| Hydroxyapatite(Ca10(PO4)6(OH)2,HA)is the main inorganic component of bones and teeth in vertebrates with high biocompatibility and bioactivity.The HA microspheres with porous structures are of wide interest in the field of drug carriers because of their good flowability,high specific surface area,and special pore structure.However,HA microspheres with monotonous structures prepared and low degradation ability by complex methods can hardly meet the needs of more diversified and functionalized drug carriers.The controlled preparation and the improvement of degradation capacity of HA porous microspheres with different microstructures in the same system by a simple and efficient synthesis method provides an effective way to expand their carrier applications.And the related mechanism study provides the theoretical significance to improve the control of HA microsphere morphology.In addition,HA porous microspheres with homogeneous size,interconnected pore structure,controlled microstructure,and high degradability are beneficial to achieve high loading and sustained release of drug molecules.In this study,HA microspheres with various sizes,microstructures,and pore forms were controllably synthesized by a hydrothermal homogeneous precipitation method.The hydrothermal parameters,phosphorus sources,additives,and doping functional ions were adjusted.The types of microspheres mainly include:diverging HA microspheres,urchin-like HA microspheres,Sr-HA microspheres with interconnected porosity,HA microspheres with core-shell structure,hollow HA microspheres,etc.The size of microspheres can be distributed from 120 μm to 2 μm,and the single types of microspheres were well-rounded and uniform in size.The nucleation and growth mechanism of HA microspheres with different structures and the effect of heat treatment on the morphology and pore parameters of the microspheres were also explored.The degradation behavior of Sr-HA microspheres was evaluated,and the effect of Sr2+ doping amounts on the degradation rate of HA microspheres was investigated.Four types of HA microspheres with different assembly units,specific surface areas,and pore structures were selected to study their loading capacity to vancomycin and BSA and pHresponsive drug release kinetics.The main conclusions of this thesis were as follows.The effects of different additives and Sr2+ on the phase and structure of HA microspheres were investigated using a hydrothermal homogeneous precipitation method.It was found that at a glutamic acid concentration of 0.06 M and an initial pH value of 3.5 of the reaction solutions,diverging HA microspheres with a uniform morphology and a size of about 100 μm were obtained;with sodium citrate as an additive,urchin-like HA microspheres with a size of about 2 μm and a uniform morphology were obtained at an ipH value lower than 3.5.The inhomogeneity of the morphology and size of the HA product was caused under the conditions of a too-high or too-low ipH value,glutamic acid,and citrate concentration.The effects of Sr2+doping on the structure and pore parameters of HA microspheres were investigated,and the results showed that Sr2+ not only inhibited the c-axis preferred orientation of HA crystals but also acted as a structure-directing agent to induce the formation of macropores in HA microspheres.When Sr2+was doped into the HA lattice with the doping concentration(Sr/(Ca+Sr)molar ratio)of 0.4,porous Sr-HA porous microspheres with interconnected porosity were obtained,which exhibited a high specific surface area(61.4509 m2/g)and complex internal interconnected pore channels.When the doping amount was 0.6,the trumpet-shaped macroporous microspheres exhibited the pore characteristics of small pores embedded in large pore walls.The effects of different phosphorus sources on the phase and microstructure of HA microspheres and the formation mechanism of microspheres with different structures were investigated.The results showed that when Na4P2O7,Na2H2P2O7,Na5P3O10,(NaPO3)6,and(NaPO3)3 were used as phosphorus sources,respectively,with or without the addition of glutamic acid,the resulting product phase was carbonated HA,and some samples contained a small amount of CaCO3.Among them,under the condition of without glutamic acid,when Na4P2O7 was used as a phosphorus source,the nanoneedles self-assembled HA microspheres with a diameter of about 30 μm were obtained;when NasP3O10 was used as the phosphorus source,nanorod-assembled microspheres with a diameter of about 2.5 μm were obtained;when(NaPO3)6 was used as the phosphorus source,the nanoneedle-assembled hollow HA porous microspheres with a diameter of about 5 μm were obtained.After glutamic acid was added,when Na2H2P2O7 was used as the phosphorus source,flake crystals assembled porous HA microspheres with a diameter of about 20 μm were obtained;when(NaPO3)6 was used as the phosphorus source,the nanorod-assembled hollow HA porous microspheres with a diameter of about 6.5 μm were obtained.The nanorods were arranged radially perpendicular to the spherical surface.The time-gradient experimental study showed that the hollow HA porous microspheres assembled by nanorods were transformed from ACP microspheres,and the formation of the hollow structure was associated with the spontaneous dissolution of the amorphous core.when(NaPO3)3 was used as the phosphorus source,the HA porous microspheres with a core-shell structure were obtained.The size of the microspheres was about 3-10)μm and there were gaps between the cores and shells.The time-gradient and phosphorus source concentration-gradient experimental study showed that the formation of the core-shell structure during the transformation of ACP microspheres into core-shell HA microspheres was related to the multistep reactions of(NaPO3)3 with OH-and the dissolution recrystallization mechanism during the nucleation growth.The adsorption positions of different kinds of amino acids on HA crystal affected the growth rate of the crystal surface,resulting in different morphology.When(NaPO3)6 was used as the phosphorus source,acidic aspartic acid(Asp),neutral serine(Ser),and basic lysine(Lys)and arginine(Arg)were used as additives,and the products were all carbonated HA,with some samples containing a small amount of CaCO3.The nanorod-assembled HA microspheres were obtained with the addition of Asp,low concentration of Ser,or high concentration of Lys.The effects of heat treatment on the hollow HA porous microspheres,HA porous microspheres with core-shell structure,and their time-gradient products of ACP and low crystallinity HA microspheres containing amorphous phase were investigated.At a heat treatment temperature of 650℃,the phases of hollow and core-shell HA porous microspheres remained unchanged,but the dissolution-recrystallization of nanocrystals occurred on the surface composed of assembly units.With the increase of heat treatment temperature,the phase of ACP microspheres transformed from γ-Ca2P2O7 at 500 ℃ to β-Ca2P2O7 at 650 and 800℃with a small amount of Ca4P6O19.With the crystallization of amorphous crystals,the surface of microspheres underwent coarsening of grains.The HA microspheres with low crystallinity containing amorphous phase gradually transformed from HA to β-Ca2P2O7 and then to β-TCP as the temperature increased.Accordingly,the nanocrystals on the surface of the microspheres grew gradually with the crystallization transformation process,and the fusion of grains occurred at 800℃.The degradation behavior of Sr-HA microspheres was evaluated.After 28 days of degradation,the degradation rate of 0.6Sr microspheres reached 31.95%,which was significantly higher than that of undoped 0Sr microspheres(11.75%)and low-doped 0.1 Sr microspheres(15.05%).It was shown that the doping of Sr2+significantly improved the degradation ability of HA microspheres,and the degradation rate increased with the doping amount of Sr2+.The diverging HA microspheres,porous Sr-HA microspheres with interconnected porosity,porous HA microspheres with core-shell structure,and hollow HA porous microspheres were loaded with vancomycin and BSA,respectively,and the drug release was carried out in media with different pH values.The results showed that the porous Sr-HA microspheres with interconnected porosity exhibited the highest vancomycin loading of 167.5 mg/g and the highest BSA loading of 138.3 mg/g.And the porous Sr-HA microspheres with interconnected porosity showed pH-responsive drug release kinetics and the most obvious sustainable drug release characteristics.It can be used as a potential drug carrier for targeted drug therapy in low pH tissues in vivo,such as bone tissue infection. |
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