| Cryopreservation of stromal vascular fraction of adipose tissue in a serum-free freezing medium.
December 8, 2009 at 7:47 am
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| | Cryopreservation of stromal vascular fraction of adipose tissue in a serum-free freezing medium. J Tissue Eng Regen Med. 2009 Dec 4; Authors: Thirumala S, Gimble JM, Devireddy RV Developing effective techniques for the cryopreservation of human adipose-derived adult stem cells could increase the usefulness of these cells in tissue engineering and regenerative medicine. Unfortunately, the use of serum and a commonly used cryoprotectant chemical, dimethyl sulphoxide (DMSO), during cryopreservation storage restricts the direct translation of adult stem cells to in vivo applications. The objective of this study was to test the hypothesis that the stromal vascular fraction (SVF) of adipose tissue can be effectively cryopreserved and stored in liquid nitrogen, using a freezing medium containing high molecular weight polymers, such as methylcellulose (MC) and/or polyvinylpyrollidone (PVP), as the cryoprotective agent (CPA) instead of DMSO. To this end, we investigated the post-freeze/thaw viability and apoptotic behaviour of SVF of adipose tissue frozen in 16 different media: (a) the traditional medium containing Dulbecco's modified Eagle's medium (DMEM) with 80% fetal calf serum (FCS) and 10% DMSO; (b) DMEM with 80% human serum (HS) and 10% DMSO; (c) DMEM with 0%, 2%, 4%, 6%, 8% or 10% DMSO; (d) DMEM with 1% MC and 10% of either HS or FCS or DMSO; (e) DMEM with 10% PVP and varying concentrations of FCS (0%, 10%, 40% or 80%); (f) DMEM with 10% PVP and 10% HS. Approximately 1 ml (10(6) cells/ml) of SVF cells were frozen overnight in a -80 degrees C freezer and stored in liquid nitrogen for 2 weeks before being rapidly thawed in a 37 degrees C water bath (1-2 min agitation), resuspended in culture medium and seeded in separate wells of a six-well plate for a 24 h incubation period at 37 degrees C. After 24 h, the thawed samples were analysed by brightfield microscopy and flow cytometry. The results suggest that the absence of DMSO (and the presence of MC) significantly increases the fraction of apoptotic and/or necrotic SVF cells. However, the percentage of viable cells obtained with 10% PVP and DMEM was comparable with that obtained in freezing medium with DMSO and serum (HS or FCS), i.e. approximately 54 +/- 14% and approximately 63 +/- 10%, respectively. Adipogenic and osteogenic differentiation behaviour of the frozen thawed cells was also assessed, using histochemical staining. Our results suggest that post-thaw SVF cell viability and adipogenic and osteogenic differentiability can be maintained even when they are frozen in the absence of serum and DMSO but with 10% PVP in DMEM. Copyright (c) 2009 John Wiley & Sons, Ltd. PMID: 19967746 [PubMed - as supplied by publisher] |
| Skeletal tissue engineering using embryonic stem cells.
December 8, 2009 at 7:47 am
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| | Skeletal tissue engineering using embryonic stem cells. J Tissue Eng Regen Med. 2009 Dec 4; Authors: Jukes JM, van Blitterswijk CA, de Boer J Various cell types have been investigated as candidate cell sources for cartilage and bone tissue engineering. In this review, we focused on chondrogenic and osteogenic differentiation of mouse and human embryonic stem cells (ESCs) and their potential in cartilage and bone tissue engineering. A decade ago, mouse ESCs were first used as a model to study cartilage and bone development and essential genes, factors and conditions for chondrogenesis and osteogenesis were unravelled. This knowledge, combined with data from the differentiation of adult stem cells, led to successful chondrogenic and osteogenic differentiation of mouse ESCs and later also human ESCs. Next, researchers focused on the use of ESCs for skeletal tissue engineering. Cartilage and bone tissue was formed in vivo using ESCs. However, the amount, homogeneity and stability of the cartilage and bone formed were still insufficient for clinical application. The current protocols require improvement not only in differentiation efficiency but also in ESC-specific hurdles, such as tumourigenicity and immunorejection. In addition, some of the general tissue engineering challenges, such as cell seeding and nutrient limitation in larger constructs, will also apply for ESCs. In conclusion, there are still many challenges, but there is potential for ESCs in skeletal tissue engineering. Copyright (c) 2009 John Wiley & Sons, Ltd. PMID: 19967745 [PubMed - as supplied by publisher] |
| Functional life-long maintenance of engineered liver tissue in mice following transplantation under the kidney capsule.
December 8, 2009 at 7:47 am
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| | Functional life-long maintenance of engineered liver tissue in mice following transplantation under the kidney capsule. J Tissue Eng Regen Med. 2009 Dec 4; Authors: Ohashi K, Koyama F, Tatsumi K, Shima M, Park F, Nakajima Y, Okano T The ability to engineer biologically active cells and tissue matrices with long-term functional maintenance has been a principal focus for investigators in the field of hepatocyte transplantation and liver tissue engineering. The present study was designed to determine the efficacy and temporal persistence of functional engineered liver tissue following transplantation under the kidney capsule of a normal mouse. Hepatocytes were isolated from human alpha-1 antitrypsin (hA1AT) transgenic mouse livers. Hepatocytes were subsequently transplanted under the kidney capsule space in combination with extracellular matrix components (Matrigel) for engineering liver tissues. The primary outcome of interest was to assess the level of engineering liver tissue function over the experimental period, which was 450 days. Long-term survival by the engineered liver tissue was confirmed by measuring the serum level of hA1AT in the recipient mice throughout the experimental period. In addition, administration of chemical compounds at day 450 resulted in the ability of the engineered liver tissue to metabolize exogenously circulating compounds and induce drug-metabolizing enzyme production. Moreover, we were able to document that the engineered tissues could retain their native regenerative potential similar to that of naïve livers. Overall, these results demonstrated that liver tissues could be engineered at a heterologous site while stably maintaining its functionality for nearly the life span of a normal mouse. Copyright (c) 2009 John Wiley & Sons, Ltd. PMID: 19967744 [PubMed - as supplied by publisher] |
| Induced adult stem (iAS) cells and induced transit amplifying progenitor (iTAP) cells-a possible alternative to induced pluripotent stem (iPS) cells?
