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Apatite-Polymer Composite Particles for Controlled Delivery of BMP-2Yong, Tseh-Hwan, Hager, Elizabeth A., Ying, Jackie Y. 01 1900 (has links)
We have developed a versatile delivery platform comprising a novel composite of two biomaterials with proven track records: apatite and poly(lactic-co-glycolic acid) (PLGA). These composites have been tested in the delivery of a model protein, bovine serum albumin (BSA), as well as a growth factor, bone morphogenetic protein-2 (BMP-2), which is a potent inducer of bone formation. The controlled release strategy is based on the use of a polymer with acidic degradation products to control the dissolution of a basic inorganic component, resulting in protein release. The release profile can be modified systematically by changing variables that affect polymer degradation and/or apatite dissolution, such as polymer molecular weight, polymer composition, apatite loading, and apatite particle size. We have found that an increase in polymer molecular weight and polymer hydrophobicity led to slower polymer degradation, and in turn, slower apatite dissolution and protein release. Protein release was enhanced by reducing apatite particle size and by lowering the apatite content in the composites. We anticipate that this delivery platform can be extended to the controlled release of other therapeutic proteins and chemicals. / Singapore-MIT Alliance (SMA)
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The role and effect of bone morphogenetic protein-2 in liver fibrosisChung, Yueh-hua 27 August 2007 (has links)
Bone Morphogenetic proteins (BMPs) belong to transforming growth factor beta (TGF-£]) superfamily. They regulate cell proliferation, cell differentiation, and bone morphogenesis. Previous evidence suggests that BMP-2, as an antagonist of TGF-£], may play an inhibitory role in tissue fibrogenesis. The aim of this study is to examine the expression profile of BMP-2 in fibrotic livers and to test whether BMP-2 gene delivery could alleviate or reverse the liver fibrogenesis models in mice including bile duct ligation (BDL) or carbon tetrachloride (CCl4) model. The results showed that the AST, ALT, and bilirubin levels in sera and the expression of TGF-£], £\-smooth muscle actin, type I collagen in livers were significantly up-regulated by BDL surgery or CCl4 administration. After BDL, the hepatic BMP-2 mRNA and protein levels in mice decreased at 7 and 14 days after surgery. Similarly, the hepatic BMP-2 mRNA and protein levels in mice decreased at day 14 and 28 after CCl4 administration. BMP-2 gene delivery alleviated the inflammation and the liver injury caused by BDL or CCl4 exposure. These findings strongly suggest that BMP-2 is involved in the pathogenesis of liver fibrosis. Moreover, BMP-2 supplementation may facilitate a novel strategy for treatment of liver fibrosis.
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BMP2 gene delivery mediated by chitosan-ss-PEI non-viral vector and investigation of BMP2 signaling regulationZhao, Xiaoli, 赵晓丽 January 2011 (has links)
Osteoporotic fractures are still the major health concerns in many developed
societies especially when the incidence of that tremendously increased with the aging
population. However, the outcomes of osteoporotic fracture treatment have not been
entirely satisfactory due to the poor quality of bone substance. Inspiringly, bone
morphogenetic protein 2 (BMP2) with the ability to accelerate bone formation
showed advantages over the conventional treatment. The only problem needed to
overcome is its short half-life which resulted in the requirement of readministration
and extremely high cost. As a solution to that, gene therapy provides a promising way
to sustainably release this protein at the regeneration site. Since viral vectors have
been hampered by genetic toxicity and immunogenicity, nanoscaled non-viral vectors
offer an attractive means for gene delivery.
Chitosan as non-viral vector has been widely investigated for its excellent
biocompatibility. Most efforts have been given to improve its low transfection
efficiency. In this study, chitosan was first modified with octaarginine, one of cell
membrane penetrating peptides, and showed enhanced transfection activity, but which
was not significant as expected. Following that, low molecular weight
polyethyleminine (PEI) was introduced to modify chitosan through bioreducible
disulfide linkage, denoted as Chitosan-ss-PEI. PEI is an efficient non-viral vector but
hampered by molecular-weight dependent toxicity. The developed Chitosan-ss-PEI
showed good biocompatibility in MTT assay in three different cell lines, during which
cells were maintained 80% of viability when the concentration of this vector was up
to 100 μg/mL. The optimal transfection efficiency of Chitosan-ss-PEI was higher than
that of PEI 25k and comparable to Lipofectamine in delivering luciferase reporter
gene. GFP expression mediated by Chitosan-ss-PEI also showed similar results.
