| |  | | | | | | | | | | | | | | | |  | | | | | | | | | | | | | | | | | | | | | | | | Numerical assessment on the effective mechanical stimuli for matrix-associated metabolism in chondrocyte-seeded constructs. J Tissue Eng Regen Med. 2010 Aug 4; Authors: Tasci A, Ferguson SJ, Büchler P The self-regeneration capacity of articular cartilage is limited, due to its avascular and aneural nature. Loaded explants and cell cultures demonstrated that chondrocyte metabolism can be regulated via physiologic loading. However, the explicit ranges of mechanical stimuli that correspond to favourable metabolic response associated with extracellular matrix (ECM) synthesis are elusive. Unsystematic protocols lacking this knowledge produce inconsistent results. This study aims to determine the intrinsic ranges of physical stimuli that increase ECM synthesis and simultaneously inhibit nitric oxide (NO) production in chondrocyte-agarose constructs, by numerically re-evaluating the experiments performed by Tsuang et al. (2008). Twelve loading patterns were simulated with poro-elastic finite element models in ABAQUS. Pressure on solid matrix, von Mises stress, maximum principle stress and pore pressure were selected as intrinsic mechanical stimuli. Their development rates and magnitudes at the steady state of cyclic loading were calculated with MATLAB at the construct level. Concurrent increase in glycosaminoglycan and collagen was observed at 2300 Pa pressure and 40 Pa/s pressure rate. Between 0-1500 Pa and 0-40 Pa/s, NO production was consistently positive with respect to controls, whereas ECM synthesis was negative in the same range. A linear correlation was found between pressure rate and NO production (R = 0.77). Stress states identified in this study are generic and could be used to develop predictive algorithms for matrix production in agarose-chondrocyte constructs of arbitrary shape, size and agarose concentration. They could also be helpful to increase the efficacy of loading protocols for avascular tissue engineering. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID: 20684030 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Mutations in GDF5 presenting as semi-dominant Brachydactyly A1. Hum Mutat. 2010 Aug 3; Authors: Byrnes AM, Racacho L, Nikkel SM, Xiao F, Macdonald H, Underhill TM, Bulman DE Brachydactyly A1 (BDA1) is an autosomal dominant disorder characterized by shortness of all middle phalanges of the hands and toes, shortness of the proximal phalanges of the first digit, and short stature. Missense mutations in the Indian Hedgehog gene (IHH) are known to cause BDA1, and a second locus has been mapped to chromosome 5p. In a consanguineous French Canadian kindred with BDA1, both IHH and the 5p locus were excluded. Microsatellites flanking GDF5 on chromosome 20q were found to cosegregate with the disease. Sequencing of the GDF5 coding region revealed that a mildly affected individual in the family was heterozygous and that all of the severely affected individuals were homozygous for a novel missense c.1195C>T mutation that predicts a p.Arg399Cys substitution at a highly conserved amino acid. Functional analysis demonstrated that while the p.Arg399Cys mutant is able to stimulate chondrogenesis, it is much less effective than wild-type GDF5. This data confirms genetic heterogeneity in BDA1, demonstrates that mutations upstream of IHH can result in BDA1 and shows that BDA1 can result from semi-dominant mutations in GDF5. (c) 2010 Wiley-Liss, Inc. PMID: 20683927 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 2010 Aug 4; Authors: Wu SC, Zhang Y DNA methylation is one of the best-characterized epigenetic modifications and has been implicated in numerous biological processes, including transposable element silencing, genomic imprinting and X chromosome inactivation. Compared with other epigenetic modifications, DNA methylation is thought to be relatively stable. Despite its role in long-term silencing, DNA methylation is more dynamic than originally thought as active DNA demethylation has been observed during specific stages of development. In the past decade, many enzymes have been proposed to carry out active DNA demethylation and growing evidence suggests that, depending on the context, this process may be achieved by multiple mechanisms. Insight into how DNA methylation is dynamically regulated will broaden our understanding of epigenetic regulation and have great implications in somatic cell reprogramming and regenerative medicine. PMID: 20683471 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Design