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Respiratory syncytial virus is a common cause of illness and hospitalization, especially among infants and immunocompromised persons, but there are no accepted antiviral therapies. In this RSV challenge study, GS-5806, a new compound, showed activity against RSV. Respiratory syncytial virus (RSV) infection accounts for substantial morbidity and mortality among infants 1 – 7 and is the most common reason for hospitalization of infants in the United States, 8 with an even greater outpatient burden of disease. Estimates indicate that among children younger than 2 years of age, the annual rate of RSV-related hospitalization is 5.2 per 1000, the rate of emergency department encounters is 32 to 57 per 1000, and the rate of outpatient visits is 66 to 177 per 1000. 2 Among infants younger than 1 year of age, the risk of death from respiratory causes is increased by a . . .

Bone marrow–derived mesenchymal stem cells (MSCs) have demonstrated potential for regenerative medicine strategies. Knowledge of the way these cells respond to their environment in in vitro culture and after implantation in vivo is crucial for successful therapy. Oxygen tension plays a pivotal role in both situations. In vivo , a hypoxic environment can lead to apoptosis, but hypoxic preconditioning of MSCs and overexpression of prosurvival genes like Akt can reduce hypoxia-induced cell death. In cell culture, hypoxia can increase proliferation rates and enhance differentiation along the different mesenchymal lineages. Hypoxia also modulates the paracrine activity of MSCs, causing upregulation of various secretable factors, among which are important angiogenic factors such as vascular endothelial growth factor and interleukin-6 ( IL6 ). Finally, hypoxia plays an important role in mobilization and homing of MSCs, primarily by its ability to induce stromal cell–derived factor-1 expression along with its receptor CXCR4 . This article reviews the current literature on the effects of hypoxia on MSCs and aims to elucidate its potential role in regenerative medicine strategies.

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions.

Background Bone grafts are required to repair large bone defects after tumour resection or large trauma. The availability of patients' own bone tissue that can be used for these procedures is limited. Thus far bone tissue engineering has not lead to an implant which could be used as alternative in bone replacement surgery. This is mainly due to problems of vascularisation of the implanted tissues leading to core necrosis and implant failure. Recently it was discovered that embryonic stem cells can form bone via the endochondral pathway, thereby turning in-vitro created cartilage into bone in-vivo. In this study we investigated the potential of human adult mesenchymal stem cells to form bone via the endochondral pathway. Methods MSCs were cultured for 28 days in chondrogenic, osteogenic or control medium prior to implantation. To further optimise this process we induced mineralisation in the chondrogenic constructs before implantation by changing to osteogenic medium during the last 7 days of culture. Results After 8 weeks of subcutaneous implantation in mice, bone and bone marrow formation was observed in 8 of 9 constructs cultured in chondrogenic medium. No bone was observed in any samples cultured in osteogenic medium. Switch to osteogenic medium for 7 days prevented formation of bone in-vivo. Addition of β-glycerophosphate to chondrogenic medium during the last 7 days in culture induced mineralisation of the matrix and still enabled formation of bone and marrow in both human and rat MSC cultures. To determine whether bone was formed by the host or by the implanted tissue we used an immunocompetent transgenic rat model. Thereby we found that osteoblasts in the bone were almost entirely of host origin but the osteocytes are of both host and donor origin. Conclusions The preliminary data presented in this manuscript demonstrates that chondrogenic priming of MSCs leads to bone formation in vivo using both human and rat cells. Furthermore, addition of β-glycerophosphate to the chondrogenic medium did not hamper this process. Using transgenic animals we also demonstrated that both host and donor cells played a role in bone formation. In conclusion these data indicate that in-vitro chondrogenic differentiation of human MSCs could lead to an alternative and superior approach for bone tissue engineering.

Osteoarthritis (OA), the most common form of arthritis, is a disabling degenerative joint disease affecting synovial joints and is associated with cartilage destruction, inflammation of the synovial membrane, and subchondral bone remodeling. Inflammation of the synovial membrane may arise secondary to degenerative processes in articular cartilage (AC), or may be a primary occurrence in OA pathogenesis. However, synovial inflammation plays a key role in the pathogenesis and disease progression of OA through the production of pro-inflammatory mediators, and is associated with cartilage destruction and pain. The triggers that initiate activation of the immune response in OA are unknown, but crosstalk between osteoarthritic chondrocytes, cartilage degradation products, and the synovium may act to perpetuate this response. Increasing evidence has emerged highlighting an important role for pro-inflammatory mediators and infiltrating inflammatory cell populations in the progression of the disease. Tissue engineering strategies hold great potential for the repair of damaged AC in an osteoarthritic joint. However, an in-depth understanding of how OA-associated inflammation impacts chondrocyte and progenitor cell behavior is required to achieve efficient cartilage regeneration in a catabolic osteoarthritic environment. In this review, we will discuss the role of inflammation in OA, and investigate novel immune modulation strategies that may prevent disease progression and facilitate successful cartilage regeneration for the treatment of OA.

