals, bioceramics and polymer biomaterials have been widely used in many fields such as orthopedics, dentistry, skin and tendon repair, cardiovascular disease treatment, and cancer treatment.
  • the purpose of the present invention is to solve the problem that medical materials lack the ability to promote cell growth and inhibit bacterial adhesion.
  • the present invention proposes a medical material surface structure with dual functions of promoting cell adhesion and growth and inhibiting bacterial adhesion and proliferation. and its processing method.
  • the surface structure is a coating or plating layer with dual functions of promoting cell growth and inhibiting bacterial adhesion and proliferation, and at the same time, the coating or plating layer has a micro-nano structure with dual functions of promoting cell adhesion and inhibiting bacterial adhesion.
  • a method for processing the surface structure of a medical material that promotes cell growth and inhibits bacterial adhesion comprising:
  • the modification is to make a coating and/or plating on the surface of the medical material.
  • micro-nano structure can be prepared only on the surface of the substrate of the biomedical material without modification of the surface composition, or only a coating and/or plating with a specific composition can be prepared on the surface without the preparation of the micro-nano structure.
  • Including one or more of Ca, Zn, Fe, Ta, Mo, Ti, Au, Pt, Cu, Ag, P, Se, B, C, N, Ar, He in the coating can improve the material resistance Abrasion resistance, corrosion resistance, antibacterial ability and biocompatibility elements.
  • the coating includes one or more compounds of hydroxyapatite, TiO 2 , SiO 2 and ZrO 2 with good wear resistance, corrosion resistance or biocompatibility.
  • the thickness of the coating and/or coating is 10nm-500 ⁇ m, and the height difference between the highest point and the lowest point of the micro-nano structure formed by stacking multiple levels of dimensions should be smaller than the thickness of the coating and/or coating.
  • the coating and/or plating may be a coating or coating containing one of the above-mentioned components, or a coating or coating containing multiple above-mentioned components, or a composite of different coatings and different coatings.
  • the coating and/or plating layer is obtained by plasma implantation, plasma sputtering coating, plasma spraying, laser cladding, pulsed laser deposition, laser alloying, sol-gel method, electrochemical deposition, electrophoretic deposition, anodic oxidation or Made by combining one or more methods of micro-arc oxidation, loaded on the surface of medical materials or added to the surface of medical materials.
  • coatings or coatings with specific thickness can be prepared on the surface of medical materials, and different functions can be given to the surface of medical materials by preparing different coatings or coatings, such as Ca, P, Ta, etc.
  • Elements and compounds such as hydroxyapatite can effectively improve the biocompatibility of the surface of medical materials, promote cell adhesion and growth, and Zn, Cu, TiO2 and other components can effectively inhibit the adhesion and proliferation of bacteria.
  • coatings or platings are prepared The surface of the final medical material is prepared with a micro-nano structure.
  • the micro-nano structure is composed of superimposed structures with three levels of sizes.
  • the first level structure is a micron-level groove structure
  • the second level structure is a submicron-level stripe structure or an array protrusion structure
  • the third level structure is a nano-level protrusion structure.
  • the first-level groove structure is composed of grooves with a width of 20-500 ⁇ m and a depth of 0.5-10 ⁇ m; the grooves can be arranged in parallel or crosswise, and the distance between two adjacent grooves is 0-500 ⁇ m.
  • the secondary structure can be composed of stripes arranged in parallel with a width of 100-1000nm, a height of 100-300nm, and a spacing of 100-1000nm, or an array of protrusions with a base size of 50-500nm and a height of 20-500nm.
  • the secondary structure is distributed in the primary structured surface.
  • the tertiary structure can be a submicron-scale protruding structure, or it can also be composed of nano-scale structures such as nanoparticles, nanorods, nanocones, nanonets, nanosheets, and nanotubes with a size of 1-200nm. The tertiary structure distribution on the surface of the secondary structure.
  • micro-nano structure composed of superposition of multiple levels of size can be processed by one or both of pulsed laser processing, electrochemical surface treatment, machining, NaOH hydrothermal method, sandblasting and acid etching, physical vapor deposition, chemical vapor deposition, and nanoimprinting. Combined processing of the above methods.
  • the medical materials include but are not limited to pure titanium and its alloys, nickel-titanium alloys, iron and its alloys, stainless steel, cobalt-chromium alloys, pure magnesium and its alloys, pure tantalum and its alloys, pure zinc and its alloys, copper alloys, Pure gold, pure silver, pure platinum and other medical metal materials, alumina ceramics, zirconia ceramics, silicon nitride ceramics, carbon materials, hydroxyapatite, tricalcium phosphate and other medical ceramic materials, as well as polyethylene, polytetrafluoroethylene Ethylene, polypropylene, polyether ether ketone and other medical polymer materials.
  • the above-mentioned primary structure effectively increases the surface area of the material, which can promote the adhesion and growth of cells.
  • the secondary structure improves the roughness of the sample surface and provides adhesion sites for cell adhesion.
  • these structures effectively reduce the number of Gram-positive bacteria and Gram-negative bacteria represented by Escherichia coli and Staphylococcus aureus. Bacteria adhesion, play a bacteriostatic effect.
  • the tertiary structure can kill bacteria without affecting cell growth.
  • the combined effects of the above three structures make the surface of medical materials have dual functions of promoting cell growth and inhibiting bacterial proliferation.
  • the present invention modifies the surface of medical materials, prepares plating and/or coatings on the surface, and simultaneously prepares a multi-level composite physical structure, which endows medical materials with dual functions of promoting cell growth and inhibiting bacterial adhesion, while ensuring that the surface
  • the long-term effectiveness and reliability of the function can solve the problem of lack of biological activity and antibacterial performance on the surface of existing medical devices.
  • Fig. 1 is three kinds of tertiary micro-nano structures obtained in one step by pulsed laser processing method using different processes in Example 1, wherein (a) (b) (c) are the first and second parts of the micro-nano composite structure respectively. , third-level structure;
  • Fig. 2 is the comparative figure of the adhesion situation of osteoblast, endothelial cell and smooth muscle cell in four kinds of surfaces in the control example 1;
  • Fig. 3 is the comparative figure of Escherichia coli and Staphylococcus aureus in four kinds of surface adhesion situations in control example 1;
  • Figure 4 is a comparison diagram of the adhesion of surface osteoblasts with different micro-nano structures
  • Figure 5 is a comparison diagram of the adhesion of Escherichia coli on surfaces with different micro-nano structures
  • Fig. 6 is the composition figure of two kinds of surfaces in embodiment 2;
  • Fig. 7 is the comparative figure of three kinds of surface osteoblast adhesion situation in the control example 3.
  • Fig. 8 is a comparison chart of the adhesion of three kinds of surface staphylococcus aureus in the control example 3;
  • Fig. 9 is the XPS high-resolution spectrogram of surface Ti element in embodiment 3.
  • Fig. 10 is a comparison chart of the adhesion of two kinds of surface endothelial cells in Comparative Example 4.
  • Fig. 11 is a comparison chart of Ni ion stripping amount on both surfaces in Comparative Example 4.
  • Fig. 12 is a composition analysis diagram of the surface in Example 6.
  • the surface coating and coating can be processed by plasma implantation, plasma sputtering coating, plasma spraying, laser cladding, pulsed laser deposition, laser alloying, sol-gel method, electrochemical deposition, electrophoretic deposition, anodic oxidation Or micro-arc oxidation and other medical material surface modification methods can also be prepared by combining two or more of the above methods.
