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Frescaline G.,University Paris Est Creteil | Bouderlique T.,University Paris Est Creteil | Mansoor L.,University Paris Est Creteil | Carpentier G.,University Paris Est Creteil | And 6 more authors.
Tissue Engineering - Part A | Year: 2013

Tissue engineering approaches to stimulate bone formation currently combine bioactive scaffolds with osteocompetent human mesenchymal stem cells (hMSC). Moreover, osteogenic and angiogenic factors are required to promote differentiation and survival of hMSC through improved vascularization through the damaged extracellular matrix (ECM). Glycosaminoglycans (GAGs) are ECM compounds acting as modulators of heparin-binding protein activities during bone development and regenerative processes. GAG mimetics have been proposed as ECM stabilizers and were previously described for their positive effects on bone formation and angiogenesis after local treatment. Here, we developed a strategy associating the GAG mimetic [OTR4120] with bone substitutes to optimize stem cell-based therapeutic products. We showed that [OTR 4120] was able to potentiate proliferation, migration, and osteogenic differentiation of hMSC in vitro. Its link to tricalcium phosphate/ hydroxyapatite scaffolds improved their colonization by hMSC. Surprisingly, when these combinations were tested in an ectopic model of bone formation in immunodeficient mice, the GAG mimetics inhibit bone formation induced by hMSC and promoted an osteoclastic activity. Moreover, the inflammatory response was modulated, and the peri-implant vascularization stimulated. All together, these findings further support the ability of GAG mimetics to organize the local ECM to coordinate the host response toward the implanted biomaterial, and to inhibit the abnormal bone formation process on a subcutaneous ectopic site. © 2013, Mary Ann Liebert, Inc.


Groah S.L.,National Rehabilitation Hospital | Libin A.,National Rehabilitation Hospital | Spungen M.,National Rehabilitation Hospital | Nguyen K.-L.,Virginia Hospital Center | And 4 more authors.
International Wound Journal | Year: 2011

The aim of this study was to determine whether a skin-specific bioengineered regenerating agent (RGTA) heparan sulphate mimetic (CACIPLIQ20) improves chronic wound healing. The design of this article is a prospective within-subject study. The setting was an urban hospital. Patients were 16 African-American individuals (mean age 42 years) with 22 wounds (mean duration 2·5 years) because of either pressure, diabetic, vascular or burn wounds. Two participants each were lost to follow-up or removed because of poor compliance, resulting in 18 wounds analysed. Sterile gauze was soaked with CACIPLIQ20 saline solution, placed on the wound for 5 min, then removed twice weekly for 4 weeks. Wounds were otherwise treated according to the standard of care. Twenty-two percent of wounds fully healed during the treatment period. Wounds showed a 15·2-18·1% decrease in wound size as measured by the vision engineering research group (VERG) digital wound measurement system and total PUSH scores, respectively, at 4 weeks (P = 0·014 and P = 0·003). At 8 weeks there was an 18-26% reduction in wound size (P = 0·04) in the remaining patients. Wound-related pain measured by the visual analogue pain scale and the wound pain scale declined 60% (P = 0·024) and 70% (P = 0·001), respectively. Patient and clinician satisfaction remained positive throughout the treatment period. It is concluded that treatment with CACIPLIQ20 significantly improved wound-related pain and may facilitate wound healing. Patient and clinician satisfaction remained high throughout the trial. © 2010 The Authors. © 2010 Blackwell Publishing Ltd and Medicalhelplines.com Inc.


