Rosalind Franklin Institute: Platform Development Project

This proposal is to develop a significant and unique instrumentation capability for the RFI that will enable game-changing observations and measurements of physical phenomena at micrometre length scales and sub-microsecond time scales applicable to a broad range of problems in the physical and life sciences in general, and biomedical imaging and therapy in particular. Funds are requested to (1) develop a one-of-a kind very-high-speed imaging facility and (2) for the initial outfitting of the INSIGHT laboratory that will support the camera, as well as future Hub activities within the INSIGHT theme.

The initial focus of the system will be understanding the physical, chemical, and biological mechanisms underpinning cavitation mediated drug delivery. However, once the instrument is completed, it can be configured in a variety of ways and applied to broad range of problems in materials science, plasma/shock physics, sonochemistry, photoacoustics, biological membrane dynamics, fluid dynamics, and even inertially-confined nuclear fusion.

The range of time and length scales involved poses a series of formidable challenges:
-Temporal resolution: imaging phenomena such as acoustic cavitation requires frame rates of the order of 100 million frames per second (fps). Conversely, imaging the biological response of cells and organisms to physical stimuli requires time lapsed imaging over hours or even days. Thus, not only is exceptional light sensitivity (quantum efficiency) required but also significant flexibility in the imaging frame rate. It should also be capable of being triggered on demand to capture specific phenomena.
-Spatial resolution: imaging of sub-cellular processes using either direct or fluorescence microscopy is vital for mechanistic understanding. Hence both the pixel resolution of the camera and the optical bandwidth must be as large as possible.
-Biological compatibility: in addition to the camera itself, a system providing a realistic biological environment is needed into which the camera and other instrumentation can be integrated.

The state of the art high speed imaging systems currently available offer only a subset of these requirements. The new system will be developed through a collaboration between an academic team at Oxford, a UK-SME specialising in high-speed imaging, Invisible Vision and supported by a UK/EU consortium of research partners. Once operational, the system will be installed at the RFI hub as an instrument and accessed as a research facility in the same way as existing instruments at RAL.

The primary users will be those working in biomedical ultrasound and optics. These are areas of research excellence in the UK that are recognised internationally and span physics, engineering, biology and medicine. Combining ultrasound and light to be able to image and deliver therapy in the body is an evolving strategy that has great potential to improve health care. One particular area of interest is understanding of the biophysical mechanisms by which drug delivery as it has been shown in recent years to be highly inefficient with most estimates for chemotherapy suggesting less than 1% of an administered dose reaches the target. There has been recently significant growth in new
strategies and technology for drug delivery using ultrasound, on account of its considerable advantages in terms of safety, cost, versatility and patient acceptability. To facilitate translation of these techniques into clinical use, however, characterisation of the underlying processes is crucial to enable optimization, safety assessment and reliable treatment monitoring.

The complexity of the interactions and the range of time and length scales involved in ultrasound
mediated drug delivery motivate the need for this camera. The ultrasound pulse will be a few tens of microseconds in duration, the biophysical processes it induces may occur over seconds or even longer; and nonlinear phenomena such as cavitation, which has been shown to play a key role in the majority of ultrasound-mediated bioeffects, occurs on times scales of less than then nanoseconds. The proposed solid-state camera has the ability to image across this range of time scales and we anticipate that the images it will generate will provide unique insights into physical processes and transform both academic research and development of pharmaceutical strategies. The range of applications will by no means be limited to ultrasound, the processes underlying cellular responses to other forms of physical stimuli e.g. for photodynamic therapy and numerous strategies for stimulated release from drug carriers are still poorly understood.

The portability, flexibility and ease of triggering of the proposed camera will open up an even broader range of research opportunities embracing the commercial, academic, government and regulatory environments. As demonstrated by the enthusiastic support from academic colleagues, the potential impact is extremely significant and the investigators already have a strong network of collaborations that will enable this to be realised. More widely, cavitation phenomena themselves represent a vast field of research in plant science and marine biology as well as fundamental fluid dynamics. In the physical sciences, the camera will be ideally suited to the arena of shock physics materials research that has a wide ranging impact in the energy, materials, automobile and aero industrial research fields. Other areas of relevance include astrophysics, mining, earth sciences, construction (blast effects) and defence.

A longer-term economic benefit can also be gleaned for UK R&D. A key barrier to regulatory approval and uptake of novel combination therapies, involving devices and drugs, is the limited understanding of the mechanisms of interaction between the therapeutic modality and nanoparticles in biological tissue, which recently led to the launch of a new "Innovation Office" by the MHRA: it is anticipated that the development of an optical tool capable of identifying and documenting these mechanisms will accelerate approval and clinical adoption of novel therapeutic strategies.