Chitosan-ss-PEI was then applied to deliver BMP2 gene to skeletal system cells
and exhibited the osteogenic ability. For C2C12 myoblast cells, this system inhibited
their myoblast differentiation and induced the osteogenic differentiation. It also
showed stronger effect in promoting the differentiation of immature osteblast-like
MG63 cells and in inducing C3H10T1/2 mesenchymal stem cells osteogenic
differentiation in term of ALP activity and mineralization ability compared with other
commercial available non-viral vectors. Primary MSCs such as bone marrow stromal
cells (BMSC) and human umbilical cord blood mesenchymal stem cells
(hUCB-MSC), are usually more difficult to transfect, but they showed stronger
osteogenic differentiation ability induced by this system comparing with the cell lines.
BMP2 usually requires extremely high concentration to realize its function.
Through the investigation of BMP2 signaling regulation in this study, it was found
that parathyroid hormone (PTH) could increase the access of BMP2 ligands to their
receptors by negatively influencing BMPs antagonist network, resulted in enhanced
BMP2 activity in bone remodeling and in promoting the commitment of MSC to
osteoblast lineage both in vitro and in vivo. This course involved the endocytosis of
PTHR with a complex of LRP6, which organized antagonist network on the cell
surface to shield the BMPs receptors. Novel approaches are expected to be developed
based on this mechanism with the purpose of intensifying the therapeutic effect of
BMPs. / published_or_final_version / Orthopaedics and Traumatology / Doctoral / Doctor of Philosophy
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Differential action of bone morphogenetic protein BMP-2 and BMP-7 on nucleus pulposus cells of intervertebral discZhou, Lixiong, 周立雄 January 2014 (has links)
Low back pain (LBP) is associated with intervertebral disc (IVD) degeneration and exerts enormous socioeconomic burdens on the society. The nucleus pulposus (NP) is the structural and functional core of the IVD, and plays vital roles in its homeostasis. Although the etiology of IVD degeneration is not fully understood, the cellular changes of the NP have been proposed to be associated with degeneration. Conventional management for IVD degeneration primarily targets to relieve LBP and other symptoms without restoring or preserving disc function. Novel therapeutic strategies have emerged with an aim to retard or even reverse disc degeneration. In particular, the use of growth factors, such as the bone morphogenetic proteins (BMP), has received considerable attention due to their anabolic effects on extracellular matrix (ECM) synthesis by NP cells.
BMP-2 and BMP-7 are of great interest for their involvement in osteogenesis, chondrogenesis, and development and maintenance of the IVD. To date, the benefits of BMP-2 on disc degeneration are controversial, given the inconsistent findings from animal model studies. The effectiveness of BMP-7 in disc repair, however, has been well demonstrated both in vitro and in vivo. A better understanding of the differences between BMP-2 and BMP-7 regulatory action on NP cells may facilitate future applications of BMP in disc repair/regeneration.
This study hypothesized that BMP-2 and BMP-7 act differentially on human NP cells via different signal transduction processes. The differential effect of BMP-2 and BMP-7 was first tested in bovine NP cells using a three-dimensional culture system (alginate beads). Both BMP-2 and BMP-7 enhanced ECM production and phenotypic characteristics of bovine NP cells. Notably, BMP-7 was significantly more potent than BMP-2 in this regard. The effects of BMPs were further tested on non-degenerated (ND-NP) and degenerated (D-NP) human NP cells. The DMMB assay revealed that BMP-7 exerted a superior up-regulatory action on GAG production of D-NP cells compared to BMP-2. Furthermore, the overall response of D-NP cells to BMP-2 and BMP-7 was significantly lower than ND-NP cells.
