Ultrafast imaging of cell-nanobubble interactions for bone repair

Bone fractures and their associated complications are a major societal problem that is set to get significantly worse as our population ages. Delayed bone healing and extended rehabilitation contribute to the 39 billion per year cost of bone injuries to the European economy. A proportion of bone fractures fail to heal appropriately with current clinical interventions, which include mechanical fixation or, more rarely, biomaterials and/or bioactive agents. New therapies are therefore urgently required. As yet, there is no clinically approved, systemic therapy for bone fracture.
We are developing such an approach. In preliminary work, we have found that ultrasound-responsive, drug-loaded nanobubbles and nanodroplets accumulate at bone injury sites following systemic administration. These bubbles can be induced to oscillate and to release their drugs selectively under remote ultrasound stimulation. This means that temporally controlled drug delivery could be directed at specific phases of fracture healing.
Before this aim can be realised, however, it is necessary to understand more fully the dynamics of the bubble/droplet interaction with cells and tissues. This is necessary for determining a number of effects on cells and tissues, including: the rate of release of a compound in the vicinity of the cells, the mechanostimulatory effect of bubble movement and fluid streaming effects at the cell membrane, and effects on cell function through intracellular uptake, cavitation and oscillation. Ultrafast imaging will enable us to achieve this aim.
In this project, the student will adapt a 5 million-frame/s ultrafast imaging system (Shimadzu HPV-X), which is currently funded under FP's EPSRC fellowship (see www.photodyn.org), for tracking bubble oscillations in the proximity to cells. Currently the imaging set-up is employed for capturing rapid deformations in biomaterials, but we believe can be conveniently adapted by coupling to an inverted microscope for ultrafast imaging of bubble/cell interactions. The student will develop methodologies for tracking in real-time the cavitation and oscillation of nanodroplets/microbubbles with high temporal resolution. The student will then explore the effect of bubbles oscillation in real-time on cells in proximity to bubbles. Both brightfield and fluorescence capabilities will be utilised to measure parameters including cell strain and strain rate, membrane fluidity and release and uptake of environmentally sensitive fluorophores.