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Ugo Ripamonti - One of the best experts on this subject based on the ideXlab platform.
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Pleiotropism of bone morphogenetic proteins: from bone Induction to cementogenesis and periodontal ligament regeneration.
Journal of the International Academy of Periodontology, 2020Co-Authors: Ugo Ripamonti, June Teare, Jean-claude PetitAbstract:: Bone morphogenetic and osteogenic proteins (BMPs/OPs), pleiotropic members of the transforming growth factor-beta (TGF-beta) supergene family, induce de novo endochondral bone formation and act as soluble signals of Tissue morphogenesis, sculpting the architecture of multicellular mineralized structures, including the periodontal Tissues. The presence of multiple forms of BMPs/OPs has a therapeutic significance and the choice of a suitable protein will be a formidable challenge to the practising periodontologist. Amino acid sequence variations in the carboxy terminal domain, the molecular basis of the structure/activity profile of each isoform, confer specialized and pleiotropic activities to each morphogenetic protein. Naturally derived BMPs/OPs regenerate cementum and alveolar bone in mandibular furcation defects of the primate Papio ursinus. Tissue morphogenesis induced by hOP-1 and hBMP-2 is qualitatively different when the morphogens are applied singly, indicating that the structure/activity profile amongst BMPs/OPs is controlling pleiotropic Tissue Induction and morphogenesis. Furcation defects of Papio ursinus with root surfaces exposed long-term to periodontal pathogens and filled with granulation Tissue after inoculation of a pathogenetic human strain of Porphyromonas gingivalis twice a month for 12 months were implanted with hOP-1 osteogenic devices. Six months after surgery there was regeneration of alveolar bone and Induction of cementogenesis, with Sharpey's fibres uniting the regenerated bone to the newly formed cementum. Although within the natural milieu of the bone matrix a plurality of morphogens may be required to initiate the cascade of pattern formation and the attainment of Tissue form and function, recombinant y-irradiated hOP-1 delivered by a xenogeneic collagenous matrix induces complete periodontal Tissue regeneration on periodontally affected root surfaces, showing an additional specific function of hOP-1 for Tissue morphogenesis in clinical contexts. The pleiotropy of the signalling molecules of the TGF-beta superfamily is additionally highlighted by the redundancy of molecular signals initiating endochondral bone Induction by the TGF-beta isoforms per se, powerful inducers of endochondral bone, but in the primate only. A novel approach in periodontal Tissue regeneration is to induce heterotopic bone to be transplanted as morcellised autogenous grafts into established periodontal defects. The Induction of bone develops a mosaic structure in which the osteogenic proteins of the TGF-beta superfamily singly, synergistically and synchronously initiate and maintain Tissue Induction and morphogenesis, with specific roles at different time points of the morphogenetic cascade.
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Cementogenesis and osteogenesis in periodontal Tissue regeneration by recombinant human transforming growth factor- β 3 : a pilot study in Papio ursinus
Journal of Clinical Periodontology, 2017Co-Authors: Ugo Ripamonti, Ruqayya Parak, Roland M. Klar, Caroline Dickens, Therese Dix-peek, Raquel DuarteAbstract:Ripamonti U, Parak R, Klar RM, Dickens C, Dix-Peek T, Duarte R. Cementogenesis and osteogenesis in periodontal Tissue regeneration by recombinant human transforming growth factor-b 3 : a pilot study in Papio ursinus. Abstract Objectives: The aim of this study was to investigate cementogenesis and alveolar bone Induction during in vivo periodontal Tissue regeneration upon implantation of hTGF-b 3 in furcation defects of Papio ursinus and to evaluate the feasibility of gene expression studies. Materials and Methods: Class II furcation defects (day 0) were prepared in mandibular first and second molars of three P. ursinus and on day 30 implanted with and without 75 lg hTGF-b 3 in Matrigel Ò matrix. On day 0, 30 and 90, cementum and alveolar bone were harvested for gene expression analyses. Coral-derived bioreactors with and without 250 lg hTGF-b 3 were implanted in the rec-tus abdominis to monitor Tissue Induction. Results: hTGF-b 3 induced cementogenesis with TGF-b 3 , Cementum Protein-1 (Cemp1) and Osteocalcin (OC) up-regulation, and down-regulation of BMP-2 and OP-1. Matrigel Ò matrix specimens showed up-regulation of BMP-2, TGF-b 3 , and
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Redefining the Induction of periodontal Tissue regeneration in primates by the osteogenic proteins of the transforming growth factor‐β supergene family
