The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model

The course of fracture healing is at least partially determined by the local mechanical environment, yet the association between local strains and tissue differentiation has yet to be directly quantified in an in vivo model. We use a combination of time-lapsed in vivo micro-computed tomography (micro-CT) and micro-finite element analysis (micro-FE) to test the following hypotheses: 1) the tissue-scale mechanical signal that precedes the onset of tissue mineralisation is higher in areas which mineralise, and 2) this local mechanical signal is independent of the magnitude of global mechanical loading of the tissue in the defect. Two groups of mice with femoral defects of length 0.85 mm (n=10) and 1.45 mm (n=9) were studied, allowing for distinct characteristics in tissue level strains. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-CT, which served as a ground truth for testing the association of local mechanical strains with the observed changes. The mechanical environment was determined by using micro-FE on baseline images. The mineralisation of the soft tissue showed strong agreement with the mechanical strain (area-under-the-curve: 0.91+/-0.04, true positive rate: 0.85+/-0.05) while surface based strains could correctly classify 43% of remodelling events. We found no significant difference between groups for the optimal effective strain. Therefore, we were able to confirm the first hypothesis and could not reject the second.