5,401 research outputs found
Scalable production of tissue engineered microunits for bone regeneration using bioactive glass microspheres and dynamic culture conditions
Bone is one of the most common tissues to be transplanted, with over 2.2 million grafting procedures performed worldwide every year (Van der Stok et al., 2011). Autologous bone grafts, while considered the current gold standard, have inherent risks including limited donor tissue availability, donor site morbidity, surgical complications, and pain of procedure. Alternative approaches to treating bone tissue defects are required based on clinically effective bone graft substitutes that can be manufactured at a commercially relevant scale. Tissue engineering is an alternative strategy that uses biocompatible scaffolds in combination with cells as a bioactive implant to induce bone repair. In this thesis, microspherical bioactive glasses have been studied as a platform for scalable bone tissue engineering that has flexibility to address diverse geometric requirements with the aim of becoming a commercially available tool. Specifically, titanium-doped phosphate glass microspheres have been studied for their ability to support bone progenitor cells. Here, the microspheres (5 and 7 mol% TiO2) were assessed in their ability to support proliferation of osteoblast-like cell (MG63) and proliferation and osteogenic differentiation of human bone-marrow derived mesenchymal stem cells (hBM-MSCs) under static and dynamic agitation culture. Scalability was assessed using scalable dimensionless Froude number to scale microwell plate cultures to 125ml Erlenmeyer flask cultures using Froude as a tool to map mixing systems at both scales. MG63 and hBM-MSC proliferation was observed on the microspheres under all conditions studied as well as extracellular matrix protein secretion, confirming the biocompatibility of the materials tested. Similar growth kinetics was observed at both scales, where moderate agitation stimulated cell proliferation, but higher agitation was damaging to cells. Upregulation of key bone expression markers (COL1A1 and SPP1) was observed also at moderate orbital agitations, while on at high agitation rates this was largely absent, except for upregulation of SPP1 on the control microsphere, Synthemax. Furthermore, biomaterial resorption was observed upon differentiating mouse-derived monocytes into osteoclasts on the titanium-phosphate glass discs. In conclusion, large-scale culture using titanium-doped phosphate glass microspheres was achieved with hBM-MSCs, with the substrate effectively supporting cell proliferation and osteogenic differentiation. This research provides a stepping stone in understanding how biomaterials processed into microcarrier format can be utilised in a commercial environment to create clinically relevant quantities of tissue engineering bone
A parameterised mathematical model to elucidate osteoblast cell growth in a phosphate-glass microcarrier culture
Tissue engineering has the potential to augment bone grafting. Employing microcarriers as cell-expansion vehicles is a promising bottom-up bone tissue engineering strategy. Here we propose a collaborative approach between experimental work and mathematical modelling to develop protocols for growing microcarrier-based engineered constructs of clinically relevant size. Experiments in 96-well plates characterise cell growth with the model human cell line MG-63 using four phosphate glass microcarrier materials. Three of the materials are doped with 5âmol% TiO2 and contain 0%, 2% or 5% CoO, and the fourth material is doped only with 7% TiO2 (0% CoO). A mathematical model of cell growth is parameterised by finding material-specific growth coefficients through data-fitting against these experiments. The parameterised mathematical model offers more insight into the material performance by comparing culture outcome against clinically relevant criteria: maximising final cell number starting with the lowest cell number in the shortest time frame. Based on this analysis, material 7% TiO2 is identified as the most promising
Assessing behaviour of osteoblastic cells in dynamic culture conditions using titanium-doped phosphate glass microcarriers
Tissue engineering is a promising approach for bone regeneration; yet challenges remain that limit successful translation to patients. It is necessary to understand how real-world manufacturing processes will affect the constituent cells and biomaterials that are needed to create engineered bone. Bioactive phosphate glasses processed into microspheres are an attractive platform for expanding bone-forming cells and also for driving their osteogenic differentiation and maturation. The aim of this study was to assess whether Ti-doped phosphate glass microspheres could support osteoblastic cell responses in dynamic cell culture environments. Dynamic culture conditions were achieved using microwell studies under orbital agitation. Dimensionless parameters such as the Froude number were used to inform the choice of agitation speeds, and the impact on cell proliferation and microunit formation was quantified. We found that phosphate glass microspheres doped with titanium dioxide at both 5 and 7âmol% provided a suitable biomaterial platform for effective culture of MG63 osteoblastic cells and was not cytotoxic. Dynamic culture conditions supported expansion of MG63 cells and both 150 and 300ârpm orbital shake resulted in higher cell yield than static cultures at the end of the culture (day 13). The Froude number analysis provided insight into how the microunit size could be manipulated to enable an appropriate agitation speed to be used, while ensuring buoyancy of the microunits. These small-scale experiments and analyses provide understanding of the impact of fluid flow on cell expansion that will have increasing importance when scaling up to process technologies that can deliver clinical quantities of cell-microsphere units. Such knowledge will enable future engineering of living bone-like material using processing systems such as bioreactors that use mixing and agitation for nutrient transfer, therefore introducing cells to dynamic culture conditions
