Biomechanical duality of fracture healing captured using virtual mechanical testing and validated in ovine bones

Abstract

Bone fractures commonly repair by forming a bridging structure called callus, which begins as soft tissue and gradually ossifies to restore rigidity to the bone. Virtual mechanical testing is a promising technique for image-based assessment of structural bone healing in both preclinical and clinical settings, but its accuracy depends on the validity of the material model used to assign tissue mechanical properties. The goal of this study was to develop a constitutive model for callus that captures the heterogeneity and biomechanical duality of the callus, which contains both soft tissue and woven bone. To achieve this, a large-scale optimization analysis was performed on 2363 variations of 3D finite element models derived from computed tomography (CT) scans of 33 osteotomized sheep under normal and delayed healing conditions. A piecewise material model was identified that produced high absolute agreement between virtual and physical tests by differentiating between soft and hard callus based on radiodensity. The results showed that the structural integrity of a healing long bone is conferred by an internal architecture of mineralized hard callus that is supported by interstitial soft tissue. These findings suggest that with appropriate material modeling, virtual mechanical testing is a reliable surrogate for physical biomechanical testing.

Combined electric and magnetic field therapy enhances bone repair and regeneration in two tibia osteotomy models in sheep.

“…Quadratic tetrahedral nite element meshes were created in 3-Matic with maximum edge lengths of 0.4 mm on surfaces and 0.85 mm for volumes. Element-wise mechanical properties were interpolated from voxel image intensities using a previously published elastic modulus scaling law for ovine cortical bone (24) and a dual-zone material model for bone and callus (25). In the operated limbs, elements comprising soft tissue with a radiodensity below 665 mg HA/cm 3 were assigned a modulus of 50 MPa.…”

Assessment of Bone Healing

“…To measure the applied load on the plate, Pelham et al 26 introduced a cantilevered indicator pin, and Rajamanthrilage et al 27 introduced a hydraulic sensor. FEA uses computed tomographic (CT) imaging to develop a virtual model of the bone and then subject it to simulated mechanical testing to assess the rigidity of the callus 28 , which has been directly correlated with fracture site healing [28][29][30] . This methodology has been used clinically, and its accuracy in assessing callus has been demonstrated 28,30 .…”

Embracing ethical research: Implementing the 3R principles into fracture healing research for sustainable scientific progress

“…Typical postmortem mechanical tests are destructive and can be mutually exclusive with biological assays such as transcriptomic analysis or histology. In contrast, large animal validation experiments have shown that image‐based virtual mechanical testing is a reliable surrogate for ex vivo bench mechanical testing, which is the current gold‐standard approach 41 . These tests are also directly translatable to clinical applications, where virtual mechanical tests can provide precise, objective measurements of bone healing that cannot be obtained by other means and are useful for predicting time to union and detecting delayed healing 42 …”

“…Mouse femoral fracture models with stable fixation are generally considered moderately painful, requiring adequate pain management 40 . Insufficiently treated pain has been shown to negatively affect study results by causing impaired wound healing, immunosuppression, or increased infection risk 41–43 . Therefore, an adapted pain management regimen not only fulfills ethical obligation but also addresses scientific merits to ensure the integrity and quality of the research performed.…”

“…In contrast, large animal validation experiments have shown that imagebased virtual mechanical testing is a reliable surrogate for ex vivo bench mechanical testing, which is the current gold-standard approach. 41 These tests are also directly translatable to clinical applications, where virtual mechanical tests can provide precise, objective measurements of bone healing that cannot be obtained by other means and are useful for predicting time to union and detecting delayed healing. 42 Future applications of this technology include new experimental designs that incorporate the 3R principles.…”