Functional fibrin-based hydrogels for the direction of cell/biomaterial interactions in biohybrid cardiovascular Implants.

本申请的目的是开发一种创新的生物基水凝胶，用于形成生物混合心脏瓣膜的功能组织。为此目的，将特定的信号分子如肝细胞生长因子（HGF）以调节的释放动力学整合到凝胶中，以避免需要耗时的体外细胞培养步骤。因此，可以直接募集自体干细胞，并且可以改善心脏瓣膜置换区域中的伤口愈合和组织整合。水凝胶的基础是纤维蛋白，其由纤维蛋白原与凝血酶的级联反应产生。在体内，它主要用于通过血浆血液凝固闭合伤口，伴随着通过材料的分层结构的所谓应变硬化，以产生更大的血液流动屏障。如果该材料用作组织工程方法中的基础，则该机械性能是有利的，因为通过非线性弹性行为防止了变形。在之前的项目阶段，用基于聚乙烯吡咯烷酮和甲基丙烯酸缩水甘油酯的线性共聚物对纤维蛋白凝胶进行了改性，结果表明纤维蛋白的机械性能得到了改善。此外，共聚物被证明是细胞相容的，它减缓了纤维蛋白纤维的降解。纤维蛋白共聚物水凝胶支持各种细胞系的细胞生长以及间充质干细胞向平滑肌细胞的分化。在下一个项目阶段，改性的天然生物聚合物如多糖现在将取代合成的线性聚合物，以增强纤维蛋白。由于它们的生物相容性和高分子量，它们特别适合于这种应用。在另一个工作包中，基于天然心脏瓣膜的结构，将使用3D打印开发由分层组成的分区材料。这些层将主要由基于纤维蛋白的水凝胶、胶原蛋白或弹性蛋白组成。此外，基于纤维蛋白的微凝胶（微珠）将通过微流体技术生产，其中应该包含生长因子或细胞。根据需要使用3D打印将这些实现到层中。通过该系统，可以分析和优化生长因子的释放以及各个层次中细胞的增殖和分化行为。这种结构设置应该能够在移植后有针对性地控制支架上和支架中的细胞行为。

The aim of the present application is to develop an innovative biobased hydrogel for the formation of functional tissues for biohybrid heart valves. For this purpose, specific signaling molecules such as the hepatocyte growth factor (HGF) are integrated with a tuned release kinetic into the gel to avoid the need for time-consuming in vitro cell culture steps. Thus, autologous stem cells can be recruited directly and wound healing and tissue integration in the area of heart valve replacement can be improved. The basis of the hydrogels is fibrin, which is produced by a cascade reaction of fibrinogen with thrombin. In vivo, it primarily serves to close wounds through plasmatic blood coagulation, accompanied by a so-called strain stiffening through the hierarchical structure of the material, in order to generate a greater barrier against blood flow. If the material is used as a basis in a tissue engineering approach, this mechanical property is advantageous, as deformations are prevented by the non-linear elastic behaviour. In the previous project phase, fibrin gels were modified with linear copolymers based on polyvinylpyrrolidone and glycidyl methacrylate and it could be shown that the mechanical properties of the fibrin were improved. Furthermore, the copolymer proved to be cytocompatible and it slowed down the degradation of the fibrin fibres. The fibrin copolymer hydrogels support the cell growth of various cell lines as well as the differentiation of mesenchymal stem cells into smooth muscle cells.In the next project phase, modified natural biopolymers such as polysaccharides will now be used instead of synthetic linear polymers, to reinforce fibrin. These are particularly suitable for this application due to their biocompatibility and their high molecular weight. In another work package, based on the structure of a natural heart valve, a compartmentalized material consisting of hierarchical layers is to be developed using 3D printing. These layers will mainly consist of fibrin-based hydrogels, collagen or elastin. In addition, fibrin-based microgels (microbeads) will be produced via microfluidics, which are supposed to contain growth factors or cells. These are implemented into the layers as needed using 3D printing. Through this system, the release of the growth factors as well as the proliferation and differentiation behaviour of the cells in the individual hierarchies can be analyzed and optimized. This structural set-up should enable targeted control of cell behaviour on and in the scaffold after transplantations.