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Sakai D.,Tokai University | Sakai D.,Collaborative Research Partner Annulus Fibrosus Repair Program | Grad S.,AO Research Institute Davos | Grad S.,Collaborative Research Partner Annulus Fibrosus Repair Program
Advanced Drug Delivery Reviews | Year: 2015

The healthy intervertebral disc (IVD) fulfils the essential function of load absorption, while maintaining multi-axial flexibility of the spine. The interrelated tissues of the IVD, the annulus fibrosus, the nucleus pulposus, and the cartilaginous endplate, are characterised by their specific niche, implying avascularity, hypoxia, acidic environment, low nutrition, and low cellularity. Anabolic and catabolic factors balance a slow physiological turnover of extracellular matrix synthesis and breakdown. Deviations in mechanical load, nutrient supply, cellular activity, matrix composition and metabolism may initiate a cascade ultimately leading to tissue dehydration, fibrosis, nerve and vessel ingrowth, disc height loss and disc herniation. Spinal instability, inflammation and neural sensitisation are sources of back pain, a worldwide leading burden that is challenging to cure. In this review, advances in cell and molecular therapy, including mobilisation and activation of endogenous progenitor cells, progenitor cell homing, and targeted delivery of cells, genes, or bioactive factors are discussed. © 2014 Elsevier B.V.


Czekanska E.M.,AO Research Institute Davos
Methods in molecular biology (Clifton, N.J.) | Year: 2011

The Alamar Blue assay is based on enzymatic reduction of indicator dye by viable cells and serves as an effective tool for assessing cell proliferation and as a screening technique. It can be applied in studies concentrating on animal, plant, yeast, and bacteria cells. Among the various methods for cell viability and cytotoxicity, it utilises all features of ideal and reliable test; it is one-step, sensitive, safe, non-toxic for cells, and cost-effective.


Loibl M.,AO Research Institute Davos
Plastic and Reconstructive Surgery | Year: 2016

BACKGROUND:: Application of platelet-rich plasma (PRP) and stem cells has become of importance in regenerative medicine. Recent literature supports the use of PRP as a cell culture media supplement to stimulate proliferation of adipose-tissue derived mesenchymal stem cells (ASCs). The underlying mechanism of proliferation stimulation by PRP has not been investigated so far. METHODS:: ASCs were cultured in α-MEM supplemented with PRP or fetal calf serum (FCS). Cell proliferation was assessed by means of cell cycle kinetics using flow cytometric analyses after 48 hours. Differences in proteome expression of ASCs exposed to PRP or FCS were analysed using a reverse phase protein array (RPPA) to quantify 214 proteins. Complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA) were performed using protein data, and confirmed by Western Blot. RESULTS:: A higher percentage of ASCs in the S-phase in the presence of PRP advocates the proliferation stimulation. IPA and GSEA confirm the involvement of our selected proteins in the process of cell growth and proliferation. IPA revealed a participation in the top-ranked canonical pathways PI3K/AKT, PTEN, ILK, and IGF-1. GSEA identified our protein set as being part of significantly regulated protein sets with the focus on cell cycle, metabolism, and the KEGG TGF-ß Signaling pathway. CONCLUSION:: The present study provides evidence that the application of PRP stimulates proliferation and induces a unique change in the proteomic profile of ASCs. The interpretation of altered expression of regulatory proteins represents a step forward towards achieving good manufacturing practice-compliant criteria for cell-based strategies. ©2016American Society of Plastic Surgeons


Rochford E.T.J.,AO Research Institute Davos | Richards R.G.,AO Research Institute Davos | Moriarty T.F.,AO Research Institute Davos
Clinical Microbiology and Infection | Year: 2012

The use of implanted devices in modern orthopaedic surgery has greatly improved the quality of life for an increasing number of patients, by facilitating the rapid and effective healing of bone after traumatic fractures, and restoring mobility after joint replacement. However, the presence of an implanted device results in an increased susceptibility to infection for the patient, owing to the creation of an immunologically compromised zone adjacent to the implant. Within this zone, the ability of the host to clear contaminating bacteria may be compromised, and this can lead to biofilm formation on the surface of the biomaterial. Currently, there are only limited data on the mechanisms behind this increased risk of infection and the role of material choice. The impacts of implant material on bacterial adhesion, immune response and infection susceptibility have been investigated individually in numerous preclinical in vitro and in vivo studies. These data provide an indication that material choice does have an impact on infection susceptibility; however, the clinical implications remain to be clearly determined. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.


Bara J.J.,AO Research Institute Davos | Richards R.G.,AO Research Institute Davos | Alini M.,AO Research Institute Davos | Stoddart M.J.,AO Research Institute Davos
Stem Cells | Year: 2014

Mesenchymal stem cells (MSCs) are increasingly being used in tissue engineering and cell-based therapies in all fields ranging from orthopedic to cardiovascular medicine. Despite years of research and numerous clinical trials, MSC therapies are still very much in development and not considered mainstream treatments. The majority of approaches rely on an in vitro cell expansion phase in monolayer to produce large cell numbers prior to implantation. It is clear from the literature that this in vitro expansion phase causes dramatic changes in MSC phenotype which has very significant implications for the development of effective therapies. Previous reviews have sought to better characterize these cells in their native and in vitro environments, described known stem cell interactions within the bone marrow, and discussed the use of innovative culture systems aiming to model the bone marrow stem cell niche. The purpose of this review is to provide an update on our knowledge of MSCs in their native environment, focusing on bone marrow-derived MSCs. We provide a detailed description of the differences between naive cells and those that have been cultured in vitro and examine the effect of isolation and culture parameters on these phenotypic changes. We explore the concept of "one step" MSC therapy and discuss the potential cellular and clinical benefits. Finally, we describe recent work attempting to model the MSC bone marrow niche, with focus on both basic research and clinical applications and consider the challenges associated with these new generation culture systems. Stem Cells 2014;32:1713-1723 © 2014 AlphaMed Press.


