|  |  |  | | | | | TE-RegenMed-StemCell feed | | | | | | | | | | | | | | | | | | The chairman of the California stem cell agency, Robert Klein, this week raised the possible size of a new bond issue to finance stem cell research to as high as $5 billion.
Klein made the comment in a piece by Ron Leuty in the San Francisco Business Times. Leuty reported that Klein, who directed the 2004 electoral campaign that created CIRM, said the new ballot measure could could come by 2016 | | | | | | | | | | | | | | | | | | | | | | | | | Analysis of human and mouse reprogramming of somatic cells to induced pluripotent stem cells. What is in the plate? PLoS One. 2010;5(9): Authors: Boué S, Paramonov I, Barrero MJ, Izpisúa Belmonte JC After the hope and controversy brought by embryonic stem cells two decades ago for regenerative medicine, a new turn has been taken in pluripotent cells research when, in 2006, Yamanaka's group reported the reprogramming of fibroblasts to pluripotent cells with the transfection of only four transcription factors. Since then many researchers have managed to reprogram somatic cells from diverse origins into pluripotent cells, though the cellular and genetic consequences of reprogramming remain largely unknown. Furthermore, it is still unclear whether induced pluripotent stem cells (iPSCs) are truly functionally equivalent to embryonic stem cells (ESCs) and if they demonstrate the same differentiation potential as ESCs. There are a large number of reprogramming experiments published so far encompassing genome-wide transcriptional profiling of the cells of origin, the iPSCs and ESCs, which are used as standards of pluripotent cells and allow us to provide here an in-depth analysis of transcriptional profiles of human and mouse cells before and after reprogramming. When compared to ESCs, iPSCs, as expected, share a common pluripotency/self-renewal network. Perhaps more importantly, they also show differences in the expression of some genes. We concentrated our efforts on the study of bivalent domain-containing genes (in ESCs) which are not expressed in ESCs, as they are supposedly important for differentiation and should possess a poised status in pluripotent cells, i.e. be ready to but not yet be expressed. We studied each iPSC line separately to estimate the quality of the reprogramming and saw a correlation of the lowest number of such genes expressed in each respective iPSC line with the stringency of the pluripotency test achieved by the line. We propose that the study of expression of bivalent domain-containing genes, which are normally silenced in ESCs, gives a valuable indication of the quality of the iPSC line, and could be used to select the best iPSC lines out of a large number of lines generated in each reprogramming experiment. PMID: 20862250 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | Immunosuppression Involving Soluble CD83 Induces Tolerogenic Dendritic Cells That Prevent Cardiac Allograft Rejection. Transplantation. 2010 Sep 22; Authors: Ge W, Arp J, Lian D, Liu W, Baroja ML, Jiang J, Ramcharran S, Eldeen FZ, Zinser E, Steinkasserer A, Chou P, Brand S, Nicolette C, Garcia B, Wang H BACKGROUND.: Dendritic cells (DCs) are crucial regulators of immunity and important in inducing and maintaining tolerance. Here, we investigated the potential of a novel DC-immunomodulating agent, soluble CD83 (sCD83), in inducing transplant tolerance. METHODS.: We used the C3H-to-C57BL/6 mouse cardiac transplantation model that exhibits a combination of severe cell-mediated rejection and moderate antibody-mediated rejection and investigated whether sCD83 could augment a combination therapy consisting of Rapamycin (Rapa) and anti-CD45RB monoclonal antibody (α-CD45) to prolong allograft survival. RESULTS.: Monotherapies consisting of Rapa and α-CD45 were incapable of preventing rejection. However, all treatments involving sCD83 were capable of (1) down-modulating expression of various DC surface molecules, such as major histocompatibility complex class II and costimulatory molecules, (2) reducing the allogeneic stimulatory capacity of the DCs, and (3) significantly inhibiting antidonor antibody responses. Most striking results were observed in the triple therapy-treated group, sCD83Rapaα-CD45, where cell-mediated rejection and antibody-mediated rejection were abrogated for over 100 days. Donor-specific tolerance was achieved in long-term surviving recipients, because donor skin transplants were readily accepted for an additional 100 days, whereas third-party skin grafts were rejected. Success of triple therapy treatment was