Physical evolution of a bentonite buffer during 18 years of heating and hydration

The FEBEX in situ experiment was a full-scale test reproducing the near-field of an underground nuclear waste repository. It was performed in a gallery excavated in granite, two heaters simulated the thermal effect of the waste canisters and a bentonite barrier composed of highly-compacted blocks surrounded them, acting as buffer between the heaters and the crystalline host rock. The barrier slowly hydrated with the natural incoming groundwater. The bentonite and rock were instrumented and the sensors provided information about the state of the barrier. Half of the experiment was dismantled after five years of operation (partial dismantling), and the other half was left running for subsequent thirteen years before the complete, final dismantling. During both the partial and the final dismantling numerous samples of bentonite were taken for the on-site determination of dry density and water content. This work compares the physical state of the bentonite barrier after two different periods of time, drawing conclusions about the performance of the barrier and the factors affecting its saturation rate and evolution. The physical state of the barrier was mostly conditioned by the heating and hydration processes, although at some points it was affected by installation particularities. The dry density gradients generated proved to be persistent, and maybe largely irreversible, since they were already observed after five years of operation and remained for another thirteen years, despite the fact that the degree of saturation at the end of the experiment was overall quite high. These gradients did not impair the performance of the barrier and its sealing ability. To properly compute the bentonite degree of saturation the differences between the microstructural and macrostructural water density have to be taken into account, and this is essential for the proper estimation of the time needed for full saturation of the barrier. In any case, the water content changes evidenced the slowing down of the hydration rate over timePeer ReviewedPostprint (author's final draft

RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is highlighted by numerous pathologies and situations of acute and chronic injury associated with dysregulation or destruction of ECM components. Heparan sulfate (HS) is a key component of the ECM, where it fulfils important functions associated with tissue homeostasis. Its degradation following tissue injury disrupts this delicate equilibrium and may impair the wound healing process. ReGeneraTing Agents (RGTA®s) are polysaccharides specifically designed to replace degraded HS in injured tissues. The unique properties of RGTA® (resistance to degradation, binding and protection of ECM structural and signaling proteins, like HS) permit the reconstruction of the ECM, restoring both structural and biochemical functions to this essential substrate, and facilitating the processes of tissue repair and regeneration. Here, we review 25 years of research surrounding this HS mimic, supporting the mode of action, pre-clinical studies and therapeutic efficacy of RGTA® in the clinic, and discuss the potential of RGTA® in new branches of regenerative medicine

Synthesis of a trisulfated heparan sulfate disaccharide analog and its use as a template for preliminary molecular imprinting studies.

A heparan sulfate disaccharide analog was synthesized by a multistep route. This synthesis was designed in such a way that one intermediate could be selectively deprotected to provide versatility during both synthesis and homologation of heparan sulfate related polysaccharides. Non-covalent imprinted polymers were prepared by using the synthesized disaccharide as a template and a primary amine functionalized acrylate as the key functional monomer suitable for specific sulfated sugar recognition. The binding of related sugars to the imprinted and non-imprinted polymers and the binding of template to the chemically modified polymers have been also investigated

Physical evolution of a bentonite buffer during 18 years of heating and hydration

The FEBEX in situ experiment was a full-scale test reproducing the near-field of an underground nuclear waste repository. It was performed in a gallery excavated in granite, two heaters simulated the thermal effect of the waste canisters and a bentonite barrier composed of highly-compacted blocks surrounded them, acting as buffer between the heaters and the crystalline host rock. The barrier slowly hydrated with the natural incoming groundwater. The bentonite and rock were instrumented and the sensors provided information about the state of the barrier. Half of the experiment was dismantled after five years of operation (partial dismantling), and the other half was left running for subsequent thirteen years before the complete, final dismantling. During both the partial and the final dismantling numerous samples of bentonite were taken for the on-site determination of dry density and water content. This work compares the physical state of the bentonite barrier after two different periods of time, drawing conclusions about the performance of the barrier and the factors affecting its saturation rate and evolution. The physical state of the barrier was mostly conditioned by the heating and hydration processes, although at some points it was affected by installation particularities. The dry density gradients generated proved to be persistent, and maybe largely irreversible, since they were already observed after five years of operation and remained for another thirteen years, despite the fact that the degree of saturation at the end of the experiment was overall quite high. These gradients did not impair the performance of the barrier and its sealing ability. To properly compute the bentonite degree of saturation the differences between the microstructural and macrostructural water density have to be taken into account, and this is essential for the proper estimation of the time needed for full saturation of the barrier. In any case, the water content changes evidenced the slowing down of the hydration rate over timePeer Reviewe

