| Genetix Pharmaceuticals Announces Global Clinical Plans to Treat Adrenoleukodystrophy (ALD)
November 6, 2009 at 9:25 am
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| Mesenchymal stromal cells for cardiovascular repair: current status and future challenges.
November 6, 2009 at 7:42 am
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| | Mesenchymal stromal cells for cardiovascular repair: current status and future challenges. Future Cardiol. 2009 Nov;5(6):605-17 Authors: Mathiasen AB, Haack-Sørensen M, Kastrup J Ischemic heart disease is the most common cause of death in most industrialized countries. Early treatment with stabilizing drugs and mechanical revascularization by percutaneous coronary intervention or coronary bypass surgery has reduced the mortality significantly. In spite of improved offers of treatments in patients with heart failure, the 1-year mortality is still approximately 20% after the diagnosis has been established. Treatment with stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. Mesenchymal stromal cells are a promising source of stem cells for regenerative therapy. Clinical studies on stem cell therapy for cardiac regeneration have shown significant improvements in ventricular pump function, ventricular remodeling, myocardial perfusion, exercise potential and clinical symptoms compared with conventionally treated control groups. The results of most studies are promising, but there are still many unanswered questions. In this review, we explore present preclinical and clinical knowledge regarding the use of stem cells in cardiovascular regenerative medicine, with special focus on mesenchymal stromal cells. We take a closer look at sources of stem cells, delivery method and methods for tracking injected cells. PMID: 19886787 [PubMed - in process] |
| Stem cells in stroke--appraisal of literature.
November 6, 2009 at 7:42 am
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| | Stem cells in stroke--appraisal of literature. J Indian Med Assoc. 2009 Jun;107(6):400, 402 Authors: Bhattacharya AK, Banik KK The repair of human brain after stroke appears unrealistic as there is loss of many different neurons and glial cells. The functional improvement after stroke or neurorestorative process includes neurogenesis, angiogenesis and synaptic plasticity. Stem cell therapy has the potential in inducing all of the above neurorestorative processes--thus facilitating functional recovery. The replacement therapy includes stem cells derived from various tissues which can generate functional neurons and glia. Stem cell research is an exciting new avenue in the field of stroke management. PMID: 19886378 [PubMed - in process] |
| A Novel Signaling by Vitamin A/Retinol Promotes Self Renewal of Mouse ES Cells by Activating PI3K/Akt Signaling Pathway Via IGF-1 Receptor.
November 6, 2009 at 6:47 am
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| | A Novel Signaling by Vitamin A/Retinol Promotes Self Renewal of Mouse ES Cells by Activating PI3K/Akt Signaling Pathway Via IGF-1 Receptor. Stem Cells. 2009 Nov 4; Authors: Chen L, Khillan JS Pluripotent embryonic stem (ES) are potential source of all types of cells for regenerative medicine. ES cells maintain pluripotency through a complex interplay of different signaling pathways and transcription factors including leukemia inhibitory factor (LIF), Nanog, Sox2 and Oct3/4. Nanog however, plays a key role in maintaining the pluripotency of mouse and human ESCs. Phosphoinositde 3-kinase (PI3K) signaling pathway that is activated in response to growth factors and cytokines also plays a critical role in promoting the survival and proliferation of ES cells. Our earlier studies have revealed that retinol the alcohol form of vitamin A enhances expression of Nanog and prevents differentiation of ES cells in long term cultures. Normally vitamin A/retinol is associated with cell differentiation via its potent metabolite retinoic acid. Thus far, no direct function has been ascribed to retinol itself. In these studies we demonstrate for the first time that retinol directly activates phosphoinositide 3 (PI3) kinase signaling pathway through IGF-1 receptor/insulin receptor substrate 1 (IRS-1) by engaging Akt/PKB-mTORC1 and mTORC2 complexes indicating a growth factor like function of vitamin A. Further, ES cells do not express enzymes to metabolize retinol into retinoic acid and lack receptors for retinol transport into the cytoplasm indicating that retinol signaling is independent of retinoic acid. The studies present a novel system to investigate how extracellular signals control the self renewal of ES cells which will be important for high quality ES cells for regenerative medicine. PMID: 19890980 [PubMed - as supplied by publisher] |
| Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells Under Xeno-Free Conditions.
