Individualized cyclic mechanical loading improves callus properties during the remodelling phase of fracture healing in mice as assessed from time-lapsed in vivo imaging

Abstract

Fracture healing is regulated by mechanical loading. Understanding the underlying mechanisms during the different healing phases is required for targeted mechanical intervention therapies. Here, the influence of individualized cyclic mechanical loading on the remodelling phase of fracture healing was assessed in a mouse femur defect model. After bridging of the defect, a loading group (n=10) received individualized cyclic mechanical loading (8-16 N, 10 Hz, 5 min, 3x/week) based on computed strain distribution in the callus using animal-specific real-time micro-finite element analysis. Controls (n=10) received 0 N treatment at the same post-operative time-points. By registration of consecutive scans, structural and dynamic callus morphometric parameters were followed in three callus sub-volumes and the adjacent cortex showing that the remodelling phase of fracture healing is highly responsive to cyclic mechanical loading with changes in dynamic parameters leading to significantly larger callus formation and mineralization. Loading-mediated maintenance of callus remodelling was associated with distinct effects on Wnt-signalling-associated molecular targets Sclerostin and Rankl in callus sub-regions and the adjacent cortex. Given these distinct local protein expression patterns induced by cyclic mechanical loading, the femur defect loading model with individualized load application seems suitable to understand the local spatio-temporal mechano-molecular regulation of the different fracture healing phases.

Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect

“…When comparing this healing to an externally-fixated mouse femoral full osteotomy defect model, mechanical loading from the fourth week onwards also significantly increased BV/TV in the defect centre region. One difference though was the patterns in the BFR and BRR once loading began 19 . Of relevance here is the phase of healing in which loading begins.…”

“…Depending on the complexity and resolution deemed suitable, it is possible to do this immediately after imaging to limit unnecessary or additional handling and anesthesia in mice. This concept is concurrently presented in a mouse femoral defect model 19 , 20 , and in combination introduce the concept of real-time finite element (rtFE) analysis to describe this approach. Since mechanical loading is effective only within a certain strain window 21 , maintaining the applied loading within this window is critical.…”

Spatio-temporal characterization of fracture healing patterns and assessment of biomaterials by time-lapsed in vivo micro-computed tomography

“…The approach could be supplemented with the registration of 2D-histology section into the 3D-micro-CT volume 52 , potentially allowing for a spatio-temporal understanding of molecular and cellular changes induced by different biomaterials. To better mimic the clinical situation, future studies should also assess the performance of biomaterials under load application, which could be achieved using a recently developed loading fixator 53 . By combining our in vivo time-lapsed micro-CT based monitoring approach with individualized loading regimes, this would allow for thorough characterization of biomaterials under clinically relevant loading conditions.…”

The Role of Surface Chemistry in the Osseointegration of PEEK Implants

“…Since the NH 2 implants promoted more pro-inflammatory macrophage responses than the other two implants, this could explain the increased thinning of the bone around the NH 2 implants. The two-week time point falls in the range where bone resorption was observed for unicortical defects in mice with PEEK implants, and the pro-inflammatory responses to the SB-NH 2 implants may have accelerated this resorption.…”