of a Bioartificial Pancreas+ J Investig Med. 2010 Jul 30; Authors: Opara EC, Mirmalek-Sani SH, Khanna O, Moya ML, Brey EM INTRODUCTION:: In type 1 diabetes, the beta-cells that secrete insulin have been destroyed such that daily exogenous insulin administration is required for the control of blood glucose in individuals with the disease. After the development of reliable techniques for the isolation of islets from the human pancreas, islet transplantation has emerged as a therapeutic option, albeit for only a few selected patients largely because there are not enough islets for the millions of patients requiring the treatment, and there is also the need to use immunosuppressive drugs to prevent transplant rejection. In 1980, the concept of islet immunoisolation by microencapsulation was introduced as a technique to overcome these 2 major barriers to islet transplantation. Microencapsulation of islets and transplantation in the peritoneal cavity was then described as a bioartificial pancreas. However, it is difficult to retrieve encapsulated islets transplanted in the peritoneal cavity, thus making it difficult to meet all the criteria for a bioartificial pancreas. A new design of a bioartificial pancreas comprising islets co-encapsulated with angiogenic protein in permselective multilayer alginate-poly-L-ornithine-alginate microcapsules and transplanted in an omentum pouch is described in this paper. MATERIALS AND METHODS:: The multilayer alginate-poly-L-ornithine-alginate microcapsules are made with ultrapure alginate using poly-L-ornithine as a semipermeable membrane separating the 2 alginate layers. The inner alginate layer is used to encapsulate the islets, and the outer layer is used to encapsulate angiogenic protein, which would induce neovascularization around the graft within the omentum pouch. RESULTS:: In in vitro studies, we found that both the wild-type and the heparin-binding growth-associated molecule (HBGAM)-fibroblast growth factor-1 chimera can be encapsulated and released in a controlled and sustained manner from the outer alginate layer with a mean diameter in the range of 113 to 164 microm when 1.25% high guluronic acid alginate is used to formulate this outer layer. DISCUSSION:: We are currently performing in vivo experiments to determine the ability of angiogenic proteins released from this outer layer to induce neovascularization around the grafts in the omentum pouch. We will subsequently examine the effect of co-encapsulation of islets with angiogenic protein on blood glucose control in diabetic animals. It is hoped that addition of tissue engineering to encapsulated islet transplantation will result in long-term survival of the islets and their ability to control blood glucose in type 1 diabetes without the necessity to use risky immunosuppressive drugs to prevent transplant rejection. PMID: 20683347 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Using a Type 1 Collagen-Based System to Understand Cell-Scaffold Interactions and to Deliver Chimeric Collagen-Binding Growth Factors for Vascular Tissue Engineering. J Investig Med. 2010 Jul 30; Authors: Pang Y, Greisler HP Vascular tissue engineering should provide more biocompatible and functional conduits than synthetic vascular grafts. Understanding cell-scaffold interactions and developing an efficient delivery system for growth factors and other biomolecules to control the signaling between the cells and the scaffold are fundamental issues in a wide range of tissue engineering research fields. Type 1 collagen is a natural scaffold extensively used in vascular tissue engineering and is a widely used vehicle in biomolecule delivery. In this article, we will discuss type 1 collagen as a vascular tissue engineering scaffold, describe strategies for elucidating the interaction between cells and type 1 collagen scaffolds using various imaging techniques, and summarize our work on the development of a chimeric collagen-binding growth factor-based local delivery system. PMID: 20683346 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Cardiac Involvement in Patients With Hematologic Malignancies. J Investig Med. 2010 Jul 30; Authors: Allegra A, Alonci A, Russo S, Cannavò A, Penna G, D'Angelo A, Bellomo G, Musolino C Authors have reviewed literature about the management of patients with cardiologic disease occurring secondary to hematologic pathology itself or its therapy, with a focus on infiltration of myocardium in acute and chronic leukemia, lymphoma, multiple myeloma, and hypereosinophilic