accompanied by enhancement of tolerogenic-DCs that conferred antigen-specific protection on adoptive transfer to recipients of an allogeneic heart graft. CONCLUSIONS.: Our study revealed that sCD83 is capable of attenuating DC maturation and function, and inducing donor-specific allograft tolerance, in the absence of toxicity. Thus, sCD83 seems to be a safe and valuable counterpart to current DC-modulating agents. PMID: 20861805 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010 Sep 1;9(17) Authors: Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP A loss of stromal caveolin-1 (Cav-1) in the tumor fibroblast compartment is associated with early tumor recurrence, lymphnode metastasis and tamoxifen-resistance, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this "lethal tumor micro-environment". Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav-1 (-/-) stromal cells revealed the upregulation of two key cancer-related miR's, namely miR-31 and miR-34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress (miR-34c) or activation of the hypoxic response/HIF1a (miR-31), which is sufficient to drive authophagy/mitophagy. Thus, via an unbiased comprehensive analysis of a lethal tumor micro-environment, we have identified a number of candidate biomarkers (ADMA, ketones and miR-31/34c) that could be used to identify high-risk cancer patients at diagnosis, for treatment stratification and/or for evaluating therapeutic efficacy during anti-cancer therapy. We propose that the levels of these key biomarkers (ADMA, ketones/BHB, miR-31 and miR-34c) could be (i) assayed using serum or plasma from cancer patients or (ii) performed directly on excised tumor tissue. Importantly, induction of oxidative stress and autophagy/mitophagy in the tumor stromal compartment provides a means by which epithelial cancer cells can directly "feed off" of stromal-derived essential nutrients, chemical building blocks (amino acids, nucleotides) and energy-rich metabolites (glutamine, pyruvate, ketones/BHB), driving tumor progression and metastasis. Essentially, aggressive cancer cells are "eating" the cancer-associated fibroblasts via autophagy/mitophagy in the tumor micro-environment. Lastly, we discuss that this "Autophagic Tumor Stroma Model of Cancer Metabolism" provides a viable solution to the "Autophagy Paradox" in cancer etiology and chemo-therapy. PMID: 20861672 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Understanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther. 2010 Sep 19;10(6) Authors: Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other stromal cells. Oxidative stress in the tumor stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer cells, thereby promoting the anabolic growth of cancer cells (via an energy imbalance). We also show that ketones and lactate help "fuel" tumor growth and cancer cell metastasis and can act as chemo-attractants for cancer cells. We have termed this new paradigm for accelerating tumor-stroma co-evolution, "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism". Heterotypic signaling in cancer-associated fibroblasts activates the transcription factors HIF1alpha and NFκB, potentiating the onset of hypoxic and inflammatory response(s), which further upregulates the autophagic program in the stromal compartment. Via stromal autophagy, this hypoxic/inflammatory response may provide a new escape mechanism for cancer cells during anti-angiogenic therapy, further exacerbating tumor recurrence and metastasis. PMID: 20861671 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Engineering extracellular matrix through nanotechnology. J R Soc Interface. 2010 Sep 22; Authors: Kelleher CM, Vacanti JP The goal of tissue engineering is the creation of a living device that can restore, maintain or improve tissue function. Behind this goal is a new idea that has emerged from twentieth century medicine, science and engineering. It is preceded by centuries of human repair and replacement with non-living materials adapted to restore function and cosmetic appearance to patients whose tissues have been destroyed by disease, trauma or congenital abnormality. The nineteenth century advanced replacement and repair strategies based on moving living structures from a site of normal tissue into a site of defects created by the same processes. Donor skin into burn wounds, tendon transfers, intestinal replacements into the urinary tract, toes to replace fingers are all examples. The most radical application is that of vital organ transplantation in which a vital part such as heart, lung or liver is removed from one