  • Tertiary micro-nano composite structures can be prepared on the surface of medical materials by methods including pulsed laser processing, electrochemical surface treatment, machining, NaOH hydrothermal method, sandblasting and acid etching, physical vapor deposition, chemical vapor deposition, and nanoimprinting. It can also be prepared by combining two or more of the above methods.
  • a plasma injection method combined with pulsed laser surface treatment was used to prepare a cell-promoting and antibacterial surface containing Ca and P with a three-level micro-nano composite structure on the pure titanium surface.
  • the specific steps are:
  • Ca and P are implanted into the titanium surface at doses of 2 ⁇ 10 15 ions/cm 2 and 1 ⁇ 10 15 ions/cm 2 , respectively.
  • Ion implantation forms an amorphous layer with a thickness of about 400nm on the titanium surface.
  • This amorphous layer effectively improves the biocompatibility of the titanium surface, can effectively promote the adhesion and proliferation of osteoblasts, and accelerate the integration of titanium and bone tissue. integrate.
  • the amorphous layer effectively improves the wear resistance and corrosion resistance of the titanium surface, and improves the long-term reliability of implanted devices.
  • the pulse laser parameters and processing ranges used are: wavelength 800nm, frequency 1kHz, pulse width 140fs, average power 5mW ⁇ 1000mW, processing speed 0.1mm/s ⁇ 10mm/s, spot diameter about 50-200 ⁇ m, laser scanning line spacing 50 ⁇ 200 ⁇ m.
  • the first processing power 100mW, frequency 1kHz, pulse width 140fs, processing speed 1mm/s, spot diameter about 100 ⁇ m, laser scanning line spacing 80 ⁇ m.
  • the second processing power 20mW, frequency 1kHz, pulse width 140fs, processing speed 1mm/s, spot diameter about 100 ⁇ m, laser scanning line spacing 80 ⁇ m.
  • the micro-nano composite structure prepared by two processes is a tertiary composite structure, the first-order structure width of this structure is about 90 ⁇ m; the second-order structure stripe width is 150-300nm, and the distance between adjacent stripes is 10-50nm;
  • the tertiary structure is non-uniformly distributed nanoparticles of 20-300nm.
  • the process of pulse laser processing removes part of the material on the outermost layer of the titanium surface. Since the thickness of the processing-affected layer is smaller than that of the Ca and P amorphous layers, Ca and P remain on the titanium surface.
  • the three-level micro-nano composite structure further improves the ability of the titanium surface to promote cells and inhibit bacteria, and the physical structure can exist stably, ensuring the long-term reliability of its functions of promoting cells and inhibiting bacteria.
  • Polished titanium surfaces are prepared by mechanical polishing methods.
  • the preparation method of the polished titanium surface after implanting Ca and P is as follows: first prepare the polished titanium surface by mechanical polishing, and then apply the plasma implantation method to implant the surface with doses of 2 ⁇ 10 15 ions/cm 2 and 1 ⁇ 10 15 ions/cm 2 respectively 2 Ca and P two elements.
  • the preparation method of the titanium surface with a tertiary micro-nano structure is as follows: the titanium surface is polished by a mechanical polishing method, and then the surface is laser processed, and the laser processing technology is the laser processing technology used in Example 1.
  • the preparation method of the titanium surface containing Ca and P on the surface and having a three-level composite structure is as follows: firstly, the titanium surface is polished by mechanical polishing, and the plasma implantation method is used to implant the surface into the surface with doses of 2 ⁇ 10 15 ions/cm 2 and 1 ⁇ 10 ions/cm 2 respectively. 15 ions/cm 2 of Ca and P, followed by laser processing to prepare a micro-nano composite structure on the surface.
  • the cell adhesion experiment was carried out. Osteoblasts, endothelial cells and smooth muscle cells were respectively inoculated on the surfaces of four samples, and the adhesion of various cells on various surfaces was detected 1 day after inoculation.
  • the experimental method is as follows: drop 40 ⁇ l of 5 ⁇ 10 4 cells/ml cell suspension on the surfaces of the four samples respectively, culture them for 24 hours, wash the surfaces with PBS, and compare the number of adherent cells on the surfaces of each sample by the CCK-8 method. As shown in Figure 2, 1 day after inoculation, the three types of cells adhered to the four types of surfaces.
  • the number of living cells on the titanium surface injected with Ca and P and the titanium surface with micro-nano composite structure was higher than that on the polished titanium surface , which shows that the amorphous layer prepared by plasma implantation on the titanium surface improves the cytocompatibility of the titanium surface, and the three-level micro-nano composite structure also promotes the adhesion of cells.
  • the number of cells on the titanium surface injected with Ca and P elements and with micro-nano composite structure is the highest, which indicates that the joint effect of Ca, P injection and micro-nano composite structure is better than that of single Ca, P injection or micro-nano composite structure on cell adhesion. The promotion effect is more obvious.
  • Bacterial adhesion experiment was carried out subsequently, the experimental method is: drop 40 ⁇ l, concentration is 10 7 /ml Escherichia coli and Staphylococcus aureus bacteria liquid respectively on the surface of three kinds of samples, after cultivating for 6 hours, wash the surface with PBS, Remove bacteria that do not adhere to the surface of the swatch. Fluorescent staining was performed on the surface, observed with a laser confocal microscope, and the fluorescence intensity at any 10 positions on each surface was counted.
  • a Sample a micron groove prepared on the titanium surface by mechanical processing, that is, the aforementioned primary structure, with a width of about 90 ⁇ m and a depth of about 1 ⁇ m.
  • the striped structure prepared on the titanium surface by the pulse laser processing method that is, the aforementioned second-level structure
  • the pulse laser parameters and processing technology used are: wavelength 800nm, frequency 1kHz, pulse width 140fs, power 40mW, processing speed 1mm/ s, the spot diameter is about 100 ⁇ m, and the laser scanning line spacing is 100 ⁇ m.
  • the prepared second-order structure stripes have a width of 150-300nm, an interval between adjacent stripes of 20-50nm, and the surface of the stripes is relatively smooth with almost no nanostructures on the surface.
  • Nanoparticles prepared on the surface of titanium by pulse laser remelting method that is, the aforementioned third-level structure.
  • the laser and processing technology used are: wavelength 1030nm, frequency 50MHz, pulse width 150fs, power 10W, processing speed 10mm/s,
  • the spot diameter is about 200 ⁇ m, and the laser scanning line spacing is 180 ⁇ m.
  • the resulting structure is densely arranged nanoparticles of 20-300 nm.
  • d Sample first apply machining to prepare micron grooves on the titanium surface.
  • the groove width is about 80 ⁇ m and the depth is about 1 ⁇ m.
  • the pulse laser parameters and processing technology used are: wavelength 800nm, frequency 1kHz, pulse width 140fs, power 40mW, processing speed 1mm/s, spot diameter about 100 ⁇ m, laser scanning line spacing 100 ⁇ m.
  • a stripe structure with a width of 150-300nm and a spacing of 20-50nm is prepared on the surface of the first-level structure, that is, the second-level structure.
  • the surface of the stripe is relatively smooth, and there is almost no nanostructure on the surface.
  • micron grooves are prepared on the titanium surface by machining.
  • the groove width is about 80 ⁇ m and the depth is about 1 ⁇ m.
  • the pulse laser parameters and processing technology used are: wavelength 1030nm, frequency 50MHz, pulse width 150fs, power 10W, processing speed 10mm/s, spot diameter about 200 ⁇ m, laser scanning line spacing 180 ⁇ m.
  • Nanoparticles with a size of 40-300nm are densely arranged on the surface of the primary structure.
