SFB 1444: Directed Cellular Self-Organisation for Advancing Bone Regeneration

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Musculoskeletal diseases and disorders are on the continuous rise due to the epidemic of obesity resulting in reduced mobility, and the increased physical activity of the elderly in an increasingly aging population. The healing potential of bone varies greatly in the different patient groups, but there is a substantial lack of understanding how the endogenous healing processes are altered due to age, metabolic status or immune experience of the individuals. This Collaborative Research Center aims to unravel the basic mechanisms that differentiate between success and failure in bone regeneration. Since bone is one of the few tissues in the body that has the general capability of scar-less healing resulting in complete functional and structural reconstitution it is an ideal model system to understand the general principals of endogenous healing, which is relevant also for regeneration processes of other tissues. Bone healing is initiated by cellular self-organisation that guides the regenerative processes throughout all consecutive regeneration phases. The early phases of bone regeneration are essential for the long-term healing success, but also delays of healing or non-unions are already initiated during these very early stages. Central to all regenerative cascades driven by cellular self-organisation are (1) a well-controlled local inflammatory response, (2) well-balanced nutrition supply and consumption, and (3) a well-structured matrix re-organization by force transmission and sensing. These are the three key mechanism that need to be closely coordinated to achieve successful endogenous tissue regeneration in bone. To prove this hypothesis, we want to understand the interdependencies between these key mechanisms of healing, which have only been studied from a one-dimensional perspective so far. The aim of this CRC is to reveal (1) how the interplay between these three key mechanisms is controlled and regulated; (2) how their interdependencies are adjusted during healthy aging so that regeneration remains - in principle – possible; and (3) how each of the three key mechanisms are challenged by distinct stressors that are associated with delayed or non-healing conditions. Over the 12-year period of this Collaborative Research Center, we will concentrate in the beginning on the understanding of the interdependencies between these three key mechanisms of healing. Within the second funding period, we aim to understand the effect of stressors on the interdependencies of the three key mechanisms of healing. Finally, in the third funding period we aim at controlling and steering the three key mechanisms and their interdependencies, specifically in impaired healing cascades of challenged clinical settings. We will validate our understanding of the “control” mechanism in both pre-clinical and first-in-men clinical studies and thereby lay the foundation for personalized therapeutic approaches.