Bio engineering and osteo-articular physiopathology
- Bone Reconstruction upon Ortho/Trauma and Cancer Conditions
- Bone Substitutes as Targeted Delivery Systems
- Injectable Bone Substitutes for Mini Invasive Procedures
- Advanced Bone Tissue Models
Bone is a highly metabolically active tissue that undergoes continuous remodelling by two counteracting processes: bone formation by osteoblasts and bone resorption involving osteoclasts. Bone remodelling is influenced by paracrine and endocrine factors, including osteoblast- and osteoclast-specific signalling proteins, transcription factors, hormones and growth factors. These molecules control bone neosynthesis or reshaping during growth, and following traumatic injuries leading to fractures. They are also involved in physio-pathological situations including aging (osteoporosis), primary bone tumours, and bone metastases from various cancers. In most of these instances, bone tissue has to be repaired and therefore, our project focused on the design and the development of innovative bone substitutes addressing these issues.
These new biomaterials are based on calcium phosphate chemistry and, depending on the requirements, they are used as calibrated microparticles or injectable cements, which are tested in vitro for interactions with bone cells, and in vivo in terms of bone tissue reconstruction. They can also be supplemented with bioactive molecules and thus, used as local drug delivery systems suitable to further enhance bone formation and/or inhibit cancer development.
To create a ‘’win-win’’ circle between basic and applied research, the bioactive biomaterials we design are used as in vitro and in vivo scaffolds suitable to study bone metabolism. This allows us to document the underlying molecular mechanisms governing bone cell and cancer cell interactions within a bone-like microenvironment and therefore, to identify new therapeutic targets.
Lastly, we develop new bone substitutes suitable to be used in minimally invasive surgical procedures performed under radiological guidance. The ultimate goal is to reduce pain, scaring and hospital stays, and to improve surgical gesture accuracy and outcomes for patients.
Among bioactive molecules, promising data support the therapeutic potential of Gallium (Ga), which exert many effects on bone tissue and on cancer cells. We aim at: (i) deciphering the molecular mechanisms underlying Ga actions at the cellular and tissue level; (ii) quantifying in vivo Ga impact on bone tissue reconstruction in sound and tumoral environments; (iii) designing new calcium phosphate-based injectable delivery systems for a controlled local release of Ga.
The use of targeted delivery systems (TDS) for the local release of Fractalkine (FKN) in bone represent an attractive strategy to treat bone tumours (primary and metastases), and to educate immune cells. We aim at: (i) deciphering the molecular mechanisms underlying FKN actions; (ii) designing TDS for FKN; (iii) quantifying in vivo FKN-TDS impact on tumour growth, and on the recruitment and the activity of immune cells; (iv) combining FKN with therapies targeting immune-checkpoints.
We propose the development of calcium phosphate-based injectable systems suitable for interventional radiology procedures. We aim at: (i) establishing the feasibility of bone substitutes implantation performed under radiological guidance, with a special focus on spine surgery; (ii) quantifying bone reconstruction, in comparison with currently used polymethyl metacrylate(PMMA)-based materials; (iii) assessing the therapeutic potential of anti-tumour compounds addition.
Engineers & Technicians
- Bujoli, B, Scimeca, JC, Verron, E. Fibrin as a Multipurpose Physiological Platform for Bone Tissue Engineering and Targeted Delivery of Bioactive Compounds. Pharmaceutics. 2019;11 (11):. doi: 10.3390/pharmaceutics11110556. PubMed PMID:31661853 PubMed Central PMC6920828.
- Amoretti, N, Diego, P, Amélie, P, Andreani, O, Foti, P, Schmid-Antomarchi, H et al.. Percutaneous vertebroplasty in tumoral spinal fractures with posterior vertebral wall involvement: Feasibility and safety. Eur J Radiol. 2018;104 :38-42. doi: 10.1016/j.ejrad.2018.04.010. PubMed PMID:29857864 .
- Schmid-Alliana, A, Schmid-Antomarchi, H, Al-Sahlanee, R, Lagadec, P, Scimeca, JC, Verron, E et al.. Understanding the Progression of Bone Metastases to Identify Novel Therapeutic Targets. Int J Mol Sci. 2018;19 (1):. doi: 10.3390/ijms19010148. PubMed PMID:29300334 PubMed Central PMC5796097.
- Le Ferrec, M, Mellier, C, Boukhechba, F, Le Corroller, T, Guenoun, D, Fayon, F et al.. Design and properties of a novel radiopaque injectable apatitic calcium phosphate cement, suitable for image-guided implantation. J Biomed Mater Res B Appl Biomater. 2018;106 (8):2786-2795. doi: 10.1002/jbm.b.34059. PubMed PMID:29226553 .
- Rouède, D, Schaub, E, Bellanger, JJ, Ezan, F, Scimeca, JC, Baffet, G et al.. Determination of extracellular matrix collagen fibril architectures and pathological remodeling by polarization dependent second harmonic microscopy. Sci Rep. 2017;7 (1):12197. doi: 10.1038/s41598-017-12398-0. PubMed PMID:28939903 PubMed Central PMC5610346.
- Lagadec, P, Balaguer, T, Boukhechba, F, Michel, G, Bouvet-Gerbettaz, S, Bouler, JM et al.. Calcium supplementation decreases BCP-induced inflammatory processes in blood cells through the NLRP3 inflammasome down-regulation. Acta Biomater. 2017;57 :462-471. doi: 10.1016/j.actbio.2017.05.039. PubMed PMID:28528118 .