  • the pulse laser processing method is used to prepare the second-level stripe structure on the titanium surface.
  • the pulse laser parameters and processing technology used are: wavelength 800nm, frequency 1kHz, pulse width 140fs, power 40mW, processing speed 1mm/s, spot diameter approx. 100 ⁇ m, laser scanning line spacing 100 ⁇ m.
  • the width of the prepared secondary structure stripes is 150-300nm, the distance between adjacent stripes is 20-50nm, the surface of the stripes is relatively smooth, and there is almost no nanostructure on the surface; then the same laser is used for the second scan, the laser wavelength is 800nm, and the frequency is 1kHz , pulse width 140fs, power 20mW, processing speed 1mm/s, spot diameter about 100 ⁇ m, laser scanning line spacing 100 ⁇ m.
  • Example 1 g sample: preparing a titanium surface with a tertiary micro-nano composite structure, the method and process used are the same as those in Example 1.
  • the polished titanium surface was prepared by mechanical grinding.
  • the specific method of the cell experiment is as follows: drop 40 ⁇ l, 5 ⁇ 10 4 /ml osteoblast suspension on the surface of eight kinds of samples, after culturing for 24 hours, wash the surface with PBS, and compare the surface adhesion of each sample by CCK-8 method. number of attached cells.
  • the OD value of the sample measured by the CCK8 method is proportional to the number of adherent cells on the surface of the sample, and the surface with higher fluorescence intensity is more obvious in promoting cell adhesion.
  • the order of promoting effect of different surfaces on cell adhesion is: d, g>a, e>b, f>c, h.
  • the promotion of cell adhesion varies. Among them, d surface and g surface promote the three kinds of cell adhesion most obviously, c surface and h surface have the least obvious promotion effect on cell adhesion, a surface and e surface have similar promotion effect on cells, b surface and f surface The surface effect is similar.
  • the primary and secondary structures can promote the adhesion of cells.
  • the primary structure increases the specific surface area of the material and increases the area that cells can adhere to.
  • the structure increases the surface roughness and provides more adhesion sites for cell adhesion.
  • the combination of the primary and secondary structures has the most obvious effect on cell adhesion, and the tertiary structure has no obvious effect on cell adhesion. .
  • the specific method of the bacterial adhesion test is as follows: drop 40 ⁇ l of Escherichia coli bacteria solution with a concentration of about 10 7 /ml on the surface of eight samples respectively, and after cultivating for 6 hours, rinse the surface with PBS to remove the bacteria that are not adhered to the surface of the sample. bacteria. Fluorescent staining was performed on the surface, observed with a laser confocal microscope, and the fluorescence intensity at any 10 positions on each surface was counted.
  • the average value of fluorescence intensity on the surface of each sample is proportional to the number of bacteria adhered to the surface, and the lower the fluorescence intensity, the stronger the effect of the surface on inhibiting bacterial adhesion.
  • the eight surfaces have different effects on the adhesion of E. coli.
  • the secondary and tertiary structures have an inhibitory effect on Escherichia coli, the secondary structure effectively reduces the adhesion area of bacteria, and the tertiary structure further reduces the area that bacteria can adhere to.
  • the tertiary nanostructure can pierce the cell membrane of the bacteria to kill the bacteria, and the second and tertiary composite structures have the most obvious inhibitory effect on the adhesion of the two bacteria.
  • the primary structure effectively increases the surface area of the material, which can promote cell adhesion and growth.
  • the secondary structure improves the roughness of the sample surface and provides an adhesion site for cell adhesion. At the same time, these structures are effective for bacterial adhesion and play an antibacterial role.
  • the tertiary structure can kill bacteria without affecting cell growth.
  • 316L stainless steel is a widely used medical alloy, but this material still has the problems of lack of surface activity and no antibacterial ability.
  • a Ti-hydroxyapatite coating was prepared on the surface of 316L stainless steel by magnetron sputtering and plasma spraying in sequence, and then a micro-nano composite structure was prepared on the surface by using a femtosecond laser processing method, and a coating with good corrosion resistance was prepared on the surface of 316L.
  • Bioactive coating with high binding strength The specific steps are:
  • Magnetron sputtering is applied to sputter pure titanium to the surface to form a dense titanium transition layer on the surface.
  • the plasma spraying method is used to spray molten hydroxyapatite powder on the surface to form a layer of hydroxyapatite ceramic layer on the surface.
  • the hydroxyapatite coating prepared by the plasma spraying method has the problems of insufficient bonding strength and no antibacterial ability, so the pulsed laser processing method is used to treat the surface.
  • the pulse laser parameters and processing technology used are: wavelength 1030nm, frequency 320kHz, pulse width 150fs, power 8W, processing speed 100mm/s, spot diameter about 50 ⁇ m, laser scanning line spacing 40 ⁇ m.
  • a multi-level micro-nano composite structure is obtained on the surface, in which the first level structure is a groove structure with a width of about 35 ⁇ m, the second level structure is a structure with a width of about 150-300 nm, and the spacing between adjacent stripes is 20-50 nm, and the third level structure
  • the structure is nanoparticles with a diameter of 200-400nm distributed on the surface of the secondary structure.
  • Figure 6 is the EDS spectra of the polished 316L stainless steel surface and the 316L stainless steel surface prepared with a titanium-hydroxyapatite coating with a micro-nano structure. Compared with the polished 316L surface, elements such as Ti, Ca, and P appeared on the surface of the 316L stainless steel prepared with a titanium-hydroxyapatite coating with a micro-nano structure.
  • osteoblasts and golden yellow were inoculated on the surface of smooth 316L stainless steel, 316L stainless steel with smooth titanium-hydroxyapatite coating, and titanium-hydroxyapatite coating 316L stainless steel with micro-nano composite structure.
  • Staphylococcus comparing the effects of three surfaces on the adhesion and growth of osteoblasts and the adhesion and proliferation of Staphylococcus aureus.
  • the above-mentioned smooth 316L stainless steel surface is prepared by mechanical polishing, and the 316L stainless steel surface with titanium-hydroxyapatite coating is prepared by the magnetron sputtering combined with plasma spraying method in Example 2, and the titanium with micro-nano composite structure -
  • the 316L stainless steel surface coated with hydroxyapatite was prepared according to the magnetron sputtering, plasma spraying and laser processing methods in Example 2.
  • the osteoblast proliferation experiment on three kinds of surfaces was carried out.
  • the experimental method was as follows: 40 ⁇ l, 5 ⁇ 10 4 /ml osteoblast suspension was dropped on the surface of the three kinds of samples, and after culturing for 24 hours, the surface was washed with PBS, and CCK-8 method was used to compare the number of adherent cells on the surface of each sample.
  • the number of osteoblasts adhered to the three surfaces from large to small is: 316L stainless steel surface with micro-nano composite structure titanium-hydroxyapatite coating, surface with smooth titanium-hydroxyapatite Coated 316L stainless steel surface, 316L stainless steel surface with micro-nano composite structure titanium-hydroxyapatite coating.
  • the surface of 316L stainless steel is a biologically inert surface.
  • the titanium-hydroxyapatite coating effectively improves the biological activity of the surface of 316L stainless steel and improves the cell compatibility, so it can promote the adhesion of osteoblasts.
  • the femtosecond laser processing method in the band The micro-nano composite structure was prepared on the surface of 316L stainless steel with smooth titanium-hydroxyapatite coating, which further improved the biological activity of the surface and promoted the adhesion and proliferation of osteoblasts on it.
