The use of ions as therapeutic agents has the potential to minimize the use of small-molecule drugs and biologics for the same purpose, thus providing a potentially more economic and less adverse means of treating, ameliorating or preventing a number of diseases. Hydroxyapatite (HAp) is a solid compound capable of accommodating foreign ions with a broad range of sizes and charges and its properties can dramatically change with the incorporation of these ionic additives. While most ionic substitutes in HAp have been monatomic cations, their lesser atomic weight, higher diffusivity, chaotropy and a lesser residence time on surfaces theoretically makes them prone to exert a lesser influence on the material/cell interaction than the more kosmotropic oxyanions. Selenite ion as an anionic substitution in HAp was explored in this study for its ability to affect the short-range and the long-range crystalline symmetry and solubility as well as for its ability to affect the osteoclast activity. We combined microstructural, crystallographic and spectroscopic analyses with quantum mechanical calculations to understand the structural effects of doping HAp with selenite. Integration of selenite ions into the crystal structure of HAp elongated the crystals along the c-axis, but isotropically lowered the crystallinity. It also increased the roughness of the material in direct proportion with the content of the selenite dopant, thus having a potentially positive effect on cell adhesion and integration with the host tissue. Selenite in total acted as a crystal structure breaker, but was also able to bring about symmetry at the local and global scales within specific concentration windows, indicating a variety of often mutually antagonistic crystallographic effects that it can induce in a concentration-dependent manner. Experimental determination of the lattice strain coupled with ab initio calculations on three different forms of carbonated HAp (A-type, B-type, AB-type) demonstrated that selenite ions initially substitute carbonates in the crystal structure of carbonated HAp, before substituting phosphates at higher concentrations. The most energetically favored selenite-doped HAp is of AB-type, followed by the B-type and only then by the A-type. This order of stability was entailed by the variation in the geometry and orientation of both the selenite ion and its neighboring phosphates and/or carbonates. The incorporation of selenite in different types of carbonated HAp also caused variations of different thermodynamic parameters, including entropy, enthalpy, heat capacity, and the Gibbs free energy. Solubility of HAp accommodating 1.2 wt% of selenite was 2.5 times higher than that of undoped HAp and the ensuing release of the selenite ion was directly responsible for inhibiting RAW264.7 osteoclasts. Dose-response curves demonstrated that the inhibition of osteoclasts was directly proportional to the concentration of selenite-doped HAp and to the selenite content in it. Meanwhile, selenite-doped HAp had a significantly less adverse effect on osteoblastic K7M2 and MC3T3-E1 cells than on RAW264.7 osteoclasts. The therapeutically promising osteoblast vs. osteoclast selectivity of inhibition was absent when the cells were challenged with undoped HAp, indicating that it is caused by selenite ions in HAp rather than by HAp alone. It is concluded that like three oxygens building the selenite pyramid, the coupling of (1) experimental materials science, (2) quantum mechanical modeling and (3) biological assaying is a triad from which a deeper understanding of ion-doped HAp and other biomaterials can emanate.

使用离子作为治疗剂有可能最大限度地减少用于同一目的的小分子药物和生物制剂的使用，从而提供潜在的更经济且更少不利的治疗、改善或预防多种疾病的方法。羟基磷灰石 (HAp) 是一种固体化合物，能够容纳各种尺寸和电荷的外来离子，其性能会随着这些离子添加剂的加入而发生巨大变化。虽然 HAp 中的大多数离子替代品都是单原子阳离子，但它们的原子量更小、扩散率更高、离液性更高，并且在表面上的停留时间更短，理论上使得它们对材料/细胞相互作用的影响比亲液性氧阴离子要小。本研究探讨了亚硒酸盐离子作为 HAp 中的阴离子取代物，因为它能够影响短程和长程晶体对称性和溶解度，以及影响破骨细胞活性。我们将微观结构、晶体学和光谱分析与量子力学计算相结合，以了解亚硒酸盐掺杂 HAp 的结构效应。亚硒酸盐离子整合到 HAp 的晶体结构中，使晶体沿 c 轴伸长，但各向同性地降低了结晶度。它还增加了材料的粗糙度，与亚硒酸盐掺杂剂的含量成正比，从而对细胞粘附和与宿主组织的整合具有潜在的积极影响。 亚硒酸盐总体上充当晶体结构破坏者，但也能够在特定浓度窗口内在局部和全局尺度上产生对称性，这表明它可以以浓度依赖性方式诱导各种通常相互拮抗的晶体学效应。对三种不同形式的碳酸化 HAp（A 型、B 型、AB 型）进行的晶格应变实验测定和从头计算表明，亚硒酸盐离子最初取代碳酸化 HAp 晶体结构中的碳酸盐，然后在更高的浓度。最受能量欢迎的亚硒酸盐掺杂 HAp 是 AB 型，其次是 B 型，最后是 A 型。这种稳定性的顺序是由亚硒酸盐离子及其邻近的磷酸盐和/或碳酸盐的几何形状和方向的变化所带来的。亚硒酸盐在不同类型的碳酸HAp中的掺入也引起了不同热力学参数的变化，包括熵、焓、热容和吉布斯自由能。含有 1.2 wt% 亚硒酸盐的 HAp 的溶解度比未掺杂的 HAp 高 2.5 倍，并且随后释放的亚硒酸盐离子直接抑制 RAW264.7 破骨细胞。剂量反应曲线表明，破骨细胞的抑制作用与亚硒酸盐掺杂HAp的浓度及其中亚硒酸盐的含量成正比。同时，亚硒酸盐掺杂的HAp对成骨细胞K7M2和MC3T3-E1细胞的不利影响明显小于对RAW264.7破骨细胞的不利影响。有治疗前景的成骨细胞与成骨细胞当细胞受到未掺杂的 HAp 攻击时，破骨细胞选择性抑制不存在，表明这是由 HAp 中的亚硒酸盐离子引起的，而不是单独由 HAp 引起的。结论是，就像构建亚硒酸盐金字塔的三个氧一样，(1) 实验材料科学、(2) 量子力学建模和 (3) 生物测定的结合是一个三元组，从中可以更深入地了解离子掺杂 HAp 和其他生物材料可以散发出来。