WO2021258427A1 - 一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层 - Google Patents

一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层 Download PDF

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WO2021258427A1
WO2021258427A1 PCT/CN2020/101204 CN2020101204W WO2021258427A1 WO 2021258427 A1 WO2021258427 A1 WO 2021258427A1 CN 2020101204 W CN2020101204 W CN 2020101204W WO 2021258427 A1 WO2021258427 A1 WO 2021258427A1
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zinc oxide
light
antibacterial
dual
responsive
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French (fr)
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廖岚
王小磊
赵思语
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南昌大学
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
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    • A61L27/06—Titanium or titanium alloys
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2420/00—Materials or methods for coatings medical devices
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    • A61L2430/00—Materials or treatment for tissue regeneration
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Definitions

  • the invention belongs to the technical field of surgical implants, and in particular relates to a dual-light-responsive zinc oxide, a preparation method thereof, and a photosensitive coating with antibacterial osteogenic properties.
  • Oral implant surgery is one of the most common implant surgery in humans.
  • the number of patients affected by peri-implant diseases (PIDs) is also increasing.
  • PIDs peri-implant diseases
  • the incidence of diseases around oral implants is as high as about 40%. This is because part of the implant is exposed to the oral microenvironment, which can easily cause bacterial invasion and peri-implant mucositis (PIM); further spread of inflammation will cause the gradual loss of supporting bone around the implant, which will lead to peri-implant inflammation (PI) happened.
  • Bacterial infections are most closely related to the PIDs of implants, which can lead to weak osseointegration around the implants, implants fall off, and ultimately lead to implant failure.
  • patients with missing teeth not only need more additional surgery to treat PIDs, sometimes even Need to go through a second implant surgery to restore missing teeth, which has a great impact on the patient's body and mind.
  • Titanium-based implants are currently the most widely used type of implants in clinical practice. However, as an inert material, titanium does not have antibacterial properties, has poor bonding with surrounding bone tissue, and has a high implant failure rate.
  • the present invention provides a dual-light-responsive zinc oxide, a preparation method thereof, and a photosensitive coating with antibacterial osteogenic properties.
  • the dual-light-responsive zinc oxide provided by the present invention has good adsorption capacity, can respond to yellow light and near-infrared light, has good antibacterial properties and light-to-heat conversion capabilities, and the coating prepared by it can significantly improve the implant’s Antibacterial and osteogenic.
  • a preparation method of dual-light-responsive zinc oxide includes the following steps:
  • hydrothermal product is sequentially freeze-dried and microwave irradiated to obtain dual-light-responsive zinc oxide.
  • the soluble zinc salt is zinc nitrate.
  • the light-to-heat conversion material is one or more of activated carbon, gold rod and black phosphor.
  • the dosage ratio of the soluble zinc salt, hexamethylenetetramine, water, sodium citrate, hydroxypropyl methylcellulose, photothermal conversion material and lignin is (1.487 ⁇ 1.488)g:(0.350 ⁇ 0.352)g:(95 ⁇ 110)mL:(0.138 ⁇ 0.142)g:(0.100 ⁇ 0.120)g:(0.025 ⁇ 0.035)g:(0.995 ⁇ 0.115)g.
  • the temperature of the first hydrothermal reaction is 65-67°C and the time is 14-16 min; the temperature of the second hydrothermal reaction is 85-87°C and the time is 10-12h.
  • the power of the microwave irradiation is more than 800W, and the time is more than 15min.
  • the present invention provides the dual-light-responsive zinc oxide prepared by the method described in the above solution.
  • the microscopic morphology of the dual-light-responsive zinc oxide is in the shape of Tremella; the dual-light-responsive zinc oxide can be Response occurs under irradiation.
  • the present invention also provides a photosensitive coating with antibacterial osteogenesis, which is prepared from the dual light-responsive zinc oxide described in the above scheme.
  • the coating is prepared by the following steps:
  • Disperse dual-light-responsive zinc oxide in a solvent coat the resulting suspension on the surface of a substrate, and dry to obtain a photosensitive coating with antibacterial osteogenic properties; the substrate is a surgical implant.
  • the raw material for preparing the coating layer further includes type I collagen powder, and the mass ratio of the dual-light-responsive zinc oxide to the type I collagen powder is 1: (1-5).
  • the present invention provides a method for preparing dual-light-responsive zinc oxide.
  • soluble zinc salt, hexamethylenetetramine and water are mixed to perform the first hydrothermal reaction, and then the reaction material liquid is mixed with sodium citrate and hydroxyl Propyl methyl cellulose, photothermal conversion material, and lignin are mixed for the second hydrothermal reaction to obtain a hydrothermal product; then the hydrothermal product is sequentially freeze-dried and microwave irradiated to obtain dual-light-responsive zinc oxide .
  • sodium citrate and hydroxypropyl methylcellulose are added during the preparation process to control the morphology of zinc oxide, the photothermal conversion material is added to make the obtained zinc oxide have photothermal conversion ability, and the zinc oxide is made by adding lignin.
  • the present invention freeze-drys the obtained hydrothermal product and then performs microwave irradiation.
  • the hydrothermal product is carbonized by microwave irradiation, so that the energy band gap of zinc oxide is further reduced and the material It has the ability to respond to long-wavelength visible light (yellow light); at the same time, the carbonization effect of microwave irradiation can also make the tremella-like fold structure of zinc oxide more obvious, thereby improving its adsorption capacity.
  • the present invention provides the dual-light-responsive zinc oxide prepared by the method described in the above scheme.
  • the dual-light-responsive zinc oxide prepared by the present invention has a Tremella-like fold structure and has good adsorption (capable of adsorbing substances such as pigments and proteins), and Good antibacterial and photothermal stability, photothermal conversion ability, photocatalytic effect under yellow light irradiation, can further improve antibacterial ability, photothermal conversion ability under near-infrared light irradiation, is a good photothermal Treatment materials.
  • the present invention also provides a photosensitive coating with antibacterial osteogenesis, which is prepared from the dual light-responsive zinc oxide described in the above scheme.
  • the coating provided by the present invention has both antibacterial and osteogenic properties.
  • the coating can be activated under safe and gentle visible light (yellow light) irradiation, and has good antibacterial properties against both Gram-positive bacteria and Gram-negative bacteria. Performance, especially for specific oral bacteria also has obvious antibacterial effect.
  • the coating exhibits good photothermal conversion ability under near infrared (NIR) irradiation, and a proper increase in temperature can effectively promote the proliferation and osteogenic gene expression of bone marrow mesenchymal stem cells (BMSCs), and promote the implant and Osseointegration of surrounding bone tissue; applying the coating of the present invention to the surface of titanium-based implants can effectively improve the antibacterial and osteogenesis effects of titanium-based implants, and its special photosensitivity can realize the antibacterial and osteogenesis functions of the implants The light control is effective and on-demand.
  • NIR near infrared
  • the raw material for preparing it also includes type I collagen powder, which has the effect of promoting osteogenesis and can further improve the osteogenesis of the coating.
