INNOVATION ARTICLES THE IDEA SUBMISSION PORTAL FROM MEDTRONIC
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Fractures, puncture wounds, diabetic foot ulcers and even tooth decay can introduce microbes into bone, causing osteomyelitis1. Badly infected tissue is often poorly served by the circulation system – just getting enough antibiotic to the infection site requires pumping the systemic circulation with high doses, risking toxic side effects. If intensive antibiotic therapy fails to prevent chronic infection, the bone can become necrosed, requiring surgical removal of infected tissue and bone grafts to fill the space. Current treatments fail for up to a third of patients, who suffer amputation or even death.
Researcher Emily Ryan was recruited into Prof Fergal O Brien’s Tissue Engineering Research Group (TERG) in the Royal College of Surgeons in Ireland to work on methods for treating osteomyelitis locally, at the site of infection, in collaboration with Dr. Cathal Kearney, also from RCSI. She initially worked on implantable biodegradable scaffolds loaded with antibiotics, an approach which builds on some commercialised products on the market. However the rising problem of antibiotic resistance limits this approach. “Patients with osteomyelitis often already have some sort of resistance to antibiotics,” says Ryan, explaining that residual slow antibiotic release from implants after the initial bolus risks contributing to resistance.
Sidestepping antibiotic resistance
The team decided to search for alternative biocidal materials that could be implanted directly into the infection site. Ryan embarked on a vast literature search of potentially antimicrobial materials and then screened her shortlist of 7 metals and other natural materials on both human mammalian cells and bacteria. “I wanted to keep as many of the mammalian cells alive while killing as many bacteria as possible,” says Ryan, “Copper showed to be a promising material. It has broad spectrum antimicrobial activity and gave an acceptable level of mammalian cell viability. Some other compounds completely killed both the mammalian cells and the bacteria – we couldn’t find the sweet spot.”
Fighting infection is only half the battle against osteomyelitis – promoting bone repair is a crucial ally in getting patients back on their feet. To create a “one stop shop” implant, the Dublin team joined forces Prof Aldo R. Boccaccini at the University of Erlangen-Nuremberg, Germany, a bioactive glass expert. “Bioactive glass is osteoinductive and osteoconductive,”says Ryan, “it basically promotes bone formation.” The German team manufactured the bioactive glass infused with copper and sent it to Dublin for integration into the collagen scaffold implant.
Building a scaffold
“Our collagen scaffolds are like a fleece,” explains Ryan, “They’re at least 99% porous which is important for cell infiltration and angiogenesis. We add in different things depending on the application. For example for cardiac repair we’d add in elastin.” To create the osteomyelitis implants, Ryan mixed the glass and copper material (a finely ground powder) into a collagen slurry, poured the mixture into moulds and freeze dried it. “This converts the slurry into the porous scaffold,” says Ryan. The scaffolds were then sterilised and cross-linked. “This helps the scaffolds resist degradation in the body a bit longer. You want the rate of degradation to match the rate of bone regeneration.”
The scaffolds could be used to both prevent and treat infection. In established osteomyelitis, the scaffold could be implanted into the space left after surgical removal of necrosed tissue. “You could also use it where there’s a high risk of infection,” says Ryan, “for example, in a compound fracture where the bone is exposed and you go into surgery, there’s a risk of gaining infection. Our scaffold could be used to prevent the infection from happening.”
The Irish and German teams recently published the results of how their scaffold fared in lab tests2. Eluate from the scaffolds successfully killed S. aureus cultures. Importantly, mammalian cells grown directly onto the scaffolds in 3D tolerated their environment well – much better than how mammalian cells tolerated copper ions alone in the preliminary experiments.
Instead of moving directly into animal testing, the team took the intermediary step of testing the scaffold on chick embryos. “We culture the chick embryo ex ovo (in a petri dish) in the incubator for up to 12 days,” explains Ryan, “we popped the scaffold on the embryo and saw that where we had added the scaffold, the cartilage had actually turned to bone, early. It accelerated bone formation.” The scaffolds also promotes growth of new blood vessels. “Chick embryos have a whole network of blood vessels on their surface. We saw that more blood vessels grew into the scaffolds with bioactive glass in them than in the control scaffolds, or no scaffolds,” says Ryan.
WE POPPED THE SCAFFOLD ON THE EMBRYO AND SAW THAT WHERE WE HAD ADDED THE SCAFFOLD, THE CARTILAGE HAD ACTUALLY TURNED TO BONE, EARLY. IT ACCELERATED BONE FORMATION.
As well as providing important results, this chick embryo model experimental design is in step with the replacement, reduction and refinement “3Rs” principal for ethical research in animals.
“We screened a number of concentrations on these eggs. We can go with the frontrunner and put these into a rabbit or a rat model of osteomyelitis,” says Ryan, who has since moved on from the RCSI lab. Despite the encouraging results, there’s no clear timeframe for bringing this innovation to the clinic. “We have to do animal studies first,” says Ryan, before moving into human studies, “it takes a long time to go from bench to bedside.” To get that far, team work is essential, says Ryan. “Our team was multidisciplinary, including biologists expert in the chick embryo model, engineers, imaging experts and our German collaborators who provided the copper-infused bioactive glass. Successful projects rely on collaboration, I don’t think anyone does a project by themselves.”
Kavanagh, N., Ryan, E., Widaa, A., Sexton, G., Fennell, J., & O'Rourke, S. et al. (2018). Staphylococcal Osteomyelitis: Disease Progression, Treatment Challenges, and Future Directions. Clinical Microbiology Reviews, 31(2). doi: 10.1128/cmr.00084-17.
Ryan, E., Ryan, A., González-Vázquez, A., Philippart, A., Ciraldo, F., & Hobbs, C. et al. (2019). Collagen scaffolds functionalised with copper-eluting bioactive glass reduce infection and enhance osteogenesis and angiogenesis both in vitro and in vivo. Biomaterials, 197, 405-416. doi: 10.1016/j.biomaterials.2019.01.031.