| Design of clinical trials for therapeutic cancer vaccines development.
October 20, 2009 at 8:02 am
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| | Design of clinical trials for therapeutic cancer vaccines development. Eur J Pharmacol. 2009 Oct 13; Authors: Mackiewicz J, Mackiewicz A Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of number of cancer vaccines has been demonstrated what focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trials objectives are: safety; dose selection and schedule of vaccination; demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate. PMID: 19835869 [PubMed - as supplied by publisher] |
| Stem cell therapy for type 1 diabetes mellitus: a review of recent clinical trials.
October 20, 2009 at 8:02 am
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| | Stem cell therapy for type 1 diabetes mellitus: a review of recent clinical trials. Diabetol Metab Syndr. 2009 Oct 16;1(1):19 Authors: Couri CE, Voltarelli JC ABSTRACT: Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases. With regard to type 1 diabetes, studies analyzing the therapeutic effects of stem cells in humans began in 2003 in the Hospital das Clinicas of the Faculty of Medicine of Ribeirao Preto - SP USP, Brazil, and since then other centers in different countries started to randomize patients in their clinical trials. Herein we summarize recent data about beta cell regeneration, different ways of immune intervention and what is being employed in type 1 diabetic patients with regard to stem cell repertoire to promote regeneration and/or preservation of beta cell mass. PMID: 19835616 [PubMed - as supplied by publisher] |
| Monitoring antioxidant defenses and free radical production in space-flight, aviation and railway engine operators, for the prevention and treatment of oxidative stress, immunological impairment, and pre-mature cell aging.
October 20, 2009 at 8:02 am
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| | Monitoring antioxidant defenses and free radical production in space-flight, aviation and railway engine operators, for the prevention and treatment of oxidative stress, immunological impairment, and pre-mature cell aging. Toxicol Ind Health. 2009 May-Jun;25(4-5):259-67 Authors: De Luca C, Deeva I, Mariani S, Maiani G, Stancato A, Korkina L Degenerative diseases, immune impairment, and premature ageing commonly affect professional categories exposed to severe environmental and psychological stress. Among these, cosmonauts routinely experience extreme conditions due to microgravity, space radiation, altered oxygen supply, physical and mental fatigue during training, spaceflight, and post-flight. Long route aviation pilots display elevated oncogenic risk, connected with cosmic radiation overexposure, and high mortality rates for cardiovascular causes. Engine drivers, like pilots, are affected by health consequences of psycho-emotional stress, and burnout syndrome. The free radical (FR)/antioxidant (AO) imbalance is a common feature in all these pathological conditions. To assess the effective relevance of oxidative stress, we analyzed blood and urine reliable markers of FR production and AO defenses in 12 Russian cosmonauts, 55 airline pilots, 63 train engine drivers, and 50 age-matched controls by measuring the following: (a) lipophilic/hydrophilic low-molecular weight AO and AO enzyme activities, (b) nitric oxide, superoxide anion, hydroperoxide production, and (c) urinary catecholamine/serotonine metabolites and lipoperoxidation markers. Cosmonauts showed elevated granulocyte superoxide and nitric oxide production, increased erythrocyte superoxide dismutase activity and glutathione oxidation, and drastically decreased plasma/leucocyte lipophilic AO levels (P < 0.001-0.01). Aviation pilots, like train drivers, displayed a mild but constant oxidative stress, more pronounced in intercontinental routes pilots, and consistent with lymphocyte chromosomal alterations, DNA oxidation, and cardiovascular malfunction. Results obtained on these selected professionals operating under wearing conditions offer a solid molecular basis for advising the regular monitoring of clinical biochemistry laboratory markers of AO/FR status, to tailor individually specific AO supplementation and diet regimen, and monitor treatment outcomes. PMID: 19651796 [PubMed - indexed for MEDLINE] |
| Mechanical stretching modulates growth direction and MMP-9 release in human keratinocyte monolayer.
