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Cluse Z.N.,Metabolic Laboratory | Fudge A.N.,Metabolic Laboratory | Whiting M.J.,Metabolic Laboratory | Mcwhinney B.,HPLC LC MS MS Chromatography Section | And 2 more authors.
Annals of Clinical Biochemistry | Year: 2012

Background: We evaluated the recently released chemiluminescence assay for 25-hydroxy vitamin D (25-OHD) on the Immunodiagnostic Systems iSYS (IDS-iSYS) automated analyser. Methods: The IDS-iSYS comparison was performed using patient samples previously measured for 25-OHD by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (n =119) and an IDS enzyme immunoassy (IDS-EIA) method (n =64). Limit of detection and limit of quantification were determined from a precision profile. Imprecision was assessed using quality control material and pooled serum. External QAP material (Vitamin D External Quality Assessment Scheme, UK) was analysed to establish inaccuracy. Linearity was assessed by two dilution studies. Cross-reactivity was determined by three serial dilution studies of patient samples with known 25-OHD2 concentrations. Results: The IDS-iSYS correlated well with both established methods (iSYS =1.03LC-MS/MS 2 6.53, R2 =0.82 and iSYS =1.07IDS-EIA 2 1.61, R2 =0.86). Imprecision of the iSYS assay for IDS control material was 13.4% at 32 nmol/L, 10% at 78 nmol/L, 9.4% at 161 nmol/L, and for the pooled material 9.3% at 72 nmol/L and 5.6% at 158 nmol/L. The evaluation found the assay to be highly accurate (IDS-iSYS =0.93ALTM {thorn} 3.79, R2 =0.94) and linear (obs1 =0.93exp1 2 5.05, R2 =0.99 (P =0.256); and obs2 =0.97exp2 + 6.07, R2 =0.97 (P =0.654); ALTM, all-laboratory trimmed mean). Cross-reactivity studies demonstrated no significant difference to the calculated total 25-OHD as measured by LC-MS/MS. Conclusions: Even though the imprecision of the iSYS was found to be greater than that of the LC-MS/MS and EIA methods, the performance characteristics of the IDS-iSYS 25-OHD assay are suitable for routine diagnostic purposes on a high throughput automated analyser.


Smith L.J.,Bone and Joint Research Laboratory | Schirer J.P.,Hysitron Inc. | Fazzalari N.L.,Bone and Joint Research Laboratory | Fazzalari N.L.,University of Adelaide
Journal of Biomechanics | Year: 2010

In trabecular bone, each remodeling event results in the resorption and/or formation of discrete structural units called 'packets'. These remodeling packets represent a fundamental level of bone's structural hierarchy at which to investigate composition and mechanical behaviors. The objective of this study was to apply the complementary techniques of quantitative backscattered electron microscopy (qBSEM) and nanoindentation to investigate inter-relationships between packet mineralization, elastic modulus, contact hardness and plastic deformation resistance. Indentation arrays were performed across nine trabecular spicules from 3 human donors; these spicules were then imaged using qBSEM, and discretized into their composite remodeling packets (127 in total). Packets were classified spatially as peripheral or central, and mean contact hardness, plastic deformation resistance, elastic modulus and calcium content calculated for each. Inter-relationships between measured parameters were analysed using linear regression analyses, and dependence on location assessed using Student's t-tests. Significant positive correlations were found between all mechanical parameters and calcium content. Elastic modulus and contact hardness were significantly correlated, however elastic modulus and plastic deformation resistance were not. Calcium content, contact hardness and elastic modulus were all significantly higher for central packets than for peripheral, confirming that packet mineral content contributes to micromechanical heterogeneity within individual trabecular spicules. Plastic deformation resistance, however, showed no such regional dependence, indicating that the plastic deformation properties in particular, are determined not only by mineral content, but also by the organic matrix and interactions between these two components. © 2010 Elsevier Ltd.


Arthur A.,University of Adelaide | Panagopoulos R.A.,University of Adelaide | Cooper L.,University of Adelaide | Menicanin D.,University of Adelaide | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2013

Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones. Copyright © 2013 American Society for Bone and Mineral Research.


