Intégrer un Master de 6 mois sur les calcifications artérielles

AP-HP: Dr. Jean-Michel DAVAINE, MD, PhD Arts et Métiers, LIFSE Laboratoire d'ingénierie des fluides et des systèmes énergétiques (Lifse): Prof. Farid BAKIR EBI, EBInnov: Dr. HDR Samar ISSA, PharmD, PhD, HDR

Context : Master’s Internship (starting March 2025)

Project Title : Exploration of Hydrogels as Controlled Release Systems for the Treatment of Arterial Calcifications.

RESEARCH PROJECT DESCRIPTION (State of the Art, Objectives, Expectations, Challenges, Barriers)

Arteries are blood vessels that originate from the heart and carry blood to the organs. With a tubular shape, arteries have three layers, starting from the lumen of the vessel: intima, media, and the outermost, adventitia. According to Nicoll & Henein(1), arterial calcification (AC) is commonly observed in atherosclerosis, renal insufficiency, and diabetes. The authors suggest that AC is considered a natural progression of atherosclerosis, where atheromatous plaques are made up of lipid deposits but also calcium salts, phosphorus, and hydroxyapatite (HA)(2), leading to AC, whose mechanisms are described as multifactorial. Several studies since 1957 have demonstrated the link between osteoporosis and atherosclerosis through shared risk factors and connections to bone metabolism, suggesting the existence of the bone-vascular axis(3).

Thus, on one hand, in bone tissue, it is continuously renewed through an osteogenesis mechanism, with osteoclasts resorbing bone matrix and osteoblasts synthesizing it. Osteoprotegerin (OPG), a member of the Tumor Necrosis Factor (TNF) receptor family, regulates osteoclast activity by inhibiting osteoclastic bone resorption via the Receptor Activator of Nuclear Factor kB-Ligand (RANKL). OPG is produced by osteoblasts and is involved in both bone and vascular metabolism. On the other hand, with age, arteries undergo several functional and structural changes, including reduced production of the vasodilator nitric oxide (NO), and the progressive replacement of arterial elastin with collagen fibers(4). One cause of bone demineralization, in conjunction with AC, could be medication-induced, such as the adverse effect of using vitamin K antagonists (VKA). The mechanism of action of VKAs is based on the inhibition of coagulation factor synthesis by inhibiting the γ-carboxylation necessary for their function. Inhibiting γ-carboxylation also inhibits the synthesis of osteocalcin, which is necessary for consolidating the bone matrix. Several therapeutic strategies have been implemented, and different therapeutic families are currently presented as potential treatments for AC(5).

This project arises from the joint initiative led by Dr. Davaine and Prof. Bakir, continuing their collaborative work(6,7). Among the various techniques implemented for the treatment of AC, the use of active balloons (Drug Eluting Stents, DES) has been explored. Research by Abbasnezhad et al. has described the main parameters involved in the prolonged release of active ingredients when using DES(8).

The project is part of a multi-step approach involving several partners working in parallel to create a solution for patients with AC.

Main objectives of the study:

1. Identify the various prolonged release techniques implemented in the treatment of AC.

2. Analyze the properties of different polymers capable of encapsulating the targeted active ingredients: hydrogels suitable for stents/active balloons.

3. Evaluate the effectiveness of prolonged release on a specific calcified surface.

Analysis tools are available to assess the prolonged release of active ingredients in dissolution in accordance with applicable regulations(9).

(1) Nicoll, R., & Henein, M. (2017). Arterial calcification: a new perspective? International journal of cardiology, 228, 11-22.

(2) Rajzbaum, G. (2007). Ostéoporose commune et maladies cardiovasculaires. La Lettre du rhumatologue, (334), 37-37.

(3) London, G. (2021). Calcifications vasculaires, décalcifications osseuses : 2 phénomènes indépendants?. JMV-Journal de Médecine Vasculaire, 46(5), S44.

(4) Périard, D., Folly, A., Meyer, M. A. R., & Gautier, E. (2010). Calcificationdes grandes. Rev Med Suisse, 6, 2200-3.

(5) Pan, W., Jie, W., & Huang, H. (2023). Vascular calcification: Molecular mechanisms and therapeutic interventions. MedComm, 4(1), e200.

(6) https://theses.fr/2014NANT20VS

(7) https://theses.fr/s373772

(8) Abbasnezhad, N., Zirak, N., Champmartin, S., Shirinbayan, M., & Bakir, F. (2022). An overview of in vitro drug release methods for drug-eluting stents. Polymers, 14(13), 2751.

(9)https://www.agilent.com/en/product/dissolution-testing/dissolution-apparatus/400-ds-apparatus-7