Muscle fiber phenotype: a culprit of abnormal metabolism and function in skeletal muscle of humans with obesity.

The proportion of the different types of fibers in a given skeletal muscle contributes to its overall metabolic and functional characteristics. Greater proportion of type I muscle fibers is associated with favorable oxidative metabolism and function of the muscle. Humans with obesity have a lower proportion of type I muscle fibers. We discuss how lower proportion of type I fibers in skeletal muscle of humans with obesity may explain metabolic and functional abnormalities reported in these individuals. These include lower muscle glucose disposal rate, mitochondrial content, protein synthesis, and quality/contractile function, as well as increased risk for heart disease, lower levels of physical activity, and propensity for weight gain/resistance to weight loss. We delineate future research directions and the need to examine hybrid muscle fiber populations, which are indicative of a transitory state of fiber phenotype within skeletal muscle. We also describe methodologies for precisely characterizing muscle fibers and gene expression at the single muscle fiber level to enhance our understanding of the regulation of muscle fiber phenotype in obesity. By contextualizing research in the field of muscle fiber type in obesity, we lay a foundation for future advancements and pave the way for translation of this knowledge to address impaired metabolism and function in obesity.

In situ synchrotron radiation µCT indentation of cortical bone: Anisotropic crack propagation, local deformation, and fracture.

The development of treatment strategies for skeletal diseases relies on the understanding of bone mechanical properties in relation to its structure at different length scales. At the microscale, indention techniques can be used to evaluate the elastic, plastic, and fracture behaviour of bone tissue. Here, we combined in situ high-resolution SRµCT indentation testing and digital volume correlation to elucidate the anisotropic crack propagation, deformation, and fracture of ovine cortical bone under Berkovich and spherical tips. Independently of the indenter type we observed significant dependence of the crack development due to the anisotropy ahead of the tip, with lower strains and smaller crack systems developing in samples indented in the transverse material direction, where the fibrillar bone ultrastructure is largely aligned perpendicular to the indentation direction. Such alignment allows to accommodate the strain energy, inhibiting crack propagation. Higher tensile hoop strains generally correlated with regions that display significant cracking radial to the indenter, indicating a predominant Mode I fracture. This was confirmed by the three-dimensional analysis of crack opening displacements and stress intensity factors along the crack front obtained for the first time from full displacement fields in bone tissue. The X-ray beam significantly influenced the relaxation behaviour independent of the tip. Raman analyses did not show significant changes in specimen composition after irradiation compared to non-irradiated tissue, suggesting an embrittlement process that may be linked to damage of the non-fibrillar organic matrix. This study highlights the importance of three-dimensional investigation of bone deformation and fracture behaviour to explore the mechanisms of bone failure in relation to structural changes due to ageing or disease. STATEMENT OF SIGNIFICANCE: Characterising the three-dimensional deformation and fracture behaviour of bone remains essential to decipher the interplay between structure, function, and composition with the aim to improve fracture prevention strategies. The experimental methodology presented here, combining high-resolution imaging, indentation testing and digital volume correlation, allows us to quantify the local deformation, crack propagation, and fracture modes of cortical bone tissue. Our results highlight the anisotropic behaviour of osteonal bone and the complex crack propagation patterns and fracture modes initiating by the intricate stress states beneath the indenter tip. This is of wide interest not only for the understanding of bone fracture but also to understand other architectured (bio)structures providing an effective way to quantify their toughening mechanisms in relation to their main mechanical function.

Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

The elasto-plastic nano- and microscale compressive behaviour of rehydrated mineralised collagen fibres.