Glycosaminoglycan mimetic improves enrichment and cell functions of human endothelial progenitor cell colonies

International audienceHuman circulating endothelial progenitor cells isolated from peripheral blood generate in culture cells with features of endothelial cells named late-outgrowth endothelial colony-forming cells (ECFC). In adult blood, ECFC display a constant quantitative and qualitative decline during life span. Even after expansion, it is difficult to reach the cell dose required for cell therapy of vascular diseases, thus limiting the clinical use of these cells. Glycosaminoglycans (GAG) are components from the extracellular matrix (ECM) that are able to interact and potentiate heparin binding growth factor (HBGF) activities. According to these relevant biological properties of GAG, we designed a GAG mimetic having the capacity to increase the yield of ECFC production from blood and to improve functionality of their endothelial outgrowth. We demonstrate that the addition of [OTR 4131 ] mimetic during the isolation process of ECFC from Cord Blood induces a 3 fold increase in the number of colonies. Moreover, addition of [OTR 4131 ] to cell culture media improves adhesion, proliferation, migration and self-renewal of ECFC. We provide evidence showing that GAG mimetics may have great interest for cell therapy applied to vascular regeneration therapy and represent an alternative to exogenous growth factor treatments to optimize potential therapeutic properties of ECFC

Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage

International audienceClinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel, that increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after radiotherapy

A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke

CERVOXYInternational audienc

Improvement of CSA after 4 months of Equitend^® treatment.

<p>Graphics represent CSA (cm²) at the time of inclusion (M0) and after 4-months (M4) treatment for each horse in placebo group (left panel) and Equitend^®-treated group (right panel). The table represent the number of horses in each treated group that improved more than 10% the CSA (■), not improved (■ Decrease or increase of CSA less than 10%), or worsened more than 10% (■). Data were compared by asymptotic Cochran-Armitage test.</p

Mean CSA measures before and during the first four months of treatment.

<p>Mean CSA measures before and during the first four months of treatment.</p

Randomized controlled trial demonstrates the benefit of RGTA^® based matrix therapy to treat tendinopathies in racing horses

<div><p>A randomized controlled trial was performed on racing horses, to evaluate the efficacy of a new class of therapeutic agents in regenerative medicine—ReGeneraTing Agents^® (RGTA^®), to treat tendinopathies. Preliminary uncontrolled studies on tendon healing in racing horses with RGTA^® (OTR4131)—Equitend^® showed encouraging results, justifying performing a randomized, controlled, multicenter study with a two-year racing performance follow up. The objective of this study was to evaluate the effect of Equitend^® versus placebo on acute superficial digital flexor tendonitis in racing French Standardbred Trotters (ST). Twenty-two ST were randomly and blindly assigned to receive with a ratio of 2 to 1, a single Equitend^® (n = 14) or placebo (n = 8) intralesional injection under ultrasonographic guidance. Horses were evaluated over 4 months, by clinical and ultrasonographic evaluations (day 0, months 1, 2, 4), and their racing performances followed up over the 2 years after treatment. During the first month of treatment, a significant decrease in the cross-sectional area (CSA) was found in the Equitend^® group (p = 0.04). After 4 months, the number of Equitend^® treated horses with an improved CSA was significantly higher than the placebo-treated horses (p = 0.03571). The Equitend^® group returned to their pre-injury performance level, racing in, and winning, significantly more races than the placebo group (p = 0.01399 and 0.0421, respectively). Furthermore, recurrence was significantly higher in the placebo group than in the Equitend^® group (71.4% vs 16.6%, p = 0.02442). In conclusion, we measured a significant, short-term, reduction effect on CSA and demonstrated a long-term beneficial effect of intralesional injection of Equitend^® for the treatment of superficial digital flexor tendonitis on racing ST, racing 2. 3 times more often than placebo, with 3.3 times fewer recurrences maintaining pre-injury performance level. This study may open the way for the development of a human treatment of tendonitis.</p></div