“…After fracture, a fracture hematoma is formed within the gap attracting immune cells and progenitor cells such as mesenchymal stromal cells (MSCs), subsequently initiating the healing cascade. Therefore, pro-inflammatory and anti-inflammatory processes in aJ o u r n a l P r e -p r o o f 19 hypoxic microenvironment are essential steps and most often determine the success of the subsequent bone regeneration.In order to simulate the key aspects of the initial phase of fracture healing, Pfeiffenberger et al[38] developed an in vitro 'fracture gap' model by combining a fracture hematoma model (controlled coagulation of human peripheral blood and MSCs measuring viability of implemented cells over time, relevant gene expression patterns and release of relevant cytokines) and bone-like components (expression of osteogenic genes and demonstration of calcification via various stainings and in vitro µCT). The results on the testing of different medications within the 3D in vitro model showed distinct processes of the initial phase of fracture healing and demonstrate the importance of including the crosstalk between immune cells and bone.…”