·       Context and challenges (scientific and societal)

This project aims to improve the survival rate of stem cells used to reconstruction of large bone defects. In 2019, 178 million bone fractures were recorded worldwide, 5 to 10% of which experienced healing complications. In addition, certain conditions (osteomyelitis, severe abscesses, tumours) require the surgical removal of bone fragments, with a high risk of complications and significant costs. Non-vascularised autologous bone grafts repair defects up to 5 cm, but are ineffective for defects larger than 6 cm. Vascularised bone grafts, although effective, remain limited by bone availability, surgical complexity and the lack of a guarantee of success. An alternative to grafts is to use the osteogenic potential of mesenchymal stem cells (MSCs), but their massive death after implantation is a major obstacle. The B3OA partner has shown that it is not oxygen but glucose that is essential for MSC survival. Based on this demonstration, B3OA has developed a fibrin and starch gel-based system, whose hydrolysis in the presence of amyloglucosidase (AMG) releases the glucose needed by the MSCs. This has significantly improved survival rates in vitro and in vivo.

·       Project objectives and expected outcomes 

The objective of GLUCOBOOST project is to develop an advanced glucose delivery system designed to maintain transplanted MSCs for 30 days. The system combines starch particles and a modified enzyme (eAMG) encapsulated in biodegradable polymer microspheres to provide controlled and regular glucose release, precisely aligned with the metabolic needs of MSCs. This system will overcome the current shortcomings, which are: (i) the lack of a controlled release mechanism for AMG, resulting in irregular enzyme availability over time, (ii) significant diffusion of free AMG outside the lesion site, (iii) incomplete degradation of starch, which could hinder effective tissue repair. The various actions of the project aim to obtain more effective enzymes at physiological pH (compared to commercial enzymes, which are optimal at pH 4.5), integrate them into microspheres to preserve their activity and limit their diffusion, and develop starch particles for slow and complete hydrolysis over 3 to 4 weeks. These objects will then be included in a fibrin gel before being implanted.

The MC2 (Creation and Behaviour of bio-based Materials) team is responsible for producing the optimised starch particles that will constitute the glucose ‘reservoir’. The starch will be transformed by various thermal and thermomechanical processes in order to control its structure (semi-crystalline, porous, etc.), which will lead to continuous and complete enzymatic hydrolysis over 3 to 4 weeks. The structure of the particles will be elucidated at different scales and their physical properties will be determined. The relationships between structure and glucose production kinetics will be established using statistical modelling approaches.

Denoeud et al, Communications Biology, 2023 (CC BY 4.0 : https://creativecommons.org/licenses/by/4.0/)

Synopsis projet

• October 2025 - october 2029
• Coordination : Hervé Petite, B3OA Biologie, Bioingénierie et Bioimagerie Ostéo-Articulaires UMR CNRS 7052 Inserm U1271, Paris
• Partners/entities involved : B3OA Biologie, Bioingénierie et Bioimagerie Ostéo-Articulaires UMR CNRS 7052 Inserm U1271; AFMB Architecture et Fonction des Macromolécules Biologiques, université de Marseille; MINT Micro et Nanomédecines Translationnelles, UMR Inserm 1066 - CNRS 6021, Angers; BIA, INRAE UR1268, Nantes.
• BIA teams involved : MC2
• Funding : ANR

Contact : Denis Lourdin