  • Figure 1 is a scanning electron microscope image of ZnO and ZnO-Col-I, the scale is 1 ⁇ m;
  • Figure 2 shows the energy spectrum of ZnO and ZC
  • Figure 3 shows the X-ray diffraction patterns of Ti and Ti-ZnO
  • Figure 4 is a standard curve of bovine serum albumin in Example 3.
  • Example 5 is a graph showing the results of adsorption of BSA by zinc oxide of different concentrations in Example 3;
  • Figure 6 is the UV absorption spectrum of the rhodamine B solution at 0h, 12h, 24h, 36h and 48h under dark and light conditions in Example 4;
  • Fig. 7 is the variation curve of the degradation rate of rhodamine B under dark and light conditions in Example 4.
  • FIG. 8 is a graph of temperature changes of different types of zinc oxide dispersion liquids under light conditions in Example 5;
  • Figure 9 is a thermal image of the titanium sample treated with different treatments in Example 5 before and after NIR irradiation
  • Figure 10 shows the antibacterial rate of Ti sample against Staphylococcus aureus (S. aureus) and the SEM observation of the bacteria in Example 6 (the scale is 1 ⁇ m);
  • Figure 11 shows the antibacterial rate of the Ti sample against E. coli and the SEM observation of the bacteria in Example 6 (the scale is 1 ⁇ m);
  • Figure 12 shows the antibacterial rate of the Ti sample against S. mutans and the SEM observation of the bacteria in Example 6 (the scale is 1 ⁇ m);
  • Figure 13 is a graph of temperature changes of cells treated with different immersion solutions in Example 7 under NIR irradiation
  • Example 14 is an infrared thermal image of cells treated with different immersion solutions in Example 7 after continuous irradiation under NIR for 10 minutes;
  • Figure 15 shows the gene expression levels of Runx2 and OCN in cells treated with different immersion solutions in Example 8.
  • Figure 16 shows the test results of the ALP staining level of cells treated with different immersion solutions in Example 8, (the scale is 200 ⁇ m).
  • the present invention provides a method for preparing dual light-responsive zinc oxide, which includes the following steps:
  • hydrothermal product is sequentially freeze-dried and microwave irradiated to obtain dual-light-responsive zinc oxide.
  • the water used in the present invention is deionized water.
  • soluble zinc salt, hexamethylenetetramine (HMT) and water are mixed to perform the first hydrothermal reaction.
  • the soluble zinc salt is preferably zinc nitrate, specifically zinc nitrate hexahydrate; the water is preferably deionized water; the temperature of the first hydrothermal reaction is preferably 65 to 67°C, more preferably 65 ⁇ 66°C, the time is preferably 14 ⁇ 16min, more preferably 15min; in the present invention, it is preferred to dissolve the soluble zinc salt and hexamethylenetetramine in water and stir for 10min to completely dissolve the soluble zinc salt and hexamethylenetetramine , And then carry out the first hydrothermal reaction; the stirring is preferably carried out under sealed conditions.
  • the present invention mixes the reaction material liquid with sodium citrate, hydroxypropyl methylcellulose (HPMC), photothermal conversion material and lignin to perform a second hydrothermal reaction to obtain a hydrothermal product.
  • the dosage ratio of the soluble zinc salt, hexamethylenetetramine, water, sodium citrate, hydroxypropyl methylcellulose, light-to-heat conversion material and lignin is preferably (1.487-1.488) g :(0.350 ⁇ 0.352)g:(95 ⁇ 110)mL:(0.138 ⁇ 0.142)g:(0.100 ⁇ 0.120)g:(0.025 ⁇ 0.035)g:(0.995 ⁇ 0.115)g, more preferably 1.4875g:0.351 g: 100mL: 0.14g: 0.1g: 0.025g: 0.1g;
  • the photothermal conversion material is preferably one or more of activated carbon, gold rod and black phosphorus, more preferably activated carbon; the sodium citrate Plays
  • the temperature of the second hydrothermal reaction is preferably 85-87°C, more preferably 85-86°C, and the time is preferably 10-12h, more preferably 10-11h.
  • HMT in the solution continues to slowly release OH - and react with zinc ions to generate more zinc oxide.
  • the photothermal conversion material, lignin and zinc oxide react to make the resulting Zinc oxide has the ability to convert light to heat, and the energy band gap is reduced.
  • the present invention preferably filters the reaction liquid, and then performs washing with absolute ethanol and washing with water in sequence to obtain a hydrothermal product; the times of washing with absolute ethanol and washing with water are preferably two. Both the absolute ethanol washing and the water washing are preferably centrifugal washing, the rotation speed of the centrifugal washing is preferably 7000 rpm, and the time for a single washing is preferably 15 min.
  • the hydrothermal product is sequentially freeze-dried and microwave irradiated to obtain dual light-responsive zinc oxide.
  • the hydrothermal product is preferably pre-frozen at -80°C and then subjected to vacuum freeze-drying; the vacuum freeze-drying time is preferably 12h; the microwave irradiation power is preferably 800W or more, more preferably 800-850W, time It is preferably 15 minutes or more, specifically 15 to 20 minutes.
  • the present invention provides a dual-light-responsive zinc oxide prepared by the method described in the above solution, wherein the microscopic appearance of the dual-light-responsive zinc oxide is a Tremella shape and is formed by stacking a wrinkled sheet structure; the dual-light-responsive zinc oxide
  • the particle size of zinc oxide is about 2 ⁇ m, and the energy band gap is 2.125 eV (thus it can respond to yellow light);
  • the dual-photo-responsive zinc oxide can respond under yellow light and near-infrared light; in the present invention In the specific embodiment, it responds specifically at 597-577nm (yellow light) and 808nm (near-infrared light);
  • the dual-light-responsive zinc oxide provided by the present invention has good adsorption capacity and can adsorb proteins, pigments and other substances, And has good antibacterial properties and light-to-heat conversion ability.
  • the present invention also provides a photosensitive coating with antibacterial osteogenesis, which is prepared from the dual light-responsive zinc oxide described in the above scheme.
  • the coating provided by the present invention has good antibacterial properties, has photocatalytic properties under yellow light, has further improved antibacterial properties, has photothermal conversion ability under near-infrared light, and the increase in temperature helps promote osteogenesis.
  • the special photosensitivity of the coating provided by the present invention can realize the light control effect and on-demand effect of the antibacterial and osteogenesis function of the implant. For example, in the oral implantation, the contact part of the oral cavity ( The cuff) is easy to cause bacteria to grow, and then spread down to the periodontal.
  • a yellow light toothbrush can be used, and the yellow light plays a photocatalytic effect to improve the antibacterial property of the implant; For example, after implanting the implant provided with the photosensitive coating of the present invention, irradiation with near-infrared light (ie, hyperthermia) is given to promote osseointegration.
  • near-infrared light ie, hyperthermia
  • the coating is preferably prepared by the following steps:
  • Disperse the dual light-responsive zinc oxide in a solvent coat the obtained suspension on the surface of the substrate, and dry to obtain a photosensitive coating with antibacterial bone formation.
