Osteogenic and angiogenic potential of mesoporous bioactive glass nanoparticles doped with molybdenum and boron

骨缺损的治疗是骨科外科面临的主要挑战。骨组织工程（Bone tissue engineering， BTE）的方法已经发展到支持骨缺损的再生，包括合成生物材料的应用。在种类繁多的合成生物材料中，生物活性玻璃（BGs）以其独特的性质脱颖而出：BGs与周围组织结合，在与体液接触后，通过在其表面形成碳酸羟基磷灰石来调节。此外，通过BGs向周围组织释放离子，骨前体细胞被刺激向成骨分化。BGs最早是由Hench等人在20世纪60年代开发的45S5-BG（组成摩尔百分比：46.1 SiO2, 24.5 CaO, 24.5 Na2O, 6.0 P2O5）。从那时起，由于BG合成过程的发展，BG家族也迅速增长，通过结合具有特定治疗活性的进一步离子，导致可能的化学成分倍增。用于BTE的生物材料的成功主要取决于两个主要特性：(i)生物材料必须刺激周围细胞向成骨分化；因此，它们必须是骨诱导的，并且（ii）生物材料必须支持血管形成；因此，它们一定是血管生成的。此外，这两种特性在体内情况下是直接相互依赖的：缺乏血管化，骨再生将无法成功。BG的成骨和血管生成特性可以通过向BG组合物中添加治疗性离子而得到实质性的改变。我们的团队开发了基于SiO2-CaO体系的溶胶-凝胶衍生的介孔生物活性玻璃纳米颗粒（MBGNs），可以作为具有成骨和/或血管生成特性的离子局部应用的载体。在准备这个项目的过程中，我们的团队已经确定了钼（Mo）和硼(B)作为可能的候选生物活性元素：作为MBGNs的一部分，Mo在初步实验中已被证明具有成骨作用，而B在之前我们团队进行的研究中被确定为具有血管生成潜力的吸引离子。因此，在本项目中，将对掺杂Mo或B的MBGNs以及同时掺杂Mo和B的MBGNs进行体外血管生成和成骨性能的评估。最后，含MBGNs的支架将在鸡绒毛膜尿囊膜实验和啮齿动物股骨缺损模型中进行体内评估，以分析其体内血管生成和成骨特性。这不仅是第一次在体内制备和研究含有MBGNs的支架，而且也是第一次评估Mo， B双掺杂MBGNs的效果-预计具有血管生成和成骨特性的离子掺杂比单独掺杂任何一种离子更能改善骨缺损的巩固。

Bone defect treatment belongs to the major challenges in orthopedic surgery. Bone tissue engineering (BTE) approaches have been developed to support the regeneration of bone defects, including the application of synthetic biomaterials. Amongst a broad variety of synthetic biomaterials, bioactive glasses (BGs) stand out by their unique properties: BGs bond to surrounding tissues, mediated by the development of carbonated hydroxyapatite on their surfaces after contact with body fluids. Furthermore, by the release of ions from the BGs to the surrounding tissue, bone precursor cells are stimulated towards osteogenic differentiation. BGs were first introduced by Hench et al. in the 1960s with the development of the 45S5-BG (composition in mol%: 46.1 SiO2, 24.5 CaO, 24.5 Na2O, 6.0 P2O5). Since then, the family of BGs grew rapidly also due to developments in the BG synthesis process, resulting in a multiplication of possible chemical compositions by incorporation of further ions with specific therapeutic activity. The success of biomaterials that are intended for the use in BTE is mainly depending on two major properties: (i) biomaterials must stimulate the surrounding cells towards osteogenic differentiation; thus, they must be osteoinductive, and (ii) biomaterials must support vascularization; thus, they must be angiogenic. Furthermore, both properties are directly depending on each other in the in-vivo situation: with a lack of vascularization, bone regeneration will not succeed. The osteogenic and angiogenic properties of BGs can be substantially modified by the addition of therapeutic ions to the BG composition. Our group developed sol-gel derived mesoporous bioactive glass nanoparticles (MBGNs) based on the SiO2–CaO system that can serve as vectors for the local application of ions with osteogenic and/or angiogenic properties. In preparation of this project, our groups have identified Molybdenum (Mo) and Boron (B) as possible candidate biologically active elements: Whilst Mo as a part of MBGNs has proven to be osteogenic in a preliminary experiment, B was identified as an attractive ion with angiogenic potential in a study conducted previously by our groups. Therefore, in this project, MBGNs doped with either Mo or B as well as MBGNs dual-doped with both, Mo and B, will be evaluated in terms of angiogenic and osteogenic properties in-vitro. Eventually, scaffolds containing MBGNs will be subjected to an in-vivo evaluation in the chicken chorioallantoic membrane assay and a rodent femoral defect model in order to analyze their angiogenic and osteogenic in-vivo properties. This will be not only the first time that MBGNs containing scaffolds are being fabricated and investigated in-vivo but also the first time the effects of Mo, B dual-doping of MBGNs will be evaluated – it is expected that ion-doping with both, angiogenic and osteogenic properties, will improve bone defect consolidation more than doping with either one of the ions separately.