Alina Levchuk

Deformable image registration and 3d strain mapping for the quantitative assessment of cortical bone microdamage

The resistance to forming microcracks is a key factor for bone to withstand critical loads without fracturing. In this study, we investigated the initiation and propagation of microcracks in murine cortical bone by combining three-dimensional images from synchrotron radiation-based computed tomography and time-lapsed biomechanical testing to observe microdamage accumulation over time. Furthermore, a novel deformable image registration procedure utilizing digital volume correlation and demons image registration was introduced to compute 3D strain maps allowing characterization of the mechanical environment of the microcracks. The displacement and strain maps were validated in a priori tests. At an image resolution of 740 nm the spatial resolution of the strain maps was 10 μm (MTF), while the errors of the displacements and strains were 130 nm and 0.013, respectively. The strain maps revealed a complex interaction of the propagating microcracks with the bone microstructure. In particular, we could show that osteocyte lacunae play a dual role as stress concentrating features reducing bone strength, while at the same time contributing to the bone toughness by blunting the crack tip. We conclude that time-lapsed biomechanical imaging in combination with three-dimensional strain mapping is suitable for the investigation of crack initiation and propagation in many porous materials under various loading scenarios.

Altered lacunar and vascular porosity in osteogenesis imperfecta mouse bone as revealed by synchrotron tomography contributes to bone fragility

Osteogenesis imperfecta (brittle bone disease) is caused by mutations in the collagen genes and results in skeletal fragility. Changes in bone porosity at the tissue level indicate changes in bone metabolism and alter bone mechanical integrity. We investigated the cortical bone tissue porosity of a mouse model of the disease, oim, in comparison to a wild type (WT-C57BL/6), and examined the influence of canal architecture on bone mechanical performance. High-resolution 3D representations of the posterior tibial and the lateral humeral mid-diaphysis of the bones were acquired for both mouse groups using synchrotron radiation-based computed tomography at a nominal resolution of 700nm. Volumetric morphometric indices were determined for cortical bone, canal network and osteocyte lacunae. The influence of canal porosity architecture on bone mechanics was investigated using microarchitectural finite element (μFE) models of the cortical bone. Bright-field microscopy of stained sections was used to determine if canals were vascular. Although total cortical porosity was comparable between oim and WT bone, oim bone had more numerous and more branched canals (p<0.001), and more osteocyte lacunae per unit volume compared to WT (p<0.001). Lacunae in oim were more spherical in shape compared to the ellipsoidal WT lacunae (p<0.001). Histology revealed blood vessels in all WT and oim canals. μFE models of cortical bone revealed that small and branched canals, typical of oim bone, increase the risk of bone failure. These results portray a state of compromised bone quality in oim bone at the tissue level, which contributes to its deficient mechanical properties.

The Clinical Biomechanics Award 2012 — Presented by the European Society of Biomechanics: Large scale simulations of trabecular bone adaptation to loading and treatment

BACKGROUND Microstructural simulations of bone remodeling are particularly relevant in the clinical management of osteoporosis. Before a model can be applied in the clinics, a validation against controlled in vivo data is crucial. Here we present a strain-adaptive feedback algorithm for the simulation of trabecular bone remodeling in response to loading and pharmaceutical treatment and report on the results of the large-scale validation against in vivo data. METHODS The algorithm follows the mechanostat principle and incorporates mechanical feedback, based on the local strain-energy density. For the validation, simulations of bone remodeling and adaptation in 180 osteopenic mice were performed. Permutations of the conditions for early (20th week) and late (26th week) loading of 8N or 0N, and treatments with bisphosphonates, or parathyroid hormone were simulated. Static and dynamic morphometry and local remodeling sites from in vivo and in silico studies were compared. FINDINGS For each study an individual set of model parameters was selected. Trabecular bone volume fraction was chosen as an indicator of the accuracy of the simulations. Overall errors for this parameter were 0.1-4.5%. Other morphometric indices were simulated with errors of less than 19%. Dynamic morphometry was more difficult to predict, which resulted in significant differences from the experimental data. INTERPRETATION We validated a new algorithm for the simulation of bone remodeling in trabecular bone. The results indicate that the simulations accurately reflect the effects of treatment and loading seen in respective experimental data, and, following adaptation to human data, could be transferred into clinics.

Analysis of sintered polymer scaffolds using concomitant synchrotron computed tomography and in situ mechanical testing

The mechanical behaviour of polymer scaffolds plays a vital role in their successful use in bone tissue engineering. The present study utilised novel sintered polymer scaffolds prepared using temperature-sensitive poly(dl-lactic acid-co-glycolic acid)/poly(ethylene glycol) particles. The microstructure of these scaffolds was monitored under compressive strain by image-guided failure assessment (IGFA), which combined synchrotron radiation computed tomography (SR CT) and in situ micro-compression. Three-dimensional CT data sets of scaffolds subjected to a strain rate of 0.01%/s illustrated particle movement within the scaffolds with no deformation or cracking. When compressed using a higher strain rate of 0.02%/s particle movement was more pronounced and cracks between sintered particles were observed. The results from this study demonstrate that IGFA based on simultaneous SR CT imaging and micro-compression testing is a useful tool for assessing structural and mechanical scaffold properties, leading to further insight into structure–function relationships in scaffolds for bone tissue engineering applications.

