An integrated experimental-computational framework to assess the influence of microstructure and material properties on fracture toughness in clinical specimens of human femoral cortical bone.

Microstructural and compositional changes that occur due to aging, pathological conditions, or pharmacological treatments alter cortical bone fracture resistance. However, the relative importance of these changes to the fracture resistance of cortical bone has not been quantified in detail. In this technical note, we developed an integrated experimental-computational framework utilizing human femoral cortical bone biopsies to advance the understanding of how fracture resistance of cortical bone is modulated due to modifications in its microstructure and material properties. Four human biopsy samples from individuals with varying fragility fracture history and osteoporosis treatment status were converted to finite element models incorporating specimen-specific material properties and were analyzed using fracture mechanics-based modeling. The results showed that cement line density and osteonal volume had a significant effect on crack volume. The removal of cement lines substantially increased the crack volume in the osteons and interstitial bone, representing straight crack growth, compared to models with cement lines due to the lack of crack deflection in the models without cement lines. Crack volume in the osteons and interstitial bone increased when mean elastic modulus and ultimate strength increased and mean fracture toughness decreased. Crack volume in the osteons and interstitial bone was reduced when material property heterogeneity was incorporated in the models. Although both the microstructure and the heterogeneity of the material properties of the cortical bone independently increased the fracture toughness, the relative contribution of the microstructure was more significant. The integrated experimental-computational framework developed here can identify the most critical microscale features of cortical bone modulated by pathological processes or pharmacological treatments that drive changes in fracture resistance and improve our understanding of the relative influence of microstructure and material properties on fracture resistance of cortical bone.

Assessment of the multifactorial causes of atypical femoral fractures using a novel multiscale finite element approach.

Atypical femoral fracture (AFF), which is a low energy fracture in the subtrochanteric or diaphysis region of the femur, has multifactorial causes that span macro- to microscale mechanisms including femoral geometry, cortical bone composition and structure. However, the extent of individual and combined influence of these factors on AFF is still not well understood. As a result, the aim of this study is to develop a multiscale fracture mechanics-based finite element modeling framework that is capable of quantifying the individual and combined influence of macroscale femoral geometrical properties as well as cortical bone microscale material properties and structure on AFF. In this study, three different femoral geometries with two different cortical bone microstructures, and two different material property distributions were investigated by first determining the critical AFF locations in the femur using macroscale stress analysis and then performing coupled macro-microscale fracture simulations. The simulation results showed that femoral geometry led to substantial differences in crack growth independent of cortical microstructure and tissue level material properties. The results suggest that multiple femoral geometrical properties, including neck-shaft angle and curvature, may contribute to the fracture behavior at AFF sites rather than a single macroscale geometrical feature. Osteonal area had a significant effect on microcrack propagation at AFF sites independent of microscale material property distribution and femoral geometry. In addition, cortical bone tissue level material heterogeneity improved the fracture resistance independent of femoral geometry and cortical microstructure. In summary, the computational approach developed in this study identified the individual, combined, and relative influence of multiscale factors on AFF risk. The new framework developed in this study could help identify the governing multiscale mechanisms of AFF and bring additional insight into the possible association of long-term bisphosphate treatment with AFF.

Material heterogeneity, microstructure, and microcracks demonstrate differential influence on crack initiation and propagation in cortical bone.

The recent studies have shown that long-term bisphosphonate use may result in a number of mechanical alterations in the bone tissue including a reduction in compositional heterogeneity and an increase in microcrack density. There are limited number of experimental and computational studies in the literature that evaluated how these modifications affect crack initiation and propagation in cortical bone. Therefore, in this study, the entire crack growth process including initiation and propagation was simulated at the microscale by using the cohesive extended finite element method. Models with homogeneous and heterogeneous material properties (represented at the microscale capturing the variability in material property values and their distribution) as well as different microcrack density and microstructure were compared. The results showed that initiation fracture resistance was higher in models with homogeneous material properties compared to heterogeneous ones, whereas an opposite trend was observed in propagation fracture resistance. The increase in material heterogeneity level up to 10 different material property sets increased the propagation fracture resistance beyond which a decrease was observed while still remaining higher than the homogeneous material distribution. The simulation results also showed that the total osteonal area influenced crack propagation and the local osteonal area near the initial crack affected the crack initiation behavior. In addition, the initiation fracture resistance was higher in models representing bisphosphonate treated bone (low material heterogeneity, high microcrack density) compared to untreated bone models (high material heterogeneity, low microcrack density), whereas an opposite trend was observed at later stages of crack growth. In summary, the results demonstrated that tissue material heterogeneity, microstructure, and microcrack density influenced crack initiation and propagation differently. The findings also elucidate how possible modifications in material heterogeneity and microcrack density due to bisphosphonate treatment may influence the initiation and propagation fracture resistance of cortical bone.