November 6, 2009 at 6:47 am
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| | Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells Under Xeno-Free Conditions. Stem Cells. 2009 Nov 3; Authors: Rodríguez-Pizà I, Richaud-Patin Y, Vassena R, González F, Barrero MJ, Veiga A, Raya A, Izpisúa Belmonte JC The availability of induced pluripotent stem cells (iPSC) has created extraordinary opportunities for modeling and perhaps treating human disease. However, all reprogramming protocols used to date involve the use of products of animal origin. Here, we set out to develop a protocol to generate and maintain human iPSC that would be entirely devoid of xenobiotics. We first developed a xeno-free cell culture media that supported the long-term propagation of human embryonic stem cells (hESC) to a similar extent as conventional media containing animal origin products or commercially available xeno-free medium. We also derived primary cultures of human dermal fibroblasts under strict xeno-free conditions (XF-HFF), and show that they can be used as both the cell source for iPSC generation as well as autologous feeder cells to support their growth. We also replaced other reagents of animal origin (trypsin, gelatin, matrigel) with their recombinant equivalents. Finally, we used vesicular stomatitis virus G (VSV-G)-pseudotyped retroviral particles expressing a polycistronic construct encoding Oct4, Sox2, Klf4, and GFP to reprogram XF-HFF cells under xeno-free conditions. A total of 10 xeno-free human iPSC lines were generated, which could be continuously passaged in xeno-free conditions and maintained characteristics indistinguishable from hESC, including colony morphology and growth behavior, expression of pluripotency-associated markers, and pluripotent differentiation ability in vitro and in teratoma assays. Overall, the results presented here demonstrate that human iPSC can be generated and maintained under strict xeno-free conditions and provide a path to GMP-applicability that should facilitate the clinical translation of iPSC-based therapies. PMID: 19890879 [PubMed - as supplied by publisher] |
| A continuum of cell States spans pluripotency and lineage commitment in human embryonic stem cells.
November 6, 2009 at 6:47 am
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| | A continuum of cell States spans pluripotency and lineage commitment in human embryonic stem cells. PLoS One. 2009;4(11):e7708 Authors: Hough SR, Laslett AL, Grimmond SB, Kolle G, Pera MF BACKGROUND: Commitment in embryonic stem cells is often depicted as a binary choice between alternate cell states, pluripotency and specification to a particular germ layer or extraembryonic lineage. However, close examination of human ES cell cultures has revealed significant heterogeneity in the stem cell compartment. METHODOLOGY/PRINCIPAL FINDINGS: We isolated subpopulations of embryonic stem cells using surface markers, then examined their expression of pluripotency genes and lineage specific transcription factors at the single cell level, and tested their ability to regenerate colonies of stem cells. Transcript analysis of single embryonic stem cells showed that there is a gradient and a hierarchy of expression of pluripotency genes in the population. Even cells at the top of the hierarchy generally express only a subset of the stem cell genes studied. Many cells co-express pluripotency and lineage specific genes. Cells along the continuum show a progressively decreasing likelihood of self renewal as their expression of stem cell surface markers and pluripotency genes wanes. Most cells that are positive for stem cell surface markers express Oct-4, but only those towards the top of the hierarchy express the nodal receptor TDGF-1 and the growth factor GDF3. SIGNIFICANCE: These findings on gene expression in single embryonic stem cells are in concert with recent studies of early mammalian development, which reveal molecular heterogeneity and a stochasticity of gene expression in blastomeres. Our work indicates that only a small fraction of the population resides at the top of the hierarchy, that lineage priming (co-expression of stem cell and lineage specific genes) characterizes pluripotent stem cell populations, and that extrinsic signaling pathways are upstream of transcription factor networks that control pluripotency. PMID: 19890402 [PubMed - in process] |
| Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction.