donor, preserved for transfer and implanted into a patient dying of end-stage organ failure. Tissue engineering and regenerative medicine have advanced a general strategy combining the cellular elements of living tissue with sophisticated biomaterials to produce living structures of sufficient size and function to improve patients' lives. Multiple strategies have evolved and the application of nanotechnology can only improve the field. In our era, by necessity, any medical advance must be successfully commercialized to allow widespread application to help the greatest number of patients. It follows that business models and regulatory agencies must adapt and change to enable these new technologies to emerge. This brief review will discuss the science of nanotechnology and how it has been applied to this evolving field. We will then briefly summarize the history of commercialization of tissue engineering and suggest that nanotechnology may be of use in breeching the barriers to commercialization although its primary mission is to improve the technology by solving some remaining and vexing problems in its science and engineering aspects. PMID: 20861039 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Therapeutic angiogenesis by transplantation of induced pluripotent stem cell-derived Flk-1 positive cells. BMC Cell Biol. 2010 Sep 22;11(1):72 Authors: Suzuki H, Shibata R, Kito T, Ishii M, Li P, Yoshikai T, Nishio N, Ito S, Numaguchi Y, Yamashita JK, Murohara T, Isobe K ABSTRACT: BACKGROUND: Induced pluripotent stem (iPS) cells are the novel stem cell population induced from somatic cells. It is anticipated that iPS will be used in the expanding field of regenerative medicine. Here, we investigated whether implantation of fetal liver kinase-1 positive (Flk-1+) cells derived from iPS cells could improve angiogenesis in a mouse hind limb model of ischemia. RESULTS: Flk-1+ cells were induced from iPS cells after four to five days of culture. Hind limb ischemia was surgically induced and sorted Flk-1+ cells were directly injected into ischemic hind limbs of athymic nude mice. Revascularization of the ischemic hind limb was accelerated in mice that were transplanted with Flk-1+ cells compared with control mice, which were transplanted with vehicle, as evaluated by laser Doppler blood flowmetry. Transplantation of Flk-1+ cells also increased expression of VEGF mRNA in ischemic tissue compared to controls. CONCLUSIONS: Direct local implantation of iPS cell-derived Flk-1+ cells would salvage tissues from ischemia. These data indicate that iPS cells could be valuable in the therapeutic induction of angiogenesis. PMID: 20860813 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Pancreatic islet transplants and IDO: when starving the enemy does you good. Diabetes. 2010 Sep;59(9):2102-4 Authors: Crisa L PMID: 20805384 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Conservation and divergence of ADAM family proteins in the Xenopus genome. BMC Evol Biol. 2010;10:211 Authors: Wei S, Whittaker CA, Xu G, Bridges LC, Shah A, White JM, Desimone DW BACKGROUND: Members of the disintegrin metalloproteinase (ADAM) family play important roles in cellular and developmental processes through their functions as proteases and/or binding partners for other proteins. The amphibian Xenopus has long been used as a model for early vertebrate development, but genome-wide analyses for large gene families were not possible until the recent completion of the X. tropicalis genome sequence and the availability of large scale expression sequence tag (EST) databases. In this study we carried out a systematic analysis of the X. tropicalis genome and uncovered several interesting features of ADAM genes in this species. RESULTS: Based on the X. tropicalis genome sequence and EST databases, we identified Xenopus orthologues of mammalian ADAMs and obtained full-length cDNA clones for these genes. The deduced protein sequences, synteny and exon-intron boundaries are conserved between most human and X. tropicalis orthologues. The alternative splicing patterns of certain Xenopus ADAM genes, such as adams 22 and 28, are similar to those of their mammalian orthologues. However, we were unable to identify an orthologue for ADAM7 or 8. The Xenopus orthologue of ADAM15, an active metalloproteinase in mammals, does not contain the conserved zinc-binding motif and is hence considered proteolytically inactive. We also found evidence for gain of ADAM genes in Xenopus as compared to other species. There is a homologue of ADAM10 in Xenopus that is missing in most mammals. Furthermore, a single