  • the substrate is preferably a surgical implant
  • the material of the surgical implant may specifically be pure titanium, titanium alloy, titanium-zirconium alloy, and the like.
  • the solvent is preferably water, physiological saline or PBS buffer; the dispersion is preferably carried out under agitation, the rotation speed of the agitation is preferably 75 rpm, and the time is preferably 2 h; the double light in the suspension
  • concentration of the responsive zinc oxide is preferably 200 ⁇ g/mL; the present invention has no special requirements on the coating amount of the suspension, as long as it can cover the surface of the substrate uniformly and comprehensively;
  • the drying temperature is preferably room temperature, the present invention There is no specific limitation on the drying time, it is better to fully dry.
  • the raw materials for preparing the coating preferably further include type I collagen powder (Col-I), and the mass ratio of the dual-light-responsive zinc oxide to the type I collagen powder is preferably 1: (1-5) , More preferably 1:(2 ⁇ 3).
  • the raw materials for preparing the coating include type I collagen powder, the type I collagen powder and the dual-light-responsive zinc oxide can be co-dispersed in the solvent.
  • Col-I is the main organic matrix of natural bone. It participates in regulating the development, differentiation activity and bone remodeling of osteoblasts, and plays an important role in tissue repair and regeneration.
  • the present invention adds Col-I, Col- I can be adsorbed in the fold structure of zinc oxide to further improve the bone formation ability of the coating.
  • Ti-ZC Preparation of Ti-ZC: Add the ZnO powder and type 1 collagen powder prepared in Example 1 to a phosphate buffered saline solution (PBS buffer) at a mass ratio of 1:1, and stir at 75rpm for 2h to obtain a suspension
  • concentration of ZnO powder in the suspension is 200 ⁇ g/mL.
  • the suspension is dropped on the surface of a titanium sample (a titanium sheet with a diameter of 10 mm and a thickness of 1 mm), and dried at room temperature.
  • the coated titanium sample is denoted as Ti-ZC.
  • Ti-ZnO Others are the same as in 1, except that type I collagen powder is not added, the concentration of ZnO in the suspension is 200 ⁇ g/mL, and the obtained sample is denoted as Ti-ZnO.
  • ZnO-Col-I Use PBS buffer to mix ZnO and Col-I at the same concentration (200 ⁇ g/ml), shake in a shaker at a speed of 75-80 rpm for 2 to 3 hours to prepare ZnO- Col-I suspension, the resulting sample is denoted as ZnO-Col-I, and subsequently referred to as ZC for short.
  • Figure 1 is a scanning electron microscope image of ZnO and ZnO-Col-I with a scale of 1 ⁇ m; according to Figure 1, it can be seen that ZnO It has a white fungus-like morphology and is composed of stacked layers of folds. According to the scanning electron micrograph of ZnO-Col-I, it can be seen that Col-I is attached to the fold structure of ZnO.
  • the particle size and potential analyzer (Zeta-sizer Nano ZS90, Malvern, UK) was used to test the size of ZnO, and the results showed that the particle size of ZnO was about 2 ⁇ m.
  • the energy band gap of ZnO was tested by the ultraviolet absorption method, and the result showed that the energy band gap of ZnO was 2.125 eV, and the ZnO under the energy band gap could be excited by yellow light.
  • the specific surface area and porosity analyzer (JW-BK132F) was used to measure the pore volume-pore size distribution of ZnO.
  • the results show that the specific surface area of ZnO is 49.857m 2 /g, the pore volume is 0.219cm 3 /g, and the average pore size is 16.207nm .
  • bovine serum albumin (BSA) was used as a simulated protein, and a BSA kit was used to detect the protein adsorption capacity of ZnO. Put different masses of ZnO (1mg, 2mg, 5mg) into 1mL BSA solution (wherein the concentration of BSA is 5mg/mL), stir at 75r/min at 37°C, and centrifuge at 7000r/min after 2h After washing twice, the supernatant was obtained. Dilute the above-mentioned supernatant 10 times and place it in a 96-well plate.
  • the standard curve adopts a known concentration of bovine serum albumin standard curve (as shown in Figure 4), and read the absorbance at 562 nm in a microplate spectrophotometer.
  • Figure 5 shows the results of different concentrations of zinc oxide adsorbing BSA.
  • concentration of ZnO is calculated as the concentration diluted 10 times.
  • the ordinate is the absorbance of BSA.
  • Figures 6-7 show the UV absorption spectra of Rhodamine B solution at 0h, 12h, 24h, 36h and 48h under dark and light conditions;
  • Figure 7 shows the UV absorption spectra of Rhodamine B under dark and light conditions. Degradation rate change curve. It can be seen from Figures 6-7 that the degradation rate of rhodamine B increases with time, and the degradation rate of rhodamine B is higher under yellow light irradiation, indicating that the zinc oxide prepared by the present invention has excellent photocatalysis performance.
  • Tremella-like zinc oxide (Tremella-like ZnO) and conventional columnar zinc oxide (ZnO rod) prepared in Example 1 were dispersed in water, both controlled to 5mg/mL, and placed under room temperature near infrared light (NIR, 808nm) irradiation conditions .
  • NIR, 808nm room temperature near infrared light
  • Figure 8 is the temperature change diagram of different types of zinc oxide dispersion under light conditions. It can be seen from Figure 8 that compared with the conventional columnar zinc oxide, the white fungus-shaped zinc oxide prepared by the present invention has stronger light-to-heat conversion ability. Under the same conditions, the water dispersion of the white fungus-shaped zinc oxide of the present invention is dispersed. The increase in temperature is even greater.
  • FIG. 9 shows the thermal imaging images of the titanium samples with different treatments before and after NIR irradiation. According to Figure 9, it can be seen that the Ti group heated up to 38.4°C after NIR irradiation, while Ti The -ZnO group can be heated to 48.6°C, and the Ti-ZC group can be heated to 46.1°C. This result shows that the zinc oxide prepared by the present invention has excellent photothermal conversion ability.
  • Staphylococcus aureus S. aureus
  • Escherichia coli E. coli
  • Streptococcus mutans S. mutans
  • S. aureus Staphylococcus aureus
  • E. coli Escherichia coli
  • S. mutans Streptococcus mutans
  • the Ti samples are Ti (original titanium sheet), Ti-ZnO, Ti-ZC, and a set of blank controls are set. No Ti samples are added to the blank controls.
  • the experimental groups in the dark environment are respectively marked as: Crtl (blank control) , Ti, Ti-ZnO, Ti-ZC, the experimental groups in the yellow light irradiation environment are respectively denoted as: YL (blank control), Ti-YL, Ti-ZnO-YL, Ti-ZC-YL.
  • Figure 10 shows the antibacterial rate of Ti samples against Staphylococcus aureus (S. aureus) and SEM observations of bacteria
  • Figure 11 shows the antibacterial effect of Ti samples against E. coli
  • Figure 12 shows the antibacterial rate of Ti samples against S. mutans and the SEM observation images of bacteria.
  • the scale of the SEM observation images is 1 ⁇ m.