November 6, 2009 at 6:47 am
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| | Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction. BJU Int. 2009 Nov 3; Authors: Füllhase C, Soler R, Gratzke C, Brodsky M, Christ GJ, Andersson KE OBJECTIVE To evaluate the urodynamic effects of fesoterodine, a new antimuscarinic agent, alone and combined with doxazosin, in a rat model of partial urethral obstruction (PUO), as 35-83% of men with bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) have overactive bladder (OAB) syndrome, and as the combination of alpha(1)-adrenoceptor- and muscarinic-receptor antagonists has been proposed to be beneficial for these patients. MATERIALS AND METHODS Thirty-seven male Sprague-Dawley rats (250 g) had surgically induced PUO; 2 weeks later they were evaluated by cystometry with no anaesthesia or any restraint. After a 1-h period either 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine, previously known as SPM 7605), doxazosin or a combination of both, was given intravenously (0.1 mg/kg body weight), and cystometry was continued for another 45 min. Fifteen healthy, age-matched rats served as a control. RESULTS At 2 weeks after surgery the obstructed rats had an greater bladder weight, threshold pressure (TP) and micturition frequency (MF), and lower bladder capacity (BCap) and micturition volume (MV) than the controls. 5-HMT did not cause urinary retention in obstructed rats, but decreased TP, maximum pressure (MP), spontaneous bladder activity (SA) and, paradoxically, increased MF. Doxazosin alone decreased TP, MP, MF and increased BCap and MV. 5-HMT and doxazosin together did not depress the ability to empty the bladder, and showed decreased TP, MP and SA. CONCLUSIONS 5-HMT, alone and in combination, did not impair the voiding ability in obstructed rats. Doxazosin counteracted some of the 'negative' effects of 5-HMT in this model (increase of MF) and did not attenuate the 'positive' effects (decrease of bladder SA). In this model, the combination of 5-HMT and doxazosin appeared to be urodynamically safe and well tolerated. PMID: 19888972 [PubMed - as supplied by publisher] |
| The tumorigenicity of diploid and aneuploid human pluripotent stem cells.
November 6, 2009 at 6:47 am
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| | The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle. 2009 Dec 14;8(23) Authors: Blum B, Benvenisty N Human embryonic stem cells (HESCs) and induced pluripotent stem cells (HiPSCs) offer an immense potential as a source of cells for regenerative medicine. However, the ability of undifferentiated HESCs and HiPSCs to produce tumors in vivo presents a major obstacle for the translation of this potential into clinical reality. Therefore, characterizing the nature of HESC- and HiPSC-derived tumors, especially their malignant potential, is extremely important in order to evaluate the risk involved in their clinical use. Here we review recent observations on the tumorigenicity of human pluripotent stem cells. We argue that diploid, early passage, HESCs produce benign teratomas without undergoing genetic modifications. Conversely, HESCs that acquired genetic or epigenetic changes upon adaptation to in vitro culture can produce malignant teratocarcinomas. We discuss the molecular mechanisms of HESC tumorigenicity and suggest approaches to prevent tumor formation from these cells. We also discuss the differences in the tumorigenicity between mouse embryonic stem cells (MESCs) and HESCs, and suggest methodologies that may help to identify cellular markers for culture adapted HESCs. PMID: 19887907 [PubMed - as supplied by publisher] |
| Pre-clinical Models for Oral and Periodontal Reconstructive Therapies.
November 6, 2009 at 6:47 am
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| | Pre-clinical Models for Oral and Periodontal Reconstructive Therapies. J Dent Res. 2009 Nov 3; Authors: Pellegrini G, Seol YJ, Gruber R, Giannobile WV The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Preclinical testing has contributed to the recent approval of NMF such as GEM 21S((R)) and INFUSE((R)) bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable preclinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use. PMID: 19887682 [PubMed - as supplied by publisher] |
| Plasticity and recovery of skeletal muscle satellite cells during limb regeneration.
