SA Pathology and Hanson Institute

Adelaide, Australia

SA Pathology and Hanson Institute

Adelaide, Australia
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Fletcher L.,University of Adelaide | Codrington J.,University of Adelaide | Codrington J.,SA Pathology and Hanson Institute | Parkinson I.,SA Pathology and Hanson Institute | Parkinson I.,University of Adelaide
Journal of Materials Science: Materials in Medicine | Year: 2014

As a composite material, cortical bone accumulates fatigue microdamage through the repetitive loading of everyday activity (e.g. walking). The accumulation of fatigue microdamage is thought to contribute to the occurrence of fragility fractures in older people. Therefore it is beneficial to understand the relationship between microcrack accumulation and the fracture resistance of cortical bone. Twenty longitudinally orientated compact tension fracture specimens were machined from a single bovine femur, ten specimens were assigned to both the control and fatigue damaged groups. The damaged group underwent a fatigue loading protocol to induce microdamage which was assessed via fluorescent microscopy. Following fatigue loading, non-linear fracture resistance tests were undertaken on both the control and damaged groups using the J-integral method. The interaction of the crack path with the fatigue induced damage and inherent toughening mechanisms were then observed using fluorescent microscopy. The results of this study show that fatigue induced damage reduces the initiation toughness of cortical bone and the growth toughness within the damage zone by three distinct mechanisms of fatigue-fracture interaction. Further analysis of the J-integral fracture resistance showed both the elastic and plastic component were reduced in the damaged group. For the elastic component this was attributed to a decreased number of ligament bridges in the crack wake while for the plastic component this was attributed to the presence of pre-existing fatigue microcracks preventing energy absorption by the formation of new microcracks. © 2014 Springer Science+Business Media.


Carpentier V.T.,SA Pathology and Hanson Institute | Carpentier V.T.,University Paris Diderot | Wong J.,SA Pathology and Hanson Institute | Yeap Y.,SA Pathology and Hanson Institute | And 8 more authors.
Bone | Year: 2012

Hypermineralized osteocyte lacunae (micropetrosis) have received little research attention. While they are a known aspect of the aging human skeleton, no data are available for pathological bone. In this study, intertrochanteric trabecular bone cores were obtained from patients at surgery for osteoporotic (OP) femoral neck fracture (10F, 4M, 65-94years), for hip osteoarthritis (OA; 7F, 8M, 62-87years), and femora at autopsy (CTL; 5F, 11M, 60-84years). Vertebral trabecular bone cores were also obtained from the vertebra of autopsy cases (CVB; 3F, 6M, 53-83years). Specimens were resin-embedded, polished, and carbon coated for quantitative backscattered electron imaging (qBEI), energy dispersive X-ray (EDX) spectrometry, and imaging analysis. Bone mineralization (Wt %Ca) was not different between OP, OA, and CTL; but was greater in femoral CTL than in CVB. The percent of hypermineralized osteocyte lacunae relative to the total number (HL/TL) was greater in OP and OA than in CTL. However, relative to bone mineral area, OP was characterised by increased hypermineralized osteocyte lacunar number density (Hd.Lc.Dn), whereas OA was characterised by decreased osteocyte lacunar number density (Lc.Dn) and total osteocyte lacunar number density (Tt.Lc.Dn). Lc.Dn was higher in CVB than in femoral CTL. The calcium-phosphorus ratio (R Ca/P) was not different between hypermineralized osteocyte lacunae and bone matrix in each group. In addition, this study focused on the phenomenon of osteocyte lacunae hypermineralization using qBEI. Seven morphological types of osteocyte lacunae hypermineralization were described according to the presence of one or several hypermineralized spherites, associated or not with a hypermineralized lacunar ring. This study has described, for the first time, the morphology of hypermineralized osteocyte lacunae in OP and OA human bone. Further studies are suggested to investigate the functional influence of hypermineralized osteocyte lacunae on bone remodeling and bone biomechanical properties. © 2011 Elsevier Inc.


