| 1. |
- Tong, Xiaoyu, et al.
(author)
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Cortical Bone Histomorphometry in Male Femoral Neck: The Investigation of Age-Association and Regional Differences
- 2015
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In: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 96:4, s. 295-306
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Journal article (peer-reviewed)abstract
- Low bone volume and changes in bone quality or microarchitecture may predispose individuals to fragility fractures. As the dominant component of the human skeleton, cortical bone plays a key role in protecting bones from fracture. However, histological investigations of the underlying structural changes, which might predispose to fracture, have been largely limited to the cancellous bone. The aim of this study was to investigate the age-association and regional differences of histomorphometric properties in the femoral neck cortical bone. Undecalcified histological sections of the femoral neck (n = 20, aged 18-82 years, males) were cut (15 mu m) and stained using modified Masson-Goldner stain. Complete femoral neck images were scanned, and cortical bone boundaries were defined using our previously established method. Cortical bone histomorphometry was performed with low (x50) and high magnification (x100). Most parameters related to cortical width (Mean Ct.Wi, Inferior Ct.Wi, Superior Ct.Wi) were negatively associated with age both before and after adjustment for height. The inferior cortex was the thickest (P < 0.001) and the superior cortex was the thinnest (P < 0.008) of all cortical regions. Both osteonal size and pores area were negatively associated with age. Osteonal area and number were higher in the antero-inferior area (P < 0.002) and infero-posterior area (P = 0.002) compared to the postero-superior area. The Haversian canal area was higher in the infero-posterior area compared to the postero-superior area (P = 0.002). Moreover, porosity was higher in the antero-superior area (P < 0.002), supero-anterior area (P < 0.002) and supero-posterior area (P < 0.002) compared to the infero-anterior area. Eroded endocortical perimeter (E.Pm/Ec.Pm) correlated positively with superior cortical width. This study describes the changes in cortical bone during ageing in healthy males. Further studies are needed to investigate whether these changes explain the increased susceptibility to femoral neck fractures.
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| 2. |
- Tong, Xiaoyu, et al.
(author)
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Histomorphometric and osteocytic characteristics of cortical bone in male subtrochanteric femoral shaft
- 2017
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In: Journal of Anatomy. - : Wiley. - 0021-8782. ; 231:5, s. 708-717
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Journal article (peer-reviewed)abstract
- The histomorphometric properties of the subtrochanteric femoral region have rarely been investigated. The aim of this study was to investigate the age-associated variations and regional differences of histomorphometric and osteocytic properties in the cortical bone of the subtrochanteric femoral shaft, and the association between osteocytic and histological cortical bone parameters. Undecalcified histological sections of the subtrochanteric femoral shaft were obtained from cadavers (n = 20, aged 18–82 years, males). They were cut and stained using modified Masson-Goldner stain. Histomorphometric parameters of cortical bone were analysed with ×50 and ×100 magnification after identifying cortical bone boundaries using our previously validated method. Within cortical bone areas, only complete osteons with typical concentric lamellae and cement line were selected and measured. Osteocytic parameters of cortical bone were analyzed under phase contrast microscopy and epifluorescence within microscopic fields (0.55 mm2 for each). The cortical widths of the medial and lateral quadrants were significantly higher than other quadrants (P < 0.01). Osteonal area per cortical bone area was lower and cortical porosities were higher in the posterior quadrant than in the other quadrants (P < 0.05). Osteocyte lacunar number per cortical bone area was found higher in the young subjects (≤ 50 years) than in the older ones (> 50 years) both before and after adjustments for body height and weight (P < 0.05). Moreover, significant but low correlations were found between the cortical bone and osteocytic parameters (0.20 ≤ R2 ≤ 0.35, P < 0.05). It can be concluded that in healthy males, the cortical histomorphometric parameters differ between the anatomical regions of the subtrochanteric femoral shaft, and are correlated with the osteocytic parameters from the same site. These findings may be of use when discussing mechanisms that predispose patients to decreasing bone strength.
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| 3. |
- Tong, Xiaoyu, et al.