Immunohistochemical staining and quantitative RT-PCR assays demonstrated that D-NP cells possess a more fibroblastic and less chondrocyte-like phenotype than ND-NP cells. At the mRNA level, the BMP receptor BMPR1A was not expressed in D-NP cells. BMP-7, but not BMP-2, induced expression of BMPR1A in D-NP cells. On the other hand, gene expression of selected TGF-β pathway components and hypoxia pathway components were significantly up-regulated by BMP-2 but down-regulated by BMP-7. These findings suggest that D-NP cells can activate differential molecular cascades in response to BMP-2 and BMP-7.
In conclusion, this study showed a superior effect of BMP7 in up-regulation of classical BMP signaling components including BMP receptor BMPR1A. The reduced responsiveness of D-NP cells to BMP-2 and BMP-7 stimulation may be related to a different expression pattern of BMP receptors. This study provides insights into the differential regulatory actions of BMP-2 and BMP-7 on human NP cells and facilitates the future application of BMPs in managing disc degeneration. / published_or_final_version / Orthopaedics and Traumatology / Doctoral / Doctor of Philosophy
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The role of bone morphogenetic proteins in d-galactosamine induced hepatic failureKong, Weisi 10 January 2013 (has links)
Bone morphogenetic proteins-2/4/7 (BMP-2/4/7) are important cytokines in systemic tissue morphogenesis. It has been demonstrated BMPs may have positive effects on liver repair and regeneration after hepatic injury. However, their function in the liver still remains unclear. D-galactosamine (D-gal) is a hepatotoxin used to induce hepatic failure. We employed D-gal and rat hepatoma cell line (1548) to investigate BMP-2/4/7 expression in hepatic injury induced by D-gal and probe their relations with liver repair and regeneration in hepatic injury. LDH release, mRNA and protein expression were detected. Results indicated that BMP-2/4/7 expression was activated by injury of rat hepatoma cells. It is indicative that repair and regeneration of the liver after hepatic injury and morphogenesis in early embryos seem to proceed through the same process. BMPs may be not only associated with hepatic injury after repair and regeneration, but also involved in chronic liver.
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The role of bone morphogenetic proteins in d-galactosamine induced hepatic failureKong, Weisi 10 January 2013 (has links)
Bone morphogenetic proteins-2/4/7 (BMP-2/4/7) are important cytokines in systemic tissue morphogenesis. It has been demonstrated BMPs may have positive effects on liver repair and regeneration after hepatic injury. However, their function in the liver still remains unclear. D-galactosamine (D-gal) is a hepatotoxin used to induce hepatic failure. We employed D-gal and rat hepatoma cell line (1548) to investigate BMP-2/4/7 expression in hepatic injury induced by D-gal and probe their relations with liver repair and regeneration in hepatic injury. LDH release, mRNA and protein expression were detected. Results indicated that BMP-2/4/7 expression was activated by injury of rat hepatoma cells. It is indicative that repair and regeneration of the liver after hepatic injury and morphogenesis in early embryos seem to proceed through the same process. BMPs may be not only associated with hepatic injury after repair and regeneration, but also involved in chronic liver.
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Investigation of bone morphogenetic protein-15 (BMP-15) in zebrafish (Danio rerio) : its role in ovarian follicle development and oocyte maturation /Clelland, Eric Stanley. January 2007 (has links)
Thesis (Ph.D.)--York University, 2007. Graduate Programme in Biology. / Typescript. Includes bibliographical references. Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:NR29321
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Differential Bmp-4 and Dickkopf-1 expression in murine primary palatogenesis a thesis submitted in partial fulfillment ... for the degree of Master of Science in Orthodontics ... /Charchut, Steven W. January 2005 (has links)
Thesis (M.S.)--University of Michigan, 2005. / Includes bibliographical references.
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The role of BMP signaling in the segmentation of the urinary tract /Anantharam, Andrea Brenner. January 2007 (has links)
Thesis (Ph. D.)--Cornell University, August, 2007. / Vita. Includes bibliographical references (leaves 99-107).
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The BMP pathway its role in retina regeneration /Gutierrez, Christian. January 2008 (has links)
Thesis (M.S.)--Miami University, Dept. of Zoology, 2008. / Title from first page of PDF document. Includes bibliographical references (p. 24-29).
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