Zoehrer R.,Flinders University | Perilli E.,SA Pathology and Hanson Institute | Perilli E.,University of Adelaide | Kuliwaba J.S.,SA Pathology and Hanson Institute | And 5 more authors.
Osteoporosis International | Year: 2012

Summary The interrelation of calcium and phosphorus was evaluated as a function of bone material quality in femoral heads from male fragility fracture patients via surface analytical imaging as well as scanning microscopy techniques. A link between fragility fractures and increased calcium to phosphorus ratio was observed despite normal mineralization density distribution. Introduction Bone fragility in men has been recently recognized as a public health issue, but little attention has been devoted to bone material quality and the possible efficacy in fracture risk prevention. Clinical routine fracture risk estimations do not consider the quality of the mineralized matrix and the critical role played by the different chemical components that are present. This study uses a combination of different imaging and analytical techniques to gain insights into both the spatial distribution and the relationship of phosphorus and calcium in bone. Methods X-ray photoelectron spectroscopy and time-offlight secondary ion mass spectrometry imaging techniques were used to investigate the relationship between calcium and phosphorus in un-embedded human femoral head specimens from fragility fracture patients and non-fracture age-matched controls. The inclusion of the bone mineral density distribution via backscattered scanning electron microscopy provides information about the mineralization status between the groups. Results A link between fragility fracture and increased calcium and decreased phosphorus in the femoral head was observed despite normal mineralization density distribution. Results exhibited significantly increased calcium to phosphorus ratio in the fragility fracture group, whereas the nonfracture control group ratio was in agreement with the literature value of 1.66 M ratio in mature bone. Conclusions Our results highlight the potential importance of the relationship between calcium and phosphorus, especially in areas of new bone formation, when estimating fracture risk of the femoral head. The determination of calcium and phosphorus fractions in bone mineral density measurements may hold the key to better fracture risk assessment as well as more targeted therapies. © The Author(s) 2011.


Fazzalari N.L.,SA Pathology and Hanson Institute | Fazzalari N.L.,University of Adelaide
Osteoporosis International | Year: 2011

Fracture healing is a multistage repair process that involves complex, well-orchestrated steps initiated in response to tissue injury. The early upregulation of IL-6, osteoprotegerin (OPG), VEGF, and BMPs indicates a central role for these factors in the initiation of cartilage and periosteal woven bone formation. In both callus fracture repair and stress fracture repair, the RANKL/OPG ratio is initially reduced, but peaks earlier in stress fracture healing than callus fracture healing. Though the understanding of the biological processes and molecular signals that coordinate fracture repair has advanced, the cause of variability observed in fracture repair is poorly understood. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011.


Perilli E.,SA Pathology and Hanson Institute | Perilli E.,University of Adelaide | Perilli E.,University of Antwerp | Le V.,SA Pathology and Hanson Institute | And 7 more authors.
Osteoporosis International | Year: 2010

This study monitored in vivo the effect on bone microarchitecture of initiating antiresorptive treatment with zoledronic acid in rats at 2 weeks following ovariectomy, an early phase at which major degenerative bone changes have been found to occur. The treatment still facilitated the full reversal of cancellous bone loss in rat tibia, highlighting the importance of the time point of initiation of antiresorptive treatment. Introduction: Injection of zoledronic acid in rats at time of ovariectomy has been found to fully preserve tibial bone microarchitecture over time, whereas injection at 8 weeks after ovariectomy has shown partial bone recovery. This study investigated the effect on microarchitecture of initiating antiresorptive treatment in the early phase following ovariectomy, at 2 weeks, a time point at which major degenerative changes in the bone have been found to occur. Methods: Female Sprague-Dawley rats were divided into ovariectomized group, ovariectomized group treated with zoledronic acid, and sham-operated group. In vivo micro-CT scanning of rat tibiae and morphometric analysis were performed at 0, 2, 4, 8, and 12 weeks after ovariectomy, with zoledronic acid treatment beginning 2 weeks after ovariectomy. Data were first analyzed with repeated measures analysis of variance (longitudinal study design) and then without repeated measures (cross-sectional study design). Results: The ovariectomized group demonstrated dramatic bone loss, first detected at week 2. Conversely, at week 4, the zoledronic acid-treated group returned microstructural parameters to baseline values. Remarkable increases in bone parameters were found after 6 weeks of treatment and maintained similar to sham group until the end. The longitudinal study design provided earlier detection of bone changes compared to the cross-sectional study design. Conclusions: Treatment with zoledronic acid as late as 2 weeks after ovariectomy still facilitates the full reversal of cancellous bone loss in the rat tibia. © 2009 International Osteoporosis Foundation and National Osteoporosis Foundation.