The hierarchical design of bio-based nanostructured materials such as bone enables them to combine unique structure-mechanical properties. As one of its main components, water plays an important role in bone's material multiscale mechanical interplay. However, its influence has not been quantified at the length-scale of a mineralised collagen fibre. Here, we couple in situ micropillar compression, and simultaneous synchrotron small angle X-ray scattering (SAXS) and X-ray diffraction (XRD) with a statistical constitutive model. Since the synchrotron data contain statistical information on the nanostructure, we establish a direct connection between experiment and model to identify the rehydrated elasto-plastic micro- and nanomechanical fibre behaviour. Rehydration led to a decrease of 65%-75% in fibre yield stress and compressive strength, and 70% in stiffness with a 3x higher effect on stresses than strains. While in agreement with bone extracellular matrix, the decrease is 1.5-3x higher compared to micro-indentation and macro-compression. Hydration influences mineral more than fibril strain with the highest difference to the macroscale when comparing mineral and tissue levels. The effect of hydration seems to be strongly mediated by ultrastructural interfaces while results provide insights towards mechanical consequences of reported water-mediated structuring of bone apatite. The missing reinforcing capacity of surrounding tissue for an excised fibril array is more pronounced in wet than dry conditions, mainly related to fibril swelling. Differences leading to higher compressive strength between mineralised tissues seem not to depend on rehydration while the lack of kink bands supports the role of water as an elastic embedding influencing energy-absorption mechanisms. STATEMENT OF SIGNIFICANCE: Characterising structure-property-function relationships in hierarchical biological materials helps us to elucidate mechanisms that enable their unique properties. Experimental and computational methods can advance our understanding of their complex behaviour with the potential to inform bio-inspired material development. In this study, we close a gap for bone's fundamental mechanical building block at micro- and nanometre length scales. We establish a direct connection between experiments and simulations by coupling in situ synchrotron tests with a statistical model and quantify the behaviour of rehydrated single mineralised collagen fibres. Results suggest a high influence of hydration on structural interfaces, and the role of water as an elastic embedding by outlining important differences between wet and dry elasto-plastic properties of mineral nanocrystals, fibrils and fibres.

Using exogenous organizational and regional hospital attributes to explain differences in case-mix adjusted hospital costs.

Diagnosis-related group (DRG) hospital reimbursement systems differentiate cases into cost-homogenous groups based on patient characteristics. However, exogenous organizational and regional factors can influence hospital costs beyond case-mix differences. Therefore, most countries using DRG systems incorporate adjustments for such factors into their reimbursement structure. This study investigates structural hospital attributes that explain differences in average case-mix adjusted hospital costs in Switzerland. Using rich patient and hospital-level data containing 4 million cases from 120 hospitals across 3 years, we show that a regression model using only five variables (number of discharges, ratio of emergency/ambulance admissions, rate of DRGs to patients, expected loss potential based on DRG mix, and location in large agglomeration) can explain more than half of the variance in average case-mix adjusted hospital costs, capture all cost variations across commonly differentiated hospital types (e.g., academic teaching hospitals, children's hospitals, birth centers, etc.), and is robust in cross-validations across several years (despite differing hospital samples). Based on our findings, we propose a simple practical approach to differentiate legitimate from inefficiency-related or unexplainable cost differences across hospitals and discuss the potential of such an approach as a transparent way to incorporate structural hospital differences into cost benchmarking and payment schemes.

Resveratrol Blunts Mitochondrial Loss in Slow and Mixed Skeletal Muscle Phenotypes of Non-Human Primates following a Long-Term High Fat/Sugar Diet.