(author)
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Iliac crest histomorphometry and skeletal heterogeneity in men
- 2017
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In: Bone Reports. - : Elsevier BV. - 2352-1872. ; 6, s. 9-16
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Journal article (peer-reviewed)abstract
- Purpose The cortical characteristics of the iliac crest in male have rarely been investigated with quantitative histomorphometry. Also it is still unknown how cortical microarchitecture may vary between the iliac crest and fractures related sites at the proximal femur. We studied the microarchitecture of both external and internal cortices within the iliac crest, and compared the results with femoral neck and subtrochanteric femoral shaft sites. Methods Undecalcified histological sections of the iliac crest were obtained bicortically from cadavers (n = 20, aged 18–82 years, males). They were cut (7 μm) and stained using modified Masson-Goldner stain. Histomorphometric parameters of cortical bone were analysed with low (× 50) and high (× 100) magnification, after identifying cortical bone boundaries using our previously validated method. Within cortical bone area, only complete osteons with typical concentric lamellae and cement line were selected and measured. Results At the iliac crest, the mean cortical width of external cortex was higher than at the internal cortex (p < 0.001). Also, osteon structural parameters, e.g. mean osteonal perimeter, were higher in the external cortex (p < 0.05). In both external and internal cortices, pore number per cortical bone area was higher in young subjects (≤ 50 years) (p < 0.05) while mean pore perimeter was higher in the old subjects (> 50 years) (p < 0.05). Several cortical parameters (e.g. osteon area per cortical bone area, pore number per cortical area) were the lowest in the femoral neck (p < 0.05). The maximal osteonal diameter and mean wall width were the highest in the external cortex of the iliac crest (p < 0.05), and the mean cortical width, osteon number per cortical area were the highest in the subtrochanteric femoral shaft (p < 0.05). Some osteonal structural parameters (e.g. min osteonal diameter) were significantly positively correlated (0.29 ≤ R2 ≤ 0.45, p < 0.05) between the external iliac crest and the femoral neck. Conclusions This study reveals heterogeneity in cortical microarchitecture between the external and internal iliac crest cortices, as well as between the iliac crest, the femoral neck and the subtrochanteric femoral shaft. Standard iliac crest biopsy does not reflect accurately cortical microarchitecture of other skeletal sites.
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| 4. |
- Tong, Xiao-Yu, et al.
(author)
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Development of new criteria for cortical bone histomorphometry in femoral neck: intra- and inter-observer reproducibility
- 2015
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In: Journal of Bone and Mineral Metabolism. - : Springer Science and Business Media LLC. - 0914-8779 .- 1435-5604. ; 33:1, s. 109-118
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Journal article (peer-reviewed)abstract
- Histomorphometry is commonly applied to study bone remodeling. Histological definitions of cortical bone boundaries have not been consistent. In this study, new criteria for specific definition of the transitional zone between the cortical and cancellous bone in the femoral neck were developed. The intra- and inter-observer reproducibility of this method was determined by quantitative histomorphometry and areal overlapping analysis. The undecalcified histological sections of femoral neck specimens (n = 6; from men aged 17-59 years) were processed and scanned to acquire histological images of complete bone sections. Specific criteria were applied to define histological boundaries. "Absolute cortex area" consisted of pure cortical bone tissue only, and was defined mainly based on the size of composite canals and their distance to an additional "guide" boundary (so-called "preliminary cortex boundary," the clear demarcation line of density between compact cortex and sparse trabeculae). Endocortical bone area was defined by recognizing characteristic endocortical structures adjacent to the preliminary cortical boundary. The present results suggested moderate to high reproducibility for low-magnification parameters (e.g., cortical bone area). The coefficient of variation (CV %) ranged from 0.02 to 5.61 in the intra-observer study and from 0.09 to 16.41 in the inter-observer study. However, the intra-observer reproducibility of some high-magnification parameters (e.g., osteoid perimeter/endocortical perimeter) was lower (CV %, 0.33-87.9). The overlapping of three histological areas in repeated analyses revealed highest intra- and inter-observer reproducibility for the absolute cortex area. This study provides specific criteria for the definition of histological boundaries for femoral neck bone specimens, which may aid more precise cortical bone histomorphometry.
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| 5. |
- Väänänen, Sami P, et al.