November 6, 2009 at 6:47 am
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| | Plasticity and recovery of skeletal muscle satellite cells during limb regeneration. FASEB J. 2009 Nov 3; Authors: Morrison JI, Borg P, Simon A Salamander limb regeneration depends on local progenitors whose progeny are recruited to the new limb. We previously identified a Pax7(+) cell population in skeletal muscle whose progeny have the potential to contribute to the regenerating limb. However, the plasticity of individual Pax7(+) cells, as well as their recovery within the new limb, was unclear. Here, we show that Pax7(+) cells remain present after multiple rounds of limb amputation/regeneration. Pax7(+) cells are found exclusively within skeletal muscle in the regenerating limb and proliferate where the myofibers are growing. Pax7 is rapidly down-regulated in the blastema, and analyses of clonal derivatives show that Pax7(+) cell progeny are not restricted to skeletal muscle during limb regeneration. Our data suggest that the newt regeneration blastema is not entirely a composite of lineage-restricted progenitors. The results demonstrate that except for a transient and subsequently blunted increase, skeletal muscle satellite cells constitute a stable pool of reserve cells for multiple limb regeneration events.-Morrison, J. I., Borg, P., Simon, A. Plasticity and recovery of skeletal muscle satellite cells during limb regeneration. PMID: 19887652 [PubMed - as supplied by publisher] |
| Lin-Sca-1+CD49fhigh Stem/Progenitors Are Tumor-Initiating Cells in the Pten-Null Prostate Cancer Model.
November 6, 2009 at 6:47 am
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| | Lin-Sca-1+CD49fhigh Stem/Progenitors Are Tumor-Initiating Cells in the Pten-Null Prostate Cancer Model. Cancer Res. 2009 Nov 3; Authors: Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H We have shown previously that Pten deletion leads to the expansion of subset of prostate cancer cells positive for CK5 and p63. Although this subpopulation may be involved in tumor initiation or progression, studies to date have not functionally validated this hypothesis. Using in vitro sphere-forming assay and in vivo prostate reconstitution assay, we show here the presence of a tumor-initiating subpopulation in the Pten prostate cancer mouse model. Specifically, we show that the Lin(-)Sca-1(+)CD49f(high) (LSC) subpopulation overlaps with CK5(+);p63(+) cells and is significantly increased during prostate cancer initiation and progression and after castration. Mutant spheres mimic the structural organization of the epithelial compartment in the Pten-null primary tumor. Sorted LSC cells from either Pten-null spheres or primary tumors are able to regenerate prostate epithelial structure with cancerous morphology, closely mimicking that of primary cancers. Therefore, the LSC subpopulation is capable of initiating a cancerous phenotype that recapitulates the pathology seen in the primary lesions of the Pten mutant prostate model. [Cancer Res 2009;69(22):8555-62]. PMID: 19887604 [PubMed - as supplied by publisher] |
| Niche recycling through division-independent egress of hematopoietic stem cells.
November 6, 2009 at 6:47 am
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| | Niche recycling through division-independent egress of hematopoietic stem cells. J Exp Med. 2009 Nov 2; Authors: Bhattacharya D, Czechowicz A, Ooi AG, Rossi DJ, Bryder D, Weissman IL Hematopoietic stem cells (HSCs) are thought to reside in discrete niches through stable adhesion, yet previous studies have suggested that host HSCs can be replaced by transplanted donor HSCs, even in the absence of cytoreductive conditioning. To explain this apparent paradox, we calculated, through cell surface phenotyping and transplantation of unfractionated blood, that approximately 1-5% of the total pool of HSCs enters into the circulation each day. Bromodeoxyuridine (BrdU) feeding experiments demonstrated that HSCs in the peripheral blood incorporate BrdU at the same rate as do HSCs in the bone marrow, suggesting that egress from the bone marrow to the blood can occur without cell division and can leave behind vacant HSC niches. Consistent with this, repetitive daily transplantations of small numbers of HSCs administered as new niches became available over the course of 7 d led to significantly higher levels of engraftment than did large, single-bolus transplantations of the same total number of HSCs. These data provide insight as to how HSC replacement can occur despite the residence of endogenous HSCs in niches, and suggest therapeutic interventions that capitalize upon physiological HSC egress. PMID: 19887396 [PubMed - as supplied by publisher] |
| Mesenchymal stromal cells for cardiovascular repair: current status and future challenges.