syndrome. Moreover, they evaluated chemotherapy-associated toxicity, particularly for new drugs such as monoclonal antibody therapy, tyrosine kinase inhibitors, arsenic trioxide, bortezomib, and epigenetic therapy. In fact, cardiac toxicity may range from asymptomatic subclinical abnormalities, such as electrocardiographic changes and left ventricular ejection decline, to life-threatening events and lead to chemotherapy dose reduction and delay and, in some cases, for patients with severe side effects, discontinuation of treatment.Finally, they discussed on the identification of early markers of cardiac injury and on cardiac stem cell therapy as a promising approach to facilitate myocardial regeneration. PMID: 20683345 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Regenerative Medicine: Basic Concepts, Current Status, and Future Applications. J Investig Med. 2010 Jul 30; Authors: Corona BT, Ward CL, Harrison BS, Christ GJ A recent report demonstrated that a laboratory-grown neobladder tissue could be successfully used for cystoplasty in young patients with myelomeningocele who were otherwise healthy. This remarkable achievement portends well for the application of tissue engineering/regenerative medicine technologies to the treatment of end-organ failure due to a variety of causes (ie, congenital, acquired, age or disease related). Nonetheless, the broader clinical use of these groundbreaking technologies awaits improved understanding of endogenous regenerative mechanisms, more detailed knowledge of the boundary conditions that define the current limits for tissue repair and replacement in vivo, and the parallel development of critical enabling technologies (ie, improved cell source, biomaterials, bioreactors). This brief report will review a number of the most salient features and recent developments in this rapidly advancing area of medical research and detail some of our own experience with bladder and skeletal muscle regeneration and replacement as examples that highlight both the promise and challenges facing regenerative medicine/tissue engineering. PMID: 20683344 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Strategies for Vascularization of Polymer Scaffolds. J Investig Med. 2010 Jul 30; Authors: Papavasiliou G, Cheng MH, Brey EM Biocompatible, degradable polymer scaffolds combined with cells or biological signals are being investigated as alternatives to traditional options for tissue reconstruction and transplantation. These approaches are already in clinical use as engineered tissues that enhance wound healing and skin regeneration. The continued enhancement of these material strategies is highly dependent on the ability to promote rapid and stable neovascularization (new blood vessel formation) within the scaffold. Whereas neovascularization therapies have shown some promise for the treatment of ischemic tissues, vascularization of polymer scaffolds in tissue engineering strategies provides a unique challenge owing to the volume and the complexity of the tissues targeted. In this article, we examine recent advances in research focused on promoting neovascularization in polymer scaffolds for tissue engineering applications. These approaches include the use of growth factors, cells, and novel surgical approaches to both enhance and control the nature of the vascular networks formed. The continued development of these approaches may lead to new tissue engineering strategies for the generation of skin and other tissues or organs. PMID: 20683343 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Analysis of power law models for the creep of nucleus pulposus tissue. Biorheology. 2010 Jan 1;47(2):143-51 Authors: Agosti CD, Bell KM, Plazek DJ, Larson J, Kang JD, Gilbertson LG, Smolinski P Tissue engineering approaches are now being investigated for altering the course of intervertebral disc degeneration (IDD). Because the disease changes the mechanical properties of the load bearing tissues of the disc, viscoelastic tissue behavior is a key measure for comparing the efficacy of treatments. To investigate the basic viscoelastic behavior of nucleus pulposus tissue, tissue from the rabbit disc was tested in torsional creep. Both the Andrade and Nutting creep models had a good fit to the data, however, the Andrade creep model gave a much better prediction of the longer term creep. This is the first application of Andrade creep to biological tissue and results indicate that this model may be particularly well suited for characterizing the viscoelastic behavior of very soft biological tissues. PMID: 20683157 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Special issue featuring articles from the 7th China-Korea Symposium on Biomaterials and Nano-Biotechnology. Biomed Mater. 