Mitochondrial biogenesis and destruction in skeletal muscle are coordinated by distinct signaling pathways that are influenced by internal and exogenous variables including, but not limited to, muscle phenotype, physical activity, dietary composition, or drug administration. Previously we found that long-term resveratrol administration (up to 480 mg/day) ameliorates the slow-to-fast phenotypic shift in soleus muscles and promotes the expression in slow myosin heavy chain in the mixed plantaris muscle of non-human primates consuming a high fat/sugar (HFS) diet. Here, we expand on these earlier findings by examining whether mitochondrial content and the markers that dictate their biogenesis and mitophagy/autophagy are similarly affected by HFS and/or influenced by resveratrol while consuming this diet (HFSR). Compared to controls (n = 9), there was a ∼20-25% decrease in mitochondrial content in HFS (n = 8) muscles as reflected in the COX2- and CYTB-to-GAPDH ratios using PCR analysis, which was blunted by resveratrol in HFSR (n = 7) soleus and, to a lesser degree, in plantaris muscles. A ∼1.5 and 3-fold increase in Rev-erb-α protein was detected in HFSR soleus and plantaris muscles compared to controls, respectively. Unlike in HFSR animals, HFS soleus and plantaris muscles exhibited a ∼2-fold elevation in phosphor-AMPKα (Thr172). HFS soleus muscles had elevated phosphorylated-to-total TANK binding protein-1 (TBK1) ratio suggesting an enhancement in mito/autophagic events. Taken together, resveratrol appears to blunt mitochondrial losses with a high fat/sugar diet by tempering mito/autophagy rather than promoting mitochondrial biogenesis, suggesting that the quantity of daily resveratrol supplement ingested and/or its long-term consumption are important considerations.Supplemental data for this article is available online at http://dx.doi.org/ .

Evaluation of Load-To-Strength Ratios in Metastatic Vertebrae and Comparison With Age- and Sex-Matched Healthy Individuals.

Vertebrae containing osteolytic and osteosclerotic bone metastases undergo pathologic vertebral fracture (PVF) when the lesioned vertebrae fail to carry daily loads. We hypothesize that task-specific spinal loading patterns amplify the risk of PVF, with a higher degree of risk in osteolytic than in osteosclerotic vertebrae. To test this hypothesis, we obtained clinical CT images of 11 cadaveric spines with bone metastases, estimated the individual vertebral strength from the CT data, and created spine-specific musculoskeletal models from the CT data. We established a musculoskeletal model for each spine to compute vertebral loading for natural standing, natural standing + weights, forward flexion + weights, and lateral bending + weights and derived the individual vertebral load-to-strength ratio (LSR). For each activity, we compared the metastatic spines' predicted LSRs with the normative LSRs generated from a population-based sample of 250 men and women of comparable ages. Bone metastases classification significantly affected the CT-estimated vertebral strength (Kruskal-Wallis, p < 0.0001). Post-test analysis showed that the estimated vertebral strength of osteosclerotic and mixed metastases vertebrae was significantly higher than that of osteolytic vertebrae (p = 0.0016 and p = 0.0003) or vertebrae without radiographic evidence of bone metastasis (p = 0.0010 and p = 0.0003). Compared with the median (50%) LSRs of the normative dataset, osteolytic vertebrae had higher median (50%) LSRs under natural standing (p = 0.0375), natural standing + weights (p = 0.0118), and lateral bending + weights (p = 0.0111). Surprisingly, vertebrae showing minimal radiographic evidence of bone metastasis presented significantly higher median (50%) LSRs under natural standing (p < 0.0001) and lateral bending + weights (p = 0.0009) than the normative dataset. Osteosclerotic vertebrae had lower median (50%) LSRs under natural standing (p < 0.0001), natural standing + weights (p = 0.0005), forward flexion + weights (p < 0.0001), and lateral bending + weights (p = 0.0002), a trend shared by vertebrae with mixed lesions. This study is the first to apply musculoskeletal modeling to estimate individual vertebral loading in pathologic spines and highlights the role of task-specific loading in augmenting PVF risk associated with specific bone metastatic types. Our finding of high LSRs in vertebrae without radiologically observed bone metastasis highlights that patients with metastatic spine disease could be at an increased risk of vertebral fractures even at levels where lesions have not been identified radiologically.

MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose.