In Silico Medicine Approach to Predict Changes in Human Vertebrae Due to Osteoporosis and Treatment

It is generally accepted that trabecular architecture plays a pivotal role in the mechanical behaviour of bone. With age, bone undergoes structural changes, which can result in osteoporosis, leading to lifethreatening fractures, and inevitable decrease in the quality of life. While mathematical laws governing bone remodelling are under continued investigation, the aim of this project was to apply a simple in silico model to simulate changes in the bone architecture due to age, as previously reported in clinical studies. In addition, the effects of the current recommended treatments were investigated. Using high-resolution three-dimensional mu CT scans of whole human vertebrae, age-related bone loss and recovery simulation produced realistic simulations of structural change over 30 years.

Modeling microdamage behavior of cortical bone

Bone is a complex material which exhibits several hierarchical levels of structural organization. At the submicron-scale, the local tissue porosity gives rise to discontinuities in the bone matrix which have been shown to influence damage behavior. Computational tools to model the damage behavior of bone at different length scales are mostly based on finite element (FE) analysis, with a range of algorithms developed for this purpose. Although the local mechanical behavior of bone tissue is influenced by microstructural features such as bone canals and osteocyte lacunae, they are often not considered in FE damage models due to the high computational cost required to simulate across several length scales, i.e., from the loads applied at the organ level down to the stresses and strains around bone canals and osteocyte lacunae. Hence, the aim of the current study was twofold: First, a multilevel FE framework was developed to compute, starting from the loads applied at the whole bone scale, the local mechanical forces acting at the micrometer and submicrometer level. Second, three simple microdamage simulation procedures based on element removal were developed and applied to bone samples at the submicrometer-scale, where cortical microporosity is included. The present microdamage algorithm produced a qualitatively analogous behavior to previous experimental tests based on stepwise mechanical compression combined with in situ synchrotron radiation computed tomography. Our results demonstrate the feasibility of simulating microdamage at a physiologically relevant scale using an image-based meshing technique and multilevel FE analysis; this allows relating microdamage behavior to intracortical bone microstructure.

In Vivo Validation of Predictive Models for Bone Remodeling and Mechanobiology

In silico modeling is a powerful tool for the prediction of bone remodeling and mechanobiology. As the method is gaining popularity a standardized measure for the in vivo validation of the quality of the produced simulations is required. In this review, we discuss current validity assessment approaches, as well as the validation ‘gold standard’, in which the experimental and computational parts are carried out concomitantly, and by the same research team. A novel validation framework for the tissue level model, based on the true geometry is introduced.

An Automated Step-Wise Micro-Compression Device for 3D Dynamic Image-Guided Failure Assessment of Bone Tissue on a Microstructural Level Using Time-Lapsed Tomography

Microstructural bone phenotypes, such as the intracortical canal network, could be directly linked to the mechanical failure behavior of cortical bone tissue. In addition, high accumulation of microdamage can significantly increase bone brittleness and thus, is a precursor of mechanical failure. Here, we discuss the development and validation of an automated step-wise micro-compression device (MCD) for dynamic image-guided failure assessment (DIGFA) of intracortical bone microstructure and bone microdamage. The device was found to be highly accurate and precise with positioning errors of less than 1 µm and force errors of less than 1.25 N. In addition, the results of a first biological study using DIGFA and time-lapsed computed tomography are presented. In short, whole mouse femora from mature C57BL/6 (B6) and C3H/He (C3H) mice with mid-diaphyseal notches were tested in step-wise compression and concomitantly imaged until failure. DIGFA was performed at the TOMCAT beamline of the Swiss Light Source using synchrotron radiation-based computed tomography (SR CT). Following the experiment, intracortical porosity was separated into the canal network, osteocyte lacunae, and microcracks for subsequent morphometric evaluation. The thicker cortex of C3H was penetrated by a dense canal network, whereas in B6 only a few scattered canals were observed. For B6, the first occurrence of crack was noted at 1.45% local strain, while for C3H, crack initiation took place only at 2.66% local strain. In addition, we were able to relate whole bone mechanics to local failure events by deriving correlations between microstructural porosity and microdamage propagation. In conclusion, initiation and accumulation of microcracks were investigated for two mouse phenotypes demonstrating that DIGFA in combination with SR CT is a suitable technique for time-lapsed three-dimensional assessment of bone morphology and bone fracture behavior down to the cellular level.

PARATHYROID HORMONE INTERFERES WITH THE MECHANOREGULATION OF BONE REMODELING

The human parathyroid peptide fragment hPTH 134 is an anabolic drug which, given intermittently, turns on bone remodeling by increasing bone formation. Its exact mode of action is however still unclear to date. In an earlier study, we found that in mechanically loaded animals, formation occurs preferentially at highly loaded areas, and resorption at lowly strained areas [1]. Here we investigate if and how PTH combined with mechanical loading alters the mechanoregulation of bone remodeling. With this, we aimed at a better understanding of the effectiveness of PTH in the treatment of bone diseases such as osteoporosis.