2010 Aug;5(4):040201 Authors: Gu N, Yang HC Novel biomaterials are expected to provide us with more effective and safer ways to treat diseases that are threatening the lives of patients, or eroding their quality of life. As the walls between the fields of science break down, research into biomaterials, which requires multidisciplinary knowledge, is receiving unlimited opportunities in resources and for information sharing, leading to the development of innovative materials. Undoubtedly, nano-biotechnology is providing scientific breakthroughs in the field of biomaterials, and vice versa. In this vein, the articles featured in this special issue reflect the desire to share ideas, and the current state of research into biomaterials and nano-biotechnology in China and Korea, whilst providing a snapshot of the types of research being undertaken. The articles were peer reviewed and selected from the 7th China-Korea Symposium on Biomaterials and Nano-Biotechnology, held in Nanjing and Suzhou, People's Republic of China, on 19-23 October 2009. The symposium topics covered biopolymers, bioceramics, biometals, biocompatibility of biomaterials, tissue engineering and nano-biotechnology. Scientists from various universities and research institutes in both countries attended the symposium and shared their experiences and ideas for future cooperation on biomaterials and nano-biotechnology research. The symposium was supported financially by the National Natural Science Foundation of China (NSFC) and the Korea Science and Engineering Foundation (KOSEF). We would like to express our thanks to all the authors for contributing to this special issue, and to Professors F-Z Cui, I-S Lee, and M Spector, the Editors-in-Chief of Biomedical Materials, for arranging the publication of these articles in this issue. PMID: 20683146 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Investigation of the cytotoxicity mechanism of silver nanoparticles in vitro. Biomed Mater. 2010 Aug;5(4):044103 Authors: Wei L, Tang J, Zhang Z, Chen Y, Zhou G, Xi T Nowadays, more and more nanotechnology products and nanomaterials are being applied in our lives. Silver nanoparticles (SNPs) are used in infection prevention and treatment due to their antimicrobial activity. However, as a kind of nanomaterial, the toxicology of SNPs has not been completely studied. The mechanism of cytotoxicity of SNPs in vitro to mouse's fibroblast cells (L929) was investigated in this study. As a contrast, silver microparticles (SMPs) were also studied. Propidium iodide (PI) single staining and Annexin-V/PI staining were carried out to unveil the influence of SNPs and SMPs on the cells. A transmission electron microscope (TEM) was used to observe SNPs' distribution in the cells. The results of cell cycle analysis indicated that the cells treated with SNPs were arrested in the G2M phase. Meanwhile, SNPs lead to apoptosis of more cells compared to SMPs at the same dose as a result of apoptosis analysis. Analysis of the cells' ultrastructure showed that SNPs could be phagocytized into the cells while SMPs could not. The mechanism of cytotoxicity of SNPs in vitro to L929 cells may be that SNPs are phagocytized into the cells and they interact with mitochondria or other organelles, even nuclei, which results in cells' apoptosis or necrosis. PMID: 20683123 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Lab-Specific Gene Expression Signatures in Pluripotent Stem Cells. Cell Stem Cell. 2010 Aug 6;7(2):258-262 Authors: Newman AM, Cooper JB Pluripotent stem cells derived from both embryonic and reprogrammed somatic cells have significant potential for human regenerative medicine. Despite similarities in developmental potential, however, several groups have found fundamental differences between embryonic stem cell (ESC) and induced-pluripotent stem cell (iPSC) lines that may have important implications for iPSC-based medical therapies. Using an unsupervised clustering algorithm, we further studied the genetic homogeneity of iPSC and ESC lines by reanalyzing microarray gene expression data from seven different laboratories. Unexpectedly, this analysis revealed a strong correlation between gene expression signatures and specific laboratories in both ESC and iPSC lines. Nearly one-third of the genes with lab-specific expression signatures are also