November 6, 2009 at 6:47 am
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| | Mesenchymal stromal cells for cardiovascular repair: current status and future challenges. Future Cardiol. 2009 Nov;5(6):605-17 Authors: Mathiasen AB, Haack-Sørensen M, Kastrup J Ischemic heart disease is the most common cause of death in most industrialized countries. Early treatment with stabilizing drugs and mechanical revascularization by percutaneous coronary intervention or coronary bypass surgery has reduced the mortality significantly. In spite of improved offers of treatments in patients with heart failure, the 1-year mortality is still approximately 20% after the diagnosis has been established. Treatment with stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. Mesenchymal stromal cells are a promising source of stem cells for regenerative therapy. Clinical studies on stem cell therapy for cardiac regeneration have shown significant improvements in ventricular pump function, ventricular remodeling, myocardial perfusion, exercise potential and clinical symptoms compared with conventionally treated control groups. The results of most studies are promising, but there are still many unanswered questions. In this review, we explore present preclinical and clinical knowledge regarding the use of stem cells in cardiovascular regenerative medicine, with special focus on mesenchymal stromal cells. We take a closer look at sources of stem cells, delivery method and methods for tracking injected cells. PMID: 19886787 [PubMed - in process] |
| Sonic Hedgehog promotes angiogenesis and osteogenesis in a co-culture system consisting of primary osteoblasts and outgrowth endothelial cells.
November 6, 2009 at 6:47 am
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| | Sonic Hedgehog promotes angiogenesis and osteogenesis in a co-culture system consisting of primary osteoblasts and outgrowth endothelial cells. Tissue Eng Part A. 2009 Nov 3; Authors: Dohle E, Fuchs S, Kolbe M, Hofmann A, Schmidt H, Kirkpatrick J A number of previous studies documented the angiogenic potential of outgrowth endothelial cells (OEC) in vitro and in vivo and provided evidence that therapeutic success could depend on co-culture or co-implantation strategies. Thus, deeper insight into the molecular mechanisms underlying this pro-angiogenic effect of co-cultures might provide new translational options for tissue engineering and regenerative medicine. One promising signaling pathway in bone repair involved in neoangiogenesis and bone formation, is the sonic hedgehog (Shh) pathway. In this paper we focus on the effect of Shh on the formation of microvessel-like structures and osteoblastic differentiation in co-cultures of primary osteoblasts (pOB) and OEC. Already after 24 hours of treatment, Shh leads to a massive increase in microvessel-like structures compared to untreated co-cultures. Increased formation of angiogenic structures seems to correlate with the upregulation of vascular endothelial growth factor (VEGF) or angiopoietins (Ang-1, Ang-2) studied at both the mRNA and protein-level. In addition, treatment with cyclopamine, an inhibitor of hedgehog signaling, blocked the formation of microvessel-like structures in the co-cultures. However, exogenous Shh also resulted in the upregulation of several osteogenic differentiation markers in real time PCR, as well as in an increased mineralization and alkaline phosphatase (ALP) activity. The present data highlight the central role of the Shh pathway in bone regeneration and vascularization. Furthermore sonic hedgehog might have the potential to improve both angiogenesis and osteogenesis in clinical applications in the future. PMID: 19886747 [PubMed - as supplied by publisher] |
| Gelatin Hydrogel Prepared by Photo-initiated Polymerization and Loaded with TGF-beta1 for Cartilage Tissue Engineering.