  • the specific method is: drop 40 ⁇ l of Staphylococcus aureus bacteria at a concentration of about 10 7 /ml on the surface of the three samples, and after cultivating for 6 hours, wash the surface with PBS to remove Bacteria that do not adhere to the surface of the specimen. Fluorescent staining was performed on the surface, observed with a laser confocal microscope, and the fluorescence intensity at any 10 positions on each surface was counted.
  • the number of Staphylococcus aureus adhered to the two smooth surfaces was the largest, and the number of Staphylococcus aureus adhered to the surface with the micro-nano composite structure was significantly less, which proved that the micro-nano composite structure has the greatest effect on Adhesion of Staphylococcus aureus is inhibited.
  • the experiment in this comparative example proves that the 316L stainless steel surface with a titanium-hydroxyapatite coating of a micro-nano composite structure prepared by the method in Example 2 can inhibit Staphylococcus aureus while promoting cell adhesion and growth of adhesion.
  • machining combined with NaOH solution hydrothermal treatment was used to prepare a TiO 2 coating with a micro-nano composite structure on the surface of TC4.
  • the specific steps are:
  • a precision five-axis machining center is used to prepare the first-level groove structure on the surface.
  • step (3) Using the precision five-axis machining center to prepare the second-level groove structure on the inner surface of the groove prepared in step (2).
  • a surface with a three-level micro-nano structure is processed, in which the first-level structure is about 400 ⁇ m wide and about 5 ⁇ m deep; the second-level stripe structure is distributed on the surface of the first-level structure, and the stripe width is about 300 nm, and the height is about 200 nm. Two adjacent stripes The distance between them is about 200nm; the tertiary structure is nano-rod-like protrusions with a diameter of about 40-80nm, and the tertiary structure is evenly distributed on the surface of the second-level stripes.
  • Fig. 9 is the result of analyzing the surface composition by X-ray photoelectron spectroscopy. The high-resolution analysis spectrum of Ti element is analyzed, and the result shows that TiO 2 is formed on the surface.
  • NiTi alloys cause superelasticity and shape memory effects and are widely used in the preparation of various types of internal stents.
  • the surface of NiTi alloys also has problems of insufficient biological activity and lack of antibacterial ability.
  • NiTi alloy devices also have the problem of biological toxicity caused by the dissolution of Ni ions. .
  • a C-containing coating surface with a micro-nano composite structure was prepared on the surface of a NiTi alloy by using a micro-arc oxidation method combined with a hydrothermal method and an ion implantation method. The specific steps are:
  • the surface to be processed is mechanically polished.
  • the endothelial cell proliferation experiment on the two surfaces was carried out.
  • the experimental method was as follows: 40 ⁇ l, 5 ⁇ 10 4 /ml endothelial cell suspension was dropped on the surface of the two samples, and after culturing for 24 hours, the surface was washed with PBS, and the surface was rinsed with CCK- 8 method to compare the number of adherent cells on the surface of each sample.
  • the amount of endothelial cell adhesion on the NiTi alloy surface with micro-nano composite structure injected with C element is basically the same as that of the NiTi alloy surface with micro-nano composite structure without C element injection. Did not affect the biocompatibility of the surface.
  • the inductively coupled plasma mass spectrometry was used to detect the dissolution of Ni ions on the two surfaces in simulated body fluid.
  • the specific method is as follows: soak the two surfaces in 1 times simulated body fluid at a constant temperature of 37°C for 24 hours, and use ICP-MS to detect the Ni ion concentration in the two leaching solutions. As shown in Fig. 11, the dissolution of Ni ions on the surface without C element implantation is significantly higher than that on the surface implanted with C element.
  • a TiO 2 coating with a tertiary composite micro-nano structure was prepared on the Ti surface by combining a machining method with an anodic oxidation method. The specific steps are:
  • the Ti surface to be processed is mechanically polished.
  • a precision five-axis machining center is used to prepare the first-level groove structure on the surface.
  • step (3) Using the precision five-axis machining center to prepare the second-level groove structure on the inner surface of the groove prepared in step (2).
  • the third-pole nanotube structure was prepared on the surface of the first and second-level structures by anodic oxidation method, and a dense TiO 2 layer was formed on the surface at the same time.
  • the anodizing process is as follows: 1% HF solution is used as the electrolyte, the anodizing treatment voltage is 30V, and the treatment time is 15 minutes.
  • a surface with a three-level micro-nano structure is processed, in which the first-level structure is about 40 ⁇ m wide and about 6 ⁇ m deep.
  • the surface of the first-level structure is distributed with a second-level stripe structure.
  • the stripe width is about 300 nm and the height is about 200 nm. The distance between them is about 200nm;
  • the tertiary structure is a nanotube with a diameter of about 10-20nm, and the tertiary structure is evenly distributed on the surface of the second-level stripes.
  • a ZrO 2 coating with a tertiary micro-nano structure was prepared on the surface of polyetheretherketone by using the sol-gel method and the pulsed laser processing method.
  • a ZrO 2 coating with a thickness of about 500nm was prepared on the surface of polyetheretherketone by sol-gel method, as shown in Figure 12, a dense ZrO 2 coating was formed on the surface.
  • the laser processing parameters are: wavelength 800nm (frequency 1kHz, pulse width 200fs), average power 30mW, processing speed 1mm/s, spot diameter about 500 ⁇ m, and laser scanning line spacing 400 ⁇ m.
  • a surface with a three-level micro-nano structure is processed, in which the first-level structure is 450 ⁇ m wide and 300 nm deep; the second-level stripe structure is distributed on the surface of the first-level structure.
  • the stripe width is about 250 nm and the height is 100 nm.
  • the distance between two adjacent stripes is 250nm; the tertiary structure is nano-protrusions with a diameter of 50-100nm, and the tertiary structure is non-uniformly distributed on the surface of the second-level stripes.