Skeletal muscle adapts to aerobic exercise training, in part, through fast-to-slow phenotypic shifts and an expansion of mitochondrial networks. Recent research suggests that the local and systemic benefits of exercise training also may be modulated by the mitochondrial-derived peptide, MOTS-c. Using a combination of acute and chronic exercise challenges, the goal of the present study was to characterize the interrelationship between MOTS-c and exercise. Compared to sedentary controls, 4-8 weeks of voluntary running increased MOTS-c protein expression ~1.5-5-fold in rodent plantaris, medial gastrocnemius, and tibialis anterior muscles and is sustained for 4-6 weeks of detraining. This MOTS-c increase coincides with elevations in mtDNA reflecting an expansion of the mitochondrial genome to aerobic training. In a second experiment, a single dose (15 mg/kg) of MOTS-c administered to untrained mice improved total running time (12% increase) and distance (15% increase) during an acute exercise test. In a final experiment, MOTS-c protein translocated from the cytoplasm into the nucleus in two of six mouse soleus muscles 1 h following a 90-min downhill running challenge; no nuclear translocation was observed in the plantaris muscles from the same animals. These findings indicate that MOTS-c protein accumulates within trained skeletal muscle likely through a concomitant increase in mtDNA. Furthermore, these data suggest that the systemic benefits of exercise are, in part, mediated by an expansion of the skeletal muscle-derived MOTS-c protein pool. The benefits of training may persist into a period of inactivity (e.g., detraining) resulting from a sustained increase in intramuscular MOTS-c proteins levels.

Influence of Metastatic Bone Lesion Type and Tumor Origin on Human Vertebral Bone Architecture, Matrix Quality, and Mechanical Properties.

Metastatic spine disease is incurable, causing increased vertebral fracture risk and severe patient morbidity. Here, we demonstrate that osteolytic, osteosclerotic, and mixed bone metastasis uniquely modify human vertebral bone architecture and quality, affecting vertebral strength and stiffness. Multivariable analysis showed bone metastasis type dominates vertebral strength and stiffness changes, with neither age nor gender having an independent effect. In osteolytic vertebrae, bone architecture rarefaction, lower tissue mineral content and connectivity, and accumulation of advanced glycation end-products (AGEs) affected low vertebral strength and stiffness. In osteosclerotic vertebrae, high trabecular number and thickness but low AGEs, suggesting a high degree of bone remodeling, yielded high vertebral strength. Our study found that bone metastasis from prostate and breast primary cancers differentially impacted the osteosclerotic bone microenvironment, yielding altered bone architecture and accumulation of AGEs. These findings indicate that therapeutic approaches should target the restoration of bone structural integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).

Identification and assessment of a comprehensive set of structural factors associated with hospital costs in Switzerland.

Structural factors can influence hospital costs beyond case-mix differences. However, accepted measures on how to distinguish hospitals with regard to cost-related organizational and regional differences are lacking in Switzerland. Therefore, the objective of this study was to identify and assess a comprehensive set of hospital attributes in relation to average case-mix adjusted costs of hospitals. Using detailed hospital and patient-level data enriched with regional information, we derived a list of 23 cost predictors, examined how they are associated with costs, each other, and with different hospital types, and identified principal components within them. Our results showed that attributes describing size, complexity, and teaching-intensity of hospitals (number of beds, discharges, departments, and rate of residents) were positively related to costs and showed the largest values in university (i.e., academic teaching) and central general hospitals. Attributes related to rarity and financial risk of patient mix (ratio of rare DRGs, ratio of children, and expected loss potential based on DRG mix) were positively associated with costs and showed the largest values in children's and university hospitals. Attributes characterizing the provision of essential healthcare functions in the service area (ratio of emergency/ ambulance admissions, admissions during weekends/ nights, and admissions from nursing homes) were positively related to costs and showed the largest values in central and regional general hospitals. Regional attributes describing the location of hospitals in large agglomerations (in contrast to smaller agglomerations and rural areas) were positively associated with costs and showed the largest values in university hospitals. Furthermore, the four principal components identified within the hospital attributes fully explained the observed cost variations across different hospital types. These uncovered relationships may serve as a foundation for objectifying discussions about cost-related heterogeneity in Swiss hospitals and support policymakers to include structural characteristics into cost benchmarking and hospital reimbursement.

