Mechanical and biological aspects of impaction bone grafting in revision hip surgery and the use of a new synthetic bone graft

AIMS: This thesis aims to examine the biological and mechanical factors which influence the strength of impacted morsellised bone graft. The use of synthetic materials as bone graft enhancers was also analysed (Controlled Release Glass - Corglaes®, Giltech Ltd, Ayr, Scotland and Tricalcium Phosphate Hydroxyapatite - TCP/HA, Stryker Howmedica Osteonics, Berkshire, UK). METHODS: Phase I - the mechanical strength of different fresh frozen human bone graft preparations were analysed in the laboratory, looking specifically at the effect of particle size, washing the graft and using synthetic additives. Phase II - mixtures of bone graft and bone graft/Corglaes®, which had been identified as being mechanically stronger than standard bone graft, were analysed for their biological response in an in-vivo ovine defect model, compared to controls. Bone densitometry and histological analysis was performed. Phase III - a mixture of bone graft and Corglaes® was compared to the current 'gold standard' of allograft bone alone, in a simulated revision in-vivo ovine femoral hip replacement model. Outcome measures of subsidence, micromotion on cyclical loading and histomorphometry were performed. RESULTS: Phase 1 - Fresh frozen human bone-graft behaves in a similar fashion to theoretical predictions based on Engineering principles. These principles follow Soil Mechanics theory and are commonly used by engineers when designing stable foundations for roads or buildings. In general, when the spread of different particle sizes is uniform over a given range, the material is stronger (more resistant to shear) than if the particles are all the same size. This allowed determination of which bone mills produce the strongest graft. These results were dependent on the degree of fluid release on graft milling, with more fluid release when the average particle size is reduced. Shear strength was improved for all mills after washing the morsellised graft or by the addition of synthetic additives (Corglaes® and TCP/HA). Phase 2 - The defect model allowed analysis of remodelling of the impacted pellets, highlighting rapid dissolution of the Corglaes®, without a significant inflammatory response. The model may be closer to a fracture model when the histological results of phase III are considered. Phase 3 - No statistically significant difference in subsidence over the implantation period (12 weeks) or micromotion of the retrieved implant / femur composites could be elicited between the two groups. Histological analysis revealed the distal impacted graft to be in an isolated environment, both from biological ingress and solution exchange. Bone graft and Corglaes® that was remodelled or resorbed after time in the Phase II defect experiments, was little changed with time in the distal femur. The proximal femur histologically behaved in a similar fashion to the defect experiments. This suggests that a defect model alone is not ideal to analyse materials for impaction grafting. CONCLUSIONS: • Graft strength is variable depending on the bone mill that produces it - washing bone graft improves the strength from all bone mills tested. • Tight compaction with smaller particles does not inhibit neovascularisation. • Novel biomaterials by themselves were inferior mechanically and biologically. • 50/50 mixes of allograft and Corglaes® are stronger mechanically and do not appear to have an adverse effect on biological incorporation. • In this sheep hemiarthroplasty model, subsidence, micromotion and histomorphometry results better replicate the equivalent reported human results than previous models, especially unloaded defect models in lower vertebrates

Enhancing the osteogenic efficacy of human bone marrow aspirate: concentrating osteoprogenitors using wave-assisted filtration

Background: recent approaches have sought to harness the potential of stem cells to regenerate bone that is lost as a consequence of trauma or disease. Bone marrow aspirate (BMA) provides an autologous source of osteoprogenitors for such applications. However, previous studies indicated that the concentration of osteoprogenitors present in BMA is less than required for robust bone regeneration. We provide further evidence for the importance of BMA enrichment for skeletal tissue engineering strategies using a novel acoustic wave-facilitated filtration strategy to concentrate BMA for osteoprogenitors, clinically applicable for intraoperative orthopedic use.Methods: femoral BMA from 15 patients of an elderly cohort was concentrated for the nucleated cell fraction against erythrocytes and excess plasma volume via size exclusion filtration facilitated by acoustic agitation. The effect of aspirate concentration was assessed by assays for colony formation, flow cytometry, multilineage differentiation and scaffold seeding efficiency.Results: BMA was filtered to achieve a mean 4.2-fold reduction in volume with a corresponding enrichment of viable and functional osteoprogenitors, indicated by flow cytometry and assays for colony formation. Enhanced osteogenic and chondrogenic differentiation was observed using concentrated aspirate and enhanced cell-seeding efficiency onto allogeneic bone graft as an effect of osteoprogenitor concentration relative specifically to the concentration of erythrocytes in the aspirate.Conclusions: these studies provide evidence for the importance of BMA nucleated cell concentration for both cell differentiation and cell seeding efficiency and demonstrate the potential of this approach for intraoperative application to enhance bone healin