Ikeda Y.,University Paris Est Creteil | Charef S.,University Paris Est Creteil | Ouidja M.-O.,University Paris Est Creteil | Barbier-Chassefiere V.,OTR3 SAS | And 8 more authors.
Biomaterials | Year: 2011

Biologically active oligosaccharides related to glycosaminoglycans are accumulating increased attention because of their therapeutic potential and for their value in mechanistic studies. Heparan mimetics (HMs) are a family of dextran based polymer known to mimic the properties of glycosaminoglycans, and particularly those of heparan sulfates, as to interact with heparin binding proteins. HMs have shown to stimulate tissue repair in various animal models. Here, we use different methods to depolymerize HMs in order to produce a library of related oligosaccharides and study their biological activities. Since HMs were resistant to endoglycanases activities, depolymerization was achieved by chemical approaches. In vitro biological studies showed that HM oligosaccharides can differentially potentiate FGF-2 mitogenic and antithrombotic activities. In vivo, a selected oligosaccharide (H-dp12) showed to be able to regenerate tissue almost as well as the related polymeric product. The very low anticoagulant activity and high biological activity of low mass oligosaccharides give to these products a new therapeutic potential. © 2010 Elsevier Ltd.


Singabraya D.,University Paris Est Creteil | Bultel L.,University of Picardie Jules Verne | Sineriz F.,OTR3 SAS | Mothere M.,University Paris Est Creteil | And 3 more authors.
Talanta | Year: 2012

Iinteractions of biologically active proteins with sulfated glycans, particularly heparan sulfates (HS), are dependent on factors involving amounts and positions of the sulfate groups in the sugars chains. Although the importance of knowing the exact positions of the sulfate groups in particular HS sequences is well recognized, at present, approaches in this area are complex and still considered as a challenge. Here, we investigated the applicability of the 'Molecular Imprinting Technology' for the generation of imprinted polymers able to specifically recognize a model HS-like disaccharide. In order to advance on the applicability of this technology to the recognition of these complex sugars, we prepared a library of imprinted polymers to investigate the impact of the polymerization reaction conditions and stoichiometry on the generation of binding sites able to specifically recognize the model sulfated sugar. Our results show that imprinted polymers able to specifically bind HS-like saccharide can readily be obtained. This constitutes a suitable option for developing novel strategies directed to study fine sulfated sugars structures. © 2012 Elsevier B.V.


Barritault D.,Societe OTR3 | Barritault D.,University Paris Est Creteil | Garcia-Filipe S.,University Paris Est Creteil | Zakine G.,Center des brules
Annales de Chirurgie Plastique et Esthetique | Year: 2010

Cells present continuous renewal, permitting permanent regeneration which is called tissue homeostasis. The signaling protein, known as growth factors, cytokines, interleukins and chemokines, but also the extracellular matrix play a key role in the cellular communication. All processes are deregulated after tissue injury, inducing scars. By reconstituting the extracellular matrix, it is possible to avoid the development of scar and to favorize the regeneration of the injured tissue. Glycosaminoglycans, and particularly heparan sulfates, by participating to the extracellular matrix structure, are implicated in cellular communication. This article describes how, by creating heparan sulfate mimetic or Regenerating Agent (RGTA), a French academic team has demonstrated that mammals have the ability to regenerate, by restoring the proper cellular micro-environment. After a first clinical development in two severe and chronic pathologies (corneal and skin ulcers), we show now the potential of these agents in plastic and reconstructive surgery, to regulate fibrosis and to enhance speed and quality of tissue healing. © 2010 Published by Elsevier Masson SAS.


Papy-Garcia D.,University Paris Est Creteil | Christophe M.,University Paris Est Creteil | Bao H.M.,University Paris Est Creteil | Fernando S.,OTR3 SAS | And 3 more authors.
Current Protein and Peptide Science | Year: 2011

A number of neurodegenerative diseases, as Parkinson, prion, and Alzheimer's diseases, has been directly associated with altered conformations of certain peptides or proteins that assemble to form highly organized aggregates, also called amyloid fibers. Glycosaminoglycans have shown to play important roles on fibrils formation, stability and resistance to proteolysis. This manuscript reviews from basic concepts on the biochemistry and biology of glycosaminoglycans to their implications in neurodegeneration with particular emphasis in pathologic protein aggregation. Prion protein, Aβ42, Tau, and α-synuclein, are all proteins that can interact with glycosaminoglycans. We document here how these interactions may modify protein conformation, aggregation kinetics, and fibers stabilization with important consequences in disease. We also raise questions which answers may make advance the understanding of the implication of GAGs in neurodegeneration. © 2011 Bentham Science Publishers Ltd.