Ten year experience with the concomitant Maze IV procedure for atrial fibrillation.

OBJECTIVE: The Maze IV (M-IV) procedure is regarded as the golden standard in treatment for surgical ablation of atrial fibrillation (AF); however, long-term follow-up results are scarce. We present our institutional 10-year experience. METHODS: We collected data of 117 consecutive patients who have undergone a concomitant M-IV procedure between April 2006 and April 2016. Primary endpoints are freedom of atrial arrhythmias and freedom of atrial arrhythmias off antiarrhythmic drugs (AAD). RESULTS: Forty-seven patients (40.2%) had paroxysmal AF. Two-thirds of the procedures included mitral valve surgery. The average follow-up time per patient was 3.8 years (SD 2.8). Freedom of AF at 1 year was 79%, at 5 years freedom of AF was 69% and freedom of AF off AAD was 56%. Predictors of AF recurrence in multivariate analysis were age, preoperative pacemakers, redo cardiac surgery and in-hospital AF. Preoperative PVI ablation was found to be a protective factor. CONCLUSIONS: The long-term outcomes of the M-IV procedure are good and remain stable over the years. Results could be improved if follow-up were to be intensified and recurrences dealt with aggressively. Key question: How many patients are free from AF in a 10-year period after concomitant M-IV surgical ablation? Key findings: In the long term around 70% of patients are free of AF with an increasing need for anti-arrhythmic drugs. Take home message: Early to midterm freedom from AF after concomitant M-IV procedure is high and remains stable after 3 years.

Non-linear explicit micro-FE models accurately predict axial pull-out force of cortical screws in human tibial cortical bone.

Screws are the most frequently used implants for treatment of bone fractures and play an essential role in determining fixation stability. Robust prediction of the bone-screw interface failure would enable development of improved fixation strategies and implant designs, ultimately reducing failure rates and improving outcomes of bone fracture treatments. This study aimed to compare the accuracy of micro-computed tomography image based bone volume measures, linear micro-finite element (FE) and non-linear micro-FE simulations in predicting pull-out force of 3.5 mm screws in human cadaveric tibial cortical bone. Axial pull-out experiments were performed in forty samples harvested from a single human tibia to measure ultimate force, which was correlated with bone volume around the screw and the predictions by both linear micro-FE and non-linear explicit micro-FE models. Correlation strength was similar for bone volume around the screw (R2 = 0.866) and linear micro-FE (R2 = 0.861), but the explicit non-linear micro-FE models were able to capture the experimental results more accurately (R2 = 0.913) and quantitatively correctly. Therefore, this technique may have potential for future in silico studies aiming at implant design optimization.

An experimentally informed statistical elasto-plastic mineralised collagen fibre model at the micrometre and nanometre lengthscale.

Bone is an intriguingly complex material. It combines high strength, toughness and lightweight via an elaborate hierarchical structure. This structure results from a biologically driven self-assembly and self-organisation, and leads to different deformation mechanisms along the length scales. Characterising multiscale bone mechanics is fundamental to better understand these mechanisms including changes due to bone-related diseases. It also guides us in the design of new bio-inspired materials. A key-gap in understanding bone's behaviour exists for its fundamental mechanical unit, the mineralised collagen fibre, a composite of organic collagen molecules and inorganic mineral nanocrystals. Here, we report an experimentally informed statistical elasto-plastic model to explain the fibre behaviour including the nanoscale interplay and load transfer with its main mechanical components. We utilise data from synchrotron nanoscale imaging, and combined micropillar compression and synchrotron X-ray scattering to develop the model. We see that a 10-15% micro- and nanomechanical heterogeneity in mechanical properties is essential to promote the ductile microscale behaviour preventing an abrupt overall failure even when individual fibrils have failed. We see that mineral particles take up 45% of strain compared to collagen molecules while interfibrillar shearing seems to enable the ductile post-yield behaviour. Our results suggest that a change in mineralisation and fibril-to-matrix interaction leads to different mechanical properties among mineralised tissues. Our model operates at crystalline-, molecular- and continuum-levels and sheds light on the micro- and nanoscale deformation of fibril-matrix reinforced composites.