  • the antibacterial efficiency of Ti and Ti-YL groups after 6 hours of incubation was lower than that of the corresponding Ti-ZnO and Ti-ZnO-YL groups.
  • the antibacterial rates of Ti against S.aureus, E.coli and S.mutans are 25.71%, 22.38% and -0.04%, respectively, while the antibacterial rates of Ti-ZnO against S.aureus, E.coli and S.mutans are 54.94, respectively. %, 64.1% and 42.41%, indicating that the presence of ZnO in the Ti-ZnO sample improves the antibacterial power of Ti.
  • Ti-ZnO when exposed to yellow light, the antibacterial rate of Ti-ZnO is significantly increased (S.aureus 70.87%, E.coli 97.9%, S.mutans 58.69%), which is similar to the light produced by ZnO under yellow light irradiation. Catalytic activity is related. ZnO can produce active oxygen under light, and active oxygen has a certain killing effect on bacteria. After loading Col-I, there is no significant effect on the antibacterial performance (Ti-ZC). When combined with yellow light, the antibacterial activity is still improved (Ti-ZC-YL).
  • the control group has a normal structure, complete membranes, and regular morphology.
  • the bacteria in the YL group, Ti group and Ti-YL group are also observed The same complete form.
  • the three bacterial morphologies in the Ti-ZnO, Ti-ZnO-YL, Ti-ZC and Ti-ZC-YL groups are all shrunken and irregular, and the cell membranes are ruptured to varying degrees (arrows).
  • the above results indicate that the coating provided by the present invention has good antibacterial properties, and its antibacterial properties can be significantly improved with the introduction of yellow light.
  • BMSCs were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO 2 and the third-generation BMSCs were used for subsequent cell detection.
  • the Ti samples were soaked in DMEM for 72 hours to obtain an immersion liquid, which was filtered with a 0.22 ⁇ m filter membrane before use; the Ti samples were Ti and Ti-ZC.
  • BMSCs were seeded into 48-well plates. Then, 500 ⁇ L of immersion solution was added to the well plate and incubated for 24 hours. Each hole was irradiated with a 808nm laser (1.0W/cm 2 ), and the temperature was recorded every 2 minutes until the temperature of the Ti-ZC group rose to about 40°C (this temperature is helpful for osteogenesis) and the irradiation was stopped. Then use an infrared thermal imaging camera to monitor the temperature of each hole to obtain an infrared image.
  • Figure 13 is a graph of temperature changes of cells treated with different immersion solutions under NIR irradiation.
  • the left side of Figure 13 is a graph of the temperature rise of cells treated with different immersion solutions with NIR irradiation.
  • On the right is the temperature change diagram of cells treated with different immersion solutions under three cycles of NIR irradiation (the Ti-ZC is heated to about 40°C and then the irradiation is stopped, and then irradiated again after the temperature is reduced to room temperature, for a total of 3 cycles).
  • the temperature of the Ti-ZC group gradually increased, and the increase in temperature was significantly higher than that of the Ti group.
  • the Ti-ZC group showed The stable temperature switching effect indicates that Ti-ZC has good light stability.
  • Figure 14 is an infrared thermal image of cells treated with different immersion solutions under NIR continuously irradiated for 10 minutes.
  • the temperature change of the Ti group was the smallest, and the temperature of the Ti-ZC group was gradually increased to about 40°C. Therefore, Ti-ZC has strong photothermal effect and good photothermal stability, and is a good candidate material for photothermal therapy.
  • This example tested the expression levels of runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) in BMSCs cells of different treatment groups. These two proteins play an important role in bone remodeling, and the up-regulation of their expression levels can promote osteogenic differentiation of cells. Specific steps are as follows:
  • the related primers were used to detect the gene expression of Runx2 and OCN. The expression levels of all targeted genes were normalized to GAPDH.
  • the cells were fixed with a paraformaldehyde solution (4%) on ice for 15 min, and then washed with PBS. After that, the cells were detected for 15 minutes using the BCIP/NBTALP (Alkaline Phosphatase) color development kit (Beyotime Institute of Biotechnology). After washing with dd H 2 O, the ALP staining level was recorded.
  • BCIP/NBTALP Alkaline Phosphatase
  • Figure 15 shows the gene expression levels of Runx2 and bone OCN of cells treated with different immersion solutions
  • Figure 16 shows the ALP staining level test results of cells treated with different immersion solutions, with a scale of 200 ⁇ m. It can be seen from Figure 15 that the expression of Runx2 and OCN in cells increased after Ti-ZC and Ti-ZC-NIR treatment. NIR radiation further increased the expression of Runx2 and OCN in BMSCs, which may have a good relationship with ZnO on the surface of Ti samples. The light and heat performance is related. The results of ALP staining (Figure 16) also verified the above conclusions.
  • the coating of the present invention has a photothermal effect, can increase ALP activity, up-regulate the expression level of Runx2, OCN and other osteogenic genes, and play an important role in promoting the osseointegration of the implant surface.