Journal of Periodontal Research, 2016Co-Authors: Ugo RipamontiAbstract:The molecular bases of periodontal Tissue Induction and regeneration are the osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family. These morphogens act as soluble mediators for the Induction of Tissues morphogenesis sculpting the multicellular mineralized structures of the periodontal Tissues with functionally oriented ligament fibers into newly formed cementum. Human TGF-β3 (hTGF-β3) in growth factor-reduced Matrigel® matrix induces cementogenesis when implanted in class II mandibular furcation defects surgically prepared in the non-human primate Chacma baboon, Papio ursinus. The newly formed periodontal ligament space is characterized by running fibers tightly attached to the cementoid surface penetrating as mineralized constructs within the newly formed cementum assembling and initiating within the mineralized dentine. Angiogenesis heralds the newly formed periodontal ligament space, and newly sprouting capillaries are lined by cellular elements with condensed chromatin interpreted as angioblasts responsible for the rapid and sustained Induction of angiogenesis. The inductive activity of hTGF-β3 in Matrigel® matrix is enhanced by the addition of autogenous morcellated fragments of the rectus abdominis muscle potentially providing myoblastic, pericytic/perivascular stem cells for continuous Tissue Induction and morphogenesis. The striated rectus abdominis muscle is endowed with stem cell niches in para/perivascular location, which can be dominant, thus imposing stem cell features or stemness to the surrounding cells. This capacity to impose stemness is morphologically shown by greater alveolar bone Induction and cementogenesis when hTGF-β3 in Matrigel® matrix is combined with morcellated fragments of autogenous rectus abdominis muscle. The Induction of periodontal Tissue morphogenesis develops as a mosaic structure in which the osteogenic proteins of the TGF-β supergene family singly, synergistically and synchronously initiate and maintain Tissue Induction and morphogenesis. In primates, the presence of several homologous yet molecularly different isoforms with osteogenic activity highlights the biological significance of this apparent redundancy and indicates multiple interactions during embryonic development and bone regeneration in postnatal life. Molecular redundancy with associated different biological functionalities in primate Tissues may simply represent the fine-tuning of speciation-related molecular evolution in anthropoid apes at the early Pliocene boundary, which resulted in finer tuning of the bone Induction cascade.
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Soluble and insoluble signals sculpt osteogenesis in angiogenesis.
World Journal of Biological Chemistry, 2010Co-Authors: Ugo RipamontiAbstract:The basic Tissue engineering paradigm is Tissue Induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata. The insoluble signal acts as a three-dimensional scaffold for the initiation of de novo Tissue Induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-β (TGF-β) supergene family, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and, uniquely in the non-human primate Papio ursinus (P. ursinus), the three mammalian TGF-β isoforms induce bone formation as a recapitulation of embryonic development. In this paper, I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus, the Induction of bone by transitional uroepithelium, and the apparent redundancy of molecular signals initiating bone formation by Induction including the three mammalian TGF-β isoforms. Amongst all mammals tested so far, the three mammalian TGF-β isoforms induce endochondral bone formation in the non-human primate P. ursinus only. Bone Tissue engineering starts by erecting scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone. The molecular scaffolding lies at the hearth of all Tissue engineering strategies including the Induction of bone formation. The novel concept of Tissue engineering is the generation of newly formed bone by the implantation of “smart” intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by Induction without exogenously applied BMPs/OPs of the TGF-β supergene family. A comprehensive digital iconographic material presents the modified Tissue engineering paradigm whereby the Induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the Induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic Induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum. The language of shape is the language of geometry; the language of geometry is the language of a sequence of repetitive concavities, which biomimetizes the remodelling cycle of the primate osteonic bone.