Characterisation of osteogenic and vascular responses of hMSCs to Ti-Co doped phosphate glass microspheres using a microfluidic perfusion platform
Using microspherical scaffolds as building blocks to repair bone defects of specific size and shape has been proposed as a tissue engineering strategy. Here, phosphate glass (PG) microcarriers doped with 5 mol % TiO2 and either 0 mol % CoO (CoO 0%) or 2 mol % CoO (CoO 2%) were investigated for their ability to support osteogenic and vascular responses of human mesenchymal stem cells (hMSCs). Together with standard culture techniques, cell-material interactions were studied using a novel perfusion microfluidic bioreactor that enabled cell culture on microspheres, along with automated processing and screening of culture variables. While titanium doping was found to support hMSCs expansion and differentiation, as well as endothelial cell-derived vessel formation, additional doping with cobalt did not improve the functionality of the microspheres. Furthermore, the microfluidic bioreactor enabled screening of culture parameters for cell culture on microspheres that could be potentially translated to a scaled-up system for tissue-engineered bone manufacturing
Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation
BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of ÂŁ20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of ÂŁ9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of ÂŁ28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (ÂŁ30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a ÂŁ20,000 threshold (ICER: ÂŁ19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of ÂŁ822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme
Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe
The Extragalactic Background Light (EBL) includes photons with wavelengths
from ultraviolet to infrared, which are effective at attenuating gamma rays
with energy above ~10 GeV during propagation from sources at cosmological
distances. This results in a redshift- and energy-dependent attenuation of the
gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts
(GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray
blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using
photons above 10 GeV collected by Fermi over more than one year of observations
for these sources, we investigate the effect of gamma-ray flux attenuation by
the EBL. We place upper limits on the gamma-ray opacity of the Universe at
various energies and redshifts, and compare this with predictions from
well-known EBL models. We find that an EBL intensity in the optical-ultraviolet
wavelengths as great as predicted by the "baseline" model of Stecker et al.
(2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication
in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A.
Reimer, L.C. Reye
Theory and Applications of Non-Relativistic and Relativistic Turbulent Reconnection
Realistic astrophysical environments are turbulent due to the extremely high
Reynolds numbers. Therefore, the theories of reconnection intended for
describing astrophysical reconnection should not ignore the effects of
turbulence on magnetic reconnection. Turbulence is known to change the nature
of many physical processes dramatically and in this review we claim that
magnetic reconnection is not an exception. We stress that not only
astrophysical turbulence is ubiquitous, but also magnetic reconnection itself
induces turbulence. Thus turbulence must be accounted for in any realistic
astrophysical reconnection setup. We argue that due to the similarities of MHD
turbulence in relativistic and non-relativistic cases the theory of magnetic
reconnection developed for the non-relativistic case can be extended to the
relativistic case and we provide numerical simulations that support this
conjecture. We also provide quantitative comparisons of the theoretical
predictions and results of numerical experiments, including the situations when
turbulent reconnection is self-driven, i.e. the turbulence in the system is
generated by the reconnection process itself. We show how turbulent
reconnection entails the violation of magnetic flux freezing, the conclusion
that has really far reaching consequences for many realistically turbulent
astrophysical environments. In addition, we consider observational testing of
turbulent reconnection as well as numerous implications of the theory. The
former includes the Sun and solar wind reconnection, while the latter include
the process of reconnection diffusion induced by turbulent reconnection, the
acceleration of energetic particles, bursts of turbulent reconnection related
to black hole sources as well as gamma ray bursts. Finally, we explain why
turbulent reconnection cannot be explained by turbulent resistivity or derived
through the mean field approach.Comment: 66 pages, 24 figures, a chapter of the book "Magnetic Reconnection -
Concepts and Applications", editors W. Gonzalez, E. N. Parke
Engolo and Capoeira. From Ethnic to Diasporic Combat Games in the Southern Atlantic
This article provides a re-examination of the main Afrocentric narrative of capoeira origins, the engolo or âZebra Danceâ, in light of historical primary sources and new ethnographic evidence gathered during fieldwork in south-west Angola. By examining engoloâs bodily techniques, its socio-historical context and cultural meanings, the piece emphasises its insertion into a pastoral lifestyle and highlights the relatively narrow ethnic character of the practice in Angola. This analysis and the comparison with capoeira helps us to develop certain hypotheses about the formation, migration, and re-invention of diasporic combat games between southern Angola and coastal Brazil, and more broadly, to increase our understanding of how African cultures spread across the southern Atlantic
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