Real-time finite element analysis allows homogenization of tissue scale strains and reduces variance in a mouse defect healing model

Abstract

Mechanical loading allows both investigation into the mechano-regulation of fracture healing as well as interventions to improve fracture-healing outcomes such as delayed healing or non-unions. However, loading is seldom individualised or even targeted to an effective mechanical stimulus level within the bone tissue. In this study, we use micro-finite element analysis to demonstrate the result of using a constant loading assumption for all mouse femurs in a given group. We then contrast this with the application of an adaptive loading approach, denoted real time Finite Element adaptation, in which micro-computed tomography images provide the basis for micro-FE based simulations and the resulting strains are manipulated and targeted to a reference distribution. Using this approach, we demonstrate that individualised femoral loading leads to a better-specified strain distribution and lower variance in tissue mechanical stimulus across all mice, both longitudinally and cross-sectionally, while making sure that no overloading is occurring leading to refracture of the femur bones.

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

“…As the study applied the same load to all animals irrespective of healing progression, differences in the induced strains might have caused the high variability within groups. We addressed this by using our recently developed RTFE based loading approach 24 , which takes into account the individual strain distribution within the mineralized callus for determining individual loading settings at weekly post-operative intervals. In a recent study by Malhotra et al 35 individualized cyclic mechanical loading (week 0–week 4, 3 × /week) was shown to significantly increase bone volume fraction in a partial vertebral defect model compared to controls.…”

“…From week 4 to week 7, individualized cyclic loading (8–16 N, 10 Hz, 3000 cycles; 3 × /week; controls—0 N) was applied via the external loading fixator (Fig. 1 b) based on computed strain distribution in the callus using animal-specific RTFE analysis (for detailed description of methods see 24 ). Briefly, after weekly micro-CT measurements of each animal, the images were pre-processed using threshold-binning to create a high-resolution multi-density FE mesh, which was then solved on a supercomputer within the same anaesthetic session for each mouse.…”

“…We aim to overcome current limitations by combining state-of-the-art time-lapsed in vivo imaging with a novel precisely controlled femur defect loading system in mice. By applying time-lapsed in vivo micro-CT and animal-specific real-time micro-finite element (RTFE) analysis, the developed femur defect loading model allows scaling of loading settings based on strain distribution in the mineralized callus 24 , thereby considering individual differences in healing speed. To follow the healing progression in each animal, a recently developed longitudinal in vivo micro-CT based approach was applied, which was previously shown to capture the different healing phases and to discriminate physiological and impaired healing patterns 25 , without significant radiation-associated effects on callus properties 26 .…”

Nonlinear micro finite element models based on digital volume correlation measurements predict early microdamage in newly formed bone

“…Micro finite element (µFE) models represent a powerful tool to non-invasively predict local and structural mechanical properties of bone during regeneration (Jaecques et al, 2004). When combined with high resolution XCT imaging, µFE models can resolve the large structural heterogeneities of newly formed bone tissue (Li et al, 2019; Paul et al, 2021; Suzuki et al, 2020). They are, therefore, useable to better understand the biomechanical strength under different loading conditions and the impact of bone defect treatments on the mechanical competence of the regenerated tissue.…”

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

“…We aim to overcome current limitations by combining state-of-the-art time-lapsed in vivo imaging with a novel precisely controlled femur defect loading system in mice. By applying time-lapsed in vivo micro-CT and animal-specific real-time micro-finite element (RTFE) analysis, the developed femur defect loading model allows scaling of loading settings based on strain distribution in the callus 16 , thereby considering individual differences in healing speed. To follow the healing progression in each animal, a recently developed longitudinal in vivo micro-CT based approach was applied, which was previously shown to capture the different healing phases and to discriminate physiological and impaired healing patterns 17 , without significant radiation-associated effects on callus properties 18 .…”