Cellules vicvantes (vertes) et mortes (rouges) ensemencées dans un hydrogel

Principal investigators: H. Petite, E. Potier, M. Bensidhoum, D. Logeart-Avramoglou

Investigators: C. Chappard , F. AnagnostouP. BizotB. IlharebordeC. Denoeud, G. LuoG. Salazar

Several studies, including those of the B3OA, already demonstrated the capacity of mesenchymal stem cells (MSCs) seeded on a porous scaffold to repair large bone defect. The reproducibility of this method, however, is mediocre and, most importantly, lower than the one of the autograft, which remains the gold standard for bone repair.
This limited success may be caused, at least in part, by the massive cell death observed after MSC transplantation, with 80-90% of cells dying within the first days. This death might be explained by the fact that the cells are transplanted in an ischemic environment (deprived of oxygen and nutrient), caused by the absence of vascularization in the defects.

The lack of oxygen was thought to be the most detrimental factor for MSC survival and function. Recent work from the B3OA, however, is questioning this paradigm: glucose (main nutrient for cell metabolism) appears to also play a critical role in MSC survival in an ischemic environment. The addition of exogenous glucose, indeed, allows MSC to survive even in a near anoxic environment (complete deprivation of oxygen). 

These findings improve our knowledge of the mechanisms involved in MSC death after transplantation. Based on this better understanding, the B2OA is developing new strategies to deliver in situ exogenous glucose in order to improve post-transplantation survival and function of MSCs. These findings are of high interest not only for bone, but also for cardiac, cartilage tissue engineering.

Models of porous scaffolds with different architectures

There are several biomaterials used as porous scaffold for MSCs. Some of the most popular for filling bone defects are calcium phosphate ceramics, owing to their biocompatibility, to their composition (similar to the inorganic phase of bone), and to their osteoconductive capacity. It also regulates internal mass-transports, cell invasion, tissue ingrowth (e.g., bone, blood-vessel), scaffold degradation, inflammatory response, and shear stress distribution, all playing a role in the clinical success of MSC based bone substitutes. Unfortunately, current manufacturing methods (e.g., gas foaming, slip-casting) suffer from high sample-to-sample variations and from partial control of the scaffold macro-architecture. Such limitations have hindered advances in bone tissue engineering. Thanks to computer-aided design and new additive manufacturing (AM) technology it is now possible to produce implants with customized external shapes as well as optimized and reproducible internal macro-architecture (e.g., pore interconnectivity, shape, size and distribution).

A project conducted at the B3OA, in collaboration with the École des Mines de Saint-Etienne, aims to optimize the scaffold macro-architecture in order to improve MSC survival  within the scaffold and thus to increase the repair potential of bone tissue engineering products.

Publications of the project

Deschepper M, Manassero M, Oudina K, Paquet J, Monfoulet LE, Bensidhoum M, Logeart-Avramoglou D, Petite H. Proangiogenic and prosurvival functions of glucose in human mesenchymal stem cells upon transplantation. Stem Cells. 2013 ;31(3):526-35. Link for the publication .

Moya A, Larochette N, Paquet J, Deschepper M, Bensidhoum M, Izzo V, Kroemer G, Petite H, Logeart-Avramoglou D. Quiescence Preconditioned Human Multipotent Stromal Cells Adopt a Metabolic Profile Favorable for Enhanced Survival under Ischemia. Stem Cells. 2017 ;35(1):181-196. Link for the publication .