Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Recently developed atrophic non-union models are a good representation of the clinical situation in which many non-unions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures.Author Summary: In light of the ageing population, the occurrence of bone fractures is expected to rise substantially in the near future. In 5 to 10% of these cases, the healing process does not succeed in repairing the bone, leading to the formation of delayed unions or even non-unions. In this study we used a combination of an animal model mimicking a clinical non-union situation and a mathematical model developed for normal fracture healing to investigate both the causes of non-union formation and potential therapeutic strategies that can be applied to restart the healing process. After showing that the mathematical model is able to simulate key aspects of the non-union formation, we have used it to investigate several treatment strategies. One of these strategies, the treatment of a non-union involving a transplantation of cells from the bone marrow to the fracture site, was also tested in a pilot animal experiment. Both the simulations and the experiments showed the formation of a bony union between the fractured bone ends. In addition, we used the mathematical model to explain some unexpected experimental observations. This study demonstrates the added value of using a combination of mathematical modelling and experimental research as well the potential of using cell transplantation for the treatment of non-unions.