- Scimeca, JC, Verron, E. The multiple therapeutic applications of miRNAs for bone regenerative medicine. Drug Discov Today. 2017;22 (7):1084-1091. doi: 10.1016/j.drudis.2017.04.007. PubMed PMID:28435060 .
- Strazic Geljic, I, Melis, N, Boukhechba, F, Schaub, S, Mellier, C, Janvier, P et al.. Gallium enhances reconstructive properties of a calcium phosphate bone biomaterial. J Tissue Eng Regen Med. 2018;12 (2):e854-e866. doi: 10.1002/term.2396. PubMed PMID:28079305 .
- Strazic-Geljic, I, Guberovic, I, Didak, B, Schmid-Antomarchi, H, Schmid-Alliana, A, Boukhechba, F et al.. Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases. Biochem Pharmacol. 2016;116 :11-21. doi: 10.1016/j.bcp.2016.06.020. PubMed PMID:27378505 .
- Bouvet-Gerbettaz, S, Boukhechba, F, Balaguer, T, Schmid-Antomarchi, H, Michiels, JF, Scimeca, JC et al.. Adaptive immune response inhibits ectopic mature bone formation induced by BMSCs/BCP/plasma composite in immune-competent mice. Tissue Eng Part A. 2014;20 (21-22):2950-62. doi: 10.1089/ten.TEA.2013.0633. PubMed PMID:24785826 .
- Verron, E, Schmid-Antomarchi, H, Pascal-Mousselard, H, Schmid-Alliana, A, Scimeca, JC, Bouler, JM et al.. Therapeutic strategies for treating osteolytic bone metastases. Drug Discov Today. 2014;19 (9):1419-26. doi: 10.1016/j.drudis.2014.04.004. PubMed PMID:24742971 .
- Mouline, CC, Beranger, GE, Schmid-Antomarchi, H, Quincey, D, Momier, D, Boukhechba, F et al.. Monocytes differentiation upon treatment with a peptide corresponding to the C-terminus of activated T cell-expressed Tirc7 protein. J Cell Physiol. 2012;227 (8):3088-98. doi: 10.1002/jcp.23059. PubMed PMID:22015593 .
- Boukhechba, F, Balaguer, T, Bouvet-Gerbettaz, S, Michiels, JF, Bouler, JM, Carle, GF et al.. Fate of bone marrow stromal cells in a syngenic model of bone formation. Tissue Eng Part A. 2011;17 (17-18):2267-78. doi: 10.1089/ten.TEA.2010.0461. PubMed PMID:21539494 .
- Mouline, CC, Quincey, D, Laugier, JP, Carle, GF, Bouler, JM, Rochet, N et al.. Osteoclastic differentiation of mouse and human monocytes in a plasma clot/biphasic calcium phosphate microparticles composite. Eur Cell Mater. 2010;20 :379-92. doi: 10.22203/ecm.v020a31. PubMed PMID:21154244 .
- Balaguer, T, Boukhechba, F, Clavé, A, Bouvet-Gerbettaz, S, Trojani, C, Michiels, JF et al.. Biphasic calcium phosphate microparticles for bone formation: benefits of combination with blood clot. Tissue Eng Part A. 2010;16 (11):3495-505. doi: 10.1089/ten.TEA.2010.0227. PubMed PMID:20590522 .
- Verron, E, Masson, M, Khoshniat, S, Duplomb, L, Wittrant, Y, Baud'huin, M et al.. Gallium modulates osteoclastic bone resorption in vitro without affecting osteoblasts. Br J Pharmacol. 2010;159 (8):1681-92. doi: 10.1111/j.1476-5381.2010.00665.x. PubMed PMID:20397300 PubMed Central PMC2925491.
- Moya, A, Tambutté, S, Béranger, G, Gaume, B, Scimeca, JC, Allemand, D et al.. Cloning and use of a coral 36B4 gene to study the differential expression of coral genes between light and dark conditions. Mar Biotechnol (NY). ;10 (6):653-63. doi: 10.1007/s10126-008-9101-1. PubMed PMID:18425549 .
- Beranger, GE, Momier, D, Rochet, N, Carle, GF, Scimeca, JC. Poly(adp-ribose) polymerase-1 regulates Tracp gene promoter activity during RANKL-induced osteoclastogenesis. J Bone Miner Res. 2008;23 (4):564-71. doi: 10.1359/jbmr.071111. PubMed PMID:18021007 .
- Beranger, GE, Momier, D, Guigonis, JM, Samson, M, Carle, GF, Scimeca, JC et al.. Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis. J Bone Miner Res. 2007;22 (7):975-83. doi: 10.1359/jbmr.070406. PubMed PMID:17419679 .
- Beranger, GE, Momier, D, Rochet, N, Quincey, D, Guigonis, JM, Samson, M et al.. RANKL treatment releases the negative regulation of the poly(ADP-ribose) polymerase-1 on Tcirg1 gene expression during osteoclastogenesis. J Bone Miner Res. 2006;21 (11):1757-69. doi: 10.1359/jbmr.060809. PubMed PMID:17002555 .
2013 - 9th Annual Lodwick Award, Harvard Medical School & Massachusetts General Hospital, Nicolas AMORETTI
iBV - Institut de Biologie Valrose
Université Nice Sophia Antipolis
Faculté de médecine
28 Avenue de Valombrose
06189 Nice cedex 2