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Abstract

一种双光响应型氧化锌，在氧化锌制备过程中加入柠檬酸钠和羟丙基甲基纤维素对形貌进行控制，加入光热转换材料使氧化锌具有光热转换能力，加入木质素降低氧化锌的能带间隙；通过微波辐照使冻干后的水热产物碳化，能带间隙进一步降低。所述的双光响应型氧化锌呈银耳状褶皱结构，对黄光和近红外光具有双重响应，具有良好的吸附性、抗菌性和光热稳定性，具有光热转换能力。含有所述双光响应型氧化锌的涂层兼具抗菌性和成骨性，应用于种植体表面能够有效提高种植体的抗菌和成骨能力，且其特殊的光敏性能够实现种植体抗菌和成骨功能的光控起效和按需作用。

Description

一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层
本申请要求于2020年6月24日提交中国专利局、申请号为202010589977.7、发明名称为“一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于外科种植体技术领域，尤其涉及一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层。
背景技术
口腔种植手术是人类最为常见的种植手术之一，与此同时，受种植体周围疾病(PIDs)影响的患者数量也在增加。不同于常规的全封闭植入体系，口腔种植体周围疾病的发病率高达40％左右。这是由于种植体部分暴露于口腔微环境，容易引起细菌入侵和种植体周围粘膜炎(PIM)；炎症的进一步扩散会导致种植体周围支撑骨的逐渐丧失，进而导致种植体周围炎(PI)的发生。细菌感染与种植体的PIDs关系最为密切，这会导致种植体周围的骨结合薄弱，种植体脱落，最终导致种植失败，这样一来，缺牙患者不仅需要更多的附加手术治疗PIDs，有时甚至需要经历二次种植手术来恢复缺牙，对患者的身心都造成了极大的影响。
钛基种植体是目前临床上应用最为广泛的一类种植体，但是钛作为一种惰性材料，本身没有抗菌性能，与周围骨组织的结合性较差，种植体失败率较高。
发明内容
有鉴于此，本发明提供了一种双光响应型氧化锌及其制备方法以及具有抗菌成骨性的光敏涂层。本发明提供的双光响应型氧化锌具有良好的吸附能力，能够对黄光和近红外光产生响应，具有良好的抗菌性和光热转换能力，利用其制备的涂层能够显著提高种植体的抗菌性和成骨性。
为了实现上述发明目的，本发明提供以下技术方案：
一种双光响应型氧化锌的制备方法，包括以下步骤：
(1)将可溶性锌盐、六亚甲基四胺和水混合进行第一水热反应，然后将反应料液和柠檬酸钠、羟丙基甲基纤维素、光热转换材料以及木质素混合进行第二水热反应，得到水热产物；
(2)将所述水热产物依次进行冷冻干燥和微波辐照，得到双光响应型氧化锌。
优选的，所述可溶性锌盐为硝酸锌。
优选的，所述光热转换材料为活性碳、金棒和黑磷中的一种或几种。
优选的，所述可溶性锌盐、六亚甲基四胺、水、柠檬酸钠、羟丙基甲基纤维素、光热转换材料和木质素的用量比为(1.487～1.488)g:(0.350～0.352)g:(95～110)mL:(0.138～0.142)g:(0.100～0.120)g:(0.025～0.035)g:(0.995～0.115)g。
优选的，所述第一水热反应的温度为65～67℃，时间为14～16min；所述第二水热反应的温度为85～87℃，时间为10～12h。
优选的，所述微波辐照的功率为800W以上，时间为15min以上。
本发明提供了上述方案所述方法制备的双光响应型氧化锌，所述双光响应型氧化锌的微观形貌呈银耳状；所述双光响应型氧化锌能够在黄光和近红外光照射下发生响应。
本发明还提供了一种具有抗菌成骨性的光敏涂层，由上述方案所述的双光响应型氧化锌制备得到。
优选的，所述涂层通过以下步骤制备得到：
将双光响应型氧化锌分散于溶剂中，将所得的悬浮液涂覆于基材表面，干燥后得到具有抗菌成骨性的光敏涂层；所述基材为外科种植体。
优选的，制备所述涂层的原料还包括一型胶原粉末，所述双光响应型氧化锌和一型胶原粉末的质量比为1:(1～5)。
本发明提供了一种双光响应型氧化锌的制备方法，本发明将可溶性锌盐、六亚甲基四胺和水混合进行第一水热反应，然后将反应料液和柠檬酸钠、羟丙基甲基纤维素、光热转换材料以及木质素混合进行第二水热反应，得到水热产物；然后将所述水热产物依次进行冷冻干燥和微波辐照，得到双光响应型氧化锌。本发明在制备过程中加入柠檬酸钠和羟丙基甲基纤维素对氧化锌的形貌进行控制，加入光热转换材料使所得氧化锌具有光 热转换能力，且通过加入木质素使氧化锌的能带间隙降低；水热完成后，本发明将所得水热产物冷冻干燥后进行微波辐照，通过微波辐照使水热产物发生碳化，从而使氧化锌的能带间隙进一步降低，使材料对长波长的可见光(黄光)具有响应能力；同时微波辐照的碳化作用也可以使氧化锌的银耳状褶皱结构更加明显，从而提高其吸附能力。
本发明提供了上述方案所述方法制备的双光响应型氧化锌，本发明制备的双光响应型氧化锌呈银耳状褶皱结构，具有良好的吸附性(能够吸附色素和蛋白等物质)，且抗菌性和光热稳定性好，具有光热转换能力，在黄光照射下具有光催化作用，能够进一步提高抗菌能力，在近红外光照射下具有光热转换能力，是一种良好的光热治疗材料。
本发明还提供了一种具有抗菌成骨性的光敏涂层，由上述方案所述的双光响应型氧化锌制备得到。本发明提供的涂层兼具抗菌性和成骨性，该涂层在安全温和的可见光(黄光)照射下可以被激活，对革兰氏阳性菌和革兰氏阴性菌均有良好的抗菌性能，特别是对特定的口腔细菌也具有明显的抑菌作用。此外，该涂层在近红外(NIR)照射下表现出良好的光热转换能力，而温度的适当升高能有效促进骨髓间充质干细胞(BMSCs)的增殖和成骨基因表达，促进种植体与周围骨组织的骨结合；将本发明的涂层应用于钛基种植体表面，能够有效提高钛基种植体的抗菌和成骨作用，且其特殊的光敏性能够实现种植体抗菌和成骨功能的光控起效和按需作用。
进一步的，本发明提供的光敏涂层，其制备原料还包括一型胶原粉末，一型胶原粉末具有促进成骨的作用，能够进一步提高所述涂层的成骨性。
说明书附图
图1为ZnO和ZnO-Col-I的扫描电镜图，标尺为1μm；
图2为ZnO和ZC的能谱图；
图3为Ti和Ti-ZnO的X射线衍射图；
图4为实施例3中牛血清白蛋白的标准曲线；
图5为实施例3中不同浓度的氧化锌吸附BSA的结果图；
图6为实施例4中黑暗和光照条件下0h、12h、24h、36h和48h 时罗丹明B溶液的紫外吸收光谱图；
图7为实施例4中黑暗和光照条件下罗丹明B的降解率变化曲线；
图8为实施例5中不同种类的氧化锌分散液在光照条件下的温度变化图；
图9为实施例5中不同处理的钛试样在NIR照射前后的热成像图；