October 20, 2009 at 8:02 am
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| | Mechanical stretching modulates growth direction and MMP-9 release in human keratinocyte monolayer. Cell Adh Migr. 2009 Jul-Sep;3(3):239-42 Authors: Renò F, Traina V, Cannas M Cells within human skin are exposed to mechanical stretching that is considered a trigger stimulus for keratinocyte proliferation, while its effect on keratinocyte migration has been poorly investigate. In order to explore the effect of stretching on keratinocyte migration spontaneously immortalized human keratinocyte (HaCaT) monolayers seeded onto collagen I-coated silicon sheets were stimulated 3 times for 1 hour every 24 hours (total time = 72 hours) by mechanical stretching increasing substrate deformations (10%) applied both as static (0 Hz) and cyclic (0.17 Hz) uniaxial stretching. At the end of stimulations monolayer areas measured in both static and cyclic samples appeared reduced and strongly oriented in a direction perpendicular to the stress direction compared to unstimulated ones. Moreover during the mechanical stimulation period HaCaT monolayers strongly increased the release in the medium of matrix metalloproteinase 9 (MMP-9), a proteolytic enzyme necessary for keratinocyte migration. PMID: 19448396 [PubMed - indexed for MEDLINE] |
| Generation of Human Induced Pluripotent Stem Cells in the Absence of Exogenous Sox2.
October 20, 2009 at 8:02 am
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| | Generation of Human Induced Pluripotent Stem Cells in the Absence of Exogenous Sox2. Stem Cells. 2009 Oct 16; Authors: Li W, Zhou H, Abujarour R, Zhu S, Joo JY, Lin T, Hao E, Schöler HR, Hayek A, Ding S Induced pluripotent stem cell technology has attracted enormous interests for potential application in regenerative medicine. Here, we reported that a specific glycogen synthase kinase 3 (GSK-3) inhibitor, CHIR99021, can induce the reprogramming of mouse embryonic fibroblasts (MEFs) transduced by only Oct4 and Klf4 two factors. When combined with Parnate (also named tranylcypromine), an inhibitor of lysine-specific demethylase 1, CHIR99021 can result in the reprogramming of human primary keratinocyte transducted with Oct4 and Klf4 two factors. To our knowledge, this is the first time to generate human iPS cells from somatic cells without exogenous Sox2 expression. Our studies suggest that the GSK-3 inhibitor might have a general application to replace transcription factors in both mouse and human reprogramming. PMID: 19839055 [PubMed - as supplied by publisher] |
| [Bone tissue engineering in clinical application : Assessment of the current situation.]
October 20, 2009 at 8:02 am
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| | [Bone tissue engineering in clinical application : Assessment of the current situation.] Orthopade. 2009 Oct 17; Authors: Bernstein P, Bornhäuser M, Günther KP, Stiehler M Treatment of severe bone defects remains a challenge in orthopaedic surgery and traumatology. Surgical techniques should provide primary stability to reach osseous integration and secondary remodeling of bone grafts and substitute materials. None of the currently available substitute materials provides osteoconduction and osteogenesis comparable to those of human allografts and autografts. To enhance osteoinductive and osteogenetic properties of these implants mesenchymal stem cells are used successfully in bone tissue engineering approaches. The aim of this report is to summarize the currently available data on bone tissue engineering and preliminary experience with a tissue engineered graft in acetabular revision surgery after loosening of a hip replacement. PMID: 19838667 [PubMed - as supplied by publisher] |
| Dental tissue - new source for stem cells.
October 20, 2009 at 8:02 am
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| | Dental tissue - new source for stem cells. ScientificWorldJournal. 2009;9:1167-77 Authors: Petrovic V, Stefanovic V Stem cells have been isolated from many tissues and organs, including dental tissue. Five types of dental stem cells have been established: dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. The main characteristics of dental stem cells are their potential for multilineage differentiation and self-renewal capacity. Dental stem cells can differentiate into odontoblasts, adipocytes, neuronal-like cells, glial cells, osteoblasts, chondrocytes, melanocytes, myotubes, and endothelial cells. Possible application of these cells in various fields of medicine makes them good candidates for future research as a new, powerful tool for therapy. Although the possible use of these cells in therapeutic purposes and tooth tissue engineering is still in the beginning stages, the results are promising. The efforts made in the research of dental stem cells have clarified many mechanisms underlying the biological processes in which these cells are involved. This review will focus on the new findings in the field of dental stem cell research and on their potential use in the therapy of various disorders. PMID: 19838602 [PubMed - in process] |
| Fabrication of polycaprolactone collagen hydrogel constructs seeded with mesenchymal stem cells for bone regeneration.