December 8, 2009 at 7:47 am
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| | Induced adult stem (iAS) cells and induced transit amplifying progenitor (iTAP) cells-a possible alternative to induced pluripotent stem (iPS) cells? J Tissue Eng Regen Med. 2009 Dec 4; Authors: Heng BC, Richards M, Ge Z, Shu Y The successful derivation of iPSC lines effectively demonstrates that it is possible to reset the 'developmental clock' of somatic cells all the way back to the initial embryonic state. Hence, it is plausible that this clock may instead be turned back half-way to a less immature developmental stage that is more directly applicable to clinical therapeutic applications or for in vitro pharmacology/toxicology screening assays. Such a suitable developmental state is postulated to be either the putative transit amplifying progenitor stage or adult stem cell stage. It is hypothetically possible to reprogram mature and terminally differentiated somatic cells back to the adult stem cell or transit amplifying progenitor stage, in a manner similar to the derivation of iPSC. It is proposed that the terminology 'Induced Adult Stem Cells' (iASC) or 'Induced Transit Amplifying Progenitor Cells' (iTAPC) be used to described such reprogrammed somatic cells. Of particular interest, is the possibility of resetting the developmental clock of mature differentiated somatic cells of the mesenchymal lineage, explanted from adipose tissue, bone marrow and cartilage. The putative adult stem cell sub-population from which these cells are derived, commonly referred to as 'mesenchymal stem cells', are highly versatile and hold much therapeutic promise in regenerative medicine, as attested to by numerous human clinical trials and animal studies. Perhaps it may be appropriate to term such reprogrammed cells as 'Induced Mesenchymal Stem Cells' (iMSC) or as 'Induced Mesenchumal Progenitor Cells' (iMPC). Given that cells from the same organ/tissue will share some commonalities in gene expression, we hypothesize that the generation of iASC or iTAPC would be more efficient as compared to iPSC generation, since a common epigenetic program must exist between the reprogrammed cells, adult stem cell or progenitor cell types and terminally differentiated cell types from the same organ/tissue. Copyright (c) 2009 John Wiley & Sons, Ltd. PMID: 19967742 [PubMed - as supplied by publisher] |
| Effects of BMP-2 and dexamethasone on osteogenic differentiation of rat dental follicle progenitor cells seeded on three-dimensional beta-TCP.
December 8, 2009 at 7:47 am
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| | Effects of BMP-2 and dexamethasone on osteogenic differentiation of rat dental follicle progenitor cells seeded on three-dimensional beta-TCP. Biomed Mater. 2009 Dec 7;4(6):65010 Authors: Xu LL, Liu HC, Wang DS, E LL, Xu L, Jin ZL, Duan YZ The aim of this study was to investigate the effects of BMP-2 and dexamethasone (Dex) on osteogenic differentiation of rat dental follicle progenitor cells (RDFCs) seeded on three-dimensional beta-TCP. The alkaline phosphatase (ALP), the calcium and phosphonium, the osteocalcin in media of the third passage RDFCs on biomaterial beta-TCP after 1-3, 3-7, 7-14 days of culture were examined respectively. The growth of cells on the scaffolds was observed by scanning electron microscope (SEM) after 3, 7 days of culture and by implanting in the backs of severe combined immunodeficient (SCID) mice for bone regeneration. The third passage RDFCs could be seen adhered, extended and proliferated on the beta-TCP by scanning electron microscopy. The ALP activity, the calcium and phosphoniums and the osteocalcin content of dexamethasone (10(-8) M) or/and BMP-2 (100 ng ml(-1)) were significantly higher than their existence in the control group. They were the significantly highest among four groups after joint application of BMP-2 and dexamethasone. After 8 weeks of implantation, the percentage of the new bones formed area in the RDFCs+beta-TCP+BMP-2+Dex group was significantly higher than that in the RDFCs+beta-TCP+BMP-2 group. In contrast, beta-TCP, RDFCs+beta-TCP+Dex and control constructs lacked new bone formation by histological staining and histomorphometric analysis. The BMP-2+Dex could significantly promote osteogenic differentiation of RDFCs on beta-TCP. beta-TCP supported fast cellular adhesion, proliferation and differentiation of RDFCs. The feasibility of its application in periodontal tissue engineering was also proved. PMID: 19966384 [PubMed - as supplied by publisher] |
| Epimorphic regeneration approach to tissue replacement in adult mammals.
December 8, 2009 at 7:47 am
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| | Epimorphic regeneration approach to tissue replacement in adult mammals. Proc Natl Acad Sci U S A. 2009 Dec 4; Authors: Agrawal V, Johnson SA, Reing J, Zhang L, Tottey S, Wang G, Hirschi KK, Braunhut S, Gudas LJ, Badylak SF Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products. PMID: 19966310 [PubMed - as supplied by publisher] |
| Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI.
December 8, 2009 at 7:47 am
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| | Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci U S A. 2009 Dec 4; Authors: Padmanabhan A, Lee JS, Ismat FA, Lu MM, Lawson ND, Kanki JP, Look AT, Epstein JA Von Recklinghausen neurofibromatosis is a common autosomal dominant genetic disorder characterized by benign and malignant tumors of neural crest origin. Significant progress in understanding the pathophysiology of this disease has occurred in recent years, largely aided by the development of relevant animal models. Von Recklinghausen neurofibromatosis is caused by mutations in the NF1 gene, which encodes neurofibromin, a large protein that modulates the activity of Ras. Here, we describe the identification and characterization of zebrafish nf1a and nf1b, orthologues of NF1, and show neural crest and cardiovascular defects resulting from morpholino knockdown, including vascular and cardiac valvular abnormalities. Development of a zebrafish model of von Recklinghausen neurofibromatosis will allow for structure-function analysis and genetic screens in this tractable vertebrate system. PMID: 19966217 [PubMed - as supplied by publisher] |
| [Autologous stem cell therapy with surgical myocardial revascularization.]
December 8, 2009 at 7:47 am
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| | [Autologous stem cell therapy with surgical myocardial revascularization.] Anadolu Kardiyol Derg. 2009 Dec;9(6):465-6 Authors: Durdu S, Cubukçuoğlu Deniz G, Akar AR PMID: 19965316 [PubMed - in process] |
| [Autologous stem cell therapy with surgical myocardial revascularization - The Rostock University experience.]
