Actualités

Nathan Wisniewski soutiendra sa thèse de doctorat intitulée "Développement d’un substitut vasculaire acellulaire d’origine humaine recouvert d’une matrice extracellulaire de gelée de Wharton fonctionnalisée pour le recrutement de cellules : caractérisation fine et évaluation ex vivo " le mercredi 17 décembre à 14h, salle Daum de la présidence-Brabois.

Le jury est composé de :

- Directrice de thèse : Pr Caroline GAUCHER, Université de Lorraine, UR CITHEFOR

- Co-directrice de thèse : Dr Reine EL OMAR, Université de Lorraine, UR CITHEFOR

- Rapporteur : Pr Halima KERDJOUDJ, Université de Reims Champagne Ardenne, UR BIOS

- Rapporteur : Pr Ulrich VALCOURT, Université Claude Bernard Lyon 1, UMR 5305 LBTI CNRS

- Examinateur : Dr Loïc STEFAN, Université de Lorraine, UMR 7375 LCPM CNRS

- Examinateur : Pr Yann PELLEQUER, Université de Bourgogne Franche-Comté, UMR 1098 RIGHT Inserm, EFS

L'article intitulé "Single-Cell Confinement on Micropatterned Glass: an AFM Topographical Profiling" vient d'être publié dans le journal "Langmuir".

Les auteurs sont : D. Pedroni, C. Gaucher, H. Alem

Doi : https://doi.org/10.1021/acs.langmuir.5c02609

Abstract :

In this study, we employed a surface micropatterning approach to isolate individual endothelial cells and examine how their topography is modulated by the available adhesion area. Human umbilical vein endothelial cells (HUVECs) were cultured on silanized glass substrates featuring bare-glass square islands of 15, 20, 25, and 30 μm per side. These defined geometries directed cell adhesion and spreading, allowing consistent atomic force microscopy (AFM) scanning across the entire surface of single and isolated cells. From the scans, we extracted key topographical parameters, including the average and root-mean-square (RMS) height profiles, root-mean-square slope (Sdq), as well as higher-order statistics such as kurtosis and skewness. A high-pass filter was applied to isolate local surface roughness from overall cell shape. Our quantitative analysis revealed that cells confined to 15 and 20 μm patterns exhibited significantly greater average height (p < 0.05) and surface roughness (p < 0.05) compared to those on 25 and 30 μm patterns. Peak cell heights on the 15 μm patterns were, on average, twice as high as those on the 25-30 μm patterns, while the mean cell height was approximately four times greater on the smaller (15-20 μm) patterns relative to the larger (25-30 μm) ones. Roughness was also markedly increased by nearly a factor of 2 for cells on 15 μm patterns compared to those on 25-30 μm. Additionally, the root-mean-square slope (Sdq) was significantly elevated on the smaller patterns (p < 0.05). Higher-order statistical moments further indicated a shift in height distribution: from platykurtic profiles on the 15 and 25 μm patterns to strongly leptokurtic and positively skewed profiles on the 30 μm patterns (p < 0.05). This transition suggests a flatter, more regular surface morphology and a more uniform volumetric distribution on the larger adhesive areas. These findings demonstrate that combining micropatterning with AFM might provide a robust platform for single-cell studies, offering enhanced reproducibility and deeper insights into how controlled cell shape modulates surface properties.

L'article intitulé "Micropatterning of Glass Substrates Using E-beam Lithography for Morphological Analysis of HUVECs" vient d'être publié dans le journal "Adv Eng Mater".

Les auteurs sont : D. Pedroni, C. Gaucher, D. Ba, L. Badie, I. raeth-Fries, H. Alem

Doi : https://doi.org/10.1002/adem.202500862

Abstract :

This study presents a micropatterning technique for glass substrates aimed at investigating the morphological adaptations of human umbilical vein endothelial cells (HUVECs). This method employs electron-beam lithography technology to produce sacrificial structures on glass prior to gas-phase deposition of polyethylene glycol-bearing silanes. HUVECs seeded on the patterned substrates exhibit a pronounced visible difference in adhesion, alignment, and morphological characteristics depending on the type of pattern, specifically influenced by the line dimensions and the spacing between them. The technique proves to be effective for generating high-resolution patterns with minimal alignment errors, making it particularly suitable for prototyping and small-scale studies. By removing the necessity of a photomask and enabling rapid design modifications, this method offers a robust platform for exploring the biochemical and morphological dynamics of cells. Notably, cell orientation is obtained only on patterns with inter-line distances of at least 10 μm, suggesting that effective directional guidance requires minimum spacing. Moreover, cells cultured on patterns with line widths below 20 μm lose their alignment after 24 h, and the increase in spacing from 10 to 15 μm has a significantly greater impact on cell morphology than the corresponding change from 15 to 20 μm.