Interaction of Microcracks and Tissue Compositional Heterogeneity in Determining Fracture Resistance of Human Cortical Bone.

Recent studies demonstrated an association between atypical femoral fracture (AFF) and long-term bisphosphonate (BP) use for osteoporosis treatment. Due to BP treatment, bone undergoes alterations including increased microcrack density and reduced tissue compositional heterogeneity. However, the effect of these changes on the fracture response of bone is not well understood. As a result, the goal of the current study is to evaluate the individual and combined effects of microcracks and tissue compositional heterogeneity on fracture resistance of cortical bone using finite element modeling (FEM) of compact tension (CT) specimen tests with varying microcrack density, location, and clustering, and material heterogeneity in three different bone samples. The simulation results showed that an increase in microcrack density improved the fracture resistance irrespective of the local material property heterogeneity and microcrack distribution. A reduction in material property heterogeneity adversely affected the fracture resistance in models both with and without microcracks. When the combined changes in microcrack density and tissue material property heterogeneity representing BP treatment were evaluated, the models corresponding to BP-treated bone demonstrated reduced fracture resistance. The simulation results also showed that although microcrack location and clustering, and microstructure significantly influenced fracture resistance, the trends observed on the effect of microcrack density and tissue material property heterogeneity did not change. In summary, these results provide new information on the interaction of microcracks, tissue material property heterogeneity, and fracture resistance and may improve the understanding of the influence of mechanical changes due to prolonged BP use on the fracture behavior of cortical bone.

Assessment of myocardial repolarisation parameters in patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a chronic, recurrent auto-inflammatory disease characterised by self-terminating attacks of fever and sterile polyserositis. The main cause of death in auto-inflammatory diseases is cardiovascular events. Additionally, auto-inflammatory diseases have potential effects on the myocardial repolarisation parameters, including the T-wave peak-to-end (Tp-Te) interval, cTp-Te interval (corrected Tp-Te) and the cTp-Te/QT ratio. The aim of this study was to analyse the efficacy of myocardial repolarisation alterations in anticipation of cardiovascular risks in patients with FMF. METHODS: This study included 66 patients with FMF and 58 healthy control subjects. Tp-Te and cTp-Te intervals and the cTp-Te/QT ratio were measured from the 12-lead electrocardiogram. RESULTS: In electrocardiographic parameters, analysis of QT, QT dispersion, corrected QT (QTc) and QTc dispersion were similar between the groups. The Tp-Te and cTp-Te intervals and Tp-Te/QT and cTp-Te/QT ratios were significantly prolonged in FMF patients. Multivariate linear regression analyses indicated that erythrocyte sedimentation rate was an independent predictor of a prolonged cTp-Te interval. CONCLUSIONS: Our study revealed that when compared with control subjects, Tp-Te and cTp-Te intervals and cTp-Te/QT ratio were increased in FMF patients.

Aortic Flow Propagation Velocity in Patients with Familial Mediterranean Fever: an Observational Study.

BACKGROUND AND OBJECTIVES: Systemic inflammation has an important role in the initiation of atherosclerosis, which is associated with arterial stiffness (AS). Aortic flow propagation velocity (APV) is a new echocardiographic parameter of aortic stiffness. The relationship between systemic inflammation and AS has not yet been described in patients with familial Mediterranean fever (FMF). We aimed to investigate the early markers of AS in patients with FMF by measuring APV and carotid intima-media thickness (CIMT). SUBJECTS AND METHODS: Sixty-one FMF patients (43 women; mean age 27.3±6.7 years) in an attack-free period and 57 healthy individuals (36 women; mean age 28.8±7.1 years) were included in this study. The individuals with atherosclerotic risk factors were excluded from the study. The flow propagation velocity of the descending aorta and CIMT were measured to assess AS. RESULTS: APV was significantly lower (60.2±16.5 vs. 89.5±11.6 cm/sec, p<0.001) and CIMT was significantly higher (0.49±0.09 vs. 0.40±0.10 mm, p<0.001) in the FMF group compared to the control group. There were significant correlations between APV and mean CIMT (r=-0.424, p<0.001), erythrocyte sedimentation rate (ESR) (r=-0.198, p=0.032), and left ventricle ejection fraction (r=0.201, p=0.029). APV and the ESR were independent predictors of FMF in logistic regression analysis (OR=-0.900, 95% CI=0.865-0.936, p<0.001 and OR=-1.078, 95% CI=1.024-1.135, p=0.004, respectively). Mean CIMT and LVEF were independent factors associated with APV in linear regression analysis (ß=-0.423, p<0.001 and ß=0.199, p=0.017, respectively). CONCLUSION: We demonstrated that APV was lower in FMF patients and is related to CIMT. According to our results, APV may be an independent predictor of FMF.

Assessment of the effect of reduced compositional heterogeneity on fracture resistance of human cortical bone using finite element modeling.