December 8, 2009 at 7:47 am
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| | [Autologous stem cell therapy with surgical myocardial revascularization - The Rostock University experience.] Anadolu Kardiyol Derg. 2009 Dec;9(6):457-64 Authors: Yerebakan C, Uğurlucan M, Kaminski A, Westphal B, Liebold A, Steinhoff G OBJECTIVE: Stem cell therapy has gained great attraction in the treatment of acute and chronic myocardial diseases in recent years. The aim was to evaluate our experience in light of the middle term results of intramyocardial stem cell treatment with concomitant coronary artery bypass surgery (CABG) since 2001. Methods: After encouraging initial results of the Phase I (safety) trial with the first 15 patients, a prospective, controlled Phase II (efficacy) study was begun with 40 patients aiming to determine functional benefit of stem cell treatment using bone marrow derived CD 133+stem cell therapy with concomitant CABG in comparison to CABG only since 2003. Medium-term results of intervention were evaluated using patient's clinical findings, Holter monitoring, echocardiography, magnetic resonance imaging, computed tomography and myocardial scintigraphy. Statistical analyses were performed using unpaired t, Mann-Whitney U, ANOVA for repeated measurements and Chi-square tests. RESULTS: Left ventricular ejection fraction (LVEF) has increased significantly at 6th and 18th months follow-up in the first 15 patients who received therapy since 2001 (preoperative: 39.0+/- 8.7%; 6th month: 50.2+/- 8.5% and 18th month: 47.9+/- 6.0%; p=0.012). In the late group of patients, LVEF increased from 37.4+/- 8.4% to 47.1+/- 8.3% (p<0.001) whilst although an increase in LVEF has been observed in the CABG alone group (from 37.9+/- 10.3% to 41.3+/- 9.1%) the increase has not been statistically significant. Mortality occurred in 2 patients [1 patient from the early and 1 patient from the medium term follow-up] due to non-cardiac reasons. Myocardial calcification, lethal ventricular arrhythmia, and tumor formation have not been observed in any of the patients in the long-term follow up. CONCLUSION: Direct injection of bone marrow derived CD 133+ stem cells into the myocardium with concomitant CABG is safe. However, this treatment modality may only be applied as standard treatment after completion of the long- term detailed results of prospective, randomized multicenter trials. PMID: 19965315 [PubMed - in process] |
| Developmental effects of low frequency magnetic fields on P19-derived neuronal cells.
December 8, 2009 at 7:47 am
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| | Developmental effects of low frequency magnetic fields on P19-derived neuronal cells. Conf Proc IEEE Eng Med Biol Soc. 2009;1:5942-5 Authors: Saito A, Takayama Y, Moriguchi H, Kotani K, Jimbo Y Modulation of pluripotent stem cell differentiation by several environmental factors, such as physical stimulation, is important theme in tissue engineering. In this study, we report the effects of extremely low frequency magnetic fields (ELF-MFs) exposure (1 mT or 10 mT, 50 Hz, sinusoidal) on the neuronal differentiation process of P19 embryonal carcinoma cells (P19 cells). Here, during induction of differentiation, the ELF-MFs exposed to embryoid bodies (EBs). After neuronal differentiation, the effects of ELF-MFs were evaluated by morphological analysis, immunochemical analysis (MAP2, GFAP), and the developmental neuronal network activities recorded by the micro-electrode arrays (MEAs). As a result, the percentage of MAP2 positive cells and the spike frequencies were increased by 10 mT ELF-MF, and then the percentage of GFAP positive cells were reduced. However, these effects were not seen in 1 mT exposed cells. Therefore, these results suggested that the intensity of a magnetic field was important for affecting a characteristic of neuronal differentiation and a functional neuronal network property. PMID: 19965063 [PubMed - in process] |
| Degradable polymers for gene delivery.
December 8, 2009 at 7:47 am
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| | Degradable polymers for gene delivery. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2412-5 Authors: Sunshine J, Bhise N, Green JJ Degradable polymers were synthesized that self-assemble with DNA to form particles that are effective for gene delivery. Small changes to polymer synthesis conditions, particle formulation conditions, and polymer structure led to significant changes to efficacy in a cell-type dependent manner. Polymers presented here are more effective than Lipofectamine 2000 or polyethylenimine for gene delivery to cancerous fibroblasts or human primary fibroblasts. These materials may be useful for cancer therapeutics and regenerative medicine. PMID: 19964958 [PubMed - in process] |
| Injectable myocardial matrix as a scaffold for myocardial tissue engineering.
December 8, 2009 at 7:47 am
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| | Injectable myocardial matrix as a scaffold for myocardial tissue engineering. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2406-8 Authors: Singelyn JM, Dequach JA, Christman KL Current injectable materials utilized in myocardial tissue engineering have been borrowed from other tissue engineering applications and have not been specifically designed for the myocardium. We have recently tested the feasibility of using an injectable form of myocardial extracellular matrix that would provide cardiac specific matrix cues as well as be amenable to minimally invasive delivery. We have demonstrated that this material self-assembles in vivo to form a nanofibrous scaffold, which supports the infiltration of neovasculature. We have also demonstrated that this material may be delivered minimally invasively through a catheter. PMID: 19964956 [PubMed - in process] |
| Temporal and spatial control over soluble protein signaling for musculoskeletal tissue engineering.
December 8, 2009 at 7:47 am
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| | Temporal and spatial control over soluble protein signaling for musculoskeletal tissue engineering. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2103-5 Authors: Murphy WL Orthopedic tissue engineering strategies have developed rapidly in response to large and growing clinical needs. However, current clinical methods for replacement of natural tissue function have significant limitations, and pragmatic challenges have hindered clinical use of emerging tissue engineering approaches. In addition, current methods are not yet capable of achieving complex spatial and temporal regulation of soluble signaling (e.g. growth factor signaling), which may be required for complex, functional tissue regeneration. We have begun to develop a series of new medical devices, which are designed to temporally and spatially regulate growth factor and cytokine signaling during tissue regeneration. The initial goal of these studies is to regulate the behavior of multipotent stem cells, and to promote formation of clinically relevant tissue interfaces (e.g. bone-tendon interfaces). The ultimate goal is to further understand and recapitulate the complex processes that lead to functional musculoskeletal development and regeneration. PMID: 19964780 [PubMed - in process] |
| Designer protein-based scaffolds for neural tissue engineering.