November 6, 2009 at 6:40 am
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| | Gelatin Hydrogel Prepared by Photo-initiated Polymerization and Loaded with TGF-beta1 for Cartilage Tissue Engineering. Macromol Biosci. 2009 Nov 3; Authors: Hu X, Ma L, Wang C, Gao C Gelatin is a nature-derived protein having good cytocompatibility, and widely used in tissue engineering particularly in a form of a hydrogel. To obtain the hydrogel with good enough mechanical properties, however, measures are still need to be taken. In this work, the gelatin molecule was modified with methacrylic acid (MA) to obtain crosslinkable gelatin (GM), which formed a chemically crosslinked hydrogel by photoinitiating polymerization. The gelation time could be easily tuned and showed an inverse relationship with the GM concentration. After photo-irradiation for 20 min there was no detectable double carbon bond in the hydrogen spectrum of high resolution magic angle spinning nuclear magnetic resonance spectroscopy ((1)H HR-MAS NMR). With the increase of the GM concentration, storage modulus and loss modulus of the hydrogels increased, but their swelling ratio and mesh size decreased. Weight loss of the hydrogels was also affected by the polymer concentration. Transform growth factor-beta1 (TGF-beta1) was incorporated into the GM hydrogel to improve its bioactivity. In vitro chondrocyte culture showed that the GM hydrogel had indeed good performance to support chondrocyte growth and maintain chondrocytic phenotype. Incorporation of TGF-beta1 could further improve the biological activity in terms of cell proliferation and extracellular matrix secretion. PMID: 19890886 [PubMed - as supplied by publisher] |
| Dynamic mechanical properties of the tissue-engineered matrix associated with individual chondrocytes.
November 6, 2009 at 6:40 am
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| | Dynamic mechanical properties of the tissue-engineered matrix associated with individual chondrocytes. J Biomech. 2009 Nov 2; Authors: Lee B, Han L, Frank EH, Chubinskaya S, Ortiz C, Grodzinsky AJ The success of cell-based tissue engineering approaches in restoring biological function will be facilitated by a comprehensive fundamental knowledge of the temporal evolution of the structure and properties of the newly synthesized matrix. Here, we quantify the dynamic oscillatory mechanical behavior of the engineered matrix associated with individual chondrocytes cultured in vitro for up to 28 days in alginate scaffolds. The magnitude of the complex modulus (|E*|) and phase shift (delta) were measured in culture medium using Atomic Force Microscopy (AFM)-based nanoindentation in response to an imposed oscillatory deformation (amplitude approximately 5nm) as a function of frequency (f=1-316Hz), probe tip geometry (2.5mum radius sphere and 50nm radius square pyramid), and in the absence and presence of growth factors (GF, insulin growth factor-1, IGF-1, and osteogenic protein-1, OP-1). |E*| for all conditions increased nonlinearly with frequency dependence approximately f(1/2) and ranged between approximately 1 and 25kPa. This result, along with theoretical calculations of the characteristic poroelastic relaxation frequency, f(p), ( approximately 50-90Hz) suggested that this time-dependent behavior was governed primarily by fluid flow-dependent poroelasticity, rather than flow-independent viscoelastic processes associated with the solid matrix. |E*(f)| increased, (f) decreased, and the hydraulic permeability, k, decreased with time in culture and with growth factor treatment. This trend of a more elastic-like response was thought to be associated with increased macromolecular biosynthesis, density, and a more mature matrix structure/organization. PMID: 19889416 [PubMed - as supplied by publisher] |
| Pre-clinical Models for Oral and Periodontal Reconstructive Therapies.
November 6, 2009 at 6:40 am
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| | Pre-clinical Models for Oral and Periodontal Reconstructive Therapies. J Dent Res. 2009 Nov 3; Authors: Pellegrini G, Seol YJ, Gruber R, Giannobile WV The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Preclinical testing has contributed to the recent approval of NMF such as GEM 21S((R)) and INFUSE((R)) bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable preclinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use. PMID: 19887682 [PubMed - as supplied by publisher] |
| Multiscale 3d scaffolds for soft tissue engineering via multimodal electrospinning.