scaffold of X. tropicalis genome contains four genes encoding ADAM28 homologues, suggesting genome duplication in this region. CONCLUSIONS: Our genome-wide analysis of ADAM genes in X. tropicalis revealed both conservation and evolutionary divergence of these genes in this amphibian species. On the one hand, all ADAMs implicated in normal development and health in other species are conserved in X. tropicalis. On the other hand, some ADAM genes and ADAM protease activities are absent, while other novel ADAM proteins in this species are predicted by this study. The conservation and unique divergence of ADAM genes in Xenopus probably reflect the particular selective pressures these amphibian species faced during evolution. PMID: 20630080 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis. Dev Dyn. 2010 Jul;239(7):2118-27 Authors: Norris RA, Moreno-Rodriguez R, Wessels A, Merot J, Bruneval P, Chester AH, Yacoub MH, Hagège A, Slaugenhaupt SA, Aikawa E, Schott JJ, Lardeux A, Harris BS, Williams LK, Richards A, Levine RA, Markwald RR Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease. PMID: 20549728 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | The pivotal role of VEGF in adipose-derived-stem-cell-mediated regeneration. Expert Opin Biol Ther. 2010 Sep 23; Authors: Song SY, Chung HM, Sung JH Importance of the field: Several lines of evidence suggest that VEGF is a key regulator of the paracrine effects of adipose-derived stem cells (ASCs), but the mechanism of action remains to be identified. Areas covered in this review: This brief review discusses the following research questions: i) Does VEGF increase the proliferation/migration and differentiation of ASCs?; ii) Does VEGF mediate the paracrine effects of ASCs?; and iii) How is VEGF synthesized, and which factors regulate VEGF secretion? What the reader will gain: External stimuli such as hypoxia may activate receptor tyrosine kinases in the membrane of ASCs, which, in turn, phosphorylate extracellular signal regulated kinase (ERK) and members of the Akt signaling pathway, stabilizing hypoxia inducible factor 1α (HIF-1α) that are primary regulators of VEGF expression. Secreted VEGF directly stimulates ASCs via VEGF receptors in an autocrine manner and regenerates damaged neighboring cells in a paracrine manner. Take home message: Most studies of stem cell regeneration have focused on differentiation of ASCs and their building block function; however, the paracrine effects of ASCs should also be the focus of attention. PMID: 20860536 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Characterization of ph- and thermosensitive hydrogel as a vehicle for controlled protein delivery. J Pharm Sci. 2010 Sep 22; Authors: Shi W, Ji Y, Zhang X, Shu S, Wu Z N-[(2-Hydroxy-3-trimethylammonium)propyl] chitosan chloride (HTCC) was chemically modified using glycidyltrimethylammonium chloride (GTMAC). A new composite hydrogel was prepared using the mixture of HTCC and α-β-glycerophosphate (α-β-GP). The gelation of HTCC/GP mainly depended on the concentration and proportion of HTCC and GP. Thermogravimetric analysis exhibited high stability of HTCC/GP hydrogels. Surface morphology assay demonstrated that HTCC/GP hydrogels were well constructed with three-dimensional (3D) porous structures in the range of 5 of 40 μm. The insulin was entrapped during the formation of hydrogel. In vitro, the insulin release was controlled by modifying the composition, drug loading, and pH condition. The hydrogel dissolved and released drug quickly under acidic condition, whereas it absorbed water and released drug slowly under neutral or basic conditions. The hydrogels were biocompatible, and the cells could adhere to and then migrated to the hydrogels. Furthermore, these cells were viable and retained 3D morphology inside the hydrogels. Interestingly, HTCC/GP hydrogel showed both thermo- and pH-sensitive properties. There are potential applications in tissue engineering, cell encapsulation, and intelligent drug delivery systems. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci. PMID: 20862775 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Bioactive glass scaffold with similar structure and mechanical properties of cancellous bone. J Biomed Mater Res B Appl Biomater. 