ENGINEERING CELLULAR SELF‐ORGANISATION BY CONTROLLING THE IMMUNO-MECHANICAL INTERPLAY

Both scar formation and restitutio ad integrum during bone regeneration rely on cellular self-organisation that involve cell contraction and fibronectin/collagen formation. This early stage of cellular self-organization is later followed by angiogenesis and mineralisation. Scar-free regeneration of physiological tissue homeostasis requires balanced downregulation of early inflammation, however little is understood of the immune-mechanical coupling involved. We aim to lay the foundation for reducing patient suffering resulting from scarring by combining two distinct scientific worlds, for which we have been a major driving force: the distinct regulation of local inflammation and the mechano-biology during regeneration. By combining both of our areas of expertise, we aim to harvest the potential of the novel cross-disciplinary field Immuno-Mechanics.This ambitious project concentrates first on identifing the different mechanical niches that immune cells experience early in successful healing and non-healing. Second, we will engineer synthetic niches to control fibroblasts and fibroblast-immune cell interactions to steer cell self-organisation and matrix formation in vitro. Third, we plan to verify that these synthetic niches reprogram hematoma composition and can thus reduce later scarring in vivo. The proposed experiments are challenging as they have never been done this way before, but are feasible since they capitalise on our strengths in osteo-immunology and mechano-biology. Novel technologies will be combined in a unique way to engineer the immune-mechanical cell niche, to passivate activated immune cells and to reprogramme cell fate. This will allow us to substantially advance the basic understanding of the interplay between immune cells and their mechanical niche during early regeneration. By harnessing the mechanisms of the immune-mechanics interplay, we will lay the foundation for advancing immune-modulatory therapies to reduce harmful scarring.