摘要
羟基磷灰石(HA)的分子结构和钙磷比与正常骨的无机成分非常近似,能与活体组织形成化学性键合,是目前国际上公认的适用于临床应用的生物活性陶瓷材料。但是由于HA陶瓷的脆性,其力学强度无法满足体内承力部位植入的需要,大大限制了它的临床应用。因此,改善HA陶瓷的力学性能至关重要。除了作为组织工程支架材料外,不同形态及孔隙结构的HA还广泛应用于离子交换、催化剂载体、生物医药等领域。
本文采用溶胶-凝胶法制备了多孔球粒、致密球粒、纤维堆积型支架等一系列不同形态及孔隙结构的HA陶瓷制品；通过自粘结和自充填工艺改善了HA支架的力学性能；采用体式显微镜(SM)、扫描电子显微镜(SEM)、X射线衍射仪(XRD)、抗压强度测试等分析手段,系统地研究了不同形态及孔隙结构HA陶瓷的性能；通过体内和体外实验比较评价了其生物学性能。获得的主要结论如下：
(1)以沉淀法制备出的纳米HA浆料为原料,采用溶胶-凝胶法成功地制备了尺寸为150-1500μm的多孔和致密HA球粒。多孔球粒的孔隙率约为20%,抗压强度6.9±0.3MPa；致密球粒孔隙率为4.7±0.6%,抗压强度为8.9±0.4MPa.
(2)改变HA加入量、搅拌速率、搅拌时间和搅拌温度以研究工艺参数对球粒性能和形态的影响。搅拌速率是影响HA球粒尺寸和球形度的最大因素,球粒的微结构主要受初始HA浆料加入量的影响,其他工艺参数对其几乎没有影响,结合粒子滤除等造孔方法可以控制多孔HA球粒的孔隙结构。保持其它制备条件不变时,随着搅拌速率的增大,球粒的平均尺寸明显减小,球形度变好；同一搅拌速率下,随着HA负载量和搅拌温度的升高球粒的平均尺寸增大,球形度变差；超过2h后,搅拌时间对球粒的平均尺寸几乎没有影响,但是搅拌时间越长,球形度越好。
(3)以微米级HA粉体为原料,采用溶胶-凝胶法得到凝胶化球粒和纤维。将凝胶化的球粒和纤维进行洗涤、干燥和常压烧结,最后采用热等静压进行二次烧结得到半透明HA球粒和纤维。半透明HA球粒的致密度为99.1±0.3%,晶粒大小为2.2μm,抗压强度为10.2±0.4MPa.
(4)对不同密度的球粒进行仿生矿化和间充质干细胞培养。矿化结果显示多孔表面生成HA的量高于致密和半透明HA陶瓷,相对于半透明HA陶瓷,致密HA陶瓷表面上形成的晶体数量较多,尺寸较小；细胞培养结果显示多孔HA陶瓷上细胞增殖情况优于致密和半透明HA陶瓷,与之相反,细胞分化水平低于致密和半透明HA陶瓷；三者均具有良好的细胞相容性,无细胞毒性。将多孔HA球粒和致密HA球粒堆积成微孔结构不同、宏孔结构相同的多孔支架后,植入狗的腹腔内1、3个月,结果显示多孔HA球粒堆积支架的异位成骨情况远优于致密HA球粒堆积支架。
(5)在纳米HA浆料中加入海藻酸钠(SA)制成混合悬浮物,通过针头挤入到氯化钙溶液中进行凝胶化赋形得到连续长纤维,将纤维洗净后堆积到模具中,加压定型后进行烧结得到贯通性良好的HA纤维堆积多孔支架。将纤维堆积支架的生坯浸入混合悬浮物中抽取真空后离心,得到HA自粘结纤维多孔支架。控制针头直径可以控制HA纤维堆积多孔支架的孔径,控制压缩高度可以控制孔隙率。当孔隙率为50%时,自粘附前后多孔支架的抗压强度分别为2.9士0.4MPa和13.2±0.6MPa,力学性能得到了有效改善。仿生矿化和细胞实验结果显示纤维支架均具有良好的生物活性,自粘结工艺处理后的多孔纤维支架具有更为粗糙的表面,细胞向内部长入的趋势更加明显。
(6)HA纤维与石蜡球共同加入HA/SA的混合悬浮物中混合均匀,填入模具后浸入氯化钙溶液中,正己烷浸泡除去石蜡球后用去离子水洗净、干燥烧结后得到HA纤维自充填多孔支架。随着石蜡球添加量的增大,孔与孔之间的贯通性增大,宏孔的孔隙表面均会出现分布均匀的微米和亚微米尺寸的微孔结构。HA纤维均匀分布在基体中,不会产生聚集,烧结过后纤维和基体之间的界面没有明显的分离。随着造孔剂加入量的增多,支架的抗压强度逐渐减小,加入纤维可以提高多孔支架的抗压强度,而且当造孔剂的量增多时,加入和未加入纤维的支架的抗压强度的差距增大。
Hydroxyapatite (HA), which has similar crystal structure and Ca/P ratio to the main inorganic component of normal bone and can form a chemical bond with live tissues, has internationally recognized as a bioactive ceramic for clinical applications. Due to the bittleness of HA ceramics, they are not suitable to be used in clinical load-bearing sites. So that the application of HA ceramics have been restricted. Therefore, it is significant to improve the mechanical properties of HA ceramics. Except as the tissue engineering scaffold material, HA with different morphology and pore structure is widely used in ionic exchange, catalytic carrier, biomedicine application, et al.
