​Context
The overarching objective of our project is to develop a medical device that aim to assist clinicians and pathologist in the prevention and effective treatment of bone metastasis. For that, we aim to create a 3D bone niche on a microfluidic device by designing a novel biomaterial based on glycosaminoglycans.
The majority of the solid tumors generate metastasis in the bone. Developing a bone on chip will therefore permit to study the aggressiveness of metastatic cells and, in the future, to test anti-metastatic drugs ^{[1, 2]}. So far, only few organ on chip devices have been developed for this purpose ^{[2, 3]} probably due to the limitations of the available tools to recreate a bone niche on a microfluidic device.
​ Glycosaminoglycans play a crucial role in presenting and modulating the bioactivity of growth factors such as the osteoinductive bone morphogenetic protein 2 (BMP2) ^{[4, 5]}. GAG-biomaterials have shown promising results in tissue engineering applications ^[6], but have not yet been studied in in vitro tests, in particular to recreate a biomimetic bone niche.

Project description​ 
The PhD student will recreated a biomimetic environment by functionalizing a 3D scaffold with specific GAG-derived oligosaccharides (in particular heparan sulfate (HS) oligosaccharides) developed in the SAGAG team at IBS (CEA Grenoble) presenting BMP2 ^[7] (Figure 1A and B).
These 3D scaffolds coated with GAGs and BMP2 will be inserted in a microfluidic device to promote osteogenic differentiation under flow conditions, which mimic the in vivo blood circulation. We will then study the metastatic invasion of cancer cells (Figure 1C). Kidney cancer will be studied as a model cancer that forms metastasis to bone.


Figure 1: schematic representation of the project: A: design of the GAG-based biomaterials studying the role of the different HS oligosaccharides presenting specific sulfation patterns on BMP2 signaling; B: engineer of the 3D scaffold presenting GAGs to promote 3D bone differentiation and C: bone differentiation in the microfluidic device and test of the kidney cancer metastasis invasion of the bone chamber

The PhD student selected for this project will have the opportunity to work alongside a team of highly skilled PhDs, Postdocs, and engineers who possess the expertise required to successfully complete all tasks of this multidisciplinary project. The PhD will be co-directed by R. Vivès at SAGAG tream at IBS (expert in GAGs structural characterization analysis of GAGs/protein interactions) and E. Migliorini (expert on biomaterials and bone differentiation) at BRM team at Biosanté laboratory and it will be in collaboration with the team of Odile Filhol at IMAC, Biosanté, (expert in kidney cancer).

PhD profile​
We offer a 3 years PhD position to a student with background in microfluidics and/or biomaterials and/or biomedical engineering or nanotechnology, who is interested in working in a multidisciplinary environment. The PhD will be part of a dynamic, interdisciplinary and international research team and will make the bridge between the three teams at Biosanté and at IBS. Therefore, good communication skills are required.

Director 
Dr. Elisa Migliorini (BRM) and Dr. Romain Vivés, (IBS)

Laboratory
Inserm UMRS_1292 Biosanté et CNRS EMR 5000 BRM Laboratoire Biologie et Biotechnologie pour la Santé - Équipe Biomimétisme et Médecine Régénératrice (BRM) (biosante-lab.fr)
​ & IBS team SAGAG

Contact for your application
Please send to Elisa Migliorini before the end of August - your CV
- a motivation letter
- at least one reference letter

Related publications:​
^[1] S. Giacosa, C. Pillet, I. Séraudie, L. Guyon, Y. Wallez, C. Roelants, C. Battail, B. Evrard, F. Chalmel, C. Barette, E. Soleilhac, M.-O. Fauvarque, Q. Franquet, C. Sarrazin, N. Peilleron, G. Fiard, J.-A. Long, J.-L. Descotes, C. Cochet, O. Filhol, Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction, Cancers 13(3) (2021) 576.
^[2] S. Hao, L. Ha, G. Cheng, Y. Wan, Y. Xia, D.M. Sosnoski, A.M. Mastro, S.Y. Zheng, A Spontaneous 3D Bone-On-a- Chip for Bone Metastasis Study of Breast Cancer Cells, Small (Weinheim an der Bergstrasse, Germany) 14(12) (2018) e1702787.
^[3] C. Arrigoni, M. Gilardi, S. Bersini, C. Candrian, M. Moretti, Bioprinting and Organ-on-Chip Applications Towards Personalized Medicine for Bone Diseases, Stem Cell Rev Rep 13(3) (2017) 407-417.
^[4] E. Migliorini, P. Horn, T. Haraszti, S. Wegner, C. Hiepen, P. Knaus, P. Richter, E. Cavalcanti-Adam, Enhanced biological activity of BMP-2 bound to surface-grafted heparan sulfate, Advanced Biosystems 1(4) (2017) 1600041.
^​[5] J. Sefkow-Werner, P. Machillot, A. Sales, E. Castro-Ramirez, M. Degardin, D. Boturyn, E.-A. Cavalcanti-Adam, C. Albiges-Rizo, C. Picart, E. Migliorini, Heparan sulfate co-immobilized with cRGD ligands and BMP2 on biomimetic platforms promotes BMP2-mediated osteogenic differentiation, Acta biomaterialia (2020).
^[6] J. Le Pennec, C. Picart, R.R. Vivès, E. Migliorini, Sweet but Challenging: Tackling the Complexity of GAGs with Engineered Tailor-Made Biomaterials, Advanced materials (Deerfield Beach, Fla.) 36(11) (2024) e2312154.
^[7] J. Le Pennec, O. Makshakova, P. Nevola, F. Fouladkar, E. Gout, P. Machillot , M. Friedel-Arboleas, C. Picart, S. Perez, A. Vortkamp, R.R. Vivès, E. Migliorini, Glycosaminoglycans exhibit distinct interactions and signaling with BMP2 according to their nature and localization Carbohydrate polymers (2024)