Effects of spatio-temporal taylored presentation of multiple growth factors in a biomimetic multilayer coating on tiotanium implants and its effects on periimplant angiogenesis and osteogenesis

在过去的几十年里，创伤、(退行性)疾病及其治疗导致牙种植体骨质整合受损的病例频率增加。一种既支持周围骨组织的再生又改善稳定整合的方法是在种植体表面装备成骨信号分子。虽然已经提出和研究了许多将信号分子锚定到植入物表面的策略，但到目前为止还不可能在体内证明显著的效果。这种效果可能是由最先进的涂层通常面临的下列限制之一造成的：(I)表面结合生长因子的技术限制浓度；(Ii)不适当的释放动力学和/或(Iii)主要限制仅呈现一种生长因子种类。然而，多种不同的细胞类型(内皮细胞、间充质前体细胞、成骨细胞和成纤维细胞)和信号通路(影响增殖、基质合成和血管生成/成骨分化)参与了血管生成和成骨。因此，在种植体表面锚定和呈现一组更复杂的信号分子以有效促进种植体周围血管生成和成骨是非常有前途的。由硫酸氨基葡聚糖(SGAG)等ECM分子组成的纳米多层膜是在种植体表面创建仿生基质的有效工具。由于血管生成和成骨信号通路中许多最重要的生长因子具有与SGAG分子高亲和力的结合域，这些涂层非常适合在仿生浓度、环境和释放谱中传递生长因子。因此，在这笔赠款中，我们将使用仿生SGAG涂层来解决以下任务：i)通过改变薄膜结构和/或应用印刷技术，在生长因子的呈现中建立时空模式，ii)确定基质结合和释放的生长因子对生物反应的贡献程度，以及iii)在一个涂层中呈现几种不同的生长因子，以实现有效的种植体周围血管生成和成骨。

Trauma, (degenerative) diseases and their medical treatment led to an increased case frequency of impaired enosseous integration of dental implants over the past decades. One approach towards both supporting the regeneration of the surrounding bone tissue and to improving the stable integration, is to equip implant surfaces with osteogenic signal molecules. Although numerous strategies to anchor signal molecules to implant surfaces have been presented and investigated, it was not possible to demonstrate significant effects in vivo up to date. This effect may result from one of the following restrictions that state-of-the-art coatings are typically facing: (i) technically limited concentration of surface bound growth factors; (ii) improper release kinetic and/or (iii) predominantly restriction to presenting only one growth factor species. However, a variety of different cell types (endothelial cells, mesenchymal precursors, osteoblasts and fibroblasts) and signaling pathways (influencing proliferation, matrix synthesis and angiogenic / osteogenic differentiation) are involved in angiogenesis and osteogenesis. Thus, it is highly promising to anchor and present a more complex collection of signaling molecules on implant surfaces for effective enhancement of periimplant angiogenesis and osteogenesis.Coatings composed of ECM molecules like sulfated glycosamino glycans (sGAG) deposited as nanometer-scale multilayers are an effective tool for creating a biomimetic matrix on the implant surface. Since many of the most important growth factors in angiogenic and osteogenic signaling cascades possess a binding domain with high affinity to sGAG molecules, these coatings are perfectly suited to deliver growth factors in a biomimetic concentration, milieu and release profile. Consequently, in this grant we will use biomimetic sGAG coatings to address the following tasks: i)establish spatio-temporal patterns in the presentation of growth factors by either varying the film architecture and/or applying printing techniques, ii) determine the extent to which matrix bound and released growth factors contribute to the biological response and iii)presentation of several different growth factors in one coating for effective periimplant angiogenesis and osteogenesis.