L'article intitulé "The Chalcogen Exchange: The Replacement of Oxygen with Sulfur and Selenium to Boost the Activity of Natural Products" vient d'être publié dans le journal "Sci".

Les auteurs sont : M.J Nasim, W. Ali, E. N. da Silva Jr, R.S.Z. Saleem, C. Gaucher, J. Handzlick, S. Pedatella, C. Jacob.

Doi : https://doi.org/10.3390/sci7020074

Abstract :

Antioxidants, such as stilbenes, anthocyanidins, coumarins, tannins and flavonoids, are often based on oxygen-containing redox systems and tend to feature several hydroxyl groups in their chemical structures. From a synthetic perspective, oxygen atoms are prone to bioisosteric replacement with sulfur and, notably, selenium. The main objective of this narrative literature review is to explore if and how bioisosteric substitution of oxygen with sulfur or selenium can enhance the biological activity of natural products. This replacement boosts the biological activity of the resulting molecules considerably as they now combine the redox and antioxidant properties of the original flavonoids and other natural products with the specific redox behavior of sulfur and selenium. Besides sequestering free radicals and peroxides, they may, for instance, also catalyze the removal of oxidative stressors, capture free metal ions and even provide scope for selenium supplementation. Since these molecules resemble their natural counterparts, they also exhibit considerable selectivity inside the body and a good pharmacokinetic profile. Still, the synthesis of such hybrid molecules integrating sulfur and selenium into flavonoids and other natural products is a challenge and requires innovative synthetic strategies and approaches. 

L'article intitulé "Heparin, an active excipient to carry biosignal molecules: Applications in tissue engineering-A review" vient d'être publié dans le journal "International Journal of Biological Macromolecules".

Les auteurs sont : Meiling Wu, Anne Sapin-Minet, Caroline Gaucher

Doi : https://doi.org/10.1016/j.ijbiomac.2025.143959

Abstract :

Drug repositioning refers to new medical application exploration for existing drugs. Heparins, beyond their well-known anticoagulant properties widely used in clinics, present the capacity to carry biosignal molecules that is responsible for other properties such as anti-inflammatory, angiogenesis. Thus, heparins interaction with different biosignal molecules such as cytokines and growth factors have recently drawn attention and have promoted heparin repositioning as an active excipient with useful applications as drug-delivery systems and biomaterial-based tissue engineering scaffolds. Indeed, biomaterial heparinization can further help in their formulation such as in self-assembled heparin-based hydrogels or nanoparticles, and improve their biocompatibility. Moreover, the capacity of heparin to carry biosignal molecules enables the direct functionalization of heparinized biomaterial for tissue engineering. Both heparin characteristics namely the biosignal molecule carrying and biomaterial heparinization are reviewed here along their combination for biomaterial functionalization in tissue engineering applications.

L'article intitulé "Heparinized collagen-based hydrogels for tissue engineering: physical, mechanical and biological properties" vient d'être publié dans le journal "International Journal of Pharmaceutics".

Les auteurs sont : Meiling Wu, Anne Sapin-Minet, Loïc Stepan, Julien Perrin, isabelle Raet-Fries, Caroline Gaucher

Doi : https://doi.org/10.1016/j.ijpharm.2024.125126

Abstract :

As the main protein forming the vascular extracellular matrix, collagen has a weak antigenicity, making it an attractive candidate for coatings of vascular grafts. In order to bring antithrombotic properties to collagen for obtaining suitable blood compatibility of surfaces and further bioactive molecule carrying capacity, heparinization appears as a method of choice. Thus, in this article, pH-driven self-assembly was used to form collagen-based hydrogels with physical incorporation of heparins, especially low molecular weight heparin or unfractionated heparin at 1 IU/mL and 6 IU/mL. These heparinized hydrogels were evaluated for their physicochemical properties including gelation kinetic, spreading, viscoelasticity, microstructure and heparin quantification, and their biocompatibility such as cytocompatibility and their capacity to release bioactive heparins with antithrombotic properties. The loading capacity of collagen-based hydrogels was higher for unfractionated heparin (60 to 80 %) than for low molecular weight heparin (20 %). Interestingly, the highest concentration (6 IU/mL) of heparin used to form collagen-based hydrogels resulted in the formation of a softer hydrogel owning a better spreadability compared to 1 IU/mL and non heparinized collagen-based hydrogel. The 3D structure observation showed a layered formation with visible pores or spaces between the layers in all types of collagen-based hydrogels. These layers are interconnected by fibrous structures, suggesting a networked architecture. Moreover, the amount of heparin released from collagen-based hydrogel prepared with 6 IU /mL was higher than from those heparinized with 1 IU/mL attested by a delay in blood coagulation (activated partial thromboplastin time and thrombin time) and the abolishment of thrombin generation. Those hydrogels were also biocompatible, with low albumin adsorption and no impact on cell viability. Finally, heparin is retained in these hydrogels for at least seven days after cell seeding, providing the possibility of long-term antithrombotic properties. Thus, we succeeded in develop/obtain coatings with antithrombogenic properties, biocompatible and able to retain heparins at least seven days, making them good candidates with a great potential for the development and application of efficient blood-contacting materials.