Abstract

本发明涉及一种促细胞生长和抑细菌粘附的医用材料及加工方法，对医用材料表面成分改性；制作由多个级别尺寸叠加构成的微纳结构；上述两个步骤选择其中之一，或者先对医用材料表面进行成分改性再由多个级别尺寸叠加构成的微纳结构。所述多个级别尺寸叠加构成的微纳结构的第一级结构为微米级沟槽结构，第二级结构为亚微米级条纹结构或阵列突起结构，第三级结构为纳米级突起结构，二级结构分布于一级结构表面，三级结构分布于二级结构表面。本发明赋予了医用材料同时具有促进细胞生长和抑制细菌粘附双重功能，同时保证了表面功能的长期有效性及可靠性，可以解决现有医疗器械存在的表面缺乏生物活性及抑菌性能的问题。

Description

促细胞生长和抑细菌粘附的医用材料及加工方法 技术领域
本发明属于医用材料领域，涉及材料的改性技术，激光加工技术，尤其是一种促细胞生长和抑细菌粘附的医用材料表面结构及加工方法。
背景技术
生物医用材料是用来对生物体进行诊断、治疗、修复或替换其病损组织、器官或增进其功能的材料。应用生物医用金属、生物陶瓷和高分子生物材料等制备的各类植介入医疗器械，已被广泛的应用于骨科、齿科、皮肤与肌腱修复、心血管病治疗、癌症治疗等众多领域。
随着临床实践的深入，对于赋予医用材料表面促组织整合、抗细菌感染功能的关注越来越广泛。由于目前应用于临床的医用材料多数为生物惰性材料，对于细胞的粘附生长和组织的整合缺乏促进作用，无法实现材料与周边组织的快速整合，疗效欠佳。同时这些材料表面还存在细菌感染的风险，可导致植入部位的炎症反应及手术失败，严重时甚至危及患者的生命。细菌存在于日常生活中的各个角落，医疗器械的制造、运输、保存及使用过程中均存在染菌风险。而细菌一旦在器械表面附着，在适宜的条件中就容易形成细菌生物膜，成膜后的菌落极易引起各类细菌感染。因此如何实现医用材料同时促细胞生长和抗菌具有迫切的临床需求。对医用材料进行表面改性是解决上述问题的重要方法。表面改性通过改变医用材料表面物理结构或化学成分，赋予医用材料表面特定功能，而不会影响材料基体的性能。
发明内容
本发明的目的是为了解决医用材料缺乏促细胞生长以及抑细菌粘附能力的问题，本发明提出了一种同时具有促进细胞粘附、生长和抑制细菌粘附、增殖双重功能的医用材料表面结构及其加工方法。该表面结构为具有促进细胞生长、抑制细菌粘附增殖的双重功能的涂层或镀层，同时该涂层或镀层具有促进细胞粘附、抑制细菌粘附的双重功能的微纳结构。
实现本发明目的的技术方案为：
一种促细胞生长和抑细菌粘附的医用材料表面结构的加工方法，包括：
对医用材料表面改性；
制作由多个级别尺寸叠加构成的微纳结构；
上述两个步骤选择其中之一，或者先对医用材料表面改性再由多个级别尺寸叠加构成的微纳结构。
所述改性是在医用材料表面制作涂层和/或镀层。
可以不进行表面成分的改性，只在生物医用材料的基体表面制备上述微纳结构，或不进行微纳结构制备，只在表面制备具有特定成分的涂层和/或镀层，也可以实现促进细胞粘附、抑制细菌粘附的效果。
所述镀层中包括Ca、Zn、Fe、Ta、Mo、Ti、Au、Pt、Cu、Ag、P、Se、B、C、N、Ar、He中的一种或两种以上能够提高材料耐磨性、耐腐蚀性、抗菌能力及生物相容性的元素。
所述涂层包括羟基磷灰石、TiO 2、SiO 2、ZrO 2中的一种或两种以上耐磨、耐腐蚀或生物相容性好的化合物。
涂层和/或镀层的厚度为10nm-500μm，多个级别尺寸叠加构成的微纳结构的最高点到最低点之间的高度差应小于涂层和/或镀层的厚度。
涂层和/或镀层可以为含有上述成分中一种成分的镀层或涂层，也可以是含有多种上述成分的涂层或镀层，或不同镀层与不同涂层的复合。
所述涂层和/或镀层通过等离子注入、等离子体溅射镀膜、等离子体喷涂、激光熔覆、脉冲激光沉积、激光合金化、溶胶-凝胶法、电化学沉积、电泳沉积、阳极氧化或微弧氧化的一种或两种以上方法组合制成，负载于医用材料表面或添加至医用材料表层。通过控制涂层或镀层制备的相关工艺，可以在医用材料表面制备具有特定厚度的涂层或镀层，通过制备不同的涂层或镀层可以赋予医用材料表面不同的功能，例如Ca、P、Ta等元素以及羟基磷灰石等化合物可以有效提高医用材料表面的生物相容性，促进细胞的粘附、生长，Zn、Cu、TiO 2等成分可以有效抑制细菌的粘附于增殖。
为使医用材料表面更有效的实现对细胞粘度、生长的促进及对细菌粘附、增殖的抑制，同时为了保证医用材料表面促细胞、抑菌功能的长效性，在制备了涂层或镀层后的医用材料表面，制备微纳结构。
所述微纳结构由三种级别尺寸的结构叠加组成，第一级结构为微米级沟槽结构，第二级结构为亚微米级条纹结构或阵列突起结构，第三级结构为纳米级突起结构。其中，第一级沟槽结构由宽20-500μm、深0.5-10μm的沟槽组成；沟槽之间可以平行或交叉排列，两相邻沟槽间距为0-500μm。二级结构可以由平行排列的宽100-1000nm、高100-300nm、间距100-1000nm的条纹组成，或由底面尺寸50-500nm、高20-500nm的阵列突起组成，二级结构分布于一级结构表面。三级结构可以为亚微米级的突起结构，也可以由尺寸为1-200nm的纳米颗粒、纳米棒、纳米锥、纳米网、纳米片、纳米管等具有纳米尺度的结构组成，三级结构分布于二级结构表面。
多个级别尺寸叠加构成的微纳结构通过脉冲激光加工、电化学表面处理、机加工、NaOH 水热法、喷砂酸蚀、物理气相沉积、化学气相沉积、纳米压印中的一种或两种以上方法组合加工制作。
所述医用材料包括但不限于纯钛及其合金、镍钛合金、铁及其合金、不锈钢、钴铬合金、纯镁及其合金、纯钽及其合金、纯锌及其合金、铜合金、纯金、纯银、纯铂等医用金属材料，氧化铝陶瓷、氧化锆陶瓷、氮化硅陶瓷、碳素材料、羟基磷灰石、磷酸三钙等医用陶瓷材料，以及聚乙烯、聚四氟乙烯、聚丙烯、聚醚醚酮等医用高分子材料。
由于尺寸效应，上述第一级结构有效增大了材料的表面积，可以促进细胞的粘附和生长。第二级结构提高了样品表面的粗糙度，为细胞粘附提供了粘附位点，同时这些结构有效减少了大肠杆菌、金黄色葡萄球菌为代表的的革兰氏阳性菌和革兰氏阴性菌的粘附，起到抑菌作用。第三级结构可以对细菌起到杀灭作用，同时对细胞生长无影响。上述三种结构的综合作用使医用材料表面同时具有促进细胞生长和抑制细菌增殖的双重功能。
本发明的优点和有益效果为：
本发明通过对医用材料表面改性，通过在表面制备镀层和/或涂层，同时制备多级复合物理结构，赋予了医用材料同时具有促进细胞生长和抑制细菌粘附双重功能，同时保证了表面功能的长期有效性及可靠性，可以解决现有医疗器械存在的表面缺乏生物活性及抑菌性能的问题。
附图说明
图1为实施例1中应用不同工艺通过脉冲激光加工方法一步制得的三种三级微纳结构，其中(a)(b)(c)分别为该微纳复合结构的第一、第二、第三级结构；
图2为对照例1中成骨细胞、内皮细胞及平滑肌细胞在四种表面粘附情况比较图；
图3为对照例1中大肠杆菌和金黄色葡萄球菌在四种表面粘附情况比较图；
图4为带有不同微纳结构的表面成骨细胞粘附情况比较图；