December 8, 2009 at 7:47 am
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| | Designer protein-based scaffolds for neural tissue engineering. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2101-2 Authors: Straley K, Heilshorn SC A key attribute missing from many current biomaterials is the ability to independently tune multiple biomaterial properties without simultaneously affecting other material parameters. Because cells are well known to respond to changes in the initial elastic modulus, degradation rate, and cell adhesivity of a biomaterial, it is critical to develop synthetic design strategies that allow decoupled tailoring of each individual parameter in order to systematically optimize cell-scaffold interactions. We present the development of a family of biomimetic scaffolds composed of chemically crosslinked, elastin-like proteins designed to support neural regeneration through a combination of cell adhesion and cell-induced degradation and remodeling. Through use of a modular protein-design strategy, a range of biomaterials is created that allows independent tuning over the initial elastic modulus, degradation rate, cell adhesivity, and neurite outgrowth. By combining these engineered proteins into composite structures, biomaterials are created with 3D patterns that emerge over time in response to cell-secreted enzymes. These dynamic 3D structures enable the delivery of multiple drugs with precise spatial and temporal resolution and also enable the design of biomaterials that adapt to changing scaffold needs. PMID: 19964779 [PubMed - in process] |
| Controlling cellular biomechanics of human mesenchymal stem cells.
December 8, 2009 at 7:47 am
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| | Controlling cellular biomechanics of human mesenchymal stem cells. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2090-3 Authors: Titushkin IA, Cho MR The therapeutic efficacy of human mesenchymal stem cells (hMSCs) depends on proper characterization and control of their unique biological, mechanical and physicochemical properties. For example, cellular biomechanics and environmental mechanical cues have been shown to critically influence cell commitment to a particular lineage. We characterized biomechanical properties of hMSCs including cytoskeleton elasticity and plasma membrane/cytoskeleton coupling. As expected, during osteogenic differentiation of hMSCs, the cellular biomechanics is remodeled, and such remodeling precedes up-regulation of the osteogenic markers. Further, application of an electrical stimulation modulates the cellular biomechanics and therefore may be used to facilitate stem cell differentiation for stem cell-based tissue engineering. PMID: 19964578 [PubMed - in process] |
| Differentiation of pluripotent stem cells on multiwalled carbon nanotubes.
December 8, 2009 at 7:47 am
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| | Differentiation of pluripotent stem cells on multiwalled carbon nanotubes. Conf Proc IEEE Eng Med Biol Soc. 2009;1:6022-5 Authors: Holy J, Perkins E, Yu X This paper studies the adhesion, growth, and differentiation of stem cells on carbon nanotube matrices. Glass coverslips were coated with multiwalled carbon nanotube (MWNT) thin films using layer-by-layer self-assembling techniques. Pluripotent P19 mouse embryonal carcinoma stem cells were seeded onto uncoated or MWNT-coated coverslips, and either maintained in an undifferentiated state or induced to differentiate by the addition of retinoic acid. We found that cell adhesion was increased on the MWNT-coated surfaces, and that the expression patterns of some differentiation markers were altered in cells grown on MWNTs. The results suggest that MWNTs will be useful in directing pluripotent stem cell differentiation for tissue engineering purposes. PMID: 19964415 [PubMed - in process] |
| Whole organ decellularization - a tool for bioscaffold fabrication and organ bioengineering.
December 8, 2009 at 7:47 am
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| | Whole organ decellularization - a tool for bioscaffold fabrication and organ bioengineering. Conf Proc IEEE Eng Med Biol Soc. 2009;1:6526-9 Authors: Baptista PM, Orlando G, Mirmalek-Sani SH, Siddiqui M, Atala A, Soker S The use of synthetic and naturally-derived scaffolds for bioengineering of solid organs has been limited due to a lack of an integrated vascular network. Here, we describe fabrication of a bioscaffold system with intact vascular tree. Animal-donor organs and tissues, ranging in size up-to thirty centimeters, were perfused with decellularization solution to selectively remove the cellular component of the tissue and leave an intact extracellular matrix and vascular network. The vascular tree demonstrated sequential fluid flow through a central inlet vessel that branched into an extensive capillary bed and coalesced back into a single outlet vessel. In one example, the liver, we used central inlet vessels to perfuse human and animal liver cells through the bioscaffold to create a functional liver tissue construct in vitro. These results demonstrate a novel yet simple and scalable method to obtain whole organ vascularized bioscaffolds with potential for liver, kidney, pancreas, intestine and other organs' bioengineering. These bioscaffolds can further provide a tool to study cells in their natural three-dimensional environment, which is superior for drug discovery platform compared with cells cultured in two-dimensional petri dishes. PMID: 19964173 [PubMed - in process] |
| Ensemble stimulation of embryoid bodies using microfabricated ITO substrates.
December 8, 2009 at 7:47 am
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| | Ensemble stimulation of embryoid bodies using microfabricated ITO substrates. Conf Proc IEEE Eng Med Biol Soc. 2009;1:5993-6 Authors: Takayama Y, Moriguchi H, Saito A, Kotani K, Jimbo Y Precise control of differentiation processes of pluripotent stem cell is key component for realization of regenerative medicine. Electrical stimulation is one of the promising techniques, particularly for regulation of neuronal regeneration. In the present study, we developed substrates with embedded electrodes, which allowed ensemble electrical stimulation of embryoid bodies (EBs) of stem cells. Microcavity-array patterns were fabricated on substrates with embedded electrodes using standard photo-lithography. Uniform-size EBs of P19 cells were prepared, inserted one by one in each microcavity, and electrical stimulation was applied through substrate electrodes. Stimulus-induced intracellular calcium transients were successfully monitored by fluorescence imaging. The results suggested that this method would be useful for applying precisely-controlled electrical stimulation to a large number of EBs of stem cells. PMID: 19964145 [PubMed - in process] |
| Cell-matrix mechanobiology: Applications to brain tumors and design of tissue engineering scaffolds.