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Bone Induction by recombinant human osteogenic protein‐1 (hOP‐1, BMP‐7) in the primate Papio ursinus with expression of mRNA of gene products of the TGF‐β superfamily
Journal of Cellular and Molecular Medicine, 2005Co-Authors: Ugo RipamontiAbstract:: Predictable bone Induction in clinical contexts requires information on the expression and cross regulation of gene products of the transforming growth factor-beta (TGF-beta) superfamily elicited by single applications of each recombinant human bone morphogenetic/osteogenic proteins (BMPs/OPs). Using the calvarium and the rectus abdominis muscle of adult baboons Papio ursinus as a model for Tissue Induction and morphogenesis, this study investigated the Induction of bone morphogenesis by gamma-irradiated hOP-1 delivered by gamma-irradiated bovine insoluble collagenous bone matrix, the hOP-1 osteogenic device, for bone Induction in heterotopic and orthotopic sites of the primate Papio ursinus and the expression patterns of OP-1, collagen type IV, BMP-3 and TGFbeta1mRNAs elicited by increasing single applications of doses of the hOP-1 osteogenic devices (0.1, 0.5 and 2.5 mg hOP-1/g of matrix) applied heterotopically in the rectus abdominis muscle and orthotopically in 48 calvarial defects of 12 adult baboons. Histology and histomorphometry on serial undecalcified sections prepared from the specimens harvested on day 15, 30 and 90 showed that all the doses of the hOP-1 osteogenic device induced bone formation culminating in complete calvarial regeneration by day 90. Type IV collagen mRNA expression, a marker of angiogenesis, was strongly expressed in both heterotopic and orthotopic Tissues. High levels of expression of OP-1 mRNA demonstrated autoInduction of OP-1 mRNAs. Expression levels of BMP-3 mRNA varied from Tissues induced in heterotopic vs. orthotopic sites with high expression in rapidly forming heterotopic ossicles together with high expression of type IV collagen mRNA. The temporal and spatial expressions of TGF-beta1 mRNAindicate a specific temporal transcriptional window during which expression of TGF-beta1 is mandatory for successful and optimal osteogenesis. The Induction of bone by hOP-1 in Papio ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-beta superfamily that singly, synergistically and synchronously initiate and maintain Tissue Induction and morphogenesis.
Raquel Duarte - One of the best experts on this subject based on the ideXlab platform.
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Cementogenesis and osteogenesis in periodontal Tissue regeneration by recombinant human transforming growth factor- β 3 : a pilot study in Papio ursinus
Journal of Clinical Periodontology, 2017Co-Authors: Ugo Ripamonti, Ruqayya Parak, Roland M. Klar, Caroline Dickens, Therese Dix-peek, Raquel DuarteAbstract:Ripamonti U, Parak R, Klar RM, Dickens C, Dix-Peek T, Duarte R. Cementogenesis and osteogenesis in periodontal Tissue regeneration by recombinant human transforming growth factor-b 3 : a pilot study in Papio ursinus. Abstract Objectives: The aim of this study was to investigate cementogenesis and alveolar bone Induction during in vivo periodontal Tissue regeneration upon implantation of hTGF-b 3 in furcation defects of Papio ursinus and to evaluate the feasibility of gene expression studies. Materials and Methods: Class II furcation defects (day 0) were prepared in mandibular first and second molars of three P. ursinus and on day 30 implanted with and without 75 lg hTGF-b 3 in Matrigel Ò matrix. On day 0, 30 and 90, cementum and alveolar bone were harvested for gene expression analyses. Coral-derived bioreactors with and without 250 lg hTGF-b 3 were implanted in the rec-tus abdominis to monitor Tissue Induction. Results: hTGF-b 3 induced cementogenesis with TGF-b 3 , Cementum Protein-1 (Cemp1) and Osteocalcin (OC) up-regulation, and down-regulation of BMP-2 and OP-1. Matrigel Ò matrix specimens showed up-regulation of BMP-2, TGF-b 3 , and