图5为带有不同微纳结构的表面大肠杆菌粘附情况对比图；
图6为实施例2中两种表面的成分图；
图7为对照例3中三种表面成骨细胞粘附情况比较图；
图8为对照例3中三种表面金黄色葡萄球菌粘附情况对比图；
图9为实施例3中表面Ti元素XPS高分辨谱图；
图10为对照例4中两种表面内皮细胞粘附情况对比图；
图11为对照例4中两表面Ni离子溶出量对比图；
图12为实施例6中表面的成分分析图。
具体实施方式
下面结合制备不同医用材料的促细胞、抑菌功能表面的实施例进行具体说明。其中，表面的涂层、镀层可以通过等离子注入、等离子体溅射镀膜、等离子体喷涂、激光熔覆、脉冲激光沉积、激光合金化、溶胶-凝胶法、电化学沉积、电泳沉积、阳极氧化或微弧氧化等医用材料表面改性方法制备，也可通过上述的两种或多种方法结合进行制备。三级微纳复合结构可以通过包括脉冲激光加工、电化学表面处理、机加工、NaOH水热法、喷砂酸蚀、物理气相沉积、化学气相沉积、纳米压印等方法在医用材料表面制备，也可以通过上述的两种或多种方法结合进行制备。
实施例1
本实施例应用等离子体注入方法结合脉冲激光表面处理，在纯钛表面制备具有三级微纳复合结构的含Ca、P的促细胞、抑菌表面。具体步骤为：
(1)首先对纯钛表面进行机械抛光。
(2)应用等离子体注入方法，分别向钛表面注入剂量分别为2×10 15ions/cm 2和1×10 15ions/cm 2的Ca和P两种元素。
离子注入使钛表面形成了厚约400nm的非晶层，这一非晶层有效的提高了钛表面的生物相容性，能够有效促进成骨细胞的粘附与增殖，加快钛与骨组织的整合。同时，非晶层有效提高了钛表面的耐磨、耐腐蚀能力，提高植入器械的长期可靠性。
(3)将样品固定于加工平台上，调节激光加工工艺，扫描整个表面。所用脉冲激光参数及加工工艺范围为：波长为800nm，频率1kHz，脉宽140fs，平均功率5mW～1000mW，加工速度0.1mm/s～10mm/s，光斑直径约50-200μm，激光扫描线间距50～200μm。
选择如下工艺在上述钛表面制备了三级复合结构：
第一次加工：功率100mW，频率1kHz，脉宽140fs，加工速度1mm/s，光斑直径约100μm，激光扫描线间距80μm。第二次加工：功率20mW，频率1kHz，脉宽140fs，加工速度1mm/s，光斑直径约100μm，激光扫描线间距80μm。
如图1所示，两次加工制备的微纳复合结构为三级复合结构，该结构的第一级结构宽约90μm；二级结构条纹宽150-300nm，相邻条纹间间距10-50nm；第三级结构为20-300nm的非均匀分布的纳米颗粒。
脉冲激光加工的过程去除了钛表面最表层的部分材料，由于加工影响层厚度小于Ca、P非晶层的厚度，因此Ca、P保留在了钛表面。三级微纳复合结构进一步提高了钛表面促细胞、抑细菌的能力，且物理结构能够稳定存在，保证了其促细胞、抑细菌功能的长期可靠。
对照例1
本对照例比较了抛光钛表面、注入Ca、P后的抛光钛表面、具有三级复合结构的钛表面和表层含有Ca、P且具有三级复合结构的钛表面对细胞及细菌粘附的影响。
抛光钛表面由机械抛光方法制备。注入Ca、P后的抛光钛表面制备方法为：先用机械抛光制备抛光钛表面，随后应用等离子体注入方法向表面注入剂量分别为2×10 15ions/cm 2和1×10 15ions/cm 2的Ca和P两种元素。带有三级微纳结构的钛表面的制备方法为：应用机械抛光方法抛光钛表面，随后对表面进行激光加工，激光加工工艺为实施例1中所用激光加工工艺。表面含有Ca、P且具有三级复合结构的钛表面制备方法为：首先用机械抛光方法抛光钛表面，应用等离子体注入方法向表面注入剂量分别为2×10 15ions/cm 2和1×10 15ions/cm 2的Ca和P两种元素，随后用激光加工方法在表面制备微纳复合结构。
首先进行细胞粘附实验，将成骨细胞、内皮细胞及平滑肌细胞分别接种于四种样品表面，检测接种1天后各种细胞在各种表面的粘附情况。实验方法为：将40μl，5×10 4个/ml细胞悬液分别滴在四种样品表面上，分别培养24h后,用PBS冲洗表面，用CCK-8法比较各样品表面粘附细胞数量。如图2所示，接种1天后，三种细胞在四种表面上均有粘附，其中，注入Ca、P的钛表面及带有微纳复合结构的钛表面活细胞数高于抛光钛表面，这说明等离子注入在钛表面制备的非晶层提高了钛表面的细胞相容性，三级微纳复合结构也促进了细胞的粘附。注入Ca、P元素且带有微纳复合结构的钛表面细胞数最高，这表明Ca、P注入和微纳复合结构的共同作用相比单一的Ca、P注入或微纳复合结构对细胞粘附的促进作用更明显。
随后进行了细菌粘附实验，实验方法为：将40μl，浓度为10 7个/ml大肠杆菌和金黄色葡萄球菌菌液分别滴在三种样品表面上，培养6小时后，用PBS冲洗表面，去除未粘附于样片表面的细菌。对表面进行荧光染色，用激光共聚焦显微镜进行观察，每个表面统计任意10个位置的荧光强度。如图3所示，接种6小时后，四个表面均有两种细菌粘附，带有微纳复合结构的两种表面相比抛光的两种表面荧光强度明显更低，表明这两种表面粘附细菌数量明显更少。这一结果证明了微纳复合结构表面对革兰氏阴性菌和革兰氏阳性菌的粘附具有明显抑制作用。
对照例2
本对照例研究了不同微纳复合结构对细菌和细胞粘附的影响。在钛表面制备了a-h七种表面，具体制备方法和表面结构为：
a样品：通过机械加工方法在钛表面制备的微米沟槽即前述的第一级结构，宽约90μm，深约1μm。
b样品：通过脉冲激光加工方法在钛表面制备的条纹结构，即前述的第二级结构，所用脉冲激光参数及加工工艺为：波长800nm，频率1kHz，脉宽140fs，功率40mW，加工速度1mm/s，光斑直径约100μm，激光扫描线间距100μm。制备的第二级结构条纹宽150-300nm，相邻条纹间间距为20-50nm，条纹表面较光滑，表面几乎没有纳米结构。
c样品：应用脉冲激光重熔方法在钛表面制备的纳米颗粒，即前述第三级结构，所用激光及加工工艺为：波长1030nm，频率50MHz，脉宽150fs，功率10W，加工速度10mm/s，光斑直径约200μm，激光扫描线间距180μm。所得的结构为20-300nm密集排布的纳米颗粒。
d样品：首先应用机加工在钛表面制备微米沟槽，沟槽宽约80μm，深约1μm，随后应用脉冲激光扫描整个表面，所用脉冲激光参数及加工工艺为：波长800nm，频率1kHz，脉宽140fs，功率40mW，加工速度1mm/s，光斑直径约100μm，激光扫描线间距100μm。在第一级结构表面制备了宽150-300nm，间距为20-50nm的条纹结构，即第二级结构，条纹表面较光滑，表面几乎没有纳米结构。
e样品：首先应用机加工在钛表面制备微米沟槽，沟槽宽约80μm，深约1μm，随后应用脉冲激光扫描整个表面，所用脉冲激光参数及加工工艺为：波长1030nm，频率50MHz，脉宽150fs，功率10W，加工速度10mm/s，光斑直径约200μm，激光扫描线间距180μm。在第一级结构表面制备了尺寸为40-300nm密集排布的纳米颗粒。