October 20, 2009 at 8:02 am
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| | Fabrication of polycaprolactone collagen hydrogel constructs seeded with mesenchymal stem cells for bone regeneration. Biomed Mater. 2009 Oct 16;4(6):65001 Authors: Reichert JC, Heymer A, Berner A, Eulert J, Nöth U The osteogenic differentiation of bone marrow-derived human mesenchymal stem cells (MSCs) in a collagen I hydrogel was investigated. Collagen hydrogels with 7.5 x 10(5) MSCs ml(-1) were fabricated and cultured for 6 weeks in a defined, osteogenic differentiation medium. Histochemistry revealed morphologically distinct, chondrocyte-like cells, surrounded by a sulfated proteoglycan-rich extracellular matrix in the group treated with bone morphogenetic protein 2 (BMP-2), while cells cultured with dexamethasone, ascorbate-2-phosphate, and beta-glycerophosphate displayed a spindle-shaped morphology and deposited a mineralized matrix. Real-time polymerase chain reaction (RT-PCR) analyses revealed a specific chondrogenic differentiation with the expression of cartilage-specific markers in the BMP-2-treated group and a distinct expression pattern of the osteogenic markers alkaline phosphatase (ALP), type I collagen, osteocalcin (OC), and cbfa-1 in the group treated with an osteogenic standard medium. The collagen gels were used to engineer a cell laden medical grade epsilon-polycaprolactone (PCL)-hydrogel construct for segmental bone repair showing good bonding at the scaffold hydrogel interface and even cell distribution. The results show that MSCs cultured in a collagen I hydrogel are able to undergo a distinct osteogenic differentiation pathway when stimulated with specific differentiation factors and suggest that collagen I hydrogels are a suitable means to facilitate cell seeding of scaffolds for bone tissue engineering applications. PMID: 19837997 [PubMed - as supplied by publisher] |
| New strategies to generate induced pluripotent stem cells.
October 20, 2009 at 8:02 am
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| | New strategies to generate induced pluripotent stem cells. Curr Opin Biotechnol. 2009 Oct 16; Authors: O'Malley J, Woltjen K, Kaji K Direct reprogramming of somatic cells to a pluripotent state, substantiated only three years prior, is one of the most rapidly developing areas of stem cell research. The generation of patient-derived pluripotent cells applicable to disease modelling, drug screening, toxicology tests and, ultimately, autologous cell-based therapies, has the potential to revolutionize medicine. Since 2006, when Takahashi and Yamanaka first reported the generation of induced pluripotent stem cells from murine fibroblasts via retroviral transduction of a defined set of transcription factors, various new methods have been developed to refine and improve reprogramming technology. This review focusses on these evolving strategies to generate genetically unmodified or reprogramming factor-free iPSCs. PMID: 19837580 [PubMed - as supplied by publisher] |
| Stem cells and liver repair.
October 20, 2009 at 8:02 am
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| | Stem cells and liver repair. Curr Opin Biotechnol. 2009 Oct 16; Authors: Kung JW, Forbes SJ The liver has considerable inherent regenerative capacity through hepatocyte division and hepatic progenitor cell proliferation. In chronic disease regeneration eventually fails and liver transplantation is the only curative treatment. Current work aims to restore liver mass and functionality either through transplantation of stem cell derived hepatocyte-like cells or by stimulating endogenous liver repair. Human embryonic stem cells (ESCs) and adult somatic cells can be differentiated into hepatocyte-like cells with potential use in drug testing, bio-artificial livers and transplantation. These cells still have some limitations in functionality, understanding further human liver development and improving tissue culture is required. The use of stem cells and their progeny in animal models of liver disease has been encouraging and stimulated clinical trials to commence. PMID: 19837579 [PubMed - as supplied by publisher] |
| Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer.
October 20, 2009 at 8:02 am
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| | Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009 Oct 16; Authors: Malam Y, Loizidou M, Seifalian AM Nanoscale drug delivery systems using liposomes and nanoparticles are emerging technologies for the rational delivery of chemotherapeutic drugs in the treatment of cancer. Their use offers improved pharmacokinetic properties, controlled and sustained release of drugs and, more importantly, lower systemic toxicity. The commercial availability of liposomal Doxil((R)) and albumin-nanoparticle-based Abraxane((R)) has focused attention on this innovative and exciting field. Recent advances in liposome technology offer better treatment of multidrug-resistant cancers and lower cardiotoxicity. Nanoparticles offer increased precision in chemotherapeutic targeting of prostate cancer and new avenues for the treatment of breast cancer. Here we review current knowledge on the two technologies and their potential applications to cancer treatment. PMID: 19837467 [PubMed - as supplied by publisher] |
| Candidate Bone Tissue Engineered Product Based on Human Bone Derived Cells and Polyurethane Scaffold.
