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(BTE)方法已被开发用于支持骨缺损的再生，包括合成生物材料的应用。在众多的合成生物材料中，生物活性玻璃(BGS)以其独特的性能脱颖而出：BGS通过与体液接触后表面碳化的羟基磷灰石的形成与周围组织结合。此外，通过将离子从BGS释放到周围组织，骨前体细胞被刺激向成骨分化。BGS最早是由Hch等人提出的。20世纪60年代，随着45S5-BG的发展(摩尔%组成：46.1 SiO_2，24.5CaO，24.5Na2O，6.0P2O5)。从那时起，BGS家族的迅速发展也是由于BG合成过程的发展，通过加入更多具有特定治疗活性的离子，导致可能的化学成分成倍增加。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方向分化；因此，它们必须具有骨诱导性；(Ii)生物材料必须支持血管形成；因此，它们必须是血管生成的。此外，在体内情况下，这两种特性是直接相互依赖的：缺乏血管形成，骨再生将不会成功。通过在BG组合物中添加治疗性离子，BGS的成骨和血管生成特性可以得到很大程度的改变。我们团队开发了基于SiO_2-CaO体系的溶胶-凝胶法制备的介孔生物活性玻璃纳米颗粒(MBGNs)，它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。在这个项目的准备过程中，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：虽然钼作为MBGNs的一部分在初步实验中被证明是成骨的，但在我们团队之前进行的一项研究中，B被确定为具有血管生成潜力的有吸引力的离子。因此，在本项目中，我们将对掺杂Mo或B的MBGNs以及同时掺杂Mo和B的MBGNs在体外的血管生成和成骨性能进行评价。最终，含有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，以分析其血管生成和体内成骨特性。这不仅是首次在体内制备和研究含有支架的MBGNs，而且还将首次评估MBGNs的Mo、B双掺杂的效果-预计同时具有血管生成和成骨特性的离子掺杂将比单独掺杂其中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.