Mapping human serum induced gene networks as a basis for the creation of biomimetic periosteum for bone repair

The periosteum is a highly vascularised, collagen-rich tissue that plays a crucial role in directing bone repair. This is orchestrated primarily by its resident progenitor cell population. Indeed, preservation of periosteum integrity is critical for bone healing. Cells extracted from the periosteum retain their osteochondrogenic properties and as such are a promising basis for tissue engineering strategies for the repair of bone defects. However, the culture expansion conditions, and the way in which the cells are reintroduced to the defect site are critical aspects of successful translation. Indeed, expansion in human serum and implantation on biomimetic materials has previously been shown to improve in vivo bone formation. As such, this study aimed to develop a protocol to allow for the expansion of human periosteum derived cells (hPDCs) in a biomimetic periosteal-like environment. The expansion conditions were defined through the investigation of the bioactive cues involved in augmenting hPDC proliferative and multipotency characteristics, based on transcriptomic analysis of cells cultured in human serum. Master regulators of transcriptional networks were identified and an optimised periosteal derived-growth factor cocktail (PD-GFC; containing β-Estradiol, FGF2, TNFα, TGFβ, IGF-1 and PDGF-BB) was generated. Expansion of hPDCs in PD-GFC resulted in serum mimicry with regards to the cell morphology, proliferative capacity and chondrogenic differentiation. When incorporated into a 3D collagen-type-1 matrix and cultured in PD-GFC, the hPDCs migrated to the surface that represented the matrix topography of the periosteum cambium layer. Furthermore, gene expression analysis revealed a downregulated Wnt and TGFβ signature and an upregulation of CREB, which may indicate the hPDCs are recreating their progenitor cell signature. This study highlights the first stage in the development of a biomimetic periosteum which may have applications in bone repair

Nocturnal Blood Pressure Dipping Relates to Insulin Sensitivity but not Vascular Function in Metabolic Syndrome

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Roel of Morning versus Evening Chronotype on Insulin Sensitivity and Central Hemodynamics in Adults with Metabolic Syndrome

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Osteomimetic matrix components alter cell migration and drug response in a 3D tumour-engineered osteosarcoma model

vulnerable to recurring disease and pulmonary metastases. Developing 3D in vitro disease models to serve as a test bed for personalised treatment is a promising approach to address this issue. This study describes the generation of 3D osteosarcoma models termed “tumouroids”, which are geometrically compartmentalised to reproduce the bone cancer mass and its surrounding. Although the tumour microenvironment impacts osteosarcoma in many ways, this model focussed on interrogating the influence of a biomimetic matrix on tumour cell behaviour. The 3D matrix was supplemented with the bone-marrow proteins laminin, fibronectin and NuOss® bone granules. This led to increased invasion of osteosarcoma cell aggregates from within the bone-like matrix into the surrounding acellular bone marrow-like ECM. The presence of bone granules also yielded an atypical molecular profile of osteosarcoma cells, suggesting malignant metabolic reprogramming. Changes include decreased MMP-9 (p < 0.05) and increased PTEN (p < 0.05), MCP-1 (p < 0.01) and MCT-4 (p < 0.05) gene expression. This complex 3D biomimetic composition also changed cellular responses to doxorubicin, a common chemotherapeutic agent used to treat osteosarcoma, and reproduced key issues of in vivo treatment like drug penetrance and doxorubicin-induced bone toxicity. This work highlights the importance of a biomimetic matrix in 3D osteosarcoma models for both basic and translational research

Mechanical loading of 3-D muscle constructs

Mechanical conditioning of many tissue engineered construct will be critical, particularly mechano-responsive tissues such as skeletal muscle. It has been shown that application of defined uniaxial loads to 3D constructs through the tensioning- culture force monitor (t-CFM), has been shown to regulate protease expression in fibroblasts (Prajapati et al. 2000). Insulin-like growth factor (IGF-1) is an important growth factor in proliferation and differentiation of skeletal myoblasts (Florini et al. 1996), along with it a recently isolated isoform, mechano-growth factor (MGF) is found to be upregulated in skeletal muscle in vivo following exercise (Yang et al. 1996)

Intradialytic Exercise Programs for Hemodialysis Patients

Although it is widely accepted that exercise is beneficial in patients with end-stage renal disease as in the general population, it is not easy to incorporate exercise programs into routine clinical practice. This review aimed to investigate the beneficial effects of exercise during hemodialysis and also to introduce various intradialytic exercise programs and their advantages as a first step in combining exercise programs into clinical practice. Aerobic and resistance exercise are beneficial not only in improving physical functioning, including maximal oxygen uptake and muscle strength, but also in improving anthropometrics, nutritional status, hematological indexes, inflammatory cytokines, depression, and health-related quality of life. However, it is not clear whether the beneficial effects of exercise are limited to only relatively healthy dialysis patients. Therefore, the effects of individualized exercise programs for elderly patients or patients with comorbid conditions need to be studied further