October 20, 2009 at 8:02 am
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| | Candidate Bone Tissue Engineered Product Based on Human Bone Derived Cells and Polyurethane Scaffold. Acta Biomater. 2009 Oct 15; Authors: Woźniak P, Bil M, Ryszkowska J, Wychowański P, Wróbel E, Ratajska A, Hoser G, Przybylski J, Kurzydłowski KJ, Lewandowska-Szumieł M Biodegradable polyurethanes (PURs) are recently investigated as candidate materials for bone regenerative medicine. There are promising reports documenting the biocompatibility of selected PURs in vivo and, on the other hand, the tolerance of certain cells toward PURs in vitro - potentially to be used as scaffolds for tissue engineered products (TEPs). The aim of the present study was to make a step forward and create a TEP using human osteogenic cells and a polyurethane scaffold, and to evaluate the obtained TEP quality in vivo. Human Bode Derived Cells (HBDCs) were seeded and cultured on polyurethane scaffolds in a bioreactor for 14 days. The TEP examination in vitro was based on the evaluation of cell number, cell phenotype and cell distribution within the scaffold. TEPs and control samples (scaffolds without cells) were implanted subcutaneously into SCID mice for 4 and 13 weeks. Explants harvested from the animals were examined using histological and immunohistochemical methods. They were also tested in mechanical trials. It was found that dynamic conditions for cell seeding and culture enable homogenous distribution, maintaining the proliferative potential and osteogenic phenotype of the HBDCs cultured on polyurethane scaffolds. It was also found that HBDCs implanted as a component of TEP survived and kept their ability to produce the specific human bone extracellular matrix, which resulted in higher mechanical properties of the harvested explants when preseeded with HBDCs. The whole system, including the investigated PUR-scaffold and the method of human cell seeding and culture, is recommended as a candidate bone TEP. PMID: 19837193 [PubMed - as supplied by publisher] |
| Pivotal Role for Beta-1 Integrin in Neurovascular Remodelling After Ischemic Stroke.
October 20, 2009 at 8:02 am
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| | Pivotal Role for Beta-1 Integrin in Neurovascular Remodelling After Ischemic Stroke. Exp Neurol. 2009 Oct 15; Authors: Lathia JD, Chigurupati S, Thundyil J, Selvaraj PK, Mughal MR, Woodruff TM, Chan SL, Karamyan VT, Mattson MP, Arumugam TV beta1 integrin is a cell surface molecule that is critical for endothelial cell adhesion, migration and survival during angiogenesis. In the present study we employed in vivo and in vitro models to elucidate the role of beta1 integrin in vascular remodelling and stroke outcomes. At 24 h after cerebral ischemia and reperfusion (I/R), the ischemic cortex (ipsilateral area) exhibited modest beta1 integrin immunoreactivity and a robust increase was observed at 72 h. Double-label immunohistochemical analysis for beta1 integrin with neuronal (NeuN), microglial (Iba-1), astrocyte (GFAP), progenitor cell (Ng2) and blood vessel (collagen 4) markers, showed that beta1 integrin expression only localized to blood vessels. In vitro studies using cultured endothelial cells and a beta1 integrin blocking antibody, confirmed that beta1 integrin is required for endothelial cell migration, proliferation and blood vessel formation. In vivo studies in the cerebral I/R model using the beta1 integrin blocking antibody further confirmed that beta1 integrin signaling is involved in vascular formation and recovery following ischemic stroke. Finally, we found that beta1 integrin is critically involved in functional deficits and survival after a stroke. These results suggest that beta1 integrin plays important roles in neurovascular remodelling and functional outcomes following stroke, and that targeting the beta1 integrin signalling may provide a novel strategy for modulating angiogenesis in ischemic stroke and other pathological conditions. PMID: 19837065 [PubMed - as supplied by publisher] |
| Encapsulation of proteins in poly(l-lactide-co-caprolactone) fibers by emulsion electrospinning.