differentially expressed between ESCs and iPSCs. These data are consistent with the hypothesis that in vitro microenvironmental context differentially impacts the gene expression signatures of both iPSCs and ESCs. PMID: 20682451 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Transient Inactivation of Rb and ARF Yields Regenerative Cells from Postmitotic Mammalian Muscle. Cell Stem Cell. 2010 Aug 6;7(2):198-213 Authors: Pajcini KV, Corbel SY, Sage J, Pomerantz JH, Blau HM An outstanding biological question is why tissue regeneration in mammals is limited, whereas urodele amphibians and teleost fish regenerate major structures, largely by cell cycle reentry. Upon inactivation of Rb, proliferation of postmitotic urodele skeletal muscle is induced, whereas in mammalian muscle this mechanism does not exist. We postulated that a tumor suppressor present in mammals but absent in regenerative vertebrates, the Ink4a product ARF (alternative reading frame), is a regeneration suppressor. Concomitant inactivation of Arf and Rb led to mammalian muscle cell cycle reentry, loss of differentiation properties, and upregulation of cytokinetic machinery. Single postmitotic myocytes were isolated by laser micro-dissection-catapulting, and transient suppression of Arf and Rb yielded myoblast colonies that retained the ability to differentiate and fuse into myofibers upon transplantation in vivo. These results show that differentiation of mammalian cells is reversed by inactivation of Arf and Rb and support the hypothesis that Arf evolved at the expense of regeneration. PMID: 20682446 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche. Cell Stem Cell. 2010 Aug 6;7(2):150-161 Authors: Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche. PMID: 20682444 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Differential DNA Damage Response in Stem and Progenitor Cells. Cell Stem Cell. 2010 Aug 6;7(2):145-147 Authors: Seita J, Rossi DJ, Weissman IL The long lifespan of tissue-specific stem cells suggests that they may respond differently to DNA damage than downstream cells. In this issue of Cell Stem Cell, two groups address this hypothesis by examining DNA damage responses in hematopoietic stem and progenitor cells (Milyavsky et al., 2010; Mohrin et al., 2010). PMID: 20682442 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | There's No Place Like Home for a Neural Stem Cell. Cell Stem Cell. 2010 Aug 6;7(2):141-143 Authors: Siegenthaler JA, Pleasure SJ Neural precursor cells (NPCs) reside in the subventricular zone in association with blood vessels and ependymal cells. In this issue of Cell Stem Cell, Kokovay et al. (2010) show that SDF1 directs the association of NPCs with this niche and regulates their lineage progression in a stage-specific manner. PMID: 20682440 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Hematopoietic stem cell lodgment in the adult bone marrow stem cell niche. Int J Lab Hematol. 2010 Aug 2; Authors: Lam BS, Adams GB Summary Treatment of malignant blood disorders, such as leukemia, that can provide a better chance of long-term remission involves myeloablation followed by transplantation of matched donor hematopoietic stem cells (HSCs). For successful engraftment and re-establishment of hematopoiesis to occur in the recipient, the transplanted HSCs must first migrate from the blood circulation to the bone marrow (BM), a process known as homing, then localize and anchor in suitable microenvironments within the BM, a process known as lodgment. After lodgment, the specific fate of the transplanted HSCs is determined through complex, bidirectional interactions with various stromal cell components in the niche. Ultimately, these interactions dictate the clinical outcome of the transplantation. Through the use of transgenic mouse models, considerable evidence has been accumulated in an attempt to unveil the possible underlying mechanisms that govern these processes. Here, we will emphasize the major factors that are involved in the regulation of lodgment of transplanted HSCs. Specifically, we will first introduce early observations on the spatial distribution of hematopoietic progenitors within the BM, then we will discuss the soluble factors, chemokines, cell-cell interactions, and cell-matrix interactions that have been studied and known to influence the site of HSC lodgment within the BM following transplantation. PMID: 20682000 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. Clin Genet. 2010 Jul 6; Authors: Lagali P, Corcoran CP, Picketts DJ Lagali PS, Corcoran CP, Picketts DJ. Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. The hippocampus is a primary region of the brain controlling the formation of memories and learned behaviours. The ability to learn or form a memory requires a neuron to translate a transient signal into gene expression changes that have a long-lasting effect on synapse activity and connectivity. Numerous studies over the past decade have detailed changes in epigenetic modifications under various learning paradigms to support a role for chromatin remodelling in these processes. Moreover, the identification of mutations in epigenetic regulators as the cause of mental retardation or intellectual disability (MR/ID) disorders further strengthens their importance to learning and memory. Animal models for many of these disorders are emerging and advancing our understanding of the molecular mechanisms linking epigenetic regulation and cognitive function. Here, we review how chromatin remodelling proteins implicated in MR/ID contribute to the development of the hippocampus and memory formation. PMID: 20681996 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Expression and secretion of interleukin-1beta, tumour necrosis factor-alpha and interleukin-10 by hypoxia- and serum-deprivation-stimulated mesenchymal stem cells. FEBS J. 2010 Jul 30; Authors: Li Z, Wei H, Deng L, Cong X, Chen X To understand the potential paracrine roles of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), the expression and secretion of these factors by rat bone marrow-derived mesenchymal cells stimulated by hypoxia (4% oxygen) and serum deprivation (hypoxia/SD) were investigated. We found that hypoxia/SD induced nuclear factor kappa Bp65-dependent IL-1beta and TNF-alpha transcription. Furthermore, hypoxia/SD stimulated the translation of pro-IL-1beta and its processing to mature IL-1beta, although the translation of TNF-alpha was unchanged. Unexpectedly, the release of IL-1beta and TNF-alpha from hypoxia/SD-stimulated mesenchymal cells was undetectable unless ATP or lipopolysaccharide was present. This result suggests that IL-1beta and TNF-alpha are not responsible for the paracrine effects of mesenchymal cells under ischaemic conditions. We also found that hypoxia/SD induced the transcription and secretion of IL-10, which were significantly enhanced by lipopolysaccharide and the proteasomal inhibitor MG132. Moreover, both the conditioned medium from hypoxia/SD-stimulated mesenchymal cells (MSC-CM) and IL-10 efficiently inhibited cardiac fibroblast proliferation and collagen expression in vitro, suggesting that mesenchymal cell-secreted IL-10 prevents cardiac fibrosis in a paracrine manner under ischaemic conditions. Taken together, these findings may improve understanding of the cellu-lar and molecular basis of the anti-inflammatory and paracrine effects of mesenchymal cells. PMID: 20681988 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Nanoparticles based on PLGA:poloxamer blends for the delivery of proangiogenic growth factors. Mol Pharm. 2010 Aug 3; Authors: d'Angelo I, Garcia-Fuentes M, Parajo Y, Welle A, Vantus T, Horvath A, Bökönyi G, Kéri G, Alonso MJ New blood vessel formation is a critical requirement for treating many vascular and ischemia related diseases, as well as for many tissue engineering applications. Angiogenesis and vasculogenesis, in fact, represent crucial processes for the functional regeneration of complex tissues through tissue engineering strategies. Several growth factors (GFs) and signalling molecules involved in blood vessels formation have been identified, but their application to the clinical setting is still strongly limited by their extremely short half-life in the body. To overcome these limitations, we have developed a new injectable controlled release device based on polymeric nanoparticles for the delivery of two natural proangiogenic GFs: Platelet Derived Growth Factor (PDGF-BB) and Fibroblast Growth Factor (FGF-2). The nanoparticle system was prepared by a modified solvent diffusion technique, encapsulating the GF both in presence and in the absence of two stabilizing agents: bovine serum albumin (BSA) and heparin sodium salt (Hp). The developed nanocarriers were characterized for morphology, size, encapsulation efficiency, release kinetics in vitro and GF activity in cell cultures. The results have indicated that the co-encapsulation of stabilizing agents can preserve the GF active structure and, in addiction, increase their encapsulation efficiency into nanoparticles. Through this optimization