Evaluation of Yahe® and Panda® 2.0 long-lasting insecticidal nets against wild pyrethroid-resistant Anopheles gambiae s.l. from Côte d'Ivoire: an experimental hut trial.

BACKGROUND: Long-lasting insecticidal nets (LLINs) have played an important role in reducing the global malaria burden since 2000. They are a core prevention tool used widely by people at risk of malaria. The Vector Control Prequalification mechanism of the Word Health Organization (WHO-Vector Control PQ) established the testing and evaluation guidelines for LLINs before registration for public use. In the present study, two new brands of deltamethrin-impregnated nets (Yahe® LN and Panda® Net 2.0) were evaluated in an experimental hut against wild pyrethroid-resistant Anopheles gambiae s.l. in M'Bé nearby Bouaké, central Côte d'Ivoire. METHODS: The performance of Yahe® LN and Panda® Net 2.0 was compared with that of PermaNet 2.0, conventionally treated nets (CTN), and untreated net to assess the blood-feeding inhibition, deterrence, induced exophily, and mortality. RESULTS: Cone bioassay results showed that Panda® Net 2.0, PermaNet 2.0 and Yahe® LN (both unwashed and washed 20 times) induced > 95% knockdown or > 80% mortality of the susceptible Anopheles gambiae Kisumu strain. With the pyrethroid-resistant M'Bé strain, mortality rate for all treated nets did not exceed 70%. There was a significant reduction in entry and blood feeding (p < 0.05) and an increase in exophily and mortality rates (p < 0.05) with all treatments compared to untreated nets, except the CTNs. However, the personal protection induced by these treated nets decreased significantly after 20 washes. The performance of Panda® Net 2.0 was equal to PermaNet® 2.0 in terms of inhibiting blood feeding, but better than PermaNet® 2.0 in terms of mortality. CONCLUSION: This study showed that Yahe® LN and Panda® Net 2.0 met the WHO Pesticide Evaluation Scheme (WHOPES) criteria to undergo phase III trial at the community level. Due to an increasing spread and development of pyrethroid resistance in malaria vectors, control of malaria transmission must evolve into an integrated vector management relying on a large variety of efficient control tools.

Prediction of the Inelastic Behaviour of Radius Segments: Damage-based Nonlinear Micro Finite Element Simulation vs Pistoia Criterion.

The Pistoia criterion (PC) is widely used to estimate the failure load of distal radius segments based on linear micro Finite Element (µFE) analyses. The advantage of the PC is that a simple strain-threshold and a tissue volume fraction can be used to predict failure properties. In this study, the PC is compared to materially nonlinear µFE analyses, where the bone tissue is modelled as an elastic, damageable material. The goal was to investigate for which outcomes the PC is sufficient and when a nonlinear (NL) simulation is required. Three types of simulation results were compared: (1) prediction of the failure load, (2) load sharing of cortical and trabecular regions, and (3) distribution of local damaged/overstrained tissue at the maximum sustainable load. The failure load obtained experimentally could be predicted well with both the PC and the NL simulations using linear regression. Although the PC strongly overestimated the failure load, it was sufficient to predict adequately normalized apparent results. An optimised PC (oPC) was proposed which uses experimental data to calibrate the individual volume of overstrained tissue. The main areas of local over-straining predicted by the oPC were the same as estimated by the NL simulation, although the oPC predicted more diffuse regions. However, the oPC relied on an individual calibration requiring the experimental failure load while the NL simulation required no a priori knowledge of the experimental failure load.

Empirical relationships between bone density and ultimate strength: A literature review.