October 20, 2009 at 8:02 am
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| | Encapsulation of proteins in poly(l-lactide-co-caprolactone) fibers by emulsion electrospinning. Colloids Surf B Biointerfaces. 2009 Sep 22; Authors: Li X, Su Y, Liu S, Tan L, Mo X, Ramakrishna S This study was aimed at investigating emulsion electrospinning to prepare biodegradable fibrous mats with encapsulation of human-nerve growth factor (NGF). One of the best methods for fabricating a bio-functional tissue engineering scaffold is to load bioactive agent into the scaffold. In this work, the feasibility of incorporating NGF into poly(l-lactide-co-caprolactone) fibers by emulsion electrospinning has been studied. The release behavior of encapsulated bovine serum albumin (BSA) was investigated. The bioactivity of NGF released from fibrous mats was verified by testing the neurite outgrowth of rat pheochromocytoma cells (PC12). Furthermore, the process of fiber forming during emulsion electrospinning was discussed. The results demonstrate that emulsion electrospun fibers can successfully encapsulate proteins and release them in a sustained manner. The bioactivity of NGF released from emulsion electrospun fibers was confirmed by PC12 bioassays. PMID: 19836931 [PubMed - as supplied by publisher] |
| Stem cells and the frontiers of neonatology.
October 20, 2009 at 8:02 am
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| | Stem cells and the frontiers of neonatology. Early Hum Dev. 2009 Oct 15; Authors: Lanfranchi A, Porta F, Chirico G The aim of the most recent studies on regenerative medicine was to focus on capability of stem cells deriving not only from haematopoietic system, but also from other organ and tissues, to regenerate damaged tissues. Stem cells derived from foetal annexes such as cord blood, placenta and amniotic fluid can be currently used in the effort to treat prenatally diagnosed genetic diseases. Cells derived from cord blood have been used since 1988 as an alternative source to realize stem cell transplantation. Compared with bone marrow, cord blood has shown the advantages of quick availability, less risk of GHVD, together with higher compatibility rates, and less risk of infections. Mesenchymal stem cells (MSCs) are multi-potent stem cells able to differentiate into different lineages, including osteocytes, chondrocytes, and adipocytes. Because of their trafficking capacity to injured tissues, clinical trials have been started evaluating the use of MSCs in the treatment of metabolic diseases like Hurler syndrome and metachromatic leukodystrophy, or Osteogenesis Imperfecta. MSCs were initially identified in adult bone marrow (BM-MSC), but cells resembling BM-MSCs have also been found in other tissues, both adult (peripheral blood, synovial membrane) and foetal (peripheral blood, liver, spleen, placenta, umbilical cord, and amniotic membrane). BM-MSCs have been widely used in clinical applications, as for cell-based therapy of Osteogenesis Imperfecta and metabolic diseases. In addition, human multi-potent MSCs present in second-trimester amniotic fluids may be a good target for prenatal gene therapy because of their expandability, their ability to differentiate into multiple lineages and their high transduction efficiency. PMID: 19836907 [PubMed - as supplied by publisher] |
| Hierarchical scaffolds via combined macro- and micro-phase separation.
October 20, 2009 at 8:02 am
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| | Hierarchical scaffolds via combined macro- and micro-phase separation. Biomaterials. 2009 Oct 15; Authors: George PA, Quinn K, Cooper-White JJ Recent advances in biomaterial surface engineering have shown that surface biomechanical, spatial and topographical properties can elicit control over fundamental biological processes such as cell shape, proliferation, differentiation and apoptosis. Along these lines, we have very recently shown that the self-assembly of block copolymers into thin films can be used as an extremely labile method to precisely position cellular adhesion molecules, at nanometre lateral spacings, to effect control over cell attachment and morphology. Here, we extend our work in 2-dimensional block copolymer films into the production of 3-dimensional porous block copolymer scaffolds. The reported method combines macro-scale temperature induced phase separation and micro-phase separation of block copolymers to produce highly porous scaffolds with surfaces comprised of nano-scale self-assembled block copolymer domains, representing a significant advance in currently available scaffold engineering technologies. The phase behaviour of these polymer-solvent systems is described and potential mechanisms leading to the observed structure formation are presented. The nano-domains have thereafter been functionalised with CGRGDS peptides throughout the scaffold and shown to effect changes in cell attachment and spreading, in agreement with previous 2-dimensional studies. These multi-scale, functional scaffolds are easy to manufacture and scaleable, making them ideal candidates for tissue engineering applications. PMID: 19836830 [PubMed - as supplied by publisher] |
| Regulation of protein loading capacity of hydroxyapatite by mercaptosuccinic acid modification.