December 8, 2009 at 7:47 am
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| | Cell-matrix mechanobiology: Applications to brain tumors and design of tissue engineering scaffolds. Conf Proc IEEE Eng Med Biol Soc. 2009;1:3350-2 Authors: Kumar S It is becoming increasingly clear that mechanical and other biophysical signals from the extracellular matrix (ECM) can powerfully influence a wide variety of fundamental cell behaviors, including proliferation, differentiation, death, and motility. This concept has significant implications both for understanding the pathophysiology of disease and the design of biointerfaces found in cellular microdevices and tissue engineering platforms. Here we briefly review recent progress from our laboratory in investigating the role of ECM-derived mechanical signals in the specific context of two systems: The growth and spread of malignant brain tumors and the design of microscale cardiac tissue engineering systems. In both cases, mechanical signals encoded in the ECM govern motility, mechanics, and/or proliferation in profound and unexpected ways and rely upon the cell's reciprocal ability to generate contractile force through myosin and its molecular regulators. PMID: 19964076 [PubMed - in process] |
| Characterizing the effects of aligned collagen fibers and ascorbic acid derivatives on behavior of rabbit corneal fibroblasts.
December 8, 2009 at 7:47 am
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| | Characterizing the effects of aligned collagen fibers and ascorbic acid derivatives on behavior of rabbit corneal fibroblasts. Conf Proc IEEE Eng Med Biol Soc. 2009;1:4242-5 Authors: Phu D, Orwin EJ The cornea is responsible for functional optical activity of the mammalian eye, as it must remain transparent in order to focus light onto the retina. Corneal disease is the second leading cause worldwide of vision loss [1]. Human donor tissue transplantation in the cornea is associated with problems such as immunorejection and recurring graft failures [1]. Tissue engineering offers a promising alternative to using human donor tissues in treating corneal diseases. A viable tissue-engineered cornea must be mechanically resilient to protect the fragile intraocular components of the eye, and optically transparent to refract light onto the retina. In the native cornea, transparency is maintained by both the cells in the stromal layer and the high organization of the extracellular matrix (ECM). This study aims to combine the effects of aligned collagen fibers and ascorbic acid derivatives to control corneal fibroblast behavior to not only express the appropriate proteins, but also to deposit aligned, small diameter collagen fibers that resemble the highly organized structure of the natural ECM. Results from this study suggest that the combined effect of an aligned scaffolding material and ascorbic acid supplements can create a cell-matrix construct that both downregulates expression of the light scattering protein a-smooth muscle actin (alpha-sma) and supports an increased number of cell layers. PMID: 19963815 [PubMed - in process] |
| Design and implementation of a two-dimensional inkjet bioprinter.
December 8, 2009 at 7:47 am
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| | Design and implementation of a two-dimensional inkjet bioprinter. Conf Proc IEEE Eng Med Biol Soc. 2009;1:6001-5 Authors: Pepper ME, Parzel CA, Burg T, Boland T, Burg KJ, Groff RE Tissue engineering has the potential to improve the current methods for replacing organs and tissues and for investigating cellular process within the scope of a tissue test system. Bioprinting technology can aid in the difficult task of arranging live mammalian cells and biomaterials in viable structures for tissue engineering purposes. This paper describes a system, based on HP26 series print cartridge technology, capable of precisely depositing multiple cell types in precise patterns. The paper discusses the research, design, and implementation of the printing system, which permits control of droplet firing parameters, including firing energy, speed, and spacing. The results demonstrate the system's fine patterning ability of viable cells, including two-dimensional patterned co-cultures of two cell types. The system has been specifically designed with the flexibility to be extended to print more than two cell types and/or materials simultaneously and to layer printed patterns to form three-dimensional constructs. With these features, the printing system will serve as the foundation for a biofabrication system capable of three-dimensional cell co-cultures, i.e. tissue test systems. PMID: 19963663 [PubMed - in process] |
| Tuning hydrogel properties for applications in tissue engineering.
December 8, 2009 at 7:47 am
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| | Tuning hydrogel properties for applications in tissue engineering. Conf Proc IEEE Eng Med Biol Soc. 2009;1:2094-6 Authors: Khetan S, Chung C, Burdick JA Biomaterial design is an important component towards tissue engineering applications. There are many parameters that may be adjusted including physical properties (i.e., degradation and mechanics) and chemical properties (e.g., adhesion and cellular interactions). These design components may dictate the success or failure of a tissue engineering approach. Our group is particularly interested in the use of swollen hydrogels as cell carriers. One material that is used to fabricate hydrogels is hyaluronic acid (HA), which is found in many tissues in the body. Here, we show the control over hydrogel degradation, both in the bulk and locally to cells to control both the distribution of extracellular matrix by cells and whether or not a cell spreads in the hydrogels. These signals are important in the final structure and mechanical properties of engineered tissues, and potentially the differentiation of encapsulated stem cells. PMID: 19963530 [PubMed - in process] |
| Bioactive nanofibers for fibroblastic differentiation of mesenchymal precursor cells for ligament/tendon tissue engineering applications.
December 8, 2009 at 7:47 am
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| | Bioactive nanofibers for fibroblastic differentiation of mesenchymal precursor cells for ligament/tendon tissue engineering applications. Differentiation. 2009 Dec 4; Authors: Sahoo S, Ang LT, Cho-Hong Goh J, Toh SL Mesenchymal stem cells and precursor cells are ideal candidates for tendon and ligament tissue engineering; however, for the stem cell-based approach to succeed, these cells would be required to proliferate and differentiate into tendon/ligament fibroblasts on the tissue engineering scaffold. Among the various fiber-based scaffolds that have been used in tendon/ligament tissue engineering, hybrid fibrous scaffolds comprising both microfibers and nanofibers have been recently shown to be particularly promising. With the nanofibrous coating presenting a biomimetic surface, the scaffolds can also potentially mimic the natural extracellular matrix in function by acting as a depot for sustained release of growth factors. In this study, we demonstrate that basic fibroblast growth factor (bFGF) could be successfully incorporated, randomly dispersed within blend-electrospun nanofibers and released in a bioactive form over 1 week. The released bioactive bFGF activated tyrosine phosphorylation signaling within seeded BMSCs. The bFGF-releasing nanofibrous scaffolds facilitated BMSC proliferation, upregulated gene expression of tendon/ligament-specific ECM proteins, increased production and deposition of collagen and tenascin-C, reduced multipotency of the BMSCs and induced tendon/ligament-like fibroblastic differentiation, indicating their potential in tendon/ligament tissue engineering applications. PMID: 19963313 [PubMed - as supplied by publisher] |
| Dose effect of tumor necrosis factor-alpha on in vitro osteogenic differentiation of mesenchymal stem cells on biodegradable polymeric microfiber scaffolds.