November 6, 2009 at 6:40 am
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| | Multiscale 3d scaffolds for soft tissue engineering via multimodal electrospinning. Acta Biomater. 2009 Oct 31; Authors: Soliman S, Pagliari S, Rinaldi A, Forte G, Fiaccavento R, Pagliari F, Franzese O, Minieri M, Nardo PD, Licoccia S, Traversa E A novel (scalable) electrospinning process was developed to fabricate bio-inspired multiscale 3D scaffolds endowed with a controlled multimodal distribution of fiber diameters and geared towards soft tissue engineering. The resulting materials finely mingle nano- and microscale fibers together. rather than simply juxtapose as commonly found in literature. A detailed proof-of-concept study was conducted on a simpler bimodal poly(epsilon-caprolactone) (PCL) scaffold with modes of the fiber distribution at 600 nm and 3.3 mum. Three conventional unimodal scaffolds with mean diameters of 300 nm, 2.6 mum, and 5.2 mum respectively were used as controls to evaluate the new materials. The characterization of microstructure (i.e. porosity, fiber distribution, and pore structure) and mechanical properties (i.e. stiffness, strength, and failure mode) indicated that the multimodal scaffold had superior mechanical properties (Young's modulus approximately 40 MPa and strength approximately 1 MPa) in comparison to the controls, despite the large porosity ( approximately 90% on average). A biological assessment was conducted with bone marrow stromal cell type (mesenchymal stem cells, mTERT-MSCs). While the new material compared favourably against the controls as far as cell viability (on the outer surface), it outperformed them in terms of cell colonization within the wall. The latter result, which could neither be practically achieved in the controls nor be expected based on current models of pore size distribution, demonstrated the greater openness of the pore structure of the bimodal material that remarkably did not come at the expense of mechanical properties. Furthermore nanofibers were seen to form a nanoweb bridging across neighbouring microfibers, which contributed to boost cell motility and survival. At last standard adipogenic and osteogenic differentiation tests served to demonstrate that the new scaffold does not hinder the multilineage potential of stem cells. PMID: 19887125 [PubMed - as supplied by publisher] |
| Small Intestinal Submucosa Gel as a Potential Scaffolding Material for Cardiac Tissue Engineering.
November 6, 2009 at 6:40 am
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| | Small Intestinal Submucosa Gel as a Potential Scaffolding Material for Cardiac Tissue Engineering. Acta Biomater. 2009 Oct 31; Authors: Crapo PM, Wang Y Cardiac tissue engineering typically utilizes protein-rich scaffolding materials and growth factors to improve cardiac tissue function in vitro and in vivo. The objectives of this preliminary study were (I) to investigate the potential of porcine small intestinal submucosa gel (SIS gel) in cardiac tissue engineering and (II) to compare the function of tissue based on either SIS gel or Matrigel, a tumor-derived benchmark material. Neonatal rat cardiac cells were combined with either SIS gel or Matrigel and cultured on porous elastomeric scaffolds composed of poly(glycerol sebacate) for 13 days. Tissue function was assessed by measuring contraction rates twice daily. Tissue morphology was compared qualitatively by H&E staining. Normalized troponin T expression (troponin T:DNA) was compared using image analysis. SIS gel constructs contracted at significantly higher rates than Matrigel constructs on days 8-11. Normalized troponin T expression was significantly higher in SIS gel constructs compared to Matrigel constructs. In summary, this research demonstrates that: (I) SIS gel can be used to create contractile engineered cardiac tissue; and (II) SIS gel produced engineered cardiac tissues with a more physiologic contraction rate and higher phenotypic protein expression based on basic in vitro examinations performed in this study. PMID: 19887120 [PubMed - as supplied by publisher] |
| Anti-TNF-alpha-Loaded Microspheres as a Prospective Novel Treatment for Crohn's Disease Fistulae.
