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）疾病及其药物治疗导致牙种植体骨结合受损的病例频率增加。支持周围骨组织再生和改善稳定整合的一种方法是使植入物表面具有成骨信号分子。尽管已经提出并研究了许多将信号分子锚到植入物表面的策略，但迄今为止还不可能在体内证明显著的效果。这种效应可能是由现有技术的涂层通常面临的以下限制之一引起的：（i）表面结合生长因子的技术上有限的浓度;（ii）不适当的释放动力学和/或（iii）主要限制为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）和信号传导途径（影响增殖、基质合成和血管生成/成骨分化）参与血管生成和骨生成。因此，它是非常有前途的锚，并提出了一个更复杂的收集信号分子植入物表面上的有效增强植入物周围的血管生成和osteogenesization.Coatings组成的ECM分子，如硫酸化糖胺聚糖（sGAG）沉积为纳米级的多层膜是一种有效的工具，用于创建一个仿生基质上的植入物表面。由于血管生成和成骨信号级联中许多最重要的生长因子具有对sGAG分子具有高亲和力的结合结构域，因此这些涂层非常适合以仿生浓度、环境和释放曲线递送生长因子。因此，在这项资助中，我们将使用仿生sGAG涂层来解决以下任务：i）通过改变膜结构和/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，和iii）在一个涂层中呈现几种不同的生长因子，用于有效的植入物周围血管生成和骨生成。

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.