December 8, 2009 at 7:47 am
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| | Dose effect of tumor necrosis factor-alpha on in vitro osteogenic differentiation of mesenchymal stem cells on biodegradable polymeric microfiber scaffolds. Biomaterials. 2009 Dec 4; Authors: Mountziaris PM, Tzouanas SN, Mikos AG This study presents a first step in the development of a bone tissue engineering strategy to trigger enhanced osteogenesis by modulating inflammation. This work focused on characterizing the effects of the concentration of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on osteogenic differentiation of mesenchymal stem cells (MSCs) grown in a 3D culture system. MSC osteogenic differentiation is typically achieved in vitro through a combination of osteogenic supplements that include the anti-inflammatory corticosteroid dexamethasone. Although simple, the use of dexamethasone is not clinically realistic, and also hampers in vitro studies of the role of inflammatory mediators in wound healing. In this study, MSCs were pre-treated with dexamethasone to induce osteogenic differentiation, and then cultured in biodegradable electrospun poly(varepsilon-caprolactone) (PCL) scaffolds, which supported continued MSC osteogenic differentiation in the absence of dexamethasone. Continuous delivery of 0.1ng/mL of recombinant rat TNF-alpha suppressed osteogenic differentiation of rat MSCs over 16 days, which was likely the result of residual dexamethasone antagonizing TNF-alpha signaling. Continuous delivery of a higher dose, 5ng/mL TNF-alpha, stimulated osteogenic differentiation for a few days, and 50ng/mL TNF-alpha resulted in significant mineralized matrix deposition over the course of the study. These findings suggest that the pro-inflammatory cytokine TNF-alpha stimulates osteogenic differentiation of MSCs, an effect that can be blocked by the presence of anti-inflammatory agents like dexamethasone, with significant implications on the interplay between inflammation and tissue regeneration. PMID: 19963268 [PubMed - as supplied by publisher] |
| Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex.
December 8, 2009 at 7:47 am
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| | Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex. Biomaterials. 2009 Dec 4; Authors: Winslow BD, Tresco PA Several hypotheses have been proposed to explain how the brain tissue reaction to single unit recording electrodes influences biocompatibility including progressive changes in the spatial distribution of reactive astrocytes, and the loss of neurons over the indwelling period. To examine these hypotheses, the spatial distribution of biomarkers associated with the foreign body response to insulated microwires placed in rat cerebral cortex was analyzed 2, 4, and 12 weeks after implantation using quantitative methods. We observed a stereotypical tissue response that was similar in some aspects to that previously reported for penetrating planar silicon microelectrode arrays with some specific differences including an overall lower degree of cortical tissue reactivity. While we found no evidence that reactive gliosis increases over time or that neuronal loss is progressive, we did find evidence of persistent inflammation and enhanced BBB permeability at the electrode brain tissue interface that extended over the 3 month indwelling period and that exhibited more animal to animal variability at 3 months than at 2 and 4 weeks. PMID: 19963267 [PubMed - as supplied by publisher] |
| Canine embryonic stem cells: State of the art.
December 8, 2009 at 7:47 am
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| | Canine embryonic stem cells: State of the art. Theriogenology. 2009 Dec 4; Authors: Schneider MR, Wolf E, Braun J, Kolb HJ, Adler H Embryonic stem cells (ESCs) are permanent cell lines that can be maintained in a pluripotent, undifferentiated state. Appropriate environmental stimuli can cause them to differentiate into cell types of all three germ layers both in vitro and in vivo. Embryonic stem cells bear many opportunities for clinical applications in tissue engineering and regenerative medicine. Whereas most of our knowledge on the biology and technology of ESCs is derived from studies with mouse cells, large animal models mimicking important aspects of human anatomy, physiology, and pathology more closely than mouse models are urgently needed for studies evaluating the safety and efficacy of cell therapies. The dog is an excellent model for studying human diseases, and the availability of canine ESCs would open new possibilities for this model in biomedical research. In addition, canine ESCs could be useful for the development of cell-based approaches for the treatment of dogs. Here, we discuss the features of recently reported canine embryo-derived cells and their potential applications in basic and translational biomedical research. PMID: 19963261 [PubMed - as supplied by publisher] |
| Differentiation of human bone marrow mesenchymal stem cells grown in terpolyesters of 3-hydroxyalkanoates scaffolds into nerve cells.
December 8, 2009 at 7:47 am
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| | Differentiation of human bone marrow mesenchymal stem cells grown in terpolyesters of 3-hydroxyalkanoates scaffolds into nerve cells. Biomaterials. 2009 Dec 3; Authors: Wang L, Wang ZH, Shen CY, You ML, Xiao JF, Chen GQ Polyhydroxyalkanoates, abbreviated as PHA, have been studied for medical applications due to their suitable mechanical properties, blood and tissue tolerance and in vivo biodegradability. As a new member of PHA family, terpolyester of 3-hydroxybutyrate, 3-hydroxyvalerate and 3-hydroxyhexanoate, abbreviated as PHBVHHx, was compared with polylactic acid (PLA), copolyester of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx) for their respective functions leading to differentiation of human bone marrow mesenchymal stem cell (hBMSC) into nerve cells. Results indicated that 3D scaffolds promoted the differentiation of hBMSC into nerve cells more intensively compared with 2D films. Smaller pore sizes of scaffolds increased differentiation of hBMSC into nerve cells, whereas decreased cell proliferation. PHBVHHx scaffolds with pore sizes of 30-60mum could be used in nerve tissue engineering for treatment of nerve injury. The above results were supported by scanning electron microscope (SEM) and confocal microscopy observation on attachment and growth of hBMSCs on PLA, PHBHHx and PHBVHHx, and by CCK-8 evaluation of cell proliferation. In addition, expressions of nerve markers nestin, GFAP and beta-III tubulin of nerve cells differentiated from hBMSC grown in PHBVHHx scaffolds were confirmed by real-time PCR. PMID: 19962755 [PubMed - as supplied by publisher] |
| The influence of structural design of PLGA/collagen hybrid scaffolds in cartilage tissue engineering.