(author)
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Automated segmentation of cortical and trabecular bone to generate finite element models for femoral bone mechanics
- 2019
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In: Medical Engineering & Physics. - : Elsevier BV. - 1873-4030 .- 1350-4533. ; 70:August 2019, s. 19-28
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Journal article (peer-reviewed)abstract
- Finite element (FE) models based on quantitative computed tomography (CT) images are better predictors of bone strength than conventional areal bone mineral density measurements. However, FE models require manual segmentation of the femur, which is not clinically applicable. This study developed a method for automated FE analyses from clinical CT images. Clinical in-vivo CT images of 13 elderly female subjects were collected to evaluate the method. Secondly, proximal cadaver femurs were harvested and imaged with clinical CT (N = 17). Of these femurs, 14 were imaged with µCT and three had earlier been tested experimentally in stance-loading, while collecting surface deformations with digital image correlation. Femurs were segmented from clinical CT images using an automated method, based on the segmentation tool Stradwin. The method automatically distinguishes trabecular and cortical bone, corrects partial volume effect and generates input for FE analysis. The manual and automatic segmentations agreed within about one voxel for in-vivo subjects (0.99 ± 0.23 mm) and cadaver femurs (0.21 ± 0.07 mm). The strains from the FE predictions closely matched with the experimentally measured strains (R2 = 0.89). The method can automatically generate meshes suitable for FE analysis. The method may bring us one step closer to enable clinical usage of patient-specific FE analyses.
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| 6. |
- Dahlberg, Leif E, et al.
(author)
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A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis
- 2016
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In: Clinical and Experimental Rheumatology. - 0392-856X. ; 34:3, s. 50-445
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA).METHODS: This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 μg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks.RESULTS: Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 μg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected.CONCLUSIONS: This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.
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| 7. |
- Grassi, Lorenzo, et al.
(author)
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Elucidating failure mechanisms in human femurs during a fall to the side using bilateral digital image correlation
- 2020
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In: Journal of Biomechanics. - : Elsevier BV. - 0021-9290. ; 106
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Journal article (peer-reviewed)abstract
- An improved understanding of the mechanical properties of human femurs is a milestone towards a more accurate assessment of fracture risk. Digital image correlation (DIC) has recently been adopted to provide full-field strain measurements during mechanical testing of femurs. However, it has typically been used to measure strains on the anterior side of the femur, whereas in both single-leg-stance and sideways fall loading conditions, the highest deformations result on the medial and lateral sides of the femoral neck. The goal of this study was to measure full-field deformations simultaneously on the medial and lateral side of the femoral neck in a configuration resembling a fall to the side. Twelve female cadaver femurs were prepared for DIC measurements and tested in sideways fall at 5 mm/s displacement rate. Two pairs of cameras recorded the medial and lateral side of the femoral neck, and deformations were calculated using DIC. The samples exhibited a two-stage failure: first, a compressive collapse on the superolateral side of the femoral neck in conjunction with peak force, followed by complete femoral neck fracture at the force drop following the post-elastic phase. DIC measurements corroborated this observation by reporting no tensile strains above yield limit for the medial side of the neck up to peak force. DIC measurements registered onto the bone micro-architecture showed strain localizations in proximity of cortical pores due to, for instance, blood vessels. This could explain previously reported discrepancies between simulations and experiments in regions rich with large pores, like the superolateral femoral neck.
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| 8. |
- Grassi, Lorenzo, et al.
(author)
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Experimental Validation Of Finite Element Model For Proximal Composite Femur Using Optical Measurements
- 2013
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In: Journal of the Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161. ; 21, s. 86-94
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Journal article (peer-reviewed)abstract
- Patient-specific finite element models have been used to predict femur strength and fracture risk in individuals. Validation of the adopted finite element modelling procedure against mechanical testing data is a crucial step when aiming for clinical applications. The majority of the works available in literature used data from strain gages to validate the model, thus having up to 15 experimental measurements. Optical techniques, such as Digital Image Correlation, can help to improve the models by providing a continuous field of deformation data over a femoral surface. The main objective of this study was to validate finite element models of six composite femora against strain data from digital image correlation, obtained during fracture tests performed in quasi-axial loading configuration. The finite element models were obtained from CT scans, by means of a semi-automatic segmentation. The principal strains both during the elastic phase and close to the fracture were compared, and showed a correlation coefficient close to 0.9. In the linear region, the slope and intercept were close to zero and unity, while for the case when fracture load was simulated, the slope decreased somewhat. The accuracy of the obtained results is comparable with the state-of-the-art literature, with the significant improvement of having around 50000 data points for each femur. This large number of measurements allows a more comprehensive validation of the predictions by the finite element models, since thousand of points are tracked along the femoral neck and trochanter region, i.e., the sites that are most critical for femur fracture. Moreover, strain measurement biases due to the strain gage reinforcement effect, were avoided. The combined experimental-numerical approach proved to be ready for application to in-vitro tests of human cadaver femurs, thus helping to develop a suitable mechanistic fracture risk criterion.
