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Endochondral ossification refers to the processes which, starting from the condensation of mesenchymal cells, leads to the formation of cartilage templates and their remodelling into bone tissue. Understanding and controlling the molecular events that occur during endochondral ossification has the potential to support the engineering/repair of cartilage and bone tissues by recapitulating developmental processes (the so-called ‘developmental engineering’ paradigm). While certain aspects of endochondral ossification have been reproduced in vitro and/or by ectopic implantation of mesenchymal stem/progenitor cells (MSC) or embryonic stem cells, the spatio-temporally ordered organisation of cartilage templates as observed during long bone development has not yet been reproduced either in culture or by regenerative approaches in vivo.Therefore, the major aim of the proposed research is to develop and implement a developmental engineering approach to endochondral ossification from MSC. The program will integrate the systematic molecular analysis of human MSC in 3-dimensional (3D) culture systems (Subproject A, I. Martin), the knowledge derived from MSC and mesenchymal progenitor cells of genetically altered mice (Subproject B, R. Zeller), the mathematical modelling and spatio-temporal simulations of molecular signalling networks (Subproject C, D. Iber), and the development of polymeric delivery systems to reproduce spatial gradients of defined soluble small molecules and recombinant proteins (Subproject D, P. Shastri). The recapitulation of endochondral ossification will rely on the controlled manipulation of the WNT and FGF pathways in order to maintain a proliferating pool of undifferentiated MSC, and of the IHH/PTHrP negative signalling feedback loop and BMPs to drive the directed chondrogenic development and differentiation of MSC. The signals released from polymeric systems, will initially be assessed for their dose-dependent effects in a spatially uniform environment and assess the effects using biological read-outs and sensors for signalling pathway activities (Workpackage I). Subsequently, these signals will be delivered from polymeric systems in the form of defined gradients in 3D culture models (Workpackage II) and ultimately assessed for their capacity to instruct orderly progression of cartilage and bone formation in vivo (Workpackage III). The proposed interdisciplinary research strategy will bring together the disciplines of tissue engineering, developmental and mouse molecular genetics, take advantage of the predictive power of mathematical modelling and incorporate material science to develop polymeric scaffolds for directed release of small molecules and proteins. The projects will bridge the gap between fundamental and translational research to progress towards the ultimate aims of (i) designing innovative models recapitulating developmental processes, and (ii) advancing the engineering of cartilage templates with medical potential for cartilage and bone repair