图10为实施例6中Ti样品对金黄色葡萄球菌(S.aureus)的抗菌率和细菌的SEM观察图(标尺为1μm)；
图11为实施例6中Ti样品对大肠杆菌(E.coli)的抗菌率和细菌的SEM观察图(标尺为1μm)；
图12为实施例6中Ti样品对变形链球菌(S.mutans)的抗菌率和细菌的SEM观察图(标尺为1μm)；
图13为实施例7中不同浸渍液处理的细胞在NIR辐照下的温度变化图；
图14为实施例7中不同浸渍液处理的细胞在NIR下连续照射10min后的红外热像图；
图15为实施例8中不同浸渍液处理后细胞的Runx2和OCN的基因表达水平；
图16为实施例8中不同浸渍液处理后细胞的ALP染色水平测试结果，(标尺为200μm)。
具体实施方式
下面结合实施例和附图对本发明进行进一步说明。
本发明提供了一种双光响应型氧化锌的制备方法，包括以下步骤：
(1)将可溶性锌盐、六亚甲基四胺和水混合进行第一水热反应，然后将反应料液和柠檬酸钠、羟丙基甲基纤维素、光热转换材料以及木质素混合进行第二水热反应，得到水热产物；
(2)将所述水热产物依次进行冷冻干燥和微波辐照，得到双光响应型氧化锌。
如无特殊说明，本发明所用水均为去离子水。
本发明将可溶性锌盐、六亚甲基四胺(HMT)和水混合进行第一水热反应。在本发明中，所述可溶性锌盐优选为硝酸锌，具体为六水合硝酸 锌；所述水优选为去离子水；所述第一水热反应的温度优选为65～67℃，更优选为65～66℃，时间优选为14～16min，更优选为15min；本发明优选将可溶性锌盐、六亚甲基四胺溶于水中，搅拌10min使可溶性锌盐、六亚甲基四胺完全溶解，之后再进行第一水热反应；所述搅拌优选为密封条件下进行。在第一水热反应过程中，可溶性锌盐提供Zn 2+，HMT在反应过程中缓慢释放OH -，Zn 2+和OH -，在水热条件下发生反应形成Zn(OH) 2胶体，然后再进一步反应生成氧化锌。
第一水热反应完成后，本发明将反应料液和柠檬酸钠、羟丙基甲基纤维素(HPMC)、光热转换材料以及木质素混合进行第二水热反应，得到水热产物。在本发明中，所述可溶性锌盐、六亚甲基四胺、水、柠檬酸钠、羟丙基甲基纤维素、光热转换材料和木质素的用量比优选为(1.487～1.488)g:(0.350～0.352)g:(95～110)mL:(0.138～0.142)g:(0.100～0.120)g:(0.025～0.035)g:(0.995～0.115)g，更优选为1.4875g：0.351g：100mL：0.14g：0.1g：0.025g：0.1g；所述光热转换材料优选为活性碳、金棒和黑磷中的一种或几种，更优选为活性碳；所述柠檬酸钠起到表面活性剂的作用，羟丙基甲基纤维素起到成型作用，二者都可以控制氧化锌的形貌，光热转换材料则可以赋予氧化锌光热转换的能力，木质素具有良好的生物相容性，可以使氧化锌的能带间隙有一定程度的降低。
在本发明中，所述第二水热反应的温度优选为85～87℃，更优选为85～86℃，时间优选为10～12h，更优选为10～11h。在第二水热反应过程中，溶液中的HMT继续缓慢释放OH -，和锌离子反应生成更多的氧化锌，并且在此过程中光热转换材料、木质素和氧化锌发生作用，使所得氧化锌具有光热转换能力，且能带间隙降低。
第二水热反应完成后，本发明优选将反应料液过滤，然后依次进行无水乙醇洗涤和水洗涤，得到水热产物；所述无水乙醇洗涤和水洗涤的次数均优选为2次，所述无水乙醇洗涤和水洗涤均优选为离心洗涤，所述离心洗涤的转速优选为7000rpm，单次洗涤的时间优选为15min。
得到水热产物后，本发明将所述水热产物依次进行冷冻干燥和微波辐照，得到双光响应型氧化锌。本发明优选将水热产物在-80℃预冷冻后进行真空冷冻干燥；所述真空冷冻干燥的时间优选为12h；所述微波辐照的 功率优选为800W以上，更优选为800～850W，时间优选为15min以上，具体为15～20min。
本发明提供了上述方案所述方法制备的双光响应型氧化锌，所述双光响应型氧化锌的微观形貌呈银耳状，由褶皱的片层结构堆叠而成；所述双光响应型氧化锌的粒径约为2μm，能带间隙为2.125eV(因而能对黄光产生响应)；所述双光响应型氧化锌能够在黄光和近红外光照射下发生响应；在本发明的具体实施例中，具体是在597～577nm(黄光)和808nm(近红外光)下发生响应；本发明提供的双光响应型氧化锌具有良好的吸附能力，能够吸附蛋白和色素等物质，且具有良好的抗菌性和光热转换能力。
本发明还提供了一种具有抗菌成骨性的光敏涂层，由上述方案所述的双光响应型氧化锌制备得到。本发明提供的涂层抗菌性好，在黄光下具有光催化性能，抗菌性进一步提高，在近红外光下具有光热转换能力，温度的升高有助于促进成骨。本发明提供的涂层具有的这种特殊的光敏性能能够实现种植体抗菌和成骨功能的光控起效和按需作用，比如在口腔种植中，种植体植入后，口腔接触的部位(袖口)就很容易引起细菌滋生，进而往下蔓延到牙周，当种植体表面含有本发明的涂层时，可以使用黄光牙刷，黄光起到光催化的作用，提高种植体的抗菌性；再如在植入设置有本发明光敏涂层的种植体后，给予近红外光照射(即热疗)，促进骨结合。
在本发明中，所述涂层优选通过以下步骤制备得到：
将双光响应型氧化锌分散于溶剂中，将得到的悬浮液涂覆于基材表面，干燥后得到具有抗菌成骨性的光敏涂层。
在本发明中，所述基材优选为外科种植体，所述外科种植体的材质具体可以为纯钛、钛合金，钛锆合金等。
在本发明中，所述溶剂优选为水、生理盐水或PBS缓冲液；所述分散优选在搅拌条件下进行，所述搅拌的转速优选为75rpm，时间优选为2h；所述悬浮液中双光响应型氧化锌的浓度优选为200μg/mL；本发明对所述悬浮液的涂覆量没有特殊要求，能够在基材表面均匀全面的覆盖即可；所述干燥的温度优选为室温，本发明对干燥的时间不做具体限定，以充分干燥为宜。
在本发明中，制备所述涂层的原料优选还包括一型胶原粉末(Col-I)，所述双光响应型氧化锌和一型胶原粉末的质量比优选为1:(1～5)，更优选为1:(2～3)。当制备涂层的原料包括一型胶原粉末时，将一型胶原粉末和双光响应型氧化锌共同分散于溶剂中即可，其他条件和上述方案一致，在此不再赘述。Col-I是天然骨的主要有机基质，参与调节成骨细胞的发育、分化活性和骨重塑，在组织修复和再生中发挥重要作用，本发明在制备涂层时加入Col-I，Col-I可以吸附在氧化锌的褶皱结构内，进一步提高涂层的成骨能力。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。
实施例1
将50mmol(1.4875g)Zn(NO 3) 2·6H 2O、25mmol(0.3505g)HMT溶于100mL去离子水中，密封搅拌10min。在65℃的水浴中加热15min后，加入0.14g Na 3C 6H 5O 7，0.1g HPMC，0.025g活性碳和0.1g木质素，水浴保持85℃10h。用无水乙醇洗涤2次，去离子水洗涤2次，均为离心洗涤，转速为7000rpm，单次洗涤时间为15min，然后再-80℃预冻后真空冷冻干燥12h，将所得产物进行微波辐照，微波辐照的功率为800W，时间为15min，得到双光响应型ZnO粉体。以实施例1制备的ZnO进行后续试验。
