Additive manufacturing of a novel class of implants with heterogeneous structures, combining different biomaterials and printing methods

微挤压的添加方法可以在室温下进行，并可同时获得多种生物可降解材料。在这里，我们的目标是创造新型的植入物和组织结构，以支持发生在组织界面上的常见缺陷的完全再生，如骨软骨单位(骨和关节软骨)或腱-骨界面(末端)。新的解决方案将通过多通道挤压印刷结合专门适应于相应组织的生物材料来开发。在室温下运行将能够将组织特定的、敏感的生物活性因子直接整合到打印过程中。该项目的一大创新是开发和利用新的印刷图案。在微挤压印刷中，印刷设计的影响仍然是一个基本上未被探索的话题，到目前为止，印刷的通常是基本的木桩几何形状。开发的重点是产生最大限度的凹面，因为这些表面已经被证明比平面和凸面更好地支持细胞黏附和迁移。此外，在细胞培养期间和植入组织缺损处后，孔的大小和可访问性将被考虑到对氧气和营养供应至关重要。由设计图案产生的脚手架的力学性能将被包括在优化过程中，并得到计算模型的支持。除了微挤出，热塑性聚合物熔体电写(MEW)的AM技术将被整合到支架设计中。如申请人的初步实验所示，微挤压(股线直径=200微米)和MEW(纤维直径约0.5-20微米)可以在一个印刷工艺中结合。与MEW一样，可以生产高度清晰的微纤维网，两种AM技术的结合允许制造具有分层结构的支架，为细胞附着和发育提供合适的表面-而且还可以模拟哺乳动物组织的细胞外基质的微纤维网络。MEW网格的整合可以提高磷酸钙支架的机械稳定性，改善不同挤出打印生物材料的连接，并为细胞的排列提供引导结构。总体而言，新一代支架和组织结构将被开发出来，它由几种可生物降解的生物材料组成，并通过在一个印刷过程中创新地结合两种AM技术来制造。利用显微镜、机械测试和最先进的人体原代细胞和人间充质干细胞体外测试，将彻底研究得到的构建物的结构、机械和生物学特性。所有这些数据都将被深入分析，以得出结构-性质关系的结论。

The additive method of micro-extrusion can be operated at room temperature and a multitude of biodegradable biomaterials is available in the meanwhile for this method. Here, we aim at creating new types of implants and tissue constructs that support full regeneration of common defects that occur at tissue interfaces like the osteochondral unit (bone and articular cartilage) or the tendon-bone interface (enthesis). Novel solutions will be developed by combining biomaterials that are specifically adapted to the respective tissues by means of multi-channel extrusion printing. Operation at room temperature will enable integration of tissue-specific, sensitive bioactive factors directly in the printing process. A major innovation of this project is the development and utilization of new printing patterns. Influence of the printing design is still a mostly unexplored topic in micro-extrusion printing, where so far commonly basic wood pile geometries are printed. Focus for the development is the generation of a maximum of concave surfaces as those have been proven to support cell adhesion and migration better than planar and convex surfaces. In addition, size and accessibility of the pores will be taken into account that are crucial for O2 and nutrient supply, both during cell culture and after implantation into the tissue defects. The mechanical properties of the scaffold resulting from the designed pattern will be included in the optimization processes, supported by computational modelling. Besides micro-extrusion, the AM technology of Melt Electrowriting (MEW) of thermoplastic polymers will be integrated in the scaffold design. As shown in preliminary experiments by the applicants, micro-extrusion (strand diameter >= 200 Mikrometer) and MEW (fiber diameter ca. 0.5-20 micromters) can be combined within one printing process. As with MEW highly defined microfiber meshes can be produced, the combination of both AM technologies allows the fabrication of scaffolds with hierarchical structures that provide suitable surfaces for cell attachment and development - but also microfiber networks that mimic the extracellular matrices of mammalian tissues. Integration of MEW meshes can enhance the mechanical stability of calcium phosphate scaffolds, improve the connection of different, extrusion-printed biomaterials and provide guiding structures for alignment of cells. Overall, a new generation of scaffolds and tissue constructs will be developed that consists of several biodegradable biomaterials and are fabricated by innovative combination of two AM technologies in one printing process. The resulting constructs will be thoroughly investigated concerning their structural, mechanical and biological properties, utilizing microscopy, mechanical testing, and state-of-the-art in vitro tests with primary human cells and human mesenchymal stem cells. All this data will be deeply analyzed to conclude about structure-property relation.