October 20, 2009 at 8:02 am
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| | Regulation of protein loading capacity of hydroxyapatite by mercaptosuccinic acid modification. Acta Biomater. 2009 Oct 14; Authors: Ishihara S, Matsumoto T, Onoki T, Uddin MH, Sohmura T, Nakahira A Loading and releasing protein in a controllable way is extremely important for the protein vehicles used in bone tissue engineering. To obtain a suitable carrier material for basic proteins, such as BMP or bFGF, hydroxyapatite particles containing mercaptosuccinic acid (mercaptosuccinic acid (Mer), (Mer-HAp)) were synthesized. Physicochemical evaluation of Mer-HAp suggested that Mer was contained in HAp particles: it either simply adsorbed onto HAp crystals or trapped among the HAp crystals. A protein adsorption study using basic and acidic model proteins indicated that the synthesized Mer-HAp had selective loading properties of the basic protein. The loaded protein was gradually released from Mer-HAp in phosphate buffered saline. The protein release rate was different in each Mer-HAp synthesized with a different concentration of Mer. In addition, the protein release from Mer-HAp showed a similar profile with the Ca dissolution in different pH solution indicating that the Mer-HAp dissolution concerned with the protein release from Mer-HAp. Thus, Mer-HAp is a useful candidate for the basic protein carrier because it has properties of loading and releasing protein in a controllable way. PMID: 19836474 [PubMed - as supplied by publisher] |
| Vascular endothelial growth factor (VEGF) as a key therapeutic trophic factor in bone marrow mesenchymal stem cell-mediated cardiac repair.
October 20, 2009 at 8:02 am
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| | Vascular endothelial growth factor (VEGF) as a key therapeutic trophic factor in bone marrow mesenchymal stem cell-mediated cardiac repair. Biochem Biophys Res Commun. 2009 Oct 14; Authors: Zisa D, Shabbir A, Suzuki G, Lee T We recently demonstrated a novel effective therapeutic regimen for treating hamster heart failure based on injection of bone marrow mesenchymal stem cells (MSCs) or MSC-conditioned medium into the skeletal muscle. The work highlights an important cardiac repair mechanism mediated by the myriad of trophic factors derived from the injected MSCs and local musculature that can be explored for non-invasive stem cell therapy. While this therapeutic regimen provides the ultimate proof that MSC-based cardiac repair is mediated by the trophic actions independent of MSC differentiation or stemness, the trophic factors responsible for cardiac regeneration after MSC therapy remain largely undefined. Toward this aim, we took advantage of the finding that human and porcine MSCs exhibit species-related differences in expression of trophic factors. We demonstrate that human MSCs when compared to porcine MSCs express and secrete 5-fold less vascular endothelial growth factor (VEGF) in conditioned medium (40 +/- 5 and 225 +/- 17 pg/ml VEGF, respectively). This deficit in VEGF output was associated with compromised cardiac therapeutic efficacy of human MSC-conditioned medium. Overexpression of VEGF in human MSCs however completely restored the therapeutic potency of the conditioned medium. This finding indicates VEGF as a key therapeutic trophic factor in MSC-mediated myocardial regeneration, and demonstrates the feasibility of human MSC therapy using trophic factor-based cell-free strategies, which can eliminate the concern of potential stem cell transformation. PMID: 19836359 [PubMed - as supplied by publisher] |
| Role of Sonic hedgehog signaling and the expression of its components in human embryonic stem cells.
October 20, 2009 at 8:02 am
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| | Role of Sonic hedgehog signaling and the expression of its components in human embryonic stem cells. Stem Cell Res. 2009 Sep 16; Authors: Wu SM, Choo AB, Yap MG, Chan KK Human embryonic stem cells (hESC) are characterized by their ability to self-renew and differentiate into all cell types of the body, making them a valuable resource for regenerative medicine. Yet, the molecular mechanisms by which hESC retain their capacity for self-renewal and differentiation remain unclear. The Hedgehog signaling pathway plays a pivotal role in organogenesis and differentiation during development, and is also involved in the proliferation and cell-fate specification of neural stem cells and neural crest stem cells. As there has been no detailed study of the Sonic hedgehog (SHH) signaling pathway in hESC, this study examines the expression and functional role of SHH during hESC self-renewal and differentiation. Here, we show the gene and protein expression of key components of the SHH signaling pathway in hESC and differentiated embryoid bodies. Despite the presence of functioning pathway components, SHH plays a minimal role in maintaining pluripotency and regulating proliferation of undifferentiated hESC. However, during differentiation with retinoic acid, a GLI-responsive luciferase assay and target genes PTCH1 and GLI1 expression reveal that the SHH signaling pathway is highly activated. Besides, addition of exogenous SHH to hESC differentiated as embryoid bodies increases the expression of neuroectodermal markers Nestin, SOX1, MAP2, MSI1, and MSX1, suggesting that SHH signaling is important during hESC differentiation toward the neuroectodermal lineage. Our findings provide a new insight in understanding the SHH signaling in hESC and the further development of hESC differentiation for regenerative medicine. PMID: 19836325 [PubMed - as supplied by publisher] |
| Neo-vascularization and bone formation mediated by fetal mesenchymal stem cell tissue-engineered bone grafts in critical-size femoral defects.