实施例2
1、Ti-ZC的制备：将实施例1制备的ZnO粉体、一型胶原粉末按照质量比1:1的加入磷酸盐缓冲盐水溶液(PBS缓冲液)中，在75rpm搅拌2h，得到悬浮液，悬浮液中ZnO粉末的浓度为200μg/mL，将该悬浮液滴加于钛试样(直径10mm，厚度1mm的钛片)表面，常温干燥，具有涂层的钛样品记为Ti-ZC。
2、Ti-ZnO的制备：其他和1中相同，仅不加入一型胶原粉末，悬浮液中ZnO的浓度为200μg/mL，所得样品记为Ti-ZnO。
3、ZnO-Col-I的制备：采用PBS缓冲液，将相同浓度(200μg/ml)的ZnO和Col-I混合，在摇床中以75～80rpm的速度摇2～3h，制备出ZnO-Col-I混悬液，所得样品记为ZnO-Col-I，后续简称为ZC。
表征：
使用扫描电镜观察ZnO和ZnO-Col-I的形貌，所得结果如图1所示，图1为ZnO和ZnO-Col-I的扫描电镜图，标尺为1μm；根据图1可以看出，ZnO呈银耳状形貌，由褶皱的片层堆叠而成，且根据ZnO-Col-I的扫描电镜图可以看出，Col-I附着在ZnO的褶皱结构内。
使用粒度和电位分析仪(Zeta-sizer Nano ZS90,Malvern,UK)测试ZnO的尺寸，结果显示ZnO的粒径为2μm左右。
采用紫外吸收法对ZnO的能带间隙进行测试，结果显示ZnO的能带间隙为2.125eV，该能带间隙下的ZnO能够被黄光激发。
利用比表面积和孔隙度分析仪(JW-BK132F)测量了ZnO的孔隙体积-孔径分布，结果显示ZnO的比表面积为49.857m 2/g，孔隙体积为0.219cm 3/g，平均孔径为16.207nm。
利用能谱仪(EDS,Zeiss/Sigma 300，日本)对ZnO和ZC(即ZnO-Col-I)进行化学成分的表征，所得结果如图2所示。根据图2可以看出，和ZnO相比，ZC中含有N元素，说明ZC实现了对一型胶原的吸附。
利用X射线衍射(XRD,BrukerD8AA25X)测定了原始Ti和Ti-ZnO样品的晶体结构，所得结果如图3所示。根据图3可以看出，Ti-ZnO中可以发现ZnO的特征性吸收峰。
实施例3蛋白吸附力
本实施例以牛血清白蛋白(BSA)为模拟蛋白，采用BSA试剂盒检测ZnO的蛋白吸附能力。将不同质量的ZnO(1mg,2mg,5mg)分别置于1mLBSA溶液(其中BSA的浓度为5mg/mL)中，37℃下以75r/min的速度搅拌，2h后，以7000r/min的速度离心二次洗涤，得到上清。将上述上清稀释10倍，放入96孔板中。标准曲线采用已知浓度的牛血清白蛋白标准曲线(如图4所示)，在微板分光光度计中读取562nm处的吸光度。
所得结果如图5所示，图5为不同浓度的氧化锌吸附BSA的结果图，其中ZnO的浓度以稀释10倍后的浓度计，其中纵坐标为BSA吸光度，吸光度值越低说明被氧化锌吸附的越多，说明氧化锌的吸附力越好；根据 图5可以看出，本发明制备的氧化锌能够吸附BSA，且随着氧化锌浓度的增大，对BSA的吸附量也越多。
实施例4光催化性能
将Ti-ZnO置于一定浓度的罗丹明B溶液中，以150rpm的速度摇动。共设置两组实验，其中一组处于黑暗环境中，另一组受黄色光照射。分别在12h、24h、36h和48h后观察罗丹明B溶液的颜色变化。用紫外分光光度计测定不同时间点的上清液，测定罗丹明B吸收峰的OD值，并计算对罗丹明B的降解率(R值)。
计算公式为：R＝C 0-C/C 0，其中C为搅拌后12h、24h、36h和48h时罗丹明B吸收峰的OD值，C 0为罗丹明B吸收峰的初始OD值。
所得结果如图6～7所示，图6为黑暗和光照条件下0h、12h、24h、36h和48h时罗丹明B溶液的紫外吸收光谱图；图7为黑暗和光照条件下罗丹明B的降解率变化曲线。根据图6～7可以看出，随着时间的延长，罗丹明B的降解率增加，且在黄光照射下罗丹明B的降解率更高，说明本发明制备的氧化锌具有优异的光催化性能。
实施例5光热转换能力
将实施例1制备的银耳状氧化锌(Tremella-like ZnO)以及常规柱状氧化锌(ZnO rod)分散于水中，均控制为5mg/mL，置于室温近红外光(NIR，808nm)照射条件下，测试升温效果，以水为对照，所得结果如图8所示，图8为不同种类的氧化锌分散液在光照条件下的温度变化图。根据图8可以看出，和常规的柱状氧化锌相比，本发明制备的银耳状氧化锌的光热转换能力更强，在相同的条件下，分散有本发明银耳状氧化锌的水分散液的升温幅度更大。
将Ti(即未经任何处理的钛片)、实施例2制备的Ti-ZC和Ti-ZnO在近红外光(NIR，808nm)条件下进行照射，照射时间为2min，使用FLIRA35红外光热成像仪进行监测，所得结果如图9所示，图9为不同处理的钛试样在NIR照射前后的热成像图；根据图9可以看出，Ti组在NIR照射后升温至38.4℃，而Ti-ZnO组可升温至48.6℃，Ti-ZC组升温至46.1℃，该结果表明，本发明制备的氧化锌具有优异的光热转化能力。
实施例6体外抗菌能力
选择金黄色葡萄球菌(S.aureus)、大肠杆菌(E.coli)和变形链球菌(S.mutans)对Ti样品进行抗菌能力评价。与细菌共培养之前，所有Ti样品被放置到48孔板，然后加入500μL细菌溶液(浓度为10 7CFU/mL)，在150rpm 37℃培养6h(一个板是在黑暗的环境中，另一块板被黄色光照射)。S.aureus和E.coli被培养到Luria-Bertani肉汤中，而S.mutans在脑心灌注肉汤(BHI)中培养。检测细菌形态，所有细菌标本用2.5％戊二醛固定，梯度乙醇(30、50、70、80、90、100％v/v)脱水，用冷冻干燥机干燥，最后通过SEM观察观察。
其中Ti样品为Ti(即原始钛片)、Ti-ZnO、Ti-ZC，并设置一组空白对照，空白对照中不加入Ti样品，黑暗环境中的实验组分别记为：Crtl(空白对照)、Ti、Ti-ZnO、Ti-ZC，黄光照射环境中的实验组分别记为：YL(空白对照)、Ti-YL、Ti-ZnO-YL、Ti-ZC-YL。
所得结果如图10～12所示，图10为Ti样品对金黄色葡萄球菌(S.aureus)的抗菌率和细菌的SEM观察图；图11为Ti样品对大肠杆菌(E.coli)的抗菌率和细菌的SEM观察图；图12为Ti样品对变形链球菌(S.mutans)的抗菌率和细菌的SEM观察图，图10～12中，SEM观察图的标尺均为1μm。