Parkinson I.H.,SA Pathology and Hanson Institute | Parkinson I.H.,University of Adelaide | Badiei A.,SA Pathology and Hanson Institute | Badiei A.,University of Adelaide | And 6 more authors.
Osteoporosis International | Year: 2012

Summary Although the amount of bone explains the largest amount of variability in bone strength, there is still a significant proportion unaccounted for. The morphology of individual bone trabeculae explains a further proportion of the variability in bone strength and bone elements that contribute to bone strength depending on the direction of loading. Introduction Micro-CT imaging enables measurement of bone microarchitecture and subsequently mechanical strength of the same sample. It is possible using micro-CT data to perform morphometric analysis on individual rod and plate bone trabeculae using a volumetric spatial decomposition algorithm and hence determine their contribution to bone strength. Methods Twelve pairs of vertebral bodies (T12/L1 or L4/ L5) were harvested from human cadavers, and bone cubes (10×10×10 mm) were obtained. After micro-CT imaging, a volumetric spatial decomposition algorithm was applied, and measures of individual trabecular elements were obtained. Bone strength was measured in compression, where one bone specimen from each vertebral segment was tested supero-inferiorly (SI) and the paired specimen was tested antero-posteriorly (AP). Results Bone volume fraction was the strongest individual determinant of SI strength (r 2 =0.77, p<0.0001) and AP (r2=0.54, p<0.0001). The determination of SI strength was improved to r2 =0.87 with the addition of mean rod length and relative plate bone volume fraction. The determination of AP strength was improved to r2 =0.85 with the addition of mean rod volume and relative rod bone volume fraction. Conclusions Microarchitectural measures of individual trabeculae that contribute to bone strength have been identified. In addition to the contribution of BV/TV, trabecular rod morphology increased the determination of AP strength by 57%, whereas measures of trabecular plate and rod morphology increased determination of SI strength by 13%. Decomposing vertebral body bone architecture into its constituent morphological elements shows that trabecular element morphology has specific functional roles to assist in maintaining skeletal integrity. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation.


Perilli E.,SA Pathology and Hanson Institute | Perilli E.,University of Adelaide | Briggs A.M.,Curtin University Australia | Briggs A.M.,Royal Melbourne Hospital | And 8 more authors.
Bone | Year: 2012

Significant relationships exist between areal bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) and bone strength. However, the predictive validity of BMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA in the lumbar spine may be improved by assessing BMD from lateral-projection scans, as these might better approximate the objective of measuring the trabecular-rich bone in the vertebral body, compared to the commonly-used posterior-anterior (PA) projections. Nowadays, X-ray micro-computed tomography (μCT) allows non-destructive three-dimensional structural characterization of entire bone segments at high resolution. In this study, human lumbar cadaver spines were examined ex situ by DXA in lateral and PA projections, as well as by μCT, with the aims (1) to investigate the ability of bone quantity measurements obtained by DXA in the lateral projection and in the PA projection, to predict variations in bone quantity measurements obtained by μCT, and (2) to assess their respective capabilities to predict whole vertebral body strength, determined experimentally.Human cadaver spines were scanned by DXA in PA projections and lateral projections. Bone mineral content (BMC) and BMD for L2 and L3 vertebrae were determined. The L2 and L3 vertebrae were then dissected and entirely scanned by μCT. Total bone volume (BVtot=cortical+trabecular), trabecular bone volume (BV), and trabecular bone volume fraction (BV/TV) were calculated over the entire vertebrae. The vertebral bodies were then mechanically tested to failure in compression, to determine ultimate load.The variables BVtot, BV, and BV/TV measured by μCT were better predicted by BMC and BMD measured by lateral-projection DXA, with higher R2 values and smaller standard errors of the estimate (R2=0.65-0.90, SEE=11%-18%), compared to PA-projection DXA (R2=0.33-0.53, SEE=22%-34%). The best predictors of ultimate load were BVtot and BV assessed by μCT (R2=0.88 and R2=0.81, respectively), and BMC and BMD from lateral-projection DXA (R2=0.82 and R2=0.70, respectively). Conversely, BMC and BMD from PA-projection DXA were lower predictors of ultimate load (R2=0.49 and R2=0.37, respectively).This ex vivo study highlights greater capabilities of lateral-projection DXA to predict variations in vertebral body bone quantity as measured by μCT, and to predict vertebral strength as assessed experimentally, compared to PA-projection DXA. This provides basis for further exploring the clinical application of lateral-projection DXA analysis. © 2012 Elsevier Inc.