Shelton T.J.,University of Utah | Shelton T.J.,Bone and Joint Research Laboratory | Peter Beck J.,Bone and Joint Research Laboratory | Bloebaum R.D.,Bone and Joint Research Laboratory | And 3 more authors.
Journal of Biomechanics | Year: 2011

Percutaneous osseointegrated prostheses are being investigated as an alternative strategy to attach prosthetic limbs to patients. Although the use of these implants has shown to be promising in clinical trials, the ability to maintain a skin seal around an osseointegrated implant interface is a major challenge to prevent superficial and deep periprosthetic infections. The specific aim of this study was to establish a translational load-bearing ovine model to assess postoperative limb compensation and gait symmetry following a percutaneous osseointegrated implant. We tested the following hypotheses: (1) the animals would return to pre-amputation limb loads within 12-months; (2) the animals would return to a symmetrical gait pattern (stride length and time in stance) within 12-months. The results demonstrated that one month following surgery, the sheep loaded their amputated limb to a mean value of nearly 80% of their pre-amputation loading condition; by 12-months, this mean had dropped to approximately 74%. There was no statistical differences between the symmetry of the amputated forelimb and the contralateral forelimb at any time point for the animals stride length or the time spent in the stance phase of their gait cycle. Thus, the data showed that while the animals maintained symmetric gait patterns, they did not return to full weight-bearing after 12-months. The results of this study showed that a large animal load-bearing model had a symmetric gait and was weight bearing for up to 12 months. While the current investigation utilizes an ovine model, the data show that osseointegrated implant technology with postoperative follow-up can help our human patients return to symmetric gait and maintain an active lifestyle, leading to an improvement in their quality of life following amputation. © 2011.


Skedros J.G.,Bone and Joint Research Laboratory | Knight A.N.,Bone and Joint Research Laboratory | Farnsworth R.W.,Bone and Joint Research Laboratory | Bloebaum R.D.,Bone and Joint Research Laboratory
Journal of Anatomy | Year: 2012

Calcanei of mature mule deer have the largest mineral content (percent ash) difference between their dorsal 'compression' and plantar 'tension' cortices of any bone that has been studied. The opposing trabecular tracts, which are contiguous with the cortices, might also show important mineral content differences and microscopic mineralization heterogeneity (reflecting increased hemi-osteonal renewal) that optimize mechanical behaviors in tension vs. compression. Support for these hypotheses could reveal a largely unrecognized capacity for phenotypic plasticity - the adaptability of trabecular bone material as a means for differentially enhancing mechanical properties for local strain environments produced by habitual bending. Fifteen skeletally mature and 15 immature deer calcanei were cut transversely into two segments (40% and 50% shaft length), and cores were removed to determine mineral (ash) content from 'tension' and 'compression' trabecular tracts and their adjacent cortices. Seven bones/group were analyzed for differences between tracts in: first, microscopic trabecular bone packets and mineralization heterogeneity (backscattered electron imaging, BSE); and second, trabecular architecture (micro-computed tomography). Among the eight architectural characteristics evaluated [including bone volume fraction (BVF) and structural model index (SMI)]: first, only the 'tension' tract of immature bones showed significantly greater BVF and more negative SMI (i.e. increased honeycomb morphology) than the 'compression' tract of immature bones; and second, the 'compression' tracts of both groups showed significantly greater structural order/alignment than the corresponding 'tension' tracts. Although mineralization heterogeneity differed between the tracts in only the immature group, in both groups the mineral content derived from BSE images was significantly greater (P<0.01), and bulk mineral (ash) content tended to be greater in the 'compression' tracts (immature 3.6%, P=0.03; mature 3.1%, P=0.09). These differences are much less than the approximately 8% greater mineral content of their 'compression' cortices (P<0.001). Published data, suggesting that these small mineralization differences are not mechanically important in the context of conventional tests, support the probability that architectural modifications primarily adapt the tracts for local demands. However, greater hemi-osteonal packets in the tension trabecular tract of only the mature bones (P=0.006) might have an important role, and possible synergism with mineralization and/or microarchitecture, in differential toughening at the trabeculum level for tension vs. compression strains. © Published 2012. This article is a US Government work and is in the public domain in the USA. Journal of Anatomy © 2012 Anatomical Society.