根据图10～12可以看出，Ti和Ti-YL组经过6h的培养后，其抗菌效率均低于相应的Ti-ZnO和Ti-ZnO-YL组。Ti对S.aureus，E.coli和S.mutans的抗菌率分别是25.71％，22.38％和-0.04％，而Ti-ZnO对S.aureus，E.coli和S.mutans的抗菌率分别是54.94％，64.1％和42.41％，表明Ti-ZnO样品中ZnO的存在提高了Ti的抗菌力。此外，当暴露于黄光下，Ti-ZnO的抗菌率又有显著提高(S.aureus 70.87％，E.coli 97.9％，S.mutans 58.69％)，这与ZnO在黄光照射下产生的光催化活性有关，ZnO在光照下能够产生活性氧，活性氧对细菌具有一定的杀伤作用。在负载Col-I后对抗菌性能无显著影响(Ti-ZC)，结合黄光时，抗菌活性仍有所提升(Ti-ZC-YL)。
根据图10～12中的不同组别细菌的微观结构的SEM观察结果可以看出，对照组为正常结构，膜完整，形态规则，YL组、Ti组和Ti-YL组的细菌中也观察到同样完整的形态。相反，Ti-ZnO、Ti-ZnO-YL、Ti-ZC和 Ti-ZC-YL组的三种细菌形态都是皱缩的、不规则的，细胞膜都有不同程度的破裂(箭头表示)。上述结果表明，本发明提供的涂层具有良好的抗菌性能，并且其抗菌性能可以随着黄光的引入得到明显提高。
实施例7体外光热能力
文献报道适当的热疗对骨重建有一定的促进作用，本实施例测试不同Ti样品在NIR条件下对BMSCs(骨髓间充质干细胞)的加热效应。
BMSCs在37℃、5％CO 2环境下，用含10％胎牛血清的DMEM培养基培养，第三代的BMSCs被用于后续的细胞检测。将Ti样品分别在DMEM中浸泡72h，得到浸渍液，浸渍液在使用之前用0.22μm的滤膜过滤；其中Ti样品为Ti和Ti-ZC。
在进行实验前24h，将BMSCs接种到48孔板中。然后，将500μL浸渍液加入孔板中，孵育至24h。每个孔用808nm激光(1.0W/cm 2)照射，每2min记录一次温度，直到Ti-ZC组温度升高到40℃左右(该温度下有助于成骨的)停止辐照。然后利用红外热成像摄像机对每个孔的温度进行监测，获得红外图像。
所得结果如图13～图14所示，图13为不同浸渍液处理的细胞在NIR辐照下的温度变化图，其中图13左为不同浸渍液处理的细胞组随NIR辐照的升温图，右边为不同浸渍液处理的细胞在三个周期NIR辐照下的温度变化图(Ti-ZC升温至40℃左右后停止辐照，降至常温后再次辐照，共进行3个周期)。根据图13可以发现，随着NIR的照射，Ti-ZC组的温度逐渐升高，且温度的升高幅度显著高于Ti组，且经过三个周期的NIR辐照，Ti-ZC组表现出稳定的温度开关效应，表明Ti-ZC有很好的光稳定性。
图14为不同浸渍液处理的细胞在NIR下连续照射10min后的红外热像图。在本实验中，Ti组的温度变化最小，Ti-ZC组则逐步升温至40℃左右。因此，Ti-ZC具有较强的光热效应和良好的光热稳定性，是一种很好的光热治疗候选材料。
实施例8成骨基因的表达
本实施例测试了不同处理组BMSCs细胞runt相关转录因子2(Runx2)和骨钙素(OCN)的表达水平。这2种蛋白质在骨重建中发挥重要作用，其表达水平的上调能够促进细胞成骨向分化。具体步骤如下：
将BMSCs接种于6孔板(每孔10 5个细胞)，在不同的浸渍液(浸渍液的制备方法和实施例6中一致，分别为Ti浸渍液和Ti-ZC浸渍液)中培养7d，一组不经近红外照射培养，另一组每天用近红外(1.0W/cm 2)照射10min，培养基在37℃、5％CO 2培养箱中，每3d更换培养基一次。用相关引物检测Runx2和OCN的基因表达。所有靶向基因表达水平均归一化至GAPDH。
仔细去除培养基后，用多聚甲醛溶液(4％)在冰上固定细胞15min，然后用PBS洗涤。之后，使用BCIP/NBTALP(碱性磷酸酶)显色试剂盒(Beyotime生物技术研究所)检测细胞15min。用dd H 2O洗涤后，记录ALP染色水平。
所得结果如图15～16所示，图15为不同浸渍液处理后细胞的Runx2和骨OCN的基因表达水平；图16为不同浸渍液处理后细胞的ALP染色水平测试结果，标尺为200μm。根据图15可以看出，Ti-ZC和Ti-ZC-NIR处理后细胞Runx2和OCN表达升高，NIR辐射进一步上调了BMSCs中Runx2和OCN的表达，这可能与ZnO在Ti样品表面具有良好的光热性能有关。ALP染色的结果(图16)也验证了上述结论。
以上实验结果证实了本发明的涂层具有光热效应，可以提高ALP活性，上调Runx2、OCN等成骨基因的表达水平，在促进种植体表面骨整合方面起着重要的作用。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 一种双光响应型氧化锌的制备方法，包括以下步骤：
    (1)将可溶性锌盐、六亚甲基四胺和水混合进行第一水热反应，然后将反应料液和柠檬酸钠、羟丙基甲基纤维素、光热转换材料以及木质素混合进行第二水热反应，得到水热产物；
    (2)将所述水热产物依次进行冷冻干燥和微波辐照，得到双光响应型氧化锌。
  2. 根据权利要求1所述的制备方法，其特征在于，所述可溶性锌盐为硝酸锌。
  3. 根据权利要求1所述的制备方法，其特征在于，所述光热转换材料为活性碳、金棒和黑磷中的一种或几种。
  4. 根据权利要求1或2或3所述的制备方法，其特征在于，所述可溶性锌盐、六亚甲基四胺、水、柠檬酸钠、羟丙基甲基纤维素、光热转换材料和木质素的用量比为(1.487～1.488)g:(0.350～0.352)g:(95～110)mL:(0.138～0.142)g:(0.100～0.120)g:(0.025～0.035)g:(0.995～0.115)g。
  5. 根据权利要求1所述的制备方法，其特征在于，所述第一水热反应的温度为65～67℃，时间为14～16min；所述第二水热反应的温度为85～87℃，时间为10～12h。
  6. 根据权利要求1所述的制备方法，其特征在于，所述微波辐照的功率为800W以上，时间为15min以上。
  7. 权利要求1～6任意一项所述方法制备的双光响应型氧化锌，其特征在于，所述双光响应型氧化锌的微观形貌呈银耳状；所述双光响应型氧化锌能够在黄光和近红外光照射下发生响应。
  8. 一种具有抗菌成骨性的光敏涂层，其特征在于，由权利要求7所述的双光响应型氧化锌制备得到。
  9. 根据权利要求8所述的光敏涂层，其特征在于，所述涂层通过以下步骤制备得到：
    将双光响应型氧化锌分散于溶剂中，将所得的悬浮液涂覆于基材表面，干燥后得到具有抗菌成骨性的光敏涂层；所述基材为外科种植体。
  10. 根据权利要求8或9所述的光敏涂层，其特征在于，制备所述涂层的原料还包括一型胶原粉末，所述双光响应型氧化锌和一型胶原粉末的质量比为1:(1～5)。
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