November 6, 2009 at 6:40 am
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| | Anti-TNF-alpha-Loaded Microspheres as a Prospective Novel Treatment for Crohn's Disease Fistulae. Tissue Eng Part C Methods. 2009 Nov 3; Authors: Foong KS, Patel R, Forbes A, Day RM Background and Aims: Antibodies to tumour necrosis factor alpha (TNF-alpha) have been successful in treating perianal fistulae in Crohn's disease, but current modes of delivery are limited. Microspheres are currently being assessed as scaffolds for tissue engineering and drug delivery devices. The aim of this study was to produce anti-TNF-alpha antibody encapsulated microspheres using thermally induced phase separation (TIPS) and to characterise their behaviour. Methods: Anti-TNF-alpha antibody was encapsulated into the microspheres (100mg infliximab/g poly(lactide-co-glycolide [PLGA]) w/w) using a novel technique combining a vibration encapsulator unit with a TIPS process, using either lyophilized particulate antibody or an aqueous solution of antibody. Microspheres were incubated in phosphate buffered saline for collection of supernatant and assessment of degradation. The amount and biological activity of the encapsulated antibody released from the microspheres was assessed by enzyme-linked immunosorbent assay (ELISA) and its ability to neutralize recombinant human (rh)TNF-alpha in vitro with a cytotoxicity assay. An in vitro wound scratch assay was used to assess the effect of released antibody on fibroblast migration. Ultrastructural characteristics of the different microspheres were characterised by scanning electron microscopy. Results: Highly porous microspheres released anti-TNF-alpha antibody under zero order kinetics and inhibited the cytotoxic activity of rhTNF-alpha, producing a significant increase in cell viability compared with cells treated with rhTNF-alpha alone. This effect was most pronounced with microspheres fabricated by blending lyophilized particulate anti-TNF-alpha antibody into the polymer solution, which also significantly reduced the release of lactate dehydrogenase. Summary and Conclusions: Anti-TNF-alpha antibody encapsulated into highly porous microspheres was released in a controlled manner and exhibited biological activity against TNF-alpha. The technique used to produce TIPS microspheres is rapid and provides high encapsulation efficiency. This technique could also be applied to other therapeutic peptides where rapid fabrication and high yields are required. PMID: 19886803 [PubMed - as supplied by publisher] |
| Sonic Hedgehog promotes angiogenesis and osteogenesis in a co-culture system consisting of primary osteoblasts and outgrowth endothelial cells.
November 6, 2009 at 6:40 am
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| | Sonic Hedgehog promotes angiogenesis and osteogenesis in a co-culture system consisting of primary osteoblasts and outgrowth endothelial cells. Tissue Eng Part A. 2009 Nov 3; Authors: Dohle E, Fuchs S, Kolbe M, Hofmann A, Schmidt H, Kirkpatrick J A number of previous studies documented the angiogenic potential of outgrowth endothelial cells (OEC) in vitro and in vivo and provided evidence that therapeutic success could depend on co-culture or co-implantation strategies. Thus, deeper insight into the molecular mechanisms underlying this pro-angiogenic effect of co-cultures might provide new translational options for tissue engineering and regenerative medicine. One promising signaling pathway in bone repair involved in neoangiogenesis and bone formation, is the sonic hedgehog (Shh) pathway. In this paper we focus on the effect of Shh on the formation of microvessel-like structures and osteoblastic differentiation in co-cultures of primary osteoblasts (pOB) and OEC. Already after 24 hours of treatment, Shh leads to a massive increase in microvessel-like structures compared to untreated co-cultures. Increased formation of angiogenic structures seems to correlate with the upregulation of vascular endothelial growth factor (VEGF) or angiopoietins (Ang-1, Ang-2) studied at both the mRNA and protein-level. In addition, treatment with cyclopamine, an inhibitor of hedgehog signaling, blocked the formation of microvessel-like structures in the co-cultures. However, exogenous Shh also resulted in the upregulation of several osteogenic differentiation markers in real time PCR, as well as in an increased mineralization and alkaline phosphatase (ALP) activity. The present data highlight the central role of the Shh pathway in bone regeneration and vascularization. Furthermore sonic hedgehog might have the potential to improve both angiogenesis and osteogenesis in clinical applications in the future. PMID: 19886747 [PubMed - as supplied by publisher] |
| Magnetic nanoparticles to simultaneously diagnose, monitor and treat
November 6, 2009 at 1:24 am
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| More on the Tale of Three Terminations
November 6, 2009 at 1:14 am
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| | Some confusion has arisen in connection with a story in the Scientist magazine concerning our account of the termination of three grants by the California stem cell agency.In an attempt to clarify the situation, we are providing more information on the decision by the California Stem Cell Report to withhold the names of the researchers and also on the actions of the California stem cell | | | 
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