process, we were able to raise the encapsulation efficiency of FGF-2 to 63%, and that of PDGF-BB to 87%. These PLGA:poloxamer blend nanoparticles loaded with GFs were able to release PDGF-BB and FGF-2 in a sustained fashion for more than a month. This works also confirms other positive features of PLGA:poloxamer nanoparticles. Namely, they are able to maintain their stability in simulated biological medium, and they are also non-toxic to cell culture models. Incubation of nanoparticles loaded with FGF-2 or PDGF-BB with endothelial cell culture models have confirmed that GFs are released in a bioactive form. Altogether, these results underline the interest of PLGA:poloxamer nanoparticles for the controlled delivery of GFs and substantiate their potential for the treatment of ischemic diseases and for tissue engineering applications. PMID: 20681555 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Comparison of development of heterotopic ossification in injured US and UK Armed Services personnel with combat-related amputations: preliminary findings and hypotheses regarding causality. J Trauma. 2010 Jul;69 Suppl 1:S116-22 Authors: Brown KV, Dharm-Datta S, Potter BK, Etherington J, Mistlin A, Hsu JR, Clasper JC BACKGROUND: Recent reports have documented the rate of heterotopic ossification (HO) formation in the residual limbs of combat-related amputees from the US Armed Forces injured in Operations Iraqi and Enduring Freedom. Final amputation level within the zone of injury and blast as the mechanism of injury were identified as possible risk factors for the occurrence and grade of HO. There has been no previous description of HO in combat-related amputees from the UK service personnel. The purpose of this study was to examine potential differences in the prevalence of HO between UK and US Allied Forces, with particular attention to these risk factors, patient exposures, and any treatment differences between these two groups. METHODS: We reviewed the medical records and radiographs of 35 combat-related amputations from the UK and contrasted them with 213 previously reported amputations in US military personnel. We evaluated prevalence and severity of residual limb HO, Injury Severity Score (ISS), the mechanism and zone of injury, type and level of amputation, number of debridements, method of wound irrigation, presence of severe head injury and/or burns injury, use of topical negative pressure therapy and pulse lavage, number of days until wound closure, type of closure, and subsequent infections. All patients had a minimum of 2-month posthospital discharge radiographic follow-up. Comparisons were made using Fisher's exact, one-way analysis of variance, and chi2 analyses. RESULTS: There was no significant difference in either the overall prevalence of HO or the prevalence of moderate to severe HO in the two populations. Twenty of 35 (57.1%) limbs in the UK amputations developed HO compared with 134 of 213 (63%) in the US amputations (p > 0.05). The UK amputations had 12 cases (34.3%) of moderate to severe HO compared with 72 cases (33.8%) in the US amputations (p > 0.05). However, there was a significant difference in the number of UK amputations 0 of 20 (0%) versus the number of US amputations 25 of 134 (12%; p = 0.04), which required excision of symptomatic lesions. There was a significant association in the development of HO in UK personnel with the use of topical negative pressure treatment (p = 0.05) and increasing ISS scores (p = 0.04) and in the development of moderate to severe HO with increasing ISS (p = 0.006) and severe HI (p = 0.04). Unlike in the previous report, no significant association was found in UK personnel between any of the remaining hypothesized risk factors and either the presence or grade of HO. CONCLUSIONS: Although no difference was identified in the overall prevalence of HO, there are inconsistencies in the possible underlying causes of HO between the two cohorts. Further research is required in an ongoing effort to determine a causal relationship between treatment and subsequent HO formation. PMID: 20622605 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Infectious complications of combat-related mangled extremity injuries in the British military. J Trauma. 