Mechano-dependency of early bone healing, angiogenesis, and their interplay across ages

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The relevance of mechanical boundary conditions as driving factor in bone regeneration and adaptation is generally well accepted. In addition, functional angiogenesis and vascular supply of a fracture zone are also considered to be key factors in healing and in the viability of regenerated tissues. However, the relationship and interdependence between tissue mechanical conditions and angiogenesis is not yet well understood. Recent work has shown the critical role of extrinsic mechanics on the self-organization of fibroblast networks in early callus formation and endothelial cell-cell interactions as reaction to the blood flow driving vascular network formation. Pericyte and vascular smooth muscle cells confer stability and diameter control to nascent vessels. But how fibroblasts and/or pericytes relay mechanical input from surrounding callus tissue to adapt vascular patterning has not been studied. Our primary goal is to understand how mechanical loading influences functional vascular network formation and early callus organization in young and aged during bone healing. This work will help to unravel the age dependent signalling pathways between externally applied load, fibroblast self-organization, pericyte response, vascular network formation, and the early soft callus and bone marrow re-organization after injury.