N. Urosevic - One of the best experts on this subject based on the ideXlab platform.
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Virus spread, Tissue inflammation and antiviral response in brains of flavivirus susceptible and resistant mice acutely infected with Murray Valley encephalitis virus
Archives of Virology, 2004Co-Authors: O. J. Silvia, L. Pantelic, J. S. Mackenzie, G. R. Shellam, J. Papadimitriou, N. UrosevicAbstract:Inborn resistance to flaviviruses, conferred by a single chromosome 5 locus Flv , is a genetic trait operative in wild mice and a few strains of laboratory mice. In this study we have used in situ hybridisation to trace the spread of flavivirus genomic RNA within the brains of flavivirus susceptible C3H/HeJARC and congenic resistant C3H.PRI- Flv ^ r mice following infection with Murray Valley encephalitis virus (MVE) in parallel to studying a brain histopathology and Induction of cellular genes involved in antiviral response. We find that in contrast to a high viral RNA content in brains of susceptible mice, viral RNA was markedly reduced in the cortex, olfactory bulb, thalamus and hypothalamus of resistant mice. Trace amounts of viral RNA were detected in the medulla oblongata while it was completely absent from the hippocampus, pons and cerebellum of resistant mice at different time points post infection. The low virus titres within brains of resistant mice coincided with a very mild inflammation, low counts of infiltrating inflammatory cells, and lower IFN I/II and TNF α gene Induction than in susceptible mice. Furthermore, transcripts of several genes belonging to a 2′,5′-oligoadenylate synthetase ( OAS ) family, implicated in IFN I-inducible OAS/RNase L antiviral pathway, showed similar brain Tissue Induction in both strains of mice suggesting only minor contribution of this pathway to the resistance phenotype.
Jean Crooks - One of the best experts on this subject based on the ideXlab platform.
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recombinant transforming growth factor β1 induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein 1 bone morphogenetic protein 7 to initiate rapid bone formation
Journal of Bone and Mineral Research, 1997Co-Authors: Ugo Ripamonti, Nicolaas Duneas, B Van Den Heever, C Bosch, Jean CrooksAbstract:Several members of the bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) families are molecular regulators of cartilage and bone regeneration, although their actual roles and combined interactions in skeletal repair are poorly understood. The presence of several molecular forms suggests multiple functions in vivo as well as synergistic interactions during both embryonic bone development and regeneration of cartilage and bone in postfetal life. Here we show for the first time that recombinant human transforming growth factor-β1 (TGF-β1) induces endochondral bone formation in extraskeletal sites of adult baboons. We also show that TGF-β1 and recombinant human osteogenic protein-1 (OP-1, bone morphogenetic protein-7) synergize in inducing large ossicles in extraskeletal sites of the primate as early as 15 days after implantation. A single application of OP-1, in conjunction with an insoluble collagenous matrix as carrier (5, 25, and 125 μg/100 mg of carrier matrix) induced bone differentiation in the rectus abdominis of the baboon. This level of Tissue Induction was raised several-fold by the simultaneous addition of comparatively low doses of TGF-β1 (0.5, 1.5, and 5 μg), which by itself induces bone formation in the rectus abdominis at doses of 5 μg/100 mg of carrier matrix. Combinations of OP-1 and TGF-β1 yielded a 2- to 3-fold increase in cross-sectional area of the newly generated ossicles, with markedly elevated key parameters of bone formation, and corticalization of the newly formed bone by day 15, culminating in bone marrow generation by day 30. The Tissue generated by the combined application of OP-1 and TGF-β1 showed distinct morphological differences when compared with OP-1–treated specimens, with large zones of endochondral development and extensive bone marrow formation. At the doses tested, synergy was optimal at a ratio of 1:20 by weight of TGF-β1 and OP-1, respectively. These results provide evidence for a novel function of TGF-β1 in the primate and the scientific basis for synergistic molecular therapeutics for the rapid regeneration of cartilage and bone.
Bahaa B. Seedhom - One of the best experts on this subject based on the ideXlab platform.
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Comparative Study of the Covered Area of Leeds–Keio (LK) Artificial Ligament and Radio Frequency Generated Glow Discharge Treated Leeds–Keio (Bio-LK) Ligament with Synovial Cells
Journal of Long-term Effects of Medical Implants, 2020Co-Authors: Satoshi Tsukazaki, Toshiyuki Kikuchi, Kyosuke Fujikawa, Tatsuo Kobayashi, Bahaa B. SeedhomAbstract:: The Leeds-Keio artificial ligament (LK), which was developed not only as a ligament substitute but also as a scaffold for Tissue Induction in knee ligament reconstruction, has been in clinical use since 1982 in Europe and Japan. Recently, we have developed radio frequency generated glow discharge (RFGD)-treated LK ligament (Bio-LK) to expedite the process of Tissue Induction and its maturation. In this study of cell adhesion to the scaffold, we report the difference in the covered area with synovial cells when using scaffolds made from treated and untreated materials. Plasma clot methods were used in this study. The covered area on LK and Bio-LK by cells was stained by 0.1% toluidine blue and analyzed using NIH image. The covered area of Bio-LK was about three times higher than that of LK (untreated) at 3 weeks. In scanning electron microscopy, more cells were observed on fibers of Bio-LK, and these filled the space among the fibers more extensively. The spreading of covered area means that cell attachment, cell proliferation, and cell migration on the fibers are likely to be improved. Our experimental study indicates that Bio-LK will possibly speed up the process of Induction of autogenous Tissue from synovium.
