Bubbles to Bond Broken Bones: targeted drug delivery for fracture repair

Bone fractures are a major societal problem costing the UK economy more than £2 billion/year. This figure is predicted to increase markedly in the future as the average age of the population increases. A significant portion of this cost can be attributed to the 5-10% of bone fractures that fail to heal appropriately with current clinical interventions, leading to patients requiring major surgery and extensive rehabilitation. Hence there is an urgent need for new, minimally invasive and cost-effective treatments to be developed.
The aim of the proposed research is to address this need by investigating the potential for targeted delivery of drugs that promote bone healing. This will be achieved using a combination of focused ultrasound applied externally to the body and drug-loaded nanodroplets (NDs) delivered by intravenous injection. NDs consist of particles (~200nm in diameter) of a volatile liquid that can be used to encapsulate a range of different types of drug. In preliminary work in a mouse model we have shown that upon exposure to ultrasound they undergo rapid expansion to form gas microbubbles, simultaneously releasing their drug payload and stimulating cell uptake. We have also demonstrated that NDs can be engineered to accumulate at bone fracture sites. These observations now provides the exciting possibility of controlling remotely the delivery of ND-loaded drugs at fracture sites. Our approach has the advantage of delivering molecules selectively to the injury site at the correct phase of healing and - importantly - also preserves the granulation and hematoma tissue, which are strong positive regulators of good fracture healing outcomes. Many molecules can have both positive and negative effects on fracture healing depending on the time and site of action, and so correct timing is fundamental to treatment efficacy.
In this project, we plan firstly to build on our established ND chemistries to enable the delivery of proteins and small molecules known to be positive regulators of fracture healing in different temporal context, for example bone morphogenetic protein (BMP) and WNT protein. Building on our preliminary data, we will concurrently test what ultrasound parameters result in the optimal release, payload uptake and intracellular pathway activation, before assessing their osteogenic effects in cell culture, bioreactor culture and ex vivo systems of cell culture. In parallel, we will determine which ultrasound parameters are optimal to ensure molecule release and activation in vivo. Finally we will test whether optimised ND preparations can promote fracture healing in vivo using a combination of high resolution computed tomography, molecular and histological techniques.
We have assembled a world-leading interdisciplinary team to conduct this research, comprising experts in ultrasound and drug release, bone repair, stem cell biology and nanoparticle chemistry. In addition, our research proposal has been developed in close collaboration with clinicians specialising in bone fracture treatment. We will also work closely with non-RCUK public sector stakeholders, Dstl, who have a strong interest in our technology as a means of better treatment of injured service personnel, and with commercial partners who will provide us with clinically approved materials and equipment. It is our aim that through these interactions, the outcomes of the work will have direct impact upon clinical practice and commercial uptake. Finally our results will also be of wide academic and applied relevance to other medical conditions for which control over timing and location of treatment delivery is important, for example, stroke and cardiovascular disease.

The project focuses on one of the highest priority healthcare Grand Challenges: developing advanced drug delivery technologies to administer novel therapeutic agents effectively and through controlled release.
Our aim is to develop a minimally invasive procedure to promote bone fracture repair. We have worked closely with our clinical colleagues in designing the experimental work to facilitate the translation of the nanodroplets into clinical use as efficiently as possible. To avoid extensive and expensive toxicity testing, the drugs and the materials from which the droplets will be manufactured have all been approved by EU/US regulators and we will utilise manufacturing techniques that can be readily scaled up and carried out in a GMP (good manufacturing practice) facility to prepare batches that can be used clinically. We will use existing clinical ultrasound systems for activating the droplets. The tests have been designed to provide appropriate preliminary data that can be presented to the MHRA (Medicine and Healthcare Regulatory Authority) as part of an application for a first-in-man trial. As detailed in the letters of support we are working with partners who can provide: (a) GMP processing technologies for clinical manufacture of nanoparticle therapeutics, and (b) clinical ultrasound systems suitable for activation and monitoring of our nanodroplet agent.
All of the investigators have considerable experience with commercialisation of their research and both Southampton and Oxford have excellent track records in translating cutting-edge technologies into commercial successes. Patents covering the underlying technology have already been applied for and we will work with our project partners and other industrial contacts as the research develops to enable assessment of the most appropriate route of exploitation.
The investigators will build on their extensive track records of engagement with the general public, policy makers and in particular school children to promote the research through exhibits at national science fairs, parliamentary events and social media. We will be working with public engagement specialists Public Policy@Southampton to develop science-to-policy activities to increase awareness both of the significant clinical need that our research addresses and the impact of EPS research in this area.