Experimental investigations and modeling of biohybrid heart valves including tissue maturation – from in vitro to in situ tissue engineering

生物杂交植入物（如心脏瓣膜）的长期功能在数量和质量方面与细胞外基质（ECM）的产生显著相关。ECM必须提供长期的结构支撑，以承受大量的机械载荷循环（每天9万次心脏瓣膜的开启和关闭程序）。提出了不同的生产方法（体外、原位和围手术期）来实现最佳的ECM生产。在生产过程中，将负载导向的纺织结构集成到植入物中，作为(i)仿生增强物和（ii） ECM生长方向的指南。在ECM上，评估承重增强和剩余生物力学刺激之间的最佳平衡，以使理想的方向进入负载方向，在经验上几乎是不可能的。因此，需要合适的模型来模拟体外和体内条件下的植入物，并进一步支持设计规划阶段。本项目的目的是加强前一个项目中开发的模拟和建模工具，以准确预测生物杂交心脏瓣膜植入物在体外和体内成熟过程中的力学行为。此外，还对注入后由于高周疲劳引起的力学性能退化和损伤进行了模拟。通过逐步纳入子项目P1（水凝胶材料）、P2（支架力学性能）、P6（材料降解行为）和P7（纺织增强材料）的结果，该模型将协助产品设计（关于纺织增强材料的技术配置）。它将产生对复杂生长和重塑过程的见解，从而支持所有培养方法的生物杂交植入物的优化。模拟工具的验证是通过在大型动物模型中使用所有三种成熟方法进行的试验来实现的。验证对于研究心脏瓣膜的长期损伤（TexValve）尤为重要。

The long-term function of biohybrid implants (e.g. heart valves) is significantly related to the production of the extracellular matrix (ECM) with regard to quantity and quality. The ECM has to provide long-term structural support to withstand a large number of mechanical load cycles (90,000 opening and closure procedures of the heart valve per day). Different production approaches (in vitro, in situ and perioperative) to achieve optimal ECM production have been proposed. The integration of a load orientated textile structure into the implant serves, during the production process, as (i) a biomimetic reinforcement and (ii) a guide for the direction of growth of the ECM. The evaluation of the optimal balance between load-bearing reinforcement and remaining biomechanical stimuli on the ECM, to cause desirable orientation into the load direction, is empirically hardly possible. As a result, a demand for suitable models arises to simulate the implant under in vitro and in vivo conditions and to further support the design planning phase. The aim of this project is to enhance the simulation and modelling tool developed in the previous project, to accurately predict the mechanical behavior of biohybrid heart valve implants throughout the in-vitro and in-vivo maturation processes. Furthermore, to model the degradation and damage of the mechanical properties after implantation due to high cycle fatigue. By gradually including the results of the subprojects P1 (hydrogel material), P2 (mechanical properties of scaffold), P6 (degradation behavior of the material) and P7 (textile reinforcement) this model will assist the product design (regarding the technical configuration of the textile reinforcement). It will generate insights into the complex growth and remodeling process and thus support the optimization of the biohybrid implant for all the cultivation methods. The validation of the simulation tool is captured by a trial in a large animal model using all three maturation methods. Validation is especially important to study the long-term damage of the heart valve (TexValve).