With this research topic we provide an overview of the main tools regenerative medicine and stem cells research have to better understand and modulate bone and cartilage cell fate, both during natural healing processes and during the development of joint pathologies. [...]the contribution to the research topic with original research articles allow a further exploration toward the most advanced research in the field. Specifically,Hendrikson et al. show how different scaffold architectures have significant influence on stress and strain distribution, but also on the effective pore size and shape, which subsequently influence the fluid shear stress distribution.Angelozzi et al.discuss how the use of microfibrous alginate scaffolds containing gelatin or the more innovative urinary bladder matrix (UBM) are able to stimulate dedifferentiated chondrocyte to re-acquire their natural phenotype. [...]as highlighted byAnderson and Johnstone, the lack of standardized methods and analysis to study chondrogenic differentiation and maintenance under this mechanical regimes make the comparison between the current literature difficult.

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

This paper presents the findings of a study into the engineering properties of two peats from the Irish Midlands that were mixed with various binders to form a stabilized soil. The study comprised an investigation of the increase in unconfined compressive strength over time achieved using different binders for both peats and a comprehensive series of triaxial and compression tests on one peat when mixed with cement. A stabilized structure (i.e., a stabilized surface layer and a stabilized column) was tested in a large testing chamber in Trinity College to compare the laboratory parameters with those interpreted from the results of the large-scale test. The study showed that the engineering properties of the peat were considerably improved when mixed with some binders, however the degrees of improvement were markedly different for the two peats that had similar organic content. The formation of the stabilized soil structure within the testing chamber significantly reduced the amount of settlement when compared with that interpreted for the untreated soil, and the rate of consolidation was accelerated. A finite element analysis of the recorded behaviour in the large testing chamber showed good agreement between the simulated and the experimental behaviour.Key words: peat, cement, stabilization, compressibility, column.

Tissue engineering approaches using progenitor cells such as mesenchymal stromal cells (MSCs) represent a promising strategy to regenerate bone. Previous work has demonstrated the potential of chondrogenically primed human MSCs to recapitulate the process of endochondral ossification and form mature bone in vivo , using immunodeficient xenogeneic models. To further the translation of such MSC-based approaches, additional investigation is required to understand the impact of interactions between human MSC constructs and host immune cells upon the success of MSC-mediated bone formation. Although human MSCs are considered hypoimmunogenic, the potential of chondrogenically primed human MSCs to induce immunogenic responses in vivo , as well as the efficacy of MSC-mediated ectopic bone formation in the presence of fully competent immune system, requires further elucidation. Therefore, the aim of this study was to investigate the capacity of chondrogenically primed human MSC constructs to persist and undergo the process of endochondral ossification in an immune competent xenogeneic model. Chondrogenically differentiated human MSC pellets were subcutaneously implanted to wild-type BALB/c mice and retrieved at 2 and 12 weeks post-implantation. The percentages of CD4 + and CD8 + T cells, B cells, and classical/non-classical monocyte subsets were not altered in the peripheral blood of mice that received chondrogenic MSC constructs compared to sham-operated controls at 2 weeks post-surgery. However, MSC-implanted mice had significantly higher levels of serum total IgG compared to sham-operated mice at this timepoint. Flow cytometric analysis of retrieved MSC constructs identified the presence of T cells and macrophages at 2 and 12 weeks post-implantation, with low levels of immune cell infiltration to implanted MSC constructs detected by CD45 and CD3 immunohistochemical staining. Despite the presence of immune cells in the tissue, MSC constructs persisted in vivo and were not degraded/resorbed. Furthermore, constructs became mineralised, with longitudinal micro-computed tomography imaging revealing an increase in mineralised tissue volume from 4 weeks post-implantation until the experimental endpoint at 12 weeks. These findings indicate that chondrogenically differentiated human MSC pellets can persist and undergo early stages of endochondral ossification following subcutaneous implantation in an immunocompetent xenogeneic model. This scaffold-free model may be further extrapolated to provide mechanistic insight to osteoimmunological processes regulating bone regeneration and homeostasis.