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The potential use of enamel matrix derivative for in situ anterior cruciate ligament Tissue engineering: a translational in vitro investigation.
Tissue Engineering, 2007Co-Authors: Michael P. Messenger, El Mustafa Raif, Bahaa B. Seedhom, Steven J. BrookesAbstract:Polyester scaffolds have been used as an alternative to autogenous Tissues for the reconstruction of the anterior cruciate ligament (ACL). They are biocompatible and encourage Tissue infiltration, leading to neoligament formation. However, rupture can occur, caused by abrasion of the scaffold against the bone tunnels through which it is implanted. Good early Tissue Induction is therefore considered essential to protect the scaffold from this abrasion. Enamel matrix derivative (EMD) is used clinically in the treatment of periodontal disease. It is a complex mix of proteins with growth factor-like activity, which enhances periodontal ligament fibroblast attachment, proliferation, and differentiation, leading to the regeneration of periodontal bone and ligament Tissues. We hypothesized that EMD might, in a similar manner, enhance Tissue Induction around scaffolds used in ACL reconstruction. This preliminary investigation adopted a translational approach, modelling in vitro 3 possible clinical modes of EMD ad...
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Cyclic straining of cell-seeded synthetic ligament scaffolds: development of apparatus and methodology.
Tissue Engineering, 2007Co-Authors: El Mostafa Raïf, Bahaa B. Seedhom, Michael Pullan, Takashi ToyodaAbstract:Cyclic tensile strains acting along a ligament implant are known to stimulate cells that colonize it to proliferate and to synthesize an extracellular matrix (ECM), which will then remodel and form a new ligament structure. However, this process of Tissue Induction is poorly understood. As a first step toward elucidating this process, we aimed to investigate the effect of cyclic tensile strain on the proliferation of, and possible ECM synthesis by, cells colonizing ligament scaffolds. Because there was no commercially available apparatus to undertake such investigation the objectives of this study were to develop an apparatus for the application of cyclic tensile strains on cell-seeded synthetic ligament scaffolds and to develop and validate (through preliminary data obtained using the apparatus) methodology for studying the effect of cyclic strain on cell proliferation. We designed a multi-station test apparatus that operated inside an incubator. It allowed the application of tensile cyclic strains of be...
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Anterior cruciate ligament reconstruction with the Leeds-Keio artificial ligament.
Journal of Long-term Effects of Medical Implants, 2000Co-Authors: Kyosuke Fujikawa, Tatsuo Kobayashi, Yoshihiro Sasazaki, Hideo Matsumoto, Bahaa B. SeedhomAbstract:The Leeds-Keio (L-K) artificial ligament, developed for knee ligament reconstruction, is made of polyester with a maximum tensile strength of 2200 N. This implant works not only as a ligament but also as a scaffold onto which natural Tissue grows from synovium. In an animal experiment, each strand of the L-K ligament was covered with new Tissue by 2-3 weeks after anterior cruciate ligament reconstruction. Eight weeks postoperatively, abundant fibrous Tissue with extensive vascularity covered the implant, which was still histologically immature. After 16 weeks, vascularization and Tissue Induction began to subside, and histologic analysis showed dense fibers running longitudinally and parallel. By 36 weeks, the new ligament looked like a natural anterior cruciate ligament, although histologically more cells could be seen than in the natural ligament. This maturation was observed only when the substitute was implanted under good tension. Clinically, the surgical procedure has been improved over the past 10 years, to the current practice in which the tape-in-tube double L-K ligament employs a small piece of autogenous Tissue to promote early Tissue Induction and maturation. Using this practice (n = 135), more than 85% of the patients were satisfied subjectively, objectively, and arthroscopically at the 5-year postoperative FU period. Few patients had joint effusion postoperatively. Sacrifice of autogenous Tissue is minimal. The patient can return to activities of daily living within 2 weeks, and more than 50% of them to sports within 10 weeks, and the new ligament is expected to keep its function for a long period as ingrowth completes the structure biologically.