METABOLic immuno-engineered biomATErials

Project Information

METABOLATE

Grant agreement ID: 101106209

DOI

10.3030/101106209

Project closed

EC signature date 9 March 2023

Start date 21 April 2023

End date 20 July 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 242 476,20

Coordinated by

ROYAL COLLEGE OF SURGEONS IN IRELAND
Ireland

Periodic Reporting for period 1 - METABOLATE (METABOLic immuno-engineered biomATErials)

Reporting period: 2023-04-21 to 2025-07-20

Summary of the context and overall objectives of the project

Delayed or non-healing bone fractures remain a major clinical problem, especially in older patients, and place a growing financial burden on healthcare systems in Europe. Current strategies such as bone grafting or the use of growth factors have clear limitations, including poor availability, risks of complications, and limited long-term effectiveness. A key obstacle is the inflammatory environment at the defect site, which reduces the regenerative potential of biomaterials.
The METABOLATE project worked intensely on this challenge by developing a novel immuno-engineering approach. The project focused on human macrophages, immune cells that play a central role in inflammation and repair. By metabolically reprogramming macrophages towards a more regenerative state, researchers generated extracellular vesicles with hybrid properties that promote both angiogenesis and osteogenesis. These vesicles were then incorporated into scaffolds, creating immuno-engineered materials designed to modulate inflammation and stimulate bone regeneration. Through this strategy, METABOLATE provides a proof of concept for combining extracellular vesicle biology, immunometabolism, and biomaterials science to develop safer and more effective regenerative therapies for large bone defects.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project investigated how human macrophage-derived extracellular vesicles influence angiogenesis and osteogenesis, and whether targeting macrophage metabolism could reprogram them into a regenerative state.
The first investigations showed that extracellular vesicles obtained from human macrophages differentially regulate both angiogenesis and osteogenesis. By modulating macrophages between pro- and anti-inflammatory states, it was possible to generate extracellular vesicles with hybrid properties that combined functional features of both pro- and anti- inflammatory macrophages, enhancing their regenerative potential.
The second line of investigation examined their incorporation into collagen–nanohydroxyapatite scaffolds. Results demonstrated that distinct extracellular vesicle populations acted at different stages of osteogenesis; some promoted early osteogenic differentiation, while others influenced later mineralisation. This indicated that pro- and anti-inflammatory macrophage-derived extracellular vesicles play complementary roles in complete bone regeneration.
The third investigation focused on the cargo content of these vesicles. It was found that even vesicles released from the same donor-derived macrophages can carry different sets of small RNAs depending on their polarisation state. These differences in molecular content were linked to distinct regulatory effects on angiogenesis and osteogenesis. This provides important mechanistic insight into how extracellular vesicles exert their regenerative functions and lays the foundation for targeted therapeutic strategies for bone repair.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

METABOLATE generated several results that extend beyond current knowledge in regenerative medicine. It demonstrated that metabolic modulation of human macrophages can generate vesicle populations with hybrid regenerative properties, capable of influencing angiogenesis and osteogenesis in distinct ways. By immobilising these vesicles on collagen–nanohydroxyapatite scaffolds, the project created an immuno-engineered material with potential applications in bone regeneration. Small RNA sequencing further showed that metabolic reprogramming reshapes the vesicle cargo, offering mechanistic understanding of their regenerative role.
These findings contribute to the development of new regenerative strategies with potential long-term benefits for patients suffering from impaired bone healing or large bone defects. The interdisciplinary integration of immunology, extracellular vesicle biology, biomaterials, and bioinformatics creates a platform for future therapeutic development. The collaboration with TAmiRNA additionally enabled an industrial partner to expand its expertise to human macrophage-derived vesicles, strengthening academia–industry links and laying the foundation for future translational applications.