Yang B.,University of Iowa | Kumar S.,SA Pathology and Hanson Institute
Cell Death and Differentiation | Year: 2010

The Nedd4 (neural precursor cell-expressed developmentally downregulated gene 4) family of ubiquitin ligases (E3s) is characterized by a distinct modular domain architecture, with each member consisting of a C2 domain, 2-4 WW domains, and a HECT-type ligase domain. Of the nine mammalian members of this family, Nedd4 and its close relative, Nedd4-2, represent the ancestral ligases with strong similarity to the yeast, Rsp5. In Saccharomyces cerevisiae Rsp5 has a key role in regulating the trafficking, sorting, and degradation of a large number of proteins in multiple cellular compartments. However, in mammals the Nedd4 family members, including Nedd4 and Nedd4-2, appear to have distinct functions, thereby suggesting that these E3s target specific proteins for ubiquitylation. In this article we focus on the biology and emerging functions of Nedd4 and Nedd4-2, and review recent in vivo studies on these E3s. © 2010 Macmillan Publishers Limited All rights reserved.


Perilli E.,Flinders University | Parkinson I.H.,SA Pathology and Hanson Institute | Reynolds K.J.,Flinders University
Annali dell'Istituto Superiore di Sanita | Year: 2012

Micro-CT systems are available that facilitate ex vivo examinations of human specimens as big as entire vertebrae, with spatial resolutions in the 10-micrometer range. This opens a new way for looking at entire bones in 3D. Accurate description of the internal microarchitecture of the entire organ can be obtained, at spatial resolutions previously achievable only on excised biopsies. These high resolution scans produce large datasets and come with costs and benefits, which have to be considered in the successful planning of an experiment. The aim of this paper is to present examples of human vertebrae scanned at high resolution (17 μm/pixel), allowing the visualization and quantification of the microarchitecture, and to discuss some aspects of using high resolution scans of such large specimens. The datasets were down-sampled to 34 μm and 68 μm pixel size, and their morphometric parameters compared to those obtained at 17 μm pixel size, in relation to data size and calculation time.


Kidd L.J.,University of Queensland | Stephens A.S.,Griffith University | Kuliwaba J.S.,SA Pathology and Hanson Institute | Fazzalari N.L.,SA Pathology and Hanson Institute | And 2 more authors.
Bone | Year: 2010

Loading of the rat ulna is an ideal model to examine stress fracture healing. The aim of this study was to undertake a detailed examination of the histology, histomorphometry and gene expression of the healing and remodelling process initiated by fatigue loading of the rat ulna. Ulnae were harvested 1, 2, 4, 6, 8, and 10 weeks following creation of a stress fracture. Stress fracture healing involved direct remodelling that progressed along the fracture line as well as woven bone proliferation at the site of the fracture. Histomorphometry demonstrated rapid progression of basic multicellular units from 1 to 4 weeks with significant slowing down of healing by 10 weeks after loading. Quantitative PCR was performed at 4 hours, 24 hours, 4 days, 7 days, and 14 days after loading. Gene expression was compared to an unloaded control group. At 4 hours after fracture, there was a marked 220-fold increase (P < 0.0001) in expression of IL-6. There were also prominent peak increases in mRNA expression for OPG, COX-2, and VEGF (all P < 0.0001). At 24 hours, there was a peak increase in mRNA expression for IL-11 (73-fold increase, P < 0.0001). At 4 days, there was a significant increase in mRNA expression for Bcl-2, COX-1, IGF-1, OPN, and SDF-1. At 7 days, there was significantly increased mRNA expression of RANKL and OPN. Prominent, upregulation of COX-2, VEGF, OPG, SDF-1, BMP-2, and SOST prior to peak expression of RANKL indicates the importance of these factors in mediating directed remodelling of the fracture line. Dramatic, early upregulation of IL-6 and IL-11 demonstrate their central role in initiating signalling events for remodelling and stress fracture healing. © 2009 Elsevier Inc. All rights reserved.

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