2010 Jul;69 Suppl 1:S109-15 Authors: Brown KV, Murray CK, Clasper JC BACKGROUND: During the wars in Iraq and Afghanistan, extremity injuries have predominated; however, no systematic review of field and stabilization care with subsequent infectious complications exists. This study evaluates the infectious complications and possible risk factors of British military casualties with mangled extremities, highlighting initial care and infections. METHODS: This is a retrospective cohort study of British military casualties in Iraq and Afghanistan between August 2003 and May 2008. Casualties with mangled extremities undergoing limb salvage were evaluated for management strategies at the time of injury through evacuation back to the United Kingdom and subsequent infections. RESULTS: There were 84 casualties with 85 extremities (20 infected and 65 uninfected). Infected extremities had more Gustilo Classification IIIb. There were no differences by Injury Severity Score, age, durations from injury to evacuation, or surgery, or arrival in England, use of clotting materials, or method of extremity stabilization between infected and uninfected extremity injuries. Tourniquet use in the field and fasciotomy were associated with infections. Antimicrobial coverage was associated with infections. Staphylococcus aureus were recovered later in casualties' clinical course in contrast to early recovery of Acinetobacter. On multivariate analysis, tourniquet in the field, antibiotics during evacuation and in the operating room, and fasciotomy were associated with infection as were certain bacteria, notably, Pseudomonas aeruginosa. CONCLUSION: Infections occurred in 24% of those with mangled extremities including 6% with osteomyelitis. Certain procedures, likely reflective of injury severity, were associated with infections along with certain bacteria, P. aeruginosa and possibly S. aureus. Continued clarification is required for antimicrobial coverage (penicillin-based regimens vs. additional anaerobic coverage) and certain surgical procedures to improve casualty care. PMID: 20622604 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Gene expression profiling of primary human articular chondrocytes in high-density micromasses reveals patterns of recovery, maintenance, re- and dedifferentiation. Gene. 2010 Aug 15;462(1-2):8-17 Authors: Dehne T, Schenk R, Perka C, Morawietz L, Pruss A, Sittinger M, Kaps C, Ringe J The high-density micromass culture has been widely applied to study chondrocyte cell physiology and pathophysiological mechanisms. Since an integrated image has not been established so far, we analyzed the phenotypic alterations of human articular chondrocytes in this model on the broad molecular level. Freshly isolated chondrocytes were assembled as micromasses and maintained up to 6 weeks in medium containing human serum. Formation of cartilaginous extracellular matrix (ECM) was evaluated by histological and immunohistochemical staining. At 0, 3 and 6 weeks, chondrocyte micromasses were subjected to gene expression analysis using oligonucleotide microarrays and real-time RT-PCR. Micromasses developed a cartilaginous ECM rich in proteoglycans and type II collagen. On gene expression level, time-dependent expression patterns was observed. The induction of genes associated with cartilage-specific ECM (COL2A1 and COL11A1) and developmental signaling (GDF5, GDF10, ID1, ID4 and FGFR1-3) indicated redifferentiation within the first 3 weeks. The repression of genes related to stress response (HSPA1A and HSPA4), apoptotic events (HYOU1, NFKBIA and TRAF1), and degradation (MMP1, MMP10 and MMP12) suggested a recovery of chondrocytes. Constant expression of other chondrogenic (ACAN, FN1 and MGP) and hypertrophic markers (COL10A1, ALPL, PTHR1 and PTHR2) indicated a pattern of phenotypic maintenance. Simultaneously, the expression of chondrogenic growth (BMP6, TGFA, FGF1 and FGF2) and transcription factors (SOX9, EGR1, HES1 and TGIF1), and other cartilage ECM-related genes (COMP and PRG4) was consistently repressed and expression of collagens related to dedifferentiation (COL1A1 and COL3A1) was steadily induced indicating a progressing loss of cartilage phenotype. Likewise, a steady increase of genes associated with proliferation (GAS6, SERPINF1, VEGFB and VEGFC) and apoptosis (DRAM, DPAK1, HSPB, GPX1, NGFRAP1 and TIA1) was observed. Sequence and interplay of identified expression patterns suggest that chondrocyte micromass cultures maintain a differentiated phenotype up to 3 weeks in vitro and might be useful for studying chondrocyte biology, pathophysiology and differentiation. Cultivation longer than 6 weeks leads to progressing dedifferentiation of chondrocytes that should be considered on long-term evaluations. PMID: 20433912 [PubMed - indexed for MEDLINE] | | | | | | | | | | |  |
No comments:
Post a Comment