Stoddart M.J.,AO Research Institute Davos
Methods in molecular biology (Clifton, N.J.) | Year: 2011

The measurement of cell viability plays a fundamental role in all forms of cell culture. Sometimes it is the main purpose of the experiment, such as in toxicity assays. Alternatively, cell viability can be used to -correlate cell behaviour to cell number, providing a more accurate picture of, for example, anabolic -activity. There are wide arrays of cell viability methods which range from the most routine trypan blue dye exclusion assay to highly complex analysis of individual cells, such as using RAMAN microscopy. The cost, speed, and complexity of equipment required will all play a role in determining the assay used. This chapter aims to provide an overview of many of the assays available today.


D'Este M.,AO Research Institute Davos | Eglin D.,AO Research Institute Davos
Acta Biomaterialia | Year: 2013

The combination of hydrogels and calcium phosphate particles is emerging as a well-established trend for bone substitutes. Besides acting as binders for the inorganic phase, hydrogels within these hybrid materials can modulate cell colonization physically and biologically. The influence of hydrogels on the healing process can also be exploited through their capability to deliver drugs and cells for tissue engineering approaches. The aim of this review is to collect some recent progress in this field, with an emphasis on design aspects and possible future directions. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Wagner D.,AO Research Institute Davos
Journal of orthopaedic research : official publication of the Orthopaedic Research Society | Year: 2014

The complex anatomy of the sacrum makes surgical fracture fixation challenging. We developed statistical models to investigate sacral anatomy with special regard to trans-sacral implant fixation. We used computed tomographies of 20 intact adult pelves to establish 3D statistical models: a surface model of the sacrum and the trans-sacral corridor S1, including principal component analysis (PCA), and an averaged gray value model of the sacrum given in Hounsfield Units. PCA demonstrated large variability in sacral anatomy markedly affecting the diameters of the trans-sacral corridors. The configuration of the sacral alae and the vertical position of the auricular surfaces were important determinants of the trans-sacral corridor dimension on level S1. The statistical model of trans-sacral corridor S1 including the adjacent parts of the iliac bones showed main variation in length; however, the diameter was the main criterion for the surgically available corridor. The averaged gray value model revealed a distinct pattern of bone mass distribution with lower density particularly in the sacral alae. These advanced 3D statistical models provide a thorough anatomical understanding demonstrating the impact of sacral anatomy on positioning trans-sacral implants. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Stoddart M.J.,AO Research Institute Davos | Bara J.,AO Research Institute Davos | Alini M.,AO Research Institute Davos
Advanced Drug Delivery Reviews | Year: 2015

Regenerative medicine approaches to cartilage tissue repair have mainly been concerned with the implantation of a scaffold material containing monolayer expanded cells into the defect, with the aim to differentiate the cells into chondrocytes. While this may be a valid approach, the secretome of the implanted cells and its effects on the endogenous resident cells, is gaining in interest. This review aims to summarize the knowledge on the secretome of mesenchymal stem cells, including knowledge from other tissues, in order to indicate how these mechanisms may be of value in repairing articular cartilage defects. Potential therapies and their effects on the repair of articular cartilage defects will be discussed, with a focus on the transition from classical cell therapy to the implantation of cell free matrices releasing specific cytokines. © 2014 Elsevier B.V.


There is great interest in how bone marrow derived stem cells make fate decisions. Numerous studies have investigated the role of individual growth factors on mesenchymal stem cell differentiation, leading to protocols for cartilage, bone and adipose tissue. However, these protocols overlook the role of biomechanics on stem cell differentiation. There have been various studies that have applied mechanical stimulation to constructs containing mesenchymal stem cells, with varying degrees of success. One critical fate decision is that between cartilage and bone. Articular motion is a combination of compressive, tensile and shear deformations; therefore, one can presume that compression alone is unlikely to be a sufficient mechanical signal to generate a cartilage-like tissue in vitro. Within this study, we aimed to determine the role of shear on the fate of stem cell differentiation. Specifically, we investigated the potential enhancing effect of surface shear, superimposed on cyclic axial compression, on chondrogenic differentiation of human bone marrow-derived stem cells. Using a custom built loading device we applied compression, shear or a combination of both stimuli onto fibrin/polyurethane composites in which human mesenchymal stem cells were embedded, while no exogenous growth-factors were added to the culture medium. Both compression or shear alone was insufficient for the chondrogenic induction of human mesenchymal stem cells. However, the application of shear superimposed upon dynamic compression led to significant increases in chondrogenic gene expression. Histological analysis detected sulphated glycosaminoglycan and collagen II only in the compression and shear group. The results obtained may provide insight into post-operative care after cell therapy involving mesenchymal stromal cells.

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