December 8, 2009 at 7:47 am
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| | The influence of structural design of PLGA/collagen hybrid scaffolds in cartilage tissue engineering. Biomaterials. 2009 Dec 3; Authors: Dai W, Kawazoe N, Lin X, Dong J, Chen G 3D biodegradable porous scaffold plays a very important role in articular cartilage tissue engineering. We developed hybrid structures of 3D scaffolds that combined the advantages of natural type I collagen and synthetic PLGA knitted mesh. The mechanically strong PLGA mesh served as a skeleton while the collagen microsponges facilitated cell seeding and tissue formation. The scaffolds were divided into 3 groups: (1) THIN: collagen microsponge formed in interstices of PLGA mesh; (2) SEMI: collagen microsponge formed on one side of PLGA mesh; (3) SANDWICH: collagen sponge formed on both sides of PLGA mesh. Bovine chondrocytes were cultured in these scaffolds and transplanted subcutaneously into nude mice for 2, 4, and 8 weeks. All three groups of transplants showed homogeneous cell distribution, natural chondrocyte morphology, and abundant cartilaginous ECM deposition. Production of GAGs per DNA and the expression of type II collagen and aggrecan mRNA were much higher in the SEMI and SANDWICH groups than in the THIN group. When compared to native articular cartilage, the mechanical strength of the engineered cartilage reached 54.8%, 49.3% in Young's modulus and 68.8%, 62.7% in stiffness, respectively, in SEMI and SANDWICH. These scaffolds could be used for the tissue engineering of articular cartilage with adjustable thickness. The design of the hybrid structures provides a strategy for the preparation of 3D porous scaffolds. PMID: 19962751 [PubMed - as supplied by publisher] |
| Biomimetic Apatite Formation on Calcium Phosphate Coated Titanium in Dulbecco's Phosphate Buffered Saline Solution Containing CaCl(2) (100 mg/L) with and without Fibronectin.
December 8, 2009 at 7:47 am
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| | Biomimetic Apatite Formation on Calcium Phosphate Coated Titanium in Dulbecco's Phosphate Buffered Saline Solution Containing CaCl(2) (100 mg/L) with and without Fibronectin. Acta Biomater. 2009 Dec 2; Authors: Chen C, Lee IS, Zhang SM, Yang HC Calcium phosphate (CaP) thin films with different degrees of crystallinity were coated on surfaces of commercially pure titanium by the electron-beam evaporation method. The details of apatite nucleation and growth on the coating layer were investigated in Dulbecco's phosphate buffered saline solutions containing calcium chloride (DPBS) or DPBS with fibronectin (DPBSF). The surfaces of samples were examined with the field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The concentration of fibronectin and calcium ions (Ca(2+)) were monitored by bicinchoninic acid method (BCA) and calcium assay kit (DICA-500), respectively. For the CaP-coated samples with the lowest degrees of crystallinity, the apatite initially formed at the fastest rate and reached the maximum Ca(2+) concentration after immersion in DPBS solution for 15 min. After the 15 min, the concentration of Ca(2+) decreased with the growth of the apatite on the coating layers. For all the samples, with crystallinity increasing, the maximum Ca(2+)concentration in the DPBS solutions decreased, and the immersion time to reach the maximum concentration increased. The presence of fibronectin in the DPBS solutions delayed the formation, and affected the morphology of the apatite. The fibronectin-incorporated apatite deposited on the surfaces of the titanium did not loss its biological activity of promoting osteoblast adhesion. PMID: 19962459 [PubMed - as supplied by publisher] |
| Genetically modified canine Schwann cells - in vitro and in vivo evaluation of their suitability for peripheral nerve tissue engineering.
December 8, 2009 at 7:47 am
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| | Genetically modified canine Schwann cells - in vitro and in vivo evaluation of their suitability for peripheral nerve tissue engineering. J Neurosci Methods. 2009 Dec 2; Authors: Schmitte R, Tipold A, Stein VM, Schenk H, Flieshardt C, Grothe C, Haastert K After peripheral nerve injury, Schwann cells (SC) guarantee for a regeneration-promoting milieu and are crucially involved in axonal regeneration. For extended nerve defects, bridging with an autologous nerve transplant is the gold standard therapy. Artificial biohybrid nerve transplants which combine a synthetic conduit with autologous SC genetically modified to express regeneration promoting proteins may provide an alternative therapy to autotransplantation. The dog seems to be an ideal translational animal model for new treatment strategies. In the present study, utilizing a new transfection protocol, we transplanted enhanced green fluorescent protein (EGFP)-expressing adult canine SC (cSC) into a 5mm epineural pouch in the sciatic nerve of adult rats (n=9). The epineurial pouch technique serves as proof of principle to follow the fate of the transplanted cSC for up to 14 days after surgery. Fluorescence microscopy and immunohistochemistry revealed survival and integration of EGFP-expressing cSC into the regenerating host nerve tissue. We demonstrate that transplanted cSC contribute to the formation of bands of Büngner and are located in close vicinity to growth-associated protein-43 (GAP-43) expressing regenerating nerve fibers. This provides first evidence that transplanted genetically modified Schwann cells do successfully integrate into the host tissue where they could actively contribute to the regeneration process. PMID: 19962404 [PubMed - as supplied by publisher] |
| Differential Contribution of Chemotaxis and Substrate Restriction to Segregation of Immature and Mature Thymocytes.
December 8, 2009 at 7:47 am
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| | Differential Contribution of Chemotaxis and Substrate Restriction to Segregation of Immature and Mature Thymocytes. Immunity. 2009 Dec 2; Authors: Ehrlich LI, Oh DY, Weissman IL, Lewis RS T cell development requires sequential localization of thymocyte subsets to distinct thymic microenvironments. To address mechanisms governing this segregation, we used two-photon microscopy to visualize migration of purified thymocyte subsets in defined microenvironments within thymic slices. Double-negative (CD4(-)8(-)) and double-positive (CD4(+)8(+)) thymocytes were confined to cortex where they moved slowly without directional bias. DP cells accumulated and migrated more rapidly in a specialized inner-cortical microenvironment, but were unable to migrate on medullary substrates. In contrast, CD4 single positive (SP) thymocytes migrated directionally toward the medulla, where they accumulated and moved very rapidly. Our results revealed a requisite two-step process governing CD4 SP cell medullary localization: the chemokine receptor CCR7 mediated chemotaxis of CD4 SP cells towards medulla, whereas a distinct pertussis-toxin sensitive pathway was required for medullary entry. These findings suggest that developmentally regulated responses to both chemotactic signals and specific migratory substrates guide thymocytes to specific locations in the thymus. PMID: 19962328 [PubMed - as supplied by publisher] |
| Extraction of high quality RNA from polysaccharide matrices using cetlytrimethylammonium bromide.