The recent reports of atypical femoral fracture (AFF) and its possible association with prolonged bisphosphonate (BP) use highlighted the importance of a thorough understanding of mechanical modifications in bone due to bisphosphonate treatment. The reduced compositional heterogeneity is one of the modifications in bone due to extensive suppression of bone turnover. Although experimental evaluations suggested that compositional changes lead to a reduction in the heterogeneity of elastic properties, there is limited information on the extent of influence of reduced heterogeneity on fracture resistance of cortical bone. As a result, the goal of the current study is to evaluate the influence of varying the number of unique elastic and fracture properties for osteons, interstitial bone, and cement lines on fracture resistance across seven different human cortical bone specimens using finite element modeling. Fracture resistance of seven human cortical bone samples under homogeneous and three different heterogeneous material levels was evaluated using a compact tension test setup. The simulation results predicted that the crack volume was the highest for the models with homogeneous material properties. Increasing heterogeneity resulted in a lower amount of crack volume indicating an increase in fracture resistance of cortical bone. This reduction was observed up to a certain level of heterogeneity after which further beneficial effects of heterogeneity diminished suggesting a possible optimum level of heterogeneity for the bone tissue. The homogeneous models demonstrated limited areas of damage with extensive crack formation. On the other hand, the heterogeneity in the material properties led to increased damage volume and a more variable distribution of damage compared to the homogeneous models. This resulted in uncracked regions which tended to have less damage accumulation preventing extensive crack propagation. The results also showed that the percent osteonal area was inversely correlated with crack volume and more evenly distributed osteons led to a lower amount of crack growth for all levels of material heterogeneity. In summary, this study developed a new computational modeling approach that directly evaluated the influence of heterogeneity in elastic and fracture material properties on fracture resistance of cortical bone. The results established new information that showed the adverse effects of reduced heterogeneity on fracture resistance in cortical bone and demonstrated the nonlinear relationship between heterogeneity and fracture resistance. This new computational modeling approach provides a tool that can be used to improve the understanding of the effects of material level changes due to prolonged BP use on the overall bone fracture behavior. It may also bring additional insight into the causes of unusual fractures, such as AFF and their possible association with long term BP use.

The relationship between the neutrophil-lymphocyte ratio and disease activity in patients with ulcerative colitis.

Preliminary evidence suggests that a higher neutrophil-lymphocyte ratio (NLR) may be an indicator of active ulcerative colitis (UC). However, it is not clear whether the NLR is a useful and simple indicator of clinical activity in UC after adjusting for the other inflammatory markers. We designed a retrospective study to evaluate the role of the NLR in estimating disease severity in UC patients. The study consisted of 71 patients with UC and 140 age- and sex-matched healthy individuals (control group). The NLR, erythrocyte sedimentation rate, C-reactive protein, and white blood cell count were measured. The NLR values of the active UC group were elevated compared with those of the patients with inactive UC and the controls (2.59 ± 1.47, 2.03 ± 1.07, and 1.98 ± 0.85, respectively; p = 0.005). The receiver operating characteristic revealed that the optimum NLR cut-off point for active UC was 2.39. A multivariable logistic analysis showed that of the parameters studied, C-reactive protein was the only parameter able to significantly discriminate active from inactive UC (B: 0.222; p = 0.017; odds ratio: 1.248; 95% confidence interval: 1.041-1.497).

Killer Cell Immunoglobulin-Like Receptor (KIR) Genotype Distribution in Familial Mediterranean Fever (FMF) Patients.

BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease predominantly affecting Mediterranean populations. The gene associated with FMF is the MEFV gene, which encodes for a protein called pyrin. Mutations of pyrin lead to uncontrolled attacks of inflammation, and subclinical inflammation continues during attack-free intervals. Killer cell immunoglobulin-like receptor (KIR) genes encode HLA class I receptors expressed by NK cells. The aim this study was to look for immunogenetic determinants in the pathogenesis of FMF and find out if KIR are related to susceptibility to disease or complications like renal amyloidosis. MATERIAL AND METHODS One hundred and five patients with FMF and 100 healthy individuals were involved in the study. Isolated DNA from peripheral blood was amplified by sequence specific PCR probes and analyzed by Luminex for KIR genotypes. Fisher Exact test was used to evaluate the variation of KIR gene distribution. RESULTS All patients and healthy controls expressed the framework genes. An activator KIR gene, KIR2DS2, was significantly more frequent in FMF patients (p=0.036). Renal amyloidosis and presence of arthritis were not associated with KIR genes and genotype. KIR3DL1 gene was more common in patients with high serum CRP (p=0.016). CONCLUSIONS According to our findings, we suggest that presence of KIR2DS2, which is an activator gene for NK cell functions, might be related to the autoinflammation in FMF. The potential effect of KIR genes on amyloidosis and other clinical features requires studies with larger sample sizes.