INTRODUCTION: Ultimate strength-density relationships for bone have been reported with widely varying results. Reliable bone strength predictions are crucial for many applications that aim to assess bone failure. Bone density and bone morphology have been proposed to explain most of the variance in measured bone strength. If this holds true, it could lead to the derivation of a single ultimate strength-density-morphology relationship for all anatomical sites. METHODS: All relevant literature was reviewed. Ultimate strength-density relationships derived from mechanical testing of human bone tissue were included. The reported relationships were translated to ultimate strength-apparent density relationships and normalized with respect to strain rate. Results were grouped based on bone tissue type (cancellous or cortical), anatomical site, and loading mode (tension vs. compression). When possible, the relationships were compared to existing ultimate strength-density-morphology relationships. RESULTS: Relationships that considered bone density and morphology covered the full spectrum of eight-fold inter-study difference in reported compressive ultimate strength-density relationships for trabecular bone. This was true for studies that tested specimens in different loading direction and tissue from different anatomical sites. Sparse data was found for ultimate strength-density relationships in tension and for cortical bone properties transverse to the main loading axis of the bone. CONCLUSIONS: Ultimate strength-density-morphology relationships could explain measured strength across anatomical sites and loading directions. We recommend testing of bone specimens in other directions than along the main trabecular alignment and to include bone morphology in studies that investigate bone material properties. The lack of tensile strength data did not allow for drawing conclusions on ultimate strength-density-morphology relationships. Further studies are needed. Ideally, these studies would investigate both tensile and compressive strength-density relationships, including morphology, to close this gap and lead to more accurate evaluation of bone failure.

Conventional finite element models estimate the strength of metastatic human vertebrae despite alterations of the bone's tissue and structure.

INTRODUCTION: Pathologic vertebral fractures are a major clinical concern in the management of cancer patients with metastatic spine disease. These fractures are a direct consequence of the effect of bone metastases on the anatomy and structure of the vertebral bone. The goals of this study were twofold. First, we evaluated the effect of lytic, blastic and mixed (both lytic and blastic) metastases on the bone structure, on its material properties, and on the overall vertebral strength. Second, we tested the ability of bone mineral content (BMC) measurements and standard FE methodologies to predict the strength of real metastatic vertebral bodies. METHODS: Fifty-seven vertebral bodies from eleven cadaver spines containing lytic, blastic, and mixed metastatic lesions from donors with breast, esophageal, kidney, lung, or prostate cancer were scanned using micro-computed tomography (µCT). Based on radiographic review, twelve vertebrae were selected for nanoindentation testing, while the remaining forty-five vertebrae were used for assessing their compressive strength. The µCT reconstruction was exploited to measure the vertebral BMC and to establish two finite element models. 1) a micro finite element (µFE) model derived at an image resolution of 24.5 µm and 2) homogenized FE (hFE) model derived at a resolution of 0.98 mm. Statistical analyses were conducted to measure the effect of the bone metastases on BV/TV, indentation modulus (Eit), ratio of plastic/total work (WPl/Wtot), and in vitro vertebral strength (Fexp). The predictive value of BMC, µFE stiffness, and hFE strength were evaluated against the in vitro measurements. RESULTS: Blastic vertebral bodies exhibit significantly higher BV/TV compared to the mixed (p = 0.0205) and lytic (p = 0.0216) vertebral bodies. No significant differences were found between lytic and mixed vertebrae (p = 0.7584). Blastic bone tissue exhibited a 5.8% lower median Eit (p< 0.001) and a 3.3% lower median Wpl/Wtot (p<0.001) compared to non-involved bone tissue. No significant differences were measured between lytic and non-involved bone tissues. Fexp ranged from 1.9 to 13.8 kN, was strongly associated with hFE strength (R2=0.78, p< 0.001) and moderately associated with BMC (R2=0.66, p< 0.001) and µFE stiffness (R2=0.66, p< 0.001), independently of the lesion type. DISCUSSION: Our findings show that tumour-induced osteoblastic metastases lead to slightly, but significantly lower bone tissue properties compared to controls, while osteolytic lesions appear to have a negligible impact. These effects may be attributed to the lower mineralization and woven nature of bone forming in blastic lesions whilst the material properties of bone in osteolytic vertebrae appeared little changed. The moderate association between BMC- and FE-based predictions to fracture strength suggest that vertebral strength is affected by the changes of bone mass induced by the metastatic lesions, rather than altered tissue properties. In a broader context, standard hFE approaches generated from CTs at clinical resolution are robust to the lesion type when predicting vertebral strength. These findings open the door for the development of FE-based prediction tools that overcomes the limitations of BMC in accounting for shape and size of the metastatic lesions. Such tools may help clinicians to decide whether a patient needs the prophylactic fixation of an impending fracture.