Source levels of social sounds in migrating humpback whales (Megaptera novaeangliae)

The source level of an animal sound is important in communication, since it affects the distance over which the sound is audible. Several measurements of source levels of whale sounds have been reported, but the accuracy of many is limited because the distance to the source and the acoustic transmission loss were estimated rather than measured. This paper presents measurements of source levels of social sounds (surface-generated and vocal sounds) of humpback whales from a sample of 998 sounds recorded from 49 migrating humpback whale groups. Sources were localized using a wide baseline five hydrophone array and transmission loss was measured for the site. Social vocalization source levels were found to range from 123 to 183 dB re 1 mu Pa @ 1 m with a median of 158 dB re 1 mu Pa @ 1 m. Source levels of surface-generated social sounds ("breaches" and "slaps") were narrower in range (133 to 171 dB re 1 mu Pa @ 1 m) but slightly higher in level (median of 162 dB re 1 mu Pa @ 1 m) compared to vocalizations. The data suggest that group composition has an effect on group vocalization source levels in that singletons and mother-calf-singing escort groups tend to vocalize at higher levels compared to other group compositions. VC 2013 Acoustical Society of America

HerMES: Current Cosmic Infrared Background Estimates Can be Explained by Known Galaxies and their Faint Companions at z < 4

We report contributions to cosmic infrared background (CIB) intensities originating from known galaxies and their faint companions at submillimeter wavelengths. Using the publicly-available UltraVISTA catalog, and maps at 250, 350, and 500 {\mu}m from the \emph{Herschel} Multi-tiered Extragalactic Survey (HerMES), we perform a novel measurement that exploits the fact that uncatalogued sources may bias stacked flux densities --- particularly if the resolution of the image is poor --- and intentionally smooth the images before stacking and summing intensities. By smoothing the maps we are capturing the contribution of faint (undetected in K_S ~ 23.4) sources that are physically associated, or correlated, with the detected sources. We find that the cumulative CIB increases with increased smoothing, reaching 9.82 +- 0.78, 5.77 +- 0.43, and 2.32 +- 0.19$\, \rm nW m^{-2} sr^{-1}$ at 250, 350, and 500 {\mu}m at 300 arcsec FWHM. This corresponds to a fraction of the fiducial CIB of 0.94 +- 0.23, 1.07 +- 0.31, and 0.97 +- 0.26 at 250, 350, and 500 {\mu}m, where the uncertainties are dominated by those of the absolute CIB. We then propose, with a simple model combining parametric descriptions for stacked flux densities and stellar mass functions, that emission from galaxies with log(M/Msun) > 8.5 can account for the most of the measured total intensities, and argue against contributions from extended, diffuse emission. Finally, we discuss prospects for future survey instruments to improve the estimates of the absolute CIB levels, and observe any potentially remaining emission at z > 4.Comment: Accepted to ApJL. 6 Pages, 3 figure

Human Skeletal Stem Cell Response to Multiscale Topography Induced by Large Area Electron Beam Irradiation Surface Treatment

The healthcare socio-economic environment is irreversibly changing as a consequence of an increasing aging population, consequent functional impairment, and patient quality of life expectations. The increasing complexity of ensuing clinical scenarios compels a critical search for novel musculoskeletal regenerative and replacement strategies. While joint arthroplasty is a highly effective treatment for arthritis and osteoporosis, further innovation and refinement of uncemented implants are essential in order to improve implant integration and reduce implant revision rate. This is critical given financial restraints and the drive to improve cost-effectiveness and quality of life outcomes. Multi-scale modulation of implant surfaces, offers an innovative approach to enhancement in implant performance. In the current study, we have examined the potential of large area electron beam melting to alter the surface nanotopography in titanium alloy (Ti6Al4V). We evaluated the in vitro osteogenic response of human skeletal stem cells to the resultant nanotopography, providing evidence of the relationship between the biological response, particularly Collagen type I and Osteocalcin gene activation, and surface nanoroughness. The current studies demonstrate osteogenic gene induction and morphological cell changes to be significantly enhanced on a topography Ra of ~40 nm with clinical implications therein for implant surface treatment and generation