L'article intitulé "Ibuprofen encapsulation inside non-conventional O/W Pickering emulsions stabilized with partially hydrophobized silica" vient d'être publié dans le journal "Frontiers in Coatings, Dyes and Interface Engineering".

Les auteurs sont : Diego Ramos, Anne Sapin-Minet, Philippe Marchal, Marianne Parent, Véronique Sadtler et Thibault Roques-Carmes

Doi : https://doi.org/10.3389/frcdi.2024.1422260

Abstract :

The encapsulation of active ingredients is an important process in various industrial sectors including pharmaceutics, foods and cosmetics. For the first time, the capacity of non-conventional anti-Bancroft oil-in-water Pickering emulsions stabilized by partially hydrophobized silica to encapsulate an apolar active is addressed. A dispersed phase volume of paraffin oil of 50% coupled to 0.5 wt.% of silica has been employed to avoid excess of silica in the continuous phase and encapsulate higher amount of ibuprofen (the model drug). Three ibuprofen contents ranging from 100 mg (1.6 mg/mL of paraffin) to 420 mg (6 mg/mL of paraffin) have been tested. The encapsulation efficiency as well as the emulsions properties are investigated by the means of light diffusion, microscopy, rheology, and HPLC coupled to mass balance. The Pickering emulsion is very efficient for the encapsulation of ibuprofen with encapsulation rates of 99% obtained inside droplets of 30 µm for all the 3 ibuprofen concentrations. This encapsulation ability is perfectly maintained, whether during ageing (during 90 days), or when the emulsion is diluted by a factor 100 inside physiological media at basic and acidic pH.

Un article intitulé "La microfluidique, un outil polyvalent en santé" vient d'être publié dans "Techniques de l'ingénieur".

Auteurs : Jérémie Gouyon, Thibault Roques-Carmes, Anne Sapin-Minet, Marianne Parent

Reférence de l'article : PHA1030 v1

Résumé :

La microfluidique est de plus en plus utilisée dans de nombreux domaines, et celui de la santé ne fait pas exception. A travers les différentes étapes de la conception d’un médicament, de la découverte d’un actif à sa formulation, l’apport de la microfluidique est illustré et discuté dans cet article. Son intérêt dans les aspects diagnostiques est également présenté. Un état des lieux large et critique fait mention des futures voies de développement abordées par les chercheurs académiciens ou industriels, ainsi que les verrous technologiques qui devront être confrontés dans les années à venir.

Un article intitulé "PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism?" vient d'être publié dans le journal "CPT-Pharmacometrics & Systems Pharmacology".

Auteurs : Justine Henriot, André Dallmann, François Dupuis, Jérémy Perrier, Sebastian Frechen

DOI :  https://doi.org/10.1002/psp4.13249

Résumé :

Gastrointestinal first-pass metabolism plays an important role in bioavailability and in drug–drug interactions. Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to integrate these processes mechanistically. However, a correct bottom-up prediction of GI first-pass metabolism is challenging and depends on various model parameters like the level of enzyme expression and the basolateral intestinal mucosa permeability (Pmucosa). This work aimed to investigate if cytochrome P450 (CYP) 3A4 expression could help predict the first-pass effect using PBPK modeling or whether additional factors like Pmucosa do play additional roles using PBPK modeling. To this end, a systematic review of the absolute CYP3A expression in the human gastrointestinal tract and liver was conducted. The resulting CYP3A4 expression profile and two previously published profiles were applied to PBPK models of seven CYP3A4 substrates (alfentanil, alprazolam, felodipine, midazolam, sildenafil, triazolam, and verapamil) built-in PK-Sim®. For each compound, it was assessed whether first-pass metabolism could be adequately predicted based on the integrated CYP3A4 expression profile alone or whether an optimization of Pmucosa was required. Evaluation criteria were the precision of the predicted interstudy bioavailabilities and area under the concentration–time curves. It was found that none of the expression profiles provided upfront an adequate description of the extent of GI metabolism and that optimization of Pmucosa as a compound-specific parameter improved the prediction of most models. Our findings indicate that a pure bottom-up prediction of gastrointestinal first-pass metabolism is currently not possible and that compound-specific features like Pmucosa must be considered as well.

Nathan Wisniewski (2ème année de thèse de doctorat), a reçu un prix pour sa communication orale "Harvesting the Wharton’s Jelly extracellular matrix to produce a biomaterial suitable for cardiovascular tissue engineering" au congrès "Biomaterials and Biofabrication", organisé à Nancy du 16 au 17 mai 2024.