f样品：首先应用脉冲激光加工方法在钛表面制备第二级条纹结构，所用脉冲激光参数及加工工艺为：波长800nm，频率1kHz，脉宽140fs，功率40mW，加工速度1mm/s，光斑直径约100μm，激光扫描线间距100μm。制备的第二级结构条纹宽150-300nm，相邻条纹间间距为20-50nm，条纹表面较光滑，表面几乎没有纳米结构；随后应用相同的激光进行第二次扫描，激光波长800nm，频率1kHz，脉宽140fs，功率20mW，加工速度1mm/s，光斑直径约100μm，激光扫描线间距100μm。
g样品：制备具有三级微纳复合结构的钛表面，所用方法和工艺与实施例1中的相同。
h样品：应用机械打磨方法制备抛光钛表面。
进行八种样品表面的细胞粘附实验和细菌粘附实验。
细胞实验的具体方法为：将40μl，5×10 4个/ml成骨细胞悬液滴在八种样品表面上，培养24小时后,用PBS冲洗表面，用CCK-8法比较各样品表面粘附细胞数量。
CCK8法测得的样品的OD值与该样品表面粘附细胞的数量成正比，荧光强度越高的表面对细胞粘附的促进作用越明显。如图4所示，不同表面对细胞粘附的促进作用排序为：d,g>a,e>b,f>c,h，这一结果表明，在材料成分相同时，不同表面的结构对细胞粘附的促进作 用不同。其中，d表面和g表面促进三种细胞粘附的作用最明显，c表面和h表面对细胞粘附的促进作用最不明显，a表面与e表面对细胞的促进作用相近，b表面与f表面作用相近，这一结果证明了第一、第二级结构对细胞的粘附具有促进作用，第一级结构增大了材料的比表面积，增大了细胞可粘附的面积，第二级结构增大了表面粗糙度，为细胞粘附提供了更多的粘附位点，第一、第二级结构复合对细胞的粘附作用最明显，第三级结构对细胞粘附没有明显影响。
细菌粘附实验的具体方法为：将40μl，浓度约为10 7个/ml大肠杆菌菌液分别滴在八种样品表面上，培养6小时后，用PBS冲洗表面，去除未粘附于样片表面的细菌。对表面进行荧光染色，用激光共聚焦显微镜进行观察，每个表面统计任意10个位置的荧光强度。
每个样品表面的荧光强度平均值与该表面粘附细菌数量成正比，荧光强度越低，表面抑制细菌粘附的作用越强。如图5所示，八种表面对大肠杆菌的粘附具有不同影响作用。细菌在抛光表面(h表面)大量粘附，a表面由于第一级结构增大了比表面积，因此细菌可粘附的面积更大，因此细菌粘附量更大，相比a、h表面，其他几种表面对细菌粘附均有抑制作用。这一结果表明，第二、第三级结构对包括大肠杆菌具有抑制作用，第二级结构有效减小了细菌的粘附面积，第三级结构进一步减小细菌可粘附的面积，同时第三级的纳米结构可以刺穿细菌的细胞膜而杀死细菌，第二、第三级复合结构对两种细菌的粘附抑制作用最明显。
这一结果证明了多级微纳复合结构对细胞和细菌在其上粘附的影响。第一级结构有效增大了材料的表面积，可以促进细胞的粘附和生长。第二级结构提高了样品表面的粗糙度，为细胞粘附提供了粘附位点，同时这些结构有效细菌的粘附，起到抑菌作用。第三级结构可以对细菌起到杀灭作用，同时对细胞生长无影响。
实施例2
316L不锈钢是一种得到广泛应用的医用合金，但这种材料次仍存在缺乏表面活性以及没有抑菌能力的问题。本实施例依次通过磁控溅射和等离子喷涂在316L不锈钢表面制备Ti-羟基磷灰石涂层，随后应用飞秒激光加工方法在表面制备微纳复合结构，在316L表面制备了耐腐蚀性能好、结合强度高的生物活性涂层。具体步骤为：
(1)应用机械抛光方法抛光316L不锈钢表面。
(2)应用磁控溅射，向表面溅射纯钛，在表面形成一层致密的钛过渡层。
(3)应用等离子喷涂法，向表面喷射熔融羟基磷灰石粉体，在表面形成一层羟基磷灰石陶瓷层。
(4)应用等离子喷涂方法制备的羟基磷灰石涂层存在结合强度不足及无具备抑菌能力的问 题，因此应用脉冲激光加工方法处理表面。所用脉冲激光参数及加工工艺为：波长1030nm，频率320kHz，脉宽150fs，功率8W，加工速度100mm/s，光斑直径约50μm，激光扫描线间距40μm。在表面得到多级微纳复合结构，其中第一级结构为宽约35μm的沟槽结构，第二级结构为宽约150-300nm的结构，相邻条纹间间距为20-50nm，第三级结构为分布于第二级结构表面的直径200-400nm的纳米颗粒。
图6分别为抛光316L不锈钢表面和制备了带有微纳结构的钛-羟基磷灰石涂层的316L不锈钢表面的EDS谱图。相比抛光316L表面，制备了带有微纳结构的钛-羟基磷灰石涂层的316L不锈钢表面出现了Ti、Ca、P等元素。
对照例3
本对照例在光滑316L不锈钢表面、带有光滑钛-羟基磷灰石涂层的316L不锈钢及带有微纳复合结构的钛-羟基磷灰石涂层316L不锈钢表面分别接种成骨细胞和金黄色葡萄球菌，比较三种表面对成骨细胞粘附、生长和金黄色葡萄球菌粘附、增殖的影响。
上述的光滑316L不锈钢表面由机械抛光方法制备，带有钛-羟基磷灰石涂层的316L不锈钢表面按实施例2中的磁控溅射结合等离子喷涂方法制备，带有微纳复合结构的钛-羟基磷灰石涂层的316L不锈钢表面按照实施例2中的磁控溅射、等离子喷涂和激光加工方法制备。
首先进行三种表面的成骨细胞增殖实验，实验方法为：将40μl，5×10 4个/ml成骨细胞悬液滴在三种样品表面上，培养24小时后,用PBS冲洗表面，用CCK-8法比较各样品表面粘附细胞数量。如图7所示，三种表面成骨细胞粘附数量从大到小依次为：带有微纳复合结构钛-羟基磷灰石涂层的316L不锈钢表面、带有光滑钛-羟基磷灰石涂层的316L不锈钢表面、带有微纳复合结构钛-羟基磷灰石涂层的316L不锈钢表面。316L不锈钢表面为生物惰性表面，钛-羟基磷灰石涂层有效提高了316L不锈钢表面的生物活性，改善了细胞相容性，因此可以促进成骨细胞的粘附，飞秒激光加工方法在带有光滑钛-羟基磷灰石涂层的316L不锈钢表面制备微纳复合结构，进一步提高了表面的生物活性，促进成骨细胞在其上的粘附、增殖。
随后进行金黄色葡萄球菌粘附实验，具体方法为：将40μl，浓度约为10 7个/ml金黄色葡萄球菌菌液滴在三种样品表面上，培养6小时后，用PBS冲洗表面，去除未粘附于样片表面的细菌。对表面进行荧光染色，用激光共聚焦显微镜进行观察，每个表面统计任意10个位置的荧光强度。如图8所示，三种表面中，两种光滑表面金黄色葡萄球菌粘附数量最多，带有微纳复合结构的表面金黄色葡萄球菌粘附数量明显更少，证明了微纳复合结构对金黄色葡萄球菌的粘附具有抑制作用。
本对照例中的实验证明了通过实施例2中方法制备的具有微纳复合结构的钛-羟基磷灰石 涂层的316L不锈钢表面能够在促进细胞粘附、生长的同时，抑制金黄色葡萄球菌的粘附。
实施例3
本实施例应用机加工结合NaOH溶液水热处理在TC4表面制备具有微纳复合结构的TiO 2涂层。具体步骤为：
(1)首先对表面进行机械抛光。
(2)应用精密五轴加工中心在表面制备第一级沟槽结构。
(3)应用精密五轴加工中心在步骤(2)制得的沟槽内表面制备第二级沟槽结构。