In this paper, a series of HA ceramics with different morphology and pore structure, such as porous spheres, dense spheres, fiber-accumulated scaffolds, et al., were fabricated by using the sol-gel method. The self-adhering and self-filled process were used to enhance the mechanical strength of HA scaffolds. Stereomicroscope (SM), scanning electron microscopy (SEM), X-ray deffractomerer (XRD) and mechanical tester were used to study the properties of HA ceramics with different morphology and pore structure. Their biological properties were evaluated by the experiments in vivo and vitro. Main conclusions are drown as follows:
(1) Using the HA slurry prepared via a precipitation process as the raw materials, porous and dense spheres with the size of150-1500um had been fabricated successfully by sol-gel method. Porous HA sphere with the porosity of20%hold a compressive strength of6.9±0.3MPa and dense HA spheres with the porosity of4.7±0.6%hold a compressive strength of8.9±0.4MPa were fabricated via a specific dried and sintered process.
(2) The factors, such as HA loading, stirring rate, stirring time and stirring temperature, which influence the property and morphology of these spheres were investigated. The stirring rate is the major influencing factor for the size and sphericity and the HA loading is the major influencing factor for the micro-structure of spheres. The other technical parameters have slight effects on the the structure. The pore structure can be controlled combined with other pore-forming method, for example, particle leaching method. The mean size decreases obviously and the sphericity becomes better as the stirring rate increases when the other preparation process keep constant. The mean size increases and the sphericity becomes worse as the HA loading and stirring temperature increases. After2h, stirring time has a slight effect on the mean size, but sphericity becomes better as the stirring time increases.
(3) Using the micro-sized HA powders as the raw materials, the gelated spheres and fibers were obtained by sol-gel method. Translucent HA spheres and fibers were obtained after rinsed, dried, and pressureless sintering and hot isostatic pressing. The HA sphere with the porosity of20%hold a grain size of2.2μm and a compressive strength of6.9±0.3MPa.
(4) Spheres with different density was biomimetic mineralized and cultured with mesenchymal cells. The mineralization results show that the amount of HA formed on the porous surface is more than that of dense and translucent HA ceramics. Compared with translucent HA ceramics, the mount of crystallines formed on the surface of dense HA is more, but the size is smaller. The results of cell cuture show that the proliferation of cells on porous HA ceramics is better than dense and translucent HA ceramics, in contast, the lever of cell differentiation is lower. All of them have good cell compatibility and have no cytotoxicity. HA scaffolds with different micro-pore structure and same macro-pore structure were fabricated by accumulating spheres. These scaffolds were implanted in the abdominal cavity of dog for1and3months. The results show the ectopic bone formation of the scaffolds accumulated by porous HA spheres is much better that that of the scaffolds accumulated by dense HA spheres.
(5) Nano-HA slurry was mixed with sodium alginate (SA) to obtain a mixed suspension and then directly injected into a fibrous structure in a CaCl2solution. Subsequent pressing in a mold and sintering allowed the formation of HA fiber-deposited scaffolds (DS) with good interconnectivity. The DS green was immersed into the mixed suspension and centrifuged to obtain the green of HA fiber-self-adhering scaffolds (BS). The diameter of fibers can be tuned by changing the needle gauge and the porosity of these scaffolds can be controlled by varying the level of compression. The compression strength is improved obviously via self-adhering process. When their porosity is50%, the compression strengths of DS and BS are2.9±0.4MPa and13.2±0.6MPa, respectively. Bio-mineralization and cell culture confirm that both of DS and BS have a good bioactivity. The scaffolds treated by self-adhering process have a more rough surface and have a clearer trend of cells grown into scaffolds.
(6) HA fibers were added into HA/SA suspension with was spheres. The mixture was filled in a mold and immersed in a CaCl2solution. Paraffin spheres were removed by soaking in n-hexane. HA fiber-self-filled porous scaffolds were obtained after washed, dried and sintered. The interconnectivity increases with the paraffin wax spheres increase. Many micro-and submicron-sized pores exist on the wall of macro-pores. In the fiber-filled scaffolds, HA fibers distribute in the matrix uniformly and the interface between fibers and matrix is tightly bound without obvious separation. The compressive strength of the scaffolds decreases as the addition of paraffin wax spheres increase. The addition of fibers can improve the compressive strength obviously, and the difference between the fiber-filled scaffolds and the scaffolds without fibers increase as the addition of paraffin wax spheres increase.
引文
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