December 8, 2009 at 7:47 am
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| | Extraction of high quality RNA from polysaccharide matrices using cetlytrimethylammonium bromide. Biomaterials. 2009 Dec 2; Authors: Wang L, Stegemann JP Polysaccharides are increasingly being used as biomaterials for tissue engineering and regenerative medicine. Quantitative analysis of gene expression from cells in three-dimensional (3D) scaffolds requires extraction of messenger RNA, which is complicated in polysaccharide materials by ionic complexing between nucleic acids and the matrix. We used a strongly cationic surfactant, cetyltrimethylammonium bromide (CTAB), to extract RNA from human mesenchymal stem cells embedded in 3D chitosan, agarose and collagen matrices. CTAB extraction was compared to conventional guanidinium thiocyanate-based methods for RNA isolation by assessing RNA yield, purity (A260/A280 and A260/A230) and integrity (28S/18S and RIN). For polysaccharide-based matrices, CTAB extraction yielded significantly more RNA with higher purity than guanidinium thiocyanate-based methods alone. The extracted RNA was largely intact as indicated by 28S/18S ratios and RIN values, while these parameters could not be measured using conventional kits alone. For pure collagen matrices, the CTAB method was comparable or better than guanidinium thiocyanate-based methods in terms of RNA yield and quality. We further validated the CTAB protocol using semi-quantitative and quantitative RT-PCR to amplify both large and small amplicons. Our results show that the CTAB-based method is a facile and effective way to extract abundant, high quality RNA from polysaccharide and protein biomaterials. PMID: 19962190 [PubMed - as supplied by publisher] |
| Design of prevascularized three-dimensional cell-dense tissues using a cell sheet stacking manipulation technology.
December 8, 2009 at 7:47 am
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| | Design of prevascularized three-dimensional cell-dense tissues using a cell sheet stacking manipulation technology. Biomaterials. 2009 Dec 2; Authors: Sasagawa T, Shimizu T, Sekiya S, Haraguchi Y, Yamato M, Sawa Y, Okano T To survive three-dimensional (3-D) cell-dense thick tissues after transplantation, the improvements of hypoxia, nutrient insufficiency, and accumulation of waste products are required. This study presents a strategy for the initiation of prevascular networks in a 3-D tissue construct by sandwiching endothelial cells between the cell sheets. For obtaining a stable stacked cell sheet construct, a sophisticated 3-D cell sheet manipulation system using temperature-responsive culture dishes and a cell sheet manipulator was developed. When sparsely cultured human umbilical vein endothelial cells (HUVECs) were sandwiched between two myoblast sheets, the inserted HUVECs sprouted and formed network structures in vitro. Additionally, when myoblast sheets and HUVECs were alternately sandwiched, endothelial cell connections through the layers and capillary-like structures were found in a five-layer construct. Moreover, the endothelial networks in the five-layer myoblast sheet construct were observed to connect to the host vessels after transplantation into the subcutaneous tissues of nude rats, resulted in a neovascularization that allow the graft to survive. These results indicated that the prevascularized myoblast sheet constructs could induce functional anastomosis. Consequently, our prevascularizing method using a cell sheet stacking manipulation technology provides a substantial advance for developing various types of three-dimensional tissues and contributes to regenerative medicine. PMID: 19962187 [PubMed - as supplied by publisher] |
| Stem cell therapy for the treatment of acute myocardial infarction.
December 8, 2009 at 7:47 am
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| | Stem cell therapy for the treatment of acute myocardial infarction. Cardiol Clin. 2010 Feb;28(1):127-38 Authors: Dinsmore JH, Dib N The last decade has been accompanied by great optimism and interest in the concept of cell or tissue regeneration in the postinfarction myocardium. However, despite the promise, progress was slow. Data derived from multiple controlled studies in hundreds of patients postmyocardial infarction have shown hints of potential benefit but not of the magnitude anticipated. The complexity and hurdles to repair the damaged myocardium have been more daunting than originally estimated. In the end analysis, progress will be made incrementally. The promise for cell therapy continues to be significant, but so are the challenges ahead. This article takes a fresh look at the progress in myocardial regeneration. The authors look at the postmyocardial environment for cues that may guide repair and they look closely at the clinical data for evidence of cardiac regeneration. This evidence is used for suggestions on how to best proceed with future work. PMID: 19962054 [PubMed - in process] |
| A cell based modelling framework for skeletal tissue engineering applications.
December 8, 2009 at 1:47 am
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| | A cell based modelling framework for skeletal tissue engineering applications. J Biomech. 2009 Dec 2; Authors: Geris L, Van Liedekerke P, Smeets B, Tijskens E, Ramon H In this study, a cell based lattice free modelling framework is proposed to study cell aggregate behaviour in bone tissue engineering applications. The model encompasses cell-to-cell and cell-environment interactions such as adhesion, repulsion and drag forces. Oxygen, nutrients, waste products, growth factors and inhibitors are explicitly represented in the model influencing cellular behaviour. Furthermore, a model for cell metabolism is incorporated representing the basic enzymic reactions of glycolysis and the Krebs cycle. Various types of cell death such as necrosis, apoptosis and anoikis are implemented. Finally, an explicit model of the cell cycle controls the proliferation process, taking into account the presence or absence of various metabolites, sufficient space and mechanical stress. Several examples are presented demonstrating the potential of the modelling framework. The behaviour of a synchronised cell aggregate under ideal circumstances is simulated, clearly showing the different stages of the cell cycle and the resulting growth of the aggregate. Also the difference in aggregate development under ideal (normoxic) and hypoxic conditions is simulated, showing hypoxia induced necrosis mainly in the centre of the aggregate grown under hypoxic conditions. The next step in this research will be the application of this modelling framework to specific experimental set-ups for bone tissue engineering applications. PMID: 19962147 [PubMed - as supplied by publisher] | | | 
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