Brignole-Baudouin F.,French Institute of Health and Medical Research | Brignole-Baudouin F.,University Pierre and Marie Curie | Brignole-Baudouin F.,French National Center for Scientific Research | Brignole-Baudouin F.,Center Hospitalier National dOphtalmologie des Quinze Vingts | And 13 more authors.
Journal Francais d'Ophtalmologie | Year: 2013

Corneal alteration potentially leading to ulceration remains a major health concern in ocular surface diseases. A treatment that would improve both the quality and speed of healing and control the inflammation would be of great interest. Regenerating agents (RGTAs) have been shown to stimulate wound healing and modulate undesired fibrosis in various in vivo systems. We investigated the effects of RGTA-OTR4120® in a rabbit corneal model in order to assess its potential use in ocular surface diseases. First, we assessed its safety for 7 and 28 days using the Draize test criteria in healthy rabbit eyes; then, we investigated the effect of a single dose (50 μl, 5 μg) in an alkali-burned cornea model. Daily follow-up of clinical signs of healing was scored, and histology was performed at D7. RGTA was well tolerated; no signs of ocular irritation were observed. In the corneal alkali-burn model, non-RGTA-treated eyes showed inflammatory clinical signs, and histology confirmed a loss of superficial corneal layers with epithelial disorganization, neovascularization and infiltration of inflammatory cells. When compared to NaCl control, RGTA treatment appeared effective in reducing clinical signs of inflammation, enhancing re-epithelialization, and improving histological patterns: edema, fibrosis, neovascularization and inflammation. Three to four layers of epithelial cells were already organized, stroma was virtually unvascularized and keratocytes well implanted in parallel collagen fibers with an overall reorganization similar to normal cornea. RGTA appears to be a promising agent for controlling ocular surface inflammation and promoting corneal healing and was well tolerated. This study offers preclinical information and supports the findings of other (compassionate or pilot) studies conducted in patients with various ocular surface diseases. © 2013 Elsevier Masson SAS. © 2013 Elsevier Masson SAS. All rights reserved.


Duval S.,University of Tours | Sineriz F.,OTR3 SAS | Arlicot N.,University of Tours | Arlicot N.,French Institute of Health and Medical Research | And 12 more authors.
IRBM | Year: 2012

The HIMIMT project aims to demonstrate that a dextran derivative, functional analog of the heparan sulfates, is able to target the damaged extracellular matrix of the tumor microenvironment. The core concept is to couple a radioisotope to the heparan mimetic, in order to visualize the tumors by scintigraphy. This article introduces the underlying technology and relevance to the field of nuclear medicine, and summarizes the chemical strategies investigated to develop this novel and innovative radiopharmaceutical agent. © 2012 Elsevier Masson SAS. All rights reserved.


PubMed | Sanofi S.A., OTR3 SAS and University Paris Est Creteil
Type: | Journal: Journal of molecular recognition : JMR | Year: 2016

Heparan sulfates are complex polysaccharides belonging to the family of glycosaminoglycans that participate to the regulation of cell behavior and tissue homeostasis. The biological activities conferred to heparan sulfates are largely dependent on the content and positioning of the sulfate groups along their saccharidic units. At present, identification of particular sulfation patterns in biologically relevant heparan sulfate sequences remains challenging. Although several approaches for structure analysis exist, the complexity of heparan sulfates makes new and original approaches still required. Here, we used molecular imprinting technologies to prepare a library of polyethylene glycol acrylate functionalized hydrogels with the aim to investigate their applicability as specific recognizing systems for fondaparinux, a synthetic pentasaccharide analog to the antithrombin binding site of heparin. Adequate choice of the hydrogel composition and controlling rebinding conditions were important determinants for improving the sulfated oligosaccharide recognition specificity and selectivity. Our results suggest that molecular imprinting approaches could be a possibility for the specific recognition of biologically active sequences in heparan sulfates.

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