Working with the immune system to improve bone repair
Large bone defects are gaps in bone that can occur after the removal of a tumour, following infection or as a result of trauma. These gaps are too large for the body to heal and require medical intervention. Current approaches include insertions of biomaterial to promote bone regeneration. Yet many of these materials are detected by the body’s immune system and are rejected, triggering inflammation. This can actually slow down healing rather than inducing a regenerative response. “Researchers like us are now trying to work with the immune system rather than against it,” says Cansu Gorgun, former Marie Skłodowska-Curie Actions(opens in new window) (MSCA) fellow at the Royal College of Surgeons in Ireland(opens in new window) and now a tenure track researcher at the University of Genoa. “Through what we call immunoengineering, we try to fine-tune the body’s response so the environment becomes more supportive of proper tissue regeneration,” she adds. Through the MSCA-funded METABOLATE project, Gorgun and her colleagues focused on extracellular vesicles (EVs), tiny particles released by cells in the body that carry biological communication signals. Gorgun aimed to develop a scaffolding that includes EVs to maximise bone repair. The idea was that when attached to biomaterials, EVs can transfer these biological messages to surrounding cells in the damaged bone area and stimulate the healing process. “EVs from stem cells have already been shown to enhance bone regeneration more effectively than cells themselves,” notes Gorgun. “But no one had tested this using EVs derived from human immune cells, and that’s exactly what our project aimed to do.”
Reprogramming macrophages to promote bone repair
METABOLATE focused on macrophages, the main immune cells involved in bone healing. When a bone is damaged, macrophages first adopt a pro-inflammatory role to clear debris and fight infection, then switch to an anti-inflammatory state that supports tissue repair and new bone formation. The researchers investigated whether this transition could be guided by reprogramming macrophage metabolism with small molecules. Using this approach, they generated hybrid EVs with both pro- and anti-inflammatory signals from reprogrammed macrophages and tested their effects on human bone marrow and endothelial stem cells. They incorporated them into collagen–nanohydroxyapatite scaffolds and tested them in in vitro settings, and – with the help of a project partner – further analysed the EVs to understand which molecular signals they carry. “All this work was carried out in the lab and there are no clinical trials yet, but the results are very encouraging,” adds Gorgun.
Opening a pathway to engineer the immune system
The key finding from the project was that there is no ‘good’ or ‘bad’ macrophage phenotype for bone healing. “We actually need both pro- and anti-inflammatory macrophages to work together for efficient regeneration,” explains Gorgun. “Most importantly, this is the first study showing the role of human macrophage-derived EVs in bone repair.” The team found that these EVs influence the formation of new blood vessels and bone tissue. “This opens a new path for engineering the immune system to support bone repair,” remarks Gorgun.
Guiding the immune system for bone regeneration
The researchers are now working on biomaterials to better understand how they behave in different stages of the healing process, and to improve the stability and longevity of the scaffolds. “We believe that by combining immunoengineering with EVs, we can design smarter implants that guide the immune system to enhance the therapeutic potential for tissue regeneration,” says Gorgun.