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| 9. |
- Grassi, Lorenzo, et al.
(author)
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Full-field Strain Measurement During Mechanical Testing of the Human Femur at Physiologically Relevant Strain Rates
- 2014
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In: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 136:11
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Journal article (peer-reviewed)abstract
- Understanding the mechanical properties of human femora is of great importance for the development of a reliable fracture criterion aimed at assessing fracture risk. Earlier ex vivo studies have been conducted by measuring strains on a limited set of locations using strain gauges. Digital Image Correlation (DIC) could instead be used to reconstruct the full-field strain pattern over the surface of the femur. The objective of this study was to measure the full-field strain response of cadaver femora tested at a physiological strain rate up to fracture in a configuration resembling single stance. The three cadaver femora were cleaned from soft tissues, and a white background paint was applied with a random black speckle pattern over the anterior surface. The mechanical tests were conducted up to fracture at a constant displacement rate of 15 mm/s, and two cameras recorded the event at 3000 frames per second. DIC was performed to retrieve the full-field displacement map, from which strains were derived. A low-pass filter was applied over the measured displacements before the crack opened in order to reduce the noise level. The noise levels were assessed using a dedicated control plate. Conversely, no filtering was applied at the frames close to fracture to get the maximum resolution. The specimens showed a linear behavior of the principal strains with respect to the applied force up to fracture. The strain rate was comparable to the values available in literature from in-vivo measurements during daily activities. The cracks opened and fully propagated in less than 1 ms, and small regions with high values of the major principal strains could be spotted just a few frames before the crack opened. This corroborates the hypothesis of a strain-driven fracture mechanism in human bone. The data represents a comprehensive collection of full-field strains, both at physiological load levels and up to fracture. About 10000 measurements were collected for each bone, providing superior spatial resolution compared to ~15 measurements typically collected using strain gauges. These experimental data collection can be further used for validation of numerical models, and for experimental verification of bone constitutive laws and fracture criteria.
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| 10. |
- Grassi, Lorenzo, et al.
(author)
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How accurately can subject-specific finite element models predict strains and strength of human femora? Investigation using full-field measurements
- 2016
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In: Journal of Biomechanics. - : Elsevier BV. - 1873-2380 .- 0021-9290. ; 49:5, s. 802-806
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Journal article (peer-reviewed)abstract
- Subject-specific finite element models have been proposed as a tool to improve fracture risk assessment in individuals. A thorough laboratory validation against experimental data is required before introducing such models in clinical practice. Results from digital image correlation can provide full-field strain distribution over the specimen surface during in vitro test, instead of at a few pre-defined locations as with strain gauges. The aim of this study was to validate finite element models of human femora against experimental data from three cadaver femora, both in terms of femoral strength and of the full-field strain distribution collected with digital image correlation. The results showed a high accuracy between predicted and measured principal strains (R2=0.93, RMSE=10%, 1600 validated data points per specimen). Femoral strength was predicted using a rate dependent material model with specific strain limit values for yield and failure. This provided an accurate prediction (<2% error) for two out of three specimens. In the third specimen, an accidental change in the boundary conditions occurred during the experiment, which compromised the femoral strength validation. The achieved strain accuracy was comparable to that obtained in state-of-the-art studies which validated their prediction accuracy against 10–16 strain gauge measurements. Fracture force was accurately predicted, with the predicted failure location being very close to the experimental fracture rim. Despite the low sample size and the single loading condition tested, the present combined numerical-experimental method showed that finite element models can predict femoral strength by providing a thorough description of the local bone mechanical response.
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