Sinclair S.K.,Bone and Joint Research Laboratory | Sinclair S.K.,University of Utah | Konz G.J.,Zimmer Spine Inc. | Dawson J.M.,Zimmer Spine Inc. | And 4 more authors.
Spine | Year: 2012

STUDY DESIGN.: In vivo assessment of polyetheretherketone (PEEK) and porous tantalum (TM) cervical interbody fusion devices in a goat model. OBJECTIVE.: Directly compare host bone response to PEEK and TM devices used for cervical interbody fusion. SUMMARY OF BACKGROUND DATA.: PEEK devices are widely used for anterior cervical discectomy and fusion but are nonporous and have limited surface area for bone attachment. METHODS.: Twenty-five goats underwent single-level anterior cervical discectomy and fusion and were alternately implanted with TM (n = 13) or PEEK devices (n = 12) for 6, 12, and 26 weeks. Both devices contained a center graft hole (GH), filled with autograft bone from the animal's own iliac crest. The percentage of bone tissue around the implant, percentage of the implant surface in direct apposition with the host bone, and evidence of bone bridging through the implant GH were assessed by using backscattered electron imaging. Bone matrix mineral apposition rate was determined through fluorochrome double labeling, and sections were stained for histological analysis. RESULTS.: The TM-implanted animals had significantly greater volumes of bone tissue at the implant interface than the PEEK animals at all-time points. The TM animals also had a significantly greater average mineral apposition rate in the GH region at 6 and 12 weeks than the PEEK animals. No difference was observed at 26 weeks. A greater number of TM-implanted animals demonstrated connection between the autograft bone and both vertebrae compared with the PEEK implants. Histological staining also showed that the TM devices elicited improved host bone attachment over the PEEK implants. CONCLUSION.: The TM implants supported bone growth into and around the implant margins better than the PEEK devices. TM's open cell porous structure facilitated host bone ingrowth and bone bridging through the device, which could be beneficial for long-term mechanical attachment and support in clinical applications. Copyright © 2012 Lippincott Williams &Wilkins.


Isackson D.,University of Utah | Isackson D.,Bone and Joint Research Laboratory | McGill L.D.,Arup | Bachus K.N.,University of Utah | Bachus K.N.,Bone and Joint Research Laboratory
Medical Engineering and Physics | Year: 2011

Osseointegrated percutaneous implants are a promising prosthetic alternative for a subset of amputees. However, as with all percutaneous implants, they have an increased risk of infection since they breach the skin barrier. Theoretically, host tissues could attach to the metal implant creating a barrier to infection. When compared with smooth surfaces, it is hypothesized that porous surfaces improve the attachment of the host tissues to the implant, and decrease the infection risk. In this study, four titanium implants, manufactured with a percutaneous post and a subcutaneous disk, were placed subcutaneously on the dorsum of eight New Zealand White rabbits. Beginning at four weeks post-op, the implants were inoculated weekly with 108 CFU Staphylococcus aureus until signs of clinical infection presented. While we were unable to detect a difference in the incidence of infection of the porous metal implants, smooth surface (no porous coating) percutaneous and subcutaneous components had a 7-fold increased risk of infection compared to the implants with a porous coating on one or both components. The porous coated implants displayed excellent tissue ingrowth into the porous structures; whereas, the smooth implants were surrounded with a thick, organized fibrotic capsule that was separated from the implant surface. This study suggests that porous coated metal percutaneous implants are at a significantly lower risk of infection when compared to smooth metal implants. The smooth surface percutaneous implants were inadequate in allowing a long-term seal to develop with the soft tissue, thus increasing vulnerability to the migration of infecting microorganisms. © 2010.


Jeyapalina S.,Bone and Joint Research Laboratory
Clinical orthopaedics and related research | Year: 2014

Percutaneous osseointegrated prosthetic (POP) devices have been used clinically in Europe for decades. Unfortunately, their introduction into the United States has been delayed, in part due to the lack of data documenting the progression of osseointegration and mechanical stability. We determined the progression of bone ingrowth into porous-coated POP devices and established the interrelationship with mechanical stability. After amputation, 64 skeletally mature sheep received a custom porous-coated POP device and were then randomized into five time groups, with subsequent measurement of percentage of bone ingrowth into the available pore spaces (n = 32) and the mechanical pullout force (n = 32). Postimplantation, there was an accelerated progression of bone ingrowth (~48% from 0 to 3 months) producing a mean pullout force of 5066 ± 1543 N. Subsequently, there was a slower but continued progression of bone ingrowth (~23% from 3 to 12 months) culminating with a mean pullout force of 13,485 ± 1855 N at 12 months postimplantation. There was a high linear correlation (R = 0.94) between the bone ingrowth and mechanical pullout stability. This weightbearing model shows an accelerated progression of bone ingrowth into the porous coating; the amount of ingrowth observed at 3 months after surgery within the porous-coated POP devices was sufficient to generate mechanical stability. The data document progression of bone ingrowth into porous-coated POP devices and establish a strong interrelationship between ingrowth and pullout strength. Further human data are needed to validate these findings.


