During the last decades, mathematical modeling and simulation have become valuable tools for investigating complex biomedical systems. They significantly contribute to understand different aspects of a biological process, often allowing to extend the study results to related, mutually conditioned processes.

This proposal is concerned with modeling, simulation and experimental validation for a prominent biomedical problem, the meniscus regeneration and involved cell and tissue-level phenomena. Clinical studies indicate that partial and total meniscectomies lead to prevalence of premature osteoarthritis in knee joints. Therefore, substantial efforts are being made towards finding adequate regenerative tissue for meniscus replacement. Although there are some solutions described in the literature, to date the optimal substitute has not been developed. Most regenerative approaches are clinically motivated and focus rather on the practical application than on the micro- and macroscopic cellular mechanisms and the interactions with the scaffold material. The latter viewpoint is promising in the sense that it aims to understand the basic control mechanisms in cell-scaffold interactions under different environmental parameters, thus providing a selective prognosis of the most significant combinations of these parameters.With respect to the in-silico modeling and simulation, a major challenge lies in the well-posed and numerically efficient coupling of the processes at the cell level with the macroscopic behavior and the mechanical properties of the tissue. The active processes at the cell level, such as cell differentiation and matrix synthesis, have a strong impact on the resulting tissue structure and quality, while macroscopic effects in turn are important stimuli for the processes at the microscopic level. Moreover, the time scales of the different processes differ vastly and call for appropriate co-simulation strategies.

A key feature of our experimental study design is the use of a nonwoven scaffold in a novel 3D printed perfusion chamber which is integrated in a bioreactor that allows in-vitro investigations of scaffolds in interaction with chondrocytes and adipose tissue-derived stem cells. In this framework, crucial stimuli to trigger relevant proliferation, migration and differentiation can be identified by state-of-the-art experimental measurements. While meaningful clinical data is very difficult to obtain from the interior meniscus tissue, this off-the-wall approach provides comprehensive underpinnings for the mathematical modeling and numerical simulation.Summarizing, the major outcome of this project will set up the rationale for the future design of regenerative meniscus replacement material.