Using microbubbles to deliver local treatments in non-union fractures

Mr Daniel Cadoux-Hudson is an ORUK Inspiration Fund Clinical Researcher and Orthopaedic surgeon at the University Hospital Southampton NHS Foundation Trust.  His research explores how microbubbles can be used to deliver drugs to fractures which fail to heal. The project is under the University of Southampton’s Bone and Joint Research Group and builds on provisional work by Professor Nick Evans and Mr Simon Tilley.

Cadoux-Hudson explained: ‘A non-union is really painful. It’s functionally difficult, because you need the stability of the bone to allow you to move and function. Then you sometimes need to have more than one operation. If we can develop a treatment, which doesn’t involve an operation, that would help reduce the cost and reduce morbidity and pain. The main treatment, surgery with its associated operating theatre time, is very expensive.’

Microbubbles consist of a  phospholipid layer, similar to cell membrane. Drugs can be placed on the outside of or mixed with the microbubbles, then delivered as an injection into the bloodstream as a targeted therapy. An ultrasound probe or device stimulates the bubbles where there’s a break in the continuity of bone, leading to deposition of a drug or material in addition to increasing local uptake through interacting with cell membranes. An example could be Bone Morphogenetic Protein (BMP), a well-known treatment for generating bone, and use of microbubbles could allow the location and dose to be better controlled. 

This treatment aims to benefit patients with an established non-union or who are at greater risk of developing a non-union, including patients who are diabetic, heavy smokers or malnourished. Fractures in particular locations, such as ulnar shaft, clavicle, tibial and scaphoid fractures have a higher risk of non-union. The microbubble treatment could also benefit those who have an infected non-union, by delivering high doses of antibiotics and BMP to help regenerate bone. ‘In the future, you might be able to deliver microbubbles on the surface for infections such as osteomyelitis, rather than a fracture,’ said Cadoux-Hudson.

‘Putting a matrix with microbubbles in it into an animal model has had relatively good effects, but that still requires putting the material into a fracture site, which would involve another operation to put the bubbles in. The treatment we’re developing wouldn’t necessarily involve any operating time. In our human trials, which use an ultrasound probe to look at microbubbles in a fracture, it takes about 20 minutes for an appointment to inject and visualise, and the bubbles are relatively cheap. In the future, I’d love to be able to refer patients to have episodes of microbubble treatment, and then to see the effects.’

Within orthopaedics, other research has focused on diagnosis and treatment within a chronic setting. The research fellow said: ‘In a very basic human pilot trial, we’ve seen the microbubbles in the fracture site, which is the first time anyone’s done that in an acute setting. It has been done in a chronic situation and there have been ultrasounds without microbubbles in acute settings, but no one’s put the two together.’

The project has partnered with Professor Eleanor Stride at the University of Oxford, whose team is exploring using microbubbles to treat liver tumours and try to break down blood-brain barriers to improve blood donations. The work has led onto a bigger Medical Research Council (MRC) grant between the Universities of Oxford and Southampton, looking at more patients. It also aims to demonstrate the technology works with an animal model. ‘We have been able to show that we are able to deploy dye-labelled microbubbles into the area we’re interested in.’

‘The fellowship has been a really interesting experience and a great opportunity. It’s really refreshing and helps academia and patients to have a fellowship aimed at people who aren’t necessarily embroiled in academia.’