2010 Sep 22; Authors: Xia W, Chang J Natural bone is an amazing material because of its structure and mechanics. It is a challenge to find a bone substituted material mimicking natural bone intended to suffice for the need for bone repair and regeneration. In this study, a biomorphic material with similar structure and mechanical properties of cancellous bone has been fabricated by using demineralized cancellous bone as a template. Well-oriented particles in the pore walls could be observed clearly. The compressive strength of this scaffold was up to about 4.9±0.2MPa, close to the lower limit of the natural bone and 30 times of bioactive glass scaffolds, even though the porosity was up to 90%. This kind of bioactive glass composite scaffolds presented high resistance to deformation and showed an excellent shape restoration property. It is very close to a natural cancellous bone with a similar macro- and micro-structure and force-extension behavior. These results suggested this material would have a good potential in bone tissue engineering. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2010. PMID: 20862767 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Development and Characterization of Acellular Porcine Corneal Matrix Using Sodium Dodecylsulfate. Cornea. 2010 Sep 21; Authors: Zhou Y, Wu Z, Ge J, Wan P, Li N, Xiang P, Gao Q, Wang Z PURPOSE:: The objective of this study was to produce a porcine corneal acellular matrix (ACM) and assess its possibility for biomedical applications. METHODS:: Porcine corneas were treated with various concentrations of sodium dodecylsulfate for different lengths of time. Optimal conditions for processing the ACM were noted regarding removal of all cellular components and retention of the spatial arrangement of the corneal stroma. The physical characteristics (including water absorption and light transmittance), biomechanics, and cytotoxicity of the ACM were also found to be conserved. Subsequently, ACM was transplanted into the interlaminar stroma of rabbit corneas. The transparency and structures of the collagen fibers were determined. RESULTS:: By immersing corneal tissues in isotonic buffer containing 0.1% sodium dodecylsulfate for 7 hours, we were able to produce an ACM whose cells were completely removed, without disrupting collagen layer structure. Although water absorption and light transmittance of the ACM decreased when compared with natural corneal stroma, ACM showed similar biomechanical properties and biocompatibility as natural ones. After xenotransplantation into rabbit corneal stromal layers for 4 weeks, both ACM and rabbit corneas showed complete transparency. Almost 1 year postoperatively, the corneas remained transparent with regular stromal structures and ACM appeared stable in situ without deliquescence or immunological rejection. CONCLUSIONS:: A simple and valid method to produce decellularized corneal matrix has been successfully developed. These acellular matrices similar to natural corneas in structure, strength, and transparency have tremendous potential for corneal transplantation as ideal implants for donors and for tissue engineering applications as suitable scaffolds. PMID: 20861730 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Engineering extracellular matrix through nanotechnology. J R Soc Interface. 2010 Sep 22; Authors: Kelleher CM, Vacanti JP The goal of tissue engineering is the creation of a living device that can restore, maintain or improve tissue function. Behind this goal is a new idea that has emerged from twentieth century medicine, science and engineering. It is preceded by centuries of human repair and replacement with non-living materials adapted to restore function and cosmetic appearance to patients whose tissues have been destroyed by disease, trauma or congenital abnormality. The nineteenth century advanced replacement and repair strategies based on moving living structures from a site of normal tissue into a site of defects created by the same processes. Donor skin into burn wounds, tendon transfers, intestinal replacements into the urinary tract, toes to replace fingers are all examples. The most radical application is that of vital organ transplantation in which a vital part such as heart, lung or liver is removed from one donor, preserved for transfer and implanted into a patient dying of end-stage organ failure. Tissue engineering and regenerative medicine have advanced a general strategy combining the cellular elements of living tissue with sophisticated biomaterials to produce living structures of sufficient size and function to improve patients' lives. Multiple strategies have evolved and the application of nanotechnology can only improve the field. In our era, by necessity, any medical advance must be successfully commercialized to allow widespread application to help the greatest number of patients. It follows that business models and regulatory agencies must adapt and