Skedros J.G.,University of Utah | Skedros J.G.,Bone and Joint Research Laboratory | Sybrowsky C.L.,Bone and Joint Research Laboratory | Anderson W.E.,Bone and Joint Research Laboratory | Chow F.,Bone and Joint Research Laboratory
Journal of Anatomy | Year: 2011

Natural loading of the calcanei of deer, elk, sheep and horses produces marked regional differences in prevalent/predominant strain modes: compression in the dorsal cortex, shear in medial-lateral cortices, and tension/shear in the plantar cortex. This consistent non-uniform strain distribution is useful for investigating mechanisms that mediate the development of the remarkable regional material variations of these bones (e.g. collagen orientation, mineralization, remodeling rates and secondary osteon morphotypes, size and population density). Regional differences in strain-mode-specific microdamage prevalence and/or morphology might evoke and sustain the remodeling that produces this material heterogeneity in accordance with local strain characteristics. Adult calcanei from 11 animals of each species (deer, elk, sheep and horses) were transversely sectioned and examined using light and confocal microscopy. With light microscopy, 20 linear microcracks were identified (deer: 10; elk: six; horse: four; sheep: none), and with confocal microscopy substantially more microdamage with typically non-linear morphology was identified (deer: 45; elk: 24; horse: 15; sheep: none). No clear regional patterns of strain-mode-specific microdamage were found in the three species with microdamage. In these species, the highest overall concentrations occurred in the plantar cortex. This might reflect increased susceptibility of microdamage in habitual tension/shear. Absence of detectable microdamage in sheep calcanei may represent the (presumably) relatively greater physical activity of deer, elk and horses. Absence of differences in microdamage prevalence/morphology between dorsal, medial and lateral cortices of these bones, and the general absence of spatial patterns of strain-mode-specific microdamage, might reflect the prior emergence of non-uniform osteon-mediated adaptations that reduce deleterious concentrations of microdamage by the adult stage of bone development. © Published 2011. This article is a U.S. Government work and is in the public domain in the USA. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.


Jeyapalina S.,Bone and Joint Research Laboratory
Clinical orthopaedics and related research | Year: 2014

Percutaneous osseointegrated prostheses (POPs) are being investigated as an alternative to conventional socket suspension and require a radiographic followup in translational studies to confirm that design objectives are being met. In this 12-month animal study, we determined (1) radiographic signs of osseointegration and (2) radiographic signs of periprosthetic bone hypertrophy and resorption (adaptation) and (3) confirmed them with the histologic evidence of host bone osseointegration and adaptation around a novel, distally porous-coated titanium POP with a collar. A POP device was designed to fit the right metacarpal bone of sheep. Amputation and implantation surgeries (n = 14) were performed, and plane-film radiographs were collected quarterly for 12 months. Radiographs were assessed for osseointegration (fixation) and bone adaptation (resorption and hypertrophy). The cortical wall and medullary canal widths were used to compute the cortical index and expressed as a percentage. Based on the cortical index changes and histologic evaluations, bone adaptation was quantified. Radiographic data showed signs of osseointegration including those with incomplete seating against the collar attachment. Cortical index data indicated distal cortical wall thinning if the collar was not seated distally. When implants were bound proximally, bone resorbed distally and the diaphyseal cortex hypertrophied. Histopathologic evidence and cortical index measurements confirmed the radiographic indications of adaptation and osseointegration. Distal bone loading, through collar attachment and porous coating, limited the distal bone resorption. Serial radiographic studies, in either animal models or preclinical trials for new POP devices, will help to determine which designs are likely to be safe over time and avoid implant failures.

Loading Bone and Joint Research Laboratory collaborators
Loading Bone and Joint Research Laboratory collaborators