(4)将带有第一、第二级复合结构的表面浸泡于NaOH溶液内，并置于高压反应釜内，应用水热法在表面生长一层第三级纳米棒状突起结构。水热反应中所用NaOH溶液浓度为1-2mol/L，反应时间3-10h，反应温度120-240℃。
加工得到具有三级微纳结构的表面，其中第一级结构宽约400μm，深约5μm；第一级结构表面分布着第二级条纹结构，条纹宽约300nm，高约200nm，相邻两条纹之间相距约200nm；第三级结构为直径约40-80nm的纳米棒状突起，第三级结构均匀分布于第二级条纹表面。图9为应用X射线光电子能谱对表面成分进行分析的结果，对Ti元素的高分辨分析谱进行分析，结果表明表面形成了TiO 2。
实施例4
NiTi合金引起超弹性和形状记忆效应广泛用于制备各类内支架，但是镍钛合金表面同样存在生物活性不足及缺乏抑菌能力的问题，同时NiTi合金器械还存在Ni离子溶出导致生物毒性的问题。本实施例应用微弧氧化方法结合水热法和离子注入方法在NiTi合金表面制备了带有微纳复合结构的含C涂层表面。具体步骤为：
(1)首先对待加工的表面进行机械抛光。
(2)将样品在乙二醇电解液中进行微弧氧化处理。表面形成了直径1-10微米、深100-500纳米的微米坑。
(3)将样品置于NaOH溶液中进行水热处理，在微米坑表面生长了一层直径约30纳米的棒状突起结构。
(4)将样品置于C 2H 2气氛中，用PIII方法向表面注入C元素。
应用上述方法，在NiTi合金表面制备了具有微纳复合结构的含C涂层。
对照例4
本对照例首先比较了注入C元素和不注入C元素的带有三级微纳结构的NiTi合金表面对内皮细胞粘附增殖的影响，随后检测了两种表面在模拟体液中的Ni离子溶出量。
首先进行两种表面的内皮细胞增殖实验，实验方法为：将40μl，5×10 4个/ml内皮细胞悬液滴在两种样品表面上，培养24小时后,用PBS冲洗表面，用CCK-8法比较各样品表面粘附细胞数量。如图10所示，注入了C元素的带有微纳复合结构的NiTi合金表面和未注入C元素的带有微纳复合结构表面的NiTi合金表面内皮细胞粘附量基本一致，C元素的注入并未影响表面的生物相容性。
随后应用电感耦合等离子体质谱法检测了两种表面在模拟体液中Ni离子的溶出量。具体方法为：将两表面分别浸泡在37℃恒温的1倍模拟体液中24小时，应用ICP-MS方法检测两浸出液中的Ni离子浓度。如图11所示，未注入C元素的表面Ni离子溶出量明显高于注入C元素的表面。
这一结果表明，C元素的注入在不影响NiTi合金表面内皮细胞相容性的前提下，有效减少了Ni离子的溶出。
实施例5
本实施例应用机加工方法结合阳极氧化法在Ti表面制备具有三级复合微纳结构的TiO 2涂层。具体步骤为：
(1)首先对待加工的Ti表面进行机械抛光。
(2)应用精密五轴加工中心在表面制备第一级沟槽结构。
(3)应用精密五轴加工中心在步骤(2)制得的沟槽内表面制备第二级沟槽结构。
(4)应用阳极氧化法在第一、第二级结构表面制备第三极纳米管结构，同时表面形成了致密的TiO 2层。其中，阳极氧化工艺为：使用1％HF溶液作为电解液，阳极氧化处理电压30V，处理时间15min。
加工得到具有三级微纳结构的表面，其中其中第一级结构宽约40μm，深约6μm，一级结构表面分布着二级条纹结构，条纹宽约300nm，高约200nm，相邻两条纹之间相距约200nm；第三级结构为直径约10-20nm的纳米管，第三级结构均匀分布于第二级条纹表面。
实施例6
本实施例应用溶胶-凝胶法和脉冲激光加工方法在聚醚醚酮表面制备带有三级微纳结构的ZrO 2涂层。
首先应用溶胶-凝胶法在聚醚醚酮表面制备了厚度约500nm的ZrO 2涂层，如图12所示，表面形成了一层致密的ZrO 2涂层。
随后应用脉冲激光处理表面，激光加工参数为：波长为800nm(频率1kHz，脉宽200fs)，平均功率30mW，加工速度1mm/s，光斑直径约500μm，激光扫描线间距400μm。加工得到 具有三级微纳结构的表面，其中第一级结构宽450μm，深300nm；第一级结构表面分布着第二级条纹结构，条纹宽约250nm，高100nm，相邻两条纹之间相距250nm；第三级结构为直径50-100nm的纳米突起，第三级结构非均匀分布于第二级条纹表面。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。

Claims (10)

  1. 一种医用材料，其特征在于：在材料的表面制有促细胞生长和抑细菌粘附的的结构，该结构为多个级别尺寸叠加构成的微纳结构，所述多个级别尺寸叠加构成的微纳结构的第一级结构为微米级沟槽结构，第二级结构为亚微米级条纹结构或阵列突起结构，第三级结构为纳米级突起结构，二级结构分布于一级结构表面，三级结构分布于二级结构表面。
  2. 根据权利要求1所述的医用材料，其特征在于：
    第一级结构的沟槽宽20-500μm、深0.5-10μm；
    第二级结构的亚微米级条纹宽100-1000nm、高100-300nm；阵列突起高20-500nm；
    第三级结构纳米级突起为1-200nm的纳米颗粒、纳米棒、纳米锥、纳米网、纳米片、纳米管的一种或两种以上形态的组合。
  3. 一种医用材料的加工方法，其特征在于：包括：
    对医用材料表面改性；
    制作由多个级别尺寸叠加构成的微纳结构；
    上述两个步骤选择其中之一，或者先对医用材料表面改性再由多个级别尺寸叠加构成的微纳结构。
  4. 根据权利要求3所述的加工方法，其特征在于：所述改性是在医用材料表面制作涂层和/或镀层。
  5. 根据权利要求4所述的加工方法，其特征在于：所述镀层中包括Ca、Zn、Fe、Ta、Mo、Ti、Au、Pt、Cu、Ag、P、Se、B、C、N、Ar、He中的一种或两种以上元素。
  6. 根据权利要求4所述的加工方法，其特征在于：所述涂层包括羟基磷灰石、TiO 2、SiO 2、ZrO 2中的一种或两种以上化合物。
  7. 根据权利要求4所述的加工方法，其特征在于：涂层和/或镀层的厚度为10nm-500μm，多个级别尺寸叠加构成的微纳结构的最高点到最低点之间的高度差应小于涂层和/或镀层的厚度。
  8. 根据权利要求4所述的加工方法，其特征在于：所述涂层和/或镀层通过等离子注入、等离子体溅射镀膜、等离子体喷涂、激光熔覆、脉冲激光沉积、激光合金化、溶胶-凝胶法、电化学沉积、电泳沉积、阳极氧化或微弧氧化的一种或两种以上方法组合制成。
  9. 根据权利要求1所述的材料或权利要求2所述的方法，其特征在于：多个级别 尺寸叠加构成的微纳结构通过脉冲激光加工、电化学表面处理、机加工、NaOH水热法、喷砂酸蚀、物理气相沉积、化学气相沉积、纳米压印中的一种或两种以上方法组合加工制作。
  10. 根据权利要求1所述的材料或权利要求2所述的方法，其特征在于：所述医用材料为医用金属材料或医用陶瓷材料或医用高分子材料。
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