change to enable these new technologies to emerge. This brief review will discuss the science of nanotechnology and how it has been applied to this evolving field. We will then briefly summarize the history of commercialization of tissue engineering and suggest that nanotechnology may be of use in breeching the barriers to commercialization although its primary mission is to improve the technology by solving some remaining and vexing problems in its science and engineering aspects. PMID: 20861039 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Stimuli-Responsive Smart Gels Realized via Modular Protein Design. J Am Chem Soc. 2010 Sep 22; Authors: Grove TZ, Osuji CO, Forster JD, Dufresne ER, Regan L Smart gels have a variety of applications, including tissue engineering and controlled drug delivery. Here we present a modular, bottom-up approach that permits the creation of protein-based smart gels with encoded morphology, functionality, and responsiveness to external stimuli. The properties of these gels are encoded by the proteins from which they are synthesized. In particular, the strength and density of the network of intermolecular cross-links are specified by the interactions of the gels' constituent protein modules with their cognate peptide ligands. Thus, these gels exhibit stimuli-responsive assembly and disassembly, dissolving (or gelling) under conditions that weaken (or strengthen) the protein-peptide interaction. We further demonstrate that such gels can encapsulate and release both proteins and small molecules and that their rheological properties are well suited for biomedical applications. PMID: 20860358 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Assessment of the human epidermal model LabCyte EPI-MODEL for In vitro skin corrosion testing according to the OECD test guideline 431. J Toxicol Sci. 2010;35(3):411-7 Authors: Katoh M, Hamajima F, Ogasawara T, Hata K A new OECD test guideline 431 (TG431) for in vitro skin corrosion tests using human reconstructed skin models was adopted by OECD in 2004. TG431 defines the criteria for the general function and performance of applicable skin models. In order to confirm that the new reconstructed human epidermal model, LabCyte EPI-MODEL is applicable for the skin corrosion test according to TG431, the predictability and repeatability of the model for the skin corrosion test was evaluated. The test was performed according to the test protocol described in TG431. Based on the knowledge that LabCyte EPI-MODEL is an epidermal model as well as EpiDerm, we decided to adopt the the Epiderm prediction model of skin corrosion for the LabCyte EPI-MODEL, using twenty test chemicals (10 corrosive chemicals and 10 non-corrosive chemicals) in the 1(st) stage. The prediction model results showed that the distinction of non-corrosion to corrosion corresponded perfectly. Therefore, it was judged that the prediction model of EpiDerm could be applied to the LabCyte EPI-MODEL. In the 2(nd) stage, the repeatability of this test protocol with the LabCyte EPI-MODEL was examined using twelve chemicals (6 corrosive chemicals and 6 non-corrosive chemicals) that are described in TG431, and these results recognized a high repeatability and accurate predictability. It was concluded that LabCyte EPI-MODEL is applicable for the skin corrosive test protocol according to TG431. PMID: 20519850 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Response of human corneal fibroblasts on silk film surface patterns. Macromol Biosci. 2010 Jun 11;10(6):664-73 Authors: Gil ES, Park SH, Marchant J, Omenetto F, Kaplan DL Transparent, biodegradable, mechanically robust, and surface-patterned silk films were evaluated for the effect of surface morphology on human corneal fibroblast (hCF) cell proliferation, orientation, and ECM deposition and alignment. A series of dimensionally different surface groove patterns were prepared from optically graded glass substrates followed by casting poly(dimethylsiloxane) (PDMS) replica molds. The features on the patterned silk films showed an array of asymmetric triangles and displayed 37-342 nm depths and 445-3 582 nm widths. hCF DNA content on all patterned films were not significantly different from that on flat silk films after 4 d in culture. However, the depth and width of the grooves influenced cell alignment, while the depth differences affected cell orientation; overall, deeper and narrower grooves induced more hCF orientation. Over 14 d in culture, cell layers and actin filament organization demonstrated that confluent hCFs and their cytoskeletal filaments were oriented