Finite element models can reproduce the effect of nucleotomy on the multi-axial compliance of human intervertebral discs.

Finite element (FE) models can unravel the link between intervertebral disc (IVD) degeneration and its mechanical behaviour. Nucleotomy may provide the data required for model verification. Three human IVDs were scanned with MRI and tested in multiple loading scenarios, prior and post nucleotomy. The resulting data was used to generate, calibrate, and verify the FE models. Nucleotomy increased the experimental range of motion by 26%, a result reproduced by the FE simulation within a 5% error. This work demonstrates the ability of FE models to reproduce the mechanical compliance of human IVDs prior and post nucleotomy.

Explicit finite element analysis can predict the mechanical response of conical implant press-fit in homogenized trabecular bone.

Prediction of primary stability is a major challenge in the surgical planning of dental and orthopedic implants. Computational methods become attractive to estimate primary stability from clinical CT images, but implicit finite element analysis of implant press-fit faces convergence issues due to contact and highly distorted elements. This study aims to develop and validate an explicit finite element method to simulate the insertion and primary stability of a rigid implant in a deformable bone while accounting for damage occurring at the bone-implant interface. Accordingly, a press-fit experiment of a conical implant into predrilled bovine trabecular bone was designed and realized for six samples. A displacement-driven cyclic protocol was used to quantify the reaction force and stiffness of the bone-implant system. Homogenized finite element analyses of the experiments were performed by modeling contact with friction and converting an existing constitutive model with elasto-plasticity and damage of bone tissue to be applicable to an explicit time integration scheme where highly distorted elements get deleted. The computed reaction forces and unloading stiffnesses showed high correlations (R2 = 0.95 and R2 = 0.94) with the experiment. Friction between bone and implant exhibited a strong influence on both reaction force and stiffness. In conclusion, the developed explicit finite element approach with frictional contact and element deletion accounts properly for bone damage during press-fit and will help optimizing dental or orthopedic implant design towards maximal primary stability.

Finite element analysis of bone strength in osteogenesis imperfecta.

As a dedicated experimentalist, John Currey praised the high potential of finite element (FE) analysis but also recognized its critical limitations. The application of the FE methodology to bone tissue is reviewed in the light of his enthusiastic and colorful statements. In the past decades, FE analysis contributed substantially to the understanding of structure-function properties in the hierarchical organization of bone and to the simulation of bone adaptation. The systematic experimental validation of FE analysis of bone strength in anatomical locations at risk of fracture led to its application in clinical studies to evaluate efficacy of antiresorptive or anabolic treatment of bone fragility. Beyond the successful analyses of healthy or osteoporotic bone, FE analysis becomes increasingly involved in the investigation of other fragility-related bone diseases. The case of osteogenesis imperfecta (OI) is exposed, the multiscale alterations of the bone tissue and the effect of treatment summarized. A few FE analyses attempting to answer open questions in OI are then reported. An original study is finally presented that explored the structural properties of the Brtl/+ murine model of OI type IV subjected to sclerostin neutralizing antibody treatment using microFE analysis. The use of identical material properties in the four-point bending FE simulations of the femora reproduced not only the experimental values but also the statistical comparisons examining the effect of disease and treatment. Further efforts are needed to build upon the extraordinary legacy of John Currey and clarify the impact of different bone diseases on the hierarchical mechanical properties of bone.