October 20, 2009 at 8:02 am
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| | Neo-vascularization and bone formation mediated by fetal mesenchymal stem cell tissue-engineered bone grafts in critical-size femoral defects. Biomaterials. 2009 Oct 14; Authors: Zhang ZY, Teoh SH, Chong MS, Lee ES, Tan LG, Mattar CN, Fisk NM, Choolani M, Chan J Tissue-engineered bone grafts (TEBG) require highly osteogenic cell sources for use in fracture repair applications. Compared to other sources of mesenchymal stem cells (MSC), human fetal MSC (hfMSC) have recently been shown to be more proliferative and osteogenic. We studied the functional performance of hfMSC-mediated TEBG in 7mm rat femoral critical-sized bone defects (CSD). Dynamically-cultured and osteogenically-primed hfMSC seeded onto macroporous poly-varepsilon-caprolactone tri-calcium phosphate scaffolds were transplanted into CSDs. After 12 weeks, hfMSC-mediated TEBG induced 2.1x more new bone formation (43.3+/-10.5 vs. 21.0+/-7.4mm(3), p<0.05), with greater compact and woven bone, and a 9.8x increase in stiffness (3.9+/-1.7 vs. 0.4+/-0.3mNm/degree, p<0.05) compared to acellular scaffolds, such that only animals transplanted with TEBG underwent full fracture repair of the CSD. Although hfMSC survived for <4 weeks, by 4 weeks they were associated with a 3.9x larger vasculature network in the defect area (35.2+/-11.1 vs. 6.5+/-3.6mm(3)p<0.05), suggesting an important role for hfMSC in the promotion of neo-vasculogenesis. We speculate that hfMSC-mediated healing of the CSD by stimulating neo-vascularization through as yet undetermined mechanisms. This proof-of-principle study demonstrates the utility of primitive MSC for bone regeneration, and may be of relevance to vascularization in other areas of regenerative medicine. PMID: 19836073 [PubMed - as supplied by publisher] |
| Foamed Surfactant Solution as a Template for Self-setting Injectable Hydroxyapatite Scaffolds for Bone Regeneration.
October 20, 2009 at 8:02 am
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| | Foamed Surfactant Solution as a Template for Self-setting Injectable Hydroxyapatite Scaffolds for Bone Regeneration. Acta Biomater. 2009 Oct 13; Authors: Montufar EB, Traykova T, Gil C, Harr I, Almirall A, Aguirrre A, Engel E, Planell JA, Ginebra MP The application of minimally invasive surgical techniques in the field of orthopaedic surgery has created a growing need of new injectable synthetic materials which can be used for bone grafting. In this work a novel fully synthetic injectable calcium phosphate foam was developed by mixing alpha- tricalcium phosphate (alpha-TCP) powder with a foamed Polysorbate 80 solution. Polysorbate 80 is a nonionic surfactant approved for parenteral applications. The foam was able to retain the porous structure after injection provided that the foamed paste was injected shortly after mixing (typically 2.5 minutes), and set through the hydrolysis of alpha-TCP to a calcium deficient hydroxyapatite, thus producing a hydroxyapatite solid foam in situ. The effect of different processing parameters on the porosity, microstructure, injectability and mechanical properties of the hydroxyapatite foams was analysed, and the ability of the pre-set foam to support osteoblastic-like cell proliferation and differentiation was assessed. Interestingly, the concentration of surfactant needed to obtain the foams was lower than that considered safe in drug formulations for parenteral administration. The possibility to gather bioactivity, injectability, macroporosity and self setting ability in a single fully synthetic material, represents a step forward in the design of new materials for bone regeneration compatible with minimally invasive surgical techniques. PMID: 19835998 [PubMed - as supplied by publisher] | | | 
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