along the direction of the silk film patterned groove axis. Collagen type V and proteoglycans (decorin and biglycan), important markers of corneal stromal tissue, were highly expressed with alignment. Understanding corneal stromal fibroblast responses to surface features on a protein-based biomaterial applicable in vivo for corneal repair potential suggests options to improve corneal tissue mimics. Further, the approaches provide fundamental biomaterial designs useful for bioengineering oriented tissue layers, an endemic feature in most biological tissue structures that lead to critical tissue functions. PMID: 20301120 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Enabling individualized therapy through nanotechnology. Pharmacol Res. 2010 Aug;62(2):57-89 Authors: Sakamoto JH, van de Ven AL, Godin B, Blanco E, Serda RE, Grattoni A, Ziemys A, Bouamrani A, Hu T, Ranganathan SI, De Rosa E, Martinez JO, Smid CA, Buchanan RM, Lee SY, Srinivasan S, Landry M, Meyn A, Tasciotti E, Liu X, Decuzzi P, Ferrari M Individualized medicine is the healthcare strategy that rebukes the idiomatic dogma of 'losing sight of the forest for the trees'. We are entering a new era of healthcare where it is no longer acceptable to develop and market a drug that is effective for only 80% of the patient population. The emergence of "-omic" technologies (e.g. genomics, transcriptomics, proteomics, metabolomics) and advances in systems biology are magnifying the deficiencies of standardized therapy, which often provide little treatment latitude for accommodating patient physiologic idiosyncrasies. A personalized approach to medicine is not a novel concept. Ever since the scientific community began unraveling the mysteries of the genome, the promise of discarding generic treatment regimens in favor of patient-specific therapies became more feasible and realistic. One of the major scientific impediments of this movement towards personalized medicine has been the need for technological enablement. Nanotechnology is projected to play a critical role in patient-specific therapy; however, this transition will depend heavily upon the evolutionary development of a systems biology approach to clinical medicine based upon "-omic" technology analysis and integration. This manuscript provides a forward looking assessment of the promise of nanomedicine as it pertains to individualized medicine and establishes a technology "snapshot" of the current state of nano-based products over a vast array of clinical indications and range of patient specificity. Other issues such as market driven hurdles and regulatory compliance reform are anticipated to "self-correct" in accordance to scientific advancement and healthcare demand. These peripheral, non-scientific concerns are not addressed at length in this manuscript; however they do exist, and their impact to the paradigm shifting healthcare transformation towards individualized medicine will be critical for its success. PMID: 20045055 [PubMed - indexed for MEDLINE] | | | | | | | | | | | | | | | | | | | | | | | | | Bone engineering-vitalisation of alloplastic and allogenic bone grafts by human osteoblast-like cells. Br J Oral Maxillofac Surg. 2010 Jul;48(5):369-73 Authors: Hinze MC, Wiedmann-Al-Ahmad M, Glaum R, Gutwald R, Schmelzeisen R, Sauerbier S Human osteoblasts on non-sintered hydroxyapatite and demineralised bone matrix (DBX) were analysed in vitro to find out whether they would be suitable for reconstruction of bones in oral surgery. Human osteoblasts were isolated from the jaw during routine dental operations and seeded onto the two biomaterials. Cells were characterised by assay of alkaline phosphatase, detection of type 1 collagen, and production of osteocalcin. After 21 days of cultivation, the cell/biomaterial constructs were examined by scanning electron microscopy, thin sections, and propidium iodide/fluorescein diacetate staining. The osteoblasts formed a vital multiple cell layer on DBX within 3 weeks of cultivation. On hydroxyapatite, the cells showed no tendency to proliferate or migrate onto the synthetic biomaterial, or to form well-spread and viable cell constructs. These findings suggest that surface morphology or the presence of osteoinductive factors may have an important role in the adhesion and proliferation of osteoblasts. Human DBX can be colonised by human osteoblast-like cells in vitro, indicating the potential of allogeneic carriers for future procedures in bone engineering. PMID: 19596502 [PubMed - indexed for MEDLINE] | | | | | | | | | |  | |  | |  |
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