Abstract
An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Recent preclinical studies of bone defect in animal models have used cross-sectional data to examine this phenomenon indirectly. In this study, a direct time-lapsed imaging approach was used to investigate the local mechanical strains that precede the formation of mineralised tissue at the tissue scale. The goal was to test two hypotheses: 1) the local 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 distributions of tissue scale strains in the defects. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-computed tomography (micro-CT), which served as a ground truth for resolving areas of mineralised tissue formation. The mechanical environment was determined using micro-finite element analysis (micro-FE) on baseline images. The formation of mineralised tissue showed strong association with areas of higher 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. These findings support our hypotheses by showing a direct association between the local mechanical strains and the formation of mineralised tissue.
Highlights
An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury
The 0.85 mm defect healed in 9/10 mice with the single atrophic non-union which was excluded from analysis
These results indicate that the production of a lowly mineralized callus and maturation of the tissue are independent processes
Summary
An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Though understanding of the mechanobiology of bone healing will have profound clinical impact, eventually allowing patient-specific treatment of fractures, a more immediate application of such knowledge might be preclinical research on biomaterials or drugs, via the use of rodent models In such models, currently a plethora of defect sizes and fixation methods are used[4]. The sensitivity of healing to mechanical stimuli confounds comparisons between studies where: different fixators or defects sizes are used; biomaterials with different stiffnesses are implanted into defects changing the tissue-scale mechanical environment; or pharmaceutical treatments potentially alter the mechanosensitivity of cells. An alternative to in silico modelling is strain mapping where local deformations are estimated using digital images of tissue in the relaxed and deformed states This method has been used to parametrise and validate finite element (FE) models[12,13] and to correlate tissue phenotypes with mechanical strains[14,15]. Qualitative associations between strain patterns and bone formation have been observed in two dimensional analysis of time-lapsed micro-CT images and FE simulations[21]
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