Bioengineering the ameloblastoma tumour to study its effect on bone nodule formation

Ameloblastoma is a benign, epithelial cancer of the jawbone, which causes bone resorption and disfigurement to patients affected. The interaction of ameloblastoma with its tumour stroma drives invasion and progression. We used stiff collagen matrices to engineer active bone forming stroma, to probe the interaction of ameloblastoma with its native tumour bone microenvironment. This bone-stroma was assessed by nano-CT, transmission electron microscopy (TEM), Raman spectroscopy and gene analysis. Furthermore, we investigated gene correlation between bone forming 3D bone stroma and ameloblastoma introduced 3D bone stroma. Ameloblastoma cells increased expression of MMP-2 and -9 and RANK temporally in 3D compared to 2D. Our 3D biomimetic model formed bone nodules of an average surface area of 0.1 mm2 and average height of 92.37 ± 7.96 μm over 21 days. We demonstrate a woven bone phenotype with distinct mineral and matrix components and increased expression of bone formation genes in our engineered bone. Introducing ameloblastoma to the bone stroma, completely inhibited bone formation, in a spatially specific manner. Multivariate gene analysis showed that ameloblastoma cells downregulate bone formation genes such as RUNX2. Through the development of a comprehensive bone stroma, we show that an ameloblastoma tumour mass prevents osteoblasts from forming new bone nodules and severely restricted the growth of existing bone nodules. We have identified potential pathways for this inhibition. More critically, we present novel findings on the interaction of stromal osteoblasts with ameloblastoma

From Poverty to Disaster and Back: a Review of the Literature

Poor people are disproportionally affected by natural hazards and disasters. This paper provides a review of the multiple factors that explain why this is the case. It explores the role of exposure (often, but not always, poor people are more likely to be affected by hazards), vulnerability (when they are affected, poor people tend to lose a larger fraction of their wealth), and socio-economic resilience (poor people have a lower ability to cope with and recover from disaster impacts). Finally, the paper highlights the vicious circle between poverty and disaster losses: poverty is a major driver of people’s vulnerability to natural disasters, which in turn increase poverty in a measurable and significant way. The main policy implication is that poverty reduction can be considered as disaster risk management, and disaster risk management can be considered as poverty reduction

Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells

Defects in the expression of either BAFF (B cell activating factor) or BAFF-R impairs B cell development beyond the immature, transitional type-1 stage and thus, prevents the formation of follicular and marginal zone B cells, whereas B-1 B cells remain unaffected. The expression of BAFF-R on all mature B cells might suggest a role for BAFF-R signaling also for their in vivo maintenance. Here, we show that, 14 days following a single injection of an anti-BAFF-R mAb that prevents BAFF binding, both follicular and marginal zone B cell numbers are drastically reduced, whereas B-1 cells are not affected. Injection of control, isotype-matched but non-blocking anti-BAFF-R mAbs does not result in B cell depletion. We also show that this depletion is neither due to antibody-dependent cellular cytotoxicity nor to complement-mediated lysis. Moreover, prevention of BAFF binding leads to a decrease in the size of the B cell follicles, an impairment of a T cell dependent humoral immune response and a reduction in the formation of memory B cells. Collectively, these results establish a central role for BAFF-BAFF-R signaling in the in vivo survival and maintenance of both follicular and marginal zone B cell pools

An appraisal of rehabilitation regimes used for improving functional outcome after total hip replacement surgery

This study aimed to systematically review the literature with regards to studies of rehabilitation programmes that have tried to improve function after total hip replacement (THR) surgery. 15 randomised controlled trials were identified of which 11 were centre-based, 2 were home based and 2 were trials comparing home and centre based interventions. The use of a progressive resistance training (PRT) programme led to significant improvement in muscle strength and function if the intervention was carried out early (< 1 month following surgery) in a centre (6/11 centre-based studies used PRT), or late (> 1 month following surgery) in a home based setting (2/2 home based studies used PRT). In direct comparison, there was no difference in functional measures between home and centre based programmes (2 studies), with PRT not included in the regimes prescribed. A limitation of the majority of these intervention studies was the short period of follow up. Centre based program delivery is expensive as high costs are associated with supervision, facility provision, and transport of patients. Early interventions are important to counteract the deficit in muscle strength in the affected limb, as well as persistent atrophy that exists around the affected hip at 2 years post-operatively. Studies of early home-based regimes featuring PRT with long term follow up are needed to address the problems currently associated with rehabilitation following THR