Unraveling the occurrence of fracture non-unions with a multiscale bioregulatory model

摘要: Introduction The healing of a bone fracture strongly depends on the development new blood vessel network (angiogenesis) in zone. In previous study, multiscale model sprouting angiogenesis during healing, including Dll4-Notch1 signalling to determine tip cell selection (MOSAIC [1]), was extended with rigorous description influence oxygen several cellular processes. Currently, we are using this mathematical as tool for more depth investigation critical size defects and possible therapies thereof. Results Discussion correctly simulated formation non-union used study underlying mechanisms. central region callus, found that all cells die due severe hypoxia, leading arrest. This finding prompted us explore vasculature from host environment outcome. Experimental evidence has previously shown vessels originating overlying muscle contribute revascularization callus [2]. Interestingly, predicts considerably improved outcome case full contribution an intermediate result if is only partially supplied (Fig 1). Figure 1: (A) geometrical domain considers one-fourth real geometry defect (assuming symmetry); 1 periosteal callus; 2 intercortical 3 endosteal 4 cortical ends. (B) Predicted spatiotemporal evolution active matrix density (x 0.1 g/ml) different contributions vascularization callus. Red dots at day zero represent endothelial environment. Motivated by these results, investigated whether injection either mesenchymal stem (MSCs), osteochondrogenic growth factors or combination thereof impaired environment, i.e. without contribution, must be delayed order allow (partial) restoration effective 2). We post (PFD) 7, 14, 28, 42 56 does not improve since tensions still become critically low area revascularization. MSCs beneficial PFD interfragmentary gap already restored, sustaining viability injected cells. Similar conclusions can drawn product, except yields better results than alone 2: amount formed 90 function which treatment, consisting single cells, thereof, initiated. Conclusions work clearly indicates importance tissue engineering. Future will focus silico design efficient strategies engineering constructs, angiogenic factor delivery vitro prevascularization References 1. Carlier A., et al. PLoS Comput Biol, 8(10), 2012. 2. Harry L., Plast Reconstr Surg, 124, 2009 Acknowledgments Aurelie PhD fellow Research Foundation Flanders (FWO-Vlaanderen). Short abstract hypothesized distribution tension, influenced amongst others consumption well timely important determinant occurrence non-unions. Therefore, performed thorough sensitivity analysis established bioregulatory unravel non-intuitive dynamics. next step knowledge potential treatment strategies. Purpose main objective use mechanisms non-unions Keywords Multiscale – hybrid