Disentangling a group of lensed submm galaxies at z∼ 2.9

MS0451.6−0305 is a rich galaxy cluster whose strong lensing is particularly prominent at submm wavelengths. We combine new Submillimetre Common-User Bolometer Array (SCUBA)-2 data with imaging from Herschel Spectral and Photometric Imaging Receiver (SPIRE) and PACS and Hubble Space Telescope in order to try to understand the nature of the sources being lensed. In the region of the ‘giant submm arc', we uncover seven multiply imaged galaxies (up from the previously known four), of which six are found to be at a redshift of z∼2.9, and possibly constitute an interacting system. Using a novel forward-modelling approach, we are able to simultaneously deblend and fit spectral energy distributions to the individual galaxies that contribute to the giant submm arc, constraining their dust temperatures, far-infrared luminosities, and star formation rates (SFRs). The submm arc first identified by SCUBA can now be seen to be composed of at least five distinct sources, four of these within a galaxy group at z∼2.9. Only a handful of lensed galaxy groups at this redshift are expected on the sky, and thus this is a unique opportunity for studying such systems in detail. The total unlensed luminosity for this galaxy group is (3.1±0.3)×1012 L⊙, which gives an unlensed SFR of (450±50) M⊙yr−1. This finding suggests that submm source multiplicity, due to physically associated groupings as opposed to chance alignment, extends to fainter flux densities than previously discovered. Many of these systems may also host optical companions undetected in the submm, as is the case her

Herschel-ATLAS: Far-infrared properties of radio-loud and radio-quiet quasars

This is pre-copyedited, author-produced pdf of an article accepted for publication in Monthly Notices of the Royal Astronomical Society following peer review. The version of record, E. Kalfountzou, et al., ‘Herschel-ATLAS: Far-infrared properties of radio-loud and radio-quiet quasars’, MNRAS, Vol 42(2): 1181-1196, first published online June 11, 2014, is available online via doi: 10.1093/mnras/stu782 Published by Oxford University Press on behalf of the Royal Astronomical Society.We have constructed a sample of radio-loud and radio-quiet quasars from the Faint Images Radio Sky at Twenty-one centimetres and the Sloan Digital Sky Survey Data Release 7, over the Herschel-ATLAS Phase 1 area (9h, 12h and 14 h . 5 ). Using a stacking analysis, we find a significant correlation between the far-infrared (FIR) luminosity and 1.4-GHz luminosity for radio-loud quasars. Partial correlation analysis confirms the intrinsic correlation after removing the redshift contribution, while for radio-quiet quasars, no partial correlation is found. Using a single-temperature grey-body model, we find a general trend of lower dust temperatures in case of radio-loud quasars compared to radio-quiet quasars. Also, radio-loud quasars are found to have almost constant mean values of dust mass along redshift and optical luminosity bins. In addition, we find that radio-loud quasars at lower optical luminosities tend to have on average higher FIR and 250-μm luminosity with respect to radio-quiet quasars with the same optical luminosites. Even if we use a two-temperature grey-body model to describe the FIR data, the FIR luminosity excess remains at lower optical luminosities. These results suggest that powerful radio jets are associated with star formation especially at lower accretion ratesPeer reviewe

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk:a large Mendelian randomisation study

Background: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 x 10(-11)), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P= 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P= 0.48). Conclusions: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven

FMOS near-IR spectroscopy of Herschel selected galaxies: star formation rates, metallicity and dust attenuation at z~1

We investigate the properties (e.g. star formation rate, dust attentuation, stellar mass and metallicity) of a sample of infrared luminous galaxies at z \sim 1 via near-IR spectroscopy with Subaru-FMOS. Our sample consists of Herschel SPIRE and Spitzer MIPS selected sources in the COSMOS field with photometric redshifts in the range 0.7 < z-phot < 1.8, which have been targeted in 2 pointings (0.5 sq. deg.) with FMOS. We find a modest success rate for emission line detections, with candidate H{\alpha} emission lines detected for 57 of 168 SPIRE sources (34 per cent). By stacking the near-IR spectra we directly measure the mean Balmer decrement for the H{\alpha} and H{\beta} lines, finding a value of = 0.51\pm0.27 for = 10^12 Lsol sources at = 1.36. By comparing star formation rates estimated from the IR and from the dust uncorrected H{\alpha} line we find a strong relationship between dust attenuation and star formation rate. This relation is broadly consistent with that previously seen in star-forming galaxies at z ~ 0.1. Finally, we investigate the metallicity via the N2 ratio, finding that z ~ 1 IR-selected sources are indistinguishable from the local mass-metallicity relation. We also find a strong correlation between dust attentuation and metallicity, with the most metal-rich IR-sources experiencing the largest levels of dust attenuation.Comment: 13 pages, 7 figures, MNRAS accepte