The proposed research project is motivated by civil and military clinical needs pertaining to the repair of large bone defects which is still a challenge for the orthopaedic, reconstructive and maxillo-facial surgeon.
Availability of pluripotent mesenchymal stem cells (MSCs) and the potential of inducing the osteogenic phenotype is motivating the exploration and development of custom-tailored materials known as “Tissue engineered constructs” (TE constructs). In such cases, the clinical scenario involves either expansion of stem cells in monolayers and loading them into a porous scaffold prior to surgery or direct cell expansion within scaffolds and implanting such novel constructs back into the donor patient. Although clinical studies were initiated and encouraging results for the repair of long bones were obtained in large animals, the therapeutic effectiveness of bone constructs has not yet met that of autologous bone grafts (the ‘golden” standard of bone repair). The reasons for this limited osteogenic potential of bone constructs are not yet fully understood but massive death of transplanted cells after engraftment into the TE construct is a primary factor. Most importantly, previous studies from B2OA have established that glucose (which acts as the main metabolic fuel for MSC in severe hypoxia) enhances significantly cell survival when supplied to MSCs exposed to severe hypoxia in vitro and in vivo.
The ultimate objective of the proposed research project is to develop a catheterized implant device that will supply glucose at physiological concentrations to transplanted MSCs. It will be made of (i) a programmable pump that will diffuse glucose at physiological concentration (i.e 1gr/L or 4,5mM), (ii) a catheter, (iii) a porous carbonated hydroxyapatite additive manufactured scaffold whose gyroid architecture will permit homogenous diffusion of glucose to cells and (iv) hMSC. Our underlying hypothesis is that glucose will act as a source of energy to implanted hMSCs. These cells will then be able to survive and remain functional for longer period of time. They will increase both they paracrine and direct contributions, which ultimately will increase TE construct mediated osteogenesis.
The proposed research is based on the following arguments:
? The current therapeutic effectiveness of TE constructs does not yet match the osteogenic capability of autologous bone grafts when assessed in bone defects of clinically-relevant volume.
? Upon implantation, MSCs are exposed to an ischemic environment, which is a primary factor for the cell death observed in vivo.
? Such massive cell death affects, and limits, the ultimate efficacy of TE constructs.
? MSCs survive in vitro exposure to long-term severe near anoxia providing that glucose (the primary fuel to cells in hypoxia/anoxia) is available.
? Porous carbonated hydroxyapatite additive manufactured scaffolds with gyroid architecture connected to a programmable pump are appropriate for an homogenous delivery of glucose to implanted MSC.
Planned on a 3-year time period, the VITABONE project is subdivided in 5 work packages (WP): (i) WP1 is dedicated to the project management; (ii) WP2 focuses on the additive manufacturing and characterization of the innovative VITABONE scaffolds. These CHA scaffolds are designed with a central channel for receiving a glucose “infusion strainer”, (iii) WP3 optimizes both the glucose delivery profile (via an implantable pump) from the scaffolds and the cell number to obtain TE constructs that exhibit both high hMSC survival rate and high osteogenic abilities, (iv) WP4 aims at a better understanding of the role of glucose dosage in TE construct mediated osteogenesis. (v) WP5 focuses on scaling up VITABONE-TE constructs to clinically relevant volume and demonstrating their efficacy for the repair of a long segmental bone defect.
Monsieur Hervé Petite (Laboratoire de Bioingénierie et Bioimagerie OstéoArticulaires)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CIS Centre Ingénirerie et Santé, EMSE, INSERM U1059
CNRS Laboratoire de Bioingénierie et Bioimagerie OstéoArticulaires
Help of the ANR 298,878 euros
Beginning and duration of the scientific project: - 36 Months