WHOLE-BODY, HIGH RESOLUTION, 3D, SMALL ANIMAL PHOTOACOUSTIC AND ULTRASOUND COMPUTED TOMOGRAPHY SYSTEM

Before a proposed new medicine reaches the stage of a clinical trial - so before it is allowed to be used on people - it must have already undergone a great deal of testing. The tests will principally examine the safety of the drug and its efficacy. Perhaps the most crucial stage in the drug development pathway prior to human trials involves testing drugs on mice. There are many reasons why mice are used, a key one being that their genetic and biological characteristics are sufficiently similar to humans that many human diseases or medical conditions can be replicated or modelled in mice. In recent years, with the advent of genetically-altered mice and the increase control it offers, mouse models have become even more useful. One of the key questions that is asked during these tests is: where has the drug ended up in the body? If the drug is designed to treat the gut, for example, does it end up in the gut or does it accumulate elsewhere in the body with potentially damaging consequences? Tests of this sort are called biodistribution studies.

The ideal tool for biodistribution studies would be a device that can provide an image of the whole mouse in 3D, in high resolution, and can pick out where in that image the drug is located, eg. by being able to detect its unique spectral signature. It would also be helpful if the imaging technique could be used on a live mouse and, furthermore, did no damage to the mouse. This latter point is especially important as it means that the same animal can be imaged at several points in time to see how the distribution of the drug changes, or see what changes are occurring in the mouse itself over time. There are several small animal imaging modalities that are in routine use today, but none of them come close to meeting this ideal.

There is rapidly growing interest in photoacoustic tomography for small animal imaging because it has the potential to become this ideal tool. Photoacoustic tomography is an emerging technique that uses short pulses of light to generate ultrasound waves within the mouse wherever the light is absorbed. The photoacoustic waves, which carry spatially-resolved information about the structure and even the molecular content of the tissue, propagate out to an array of detectors. A numerical algorithm is then used to reconstruct a 3D volumetric image of the interior of the mouse. The technique is non-invasive, harmless (as it uses non-ionising radiation), and, because it is based on optical absorption, it has the potential to identify components within the tissue based on their optical spectra (which are unique to every type of molecule).

There is one factor holding photoacoustic tomography back from becoming the default approach for small animal imaging the world over: the image quality is not yet as good as it could be. There are three reasons for this. First, the most readily-available sensors cannot detect the full frequency bandwidth of the photoacoustic signals and so fail to capture key information; second, most imaging systems do not detect from all around the animal due to the fabrication complexity and cost of the arrays that would be needed, resulting in image artefacts; third, distortions of the photoacoustic waves due to sound speed variations between and within the different tissue types leads to aberration and blurring in the image, especially at depth.

The scanner proposed here will overcome all three of these limitations of the currently available technologies, through the use of optical detection and generation of ultrasound, and by using ultrasound computed tomography as a adjunct modality to facilitate aberration correction during the image reconstruction.

The goal of this proposal is to develop a new type of small animal scanner which will provide 3D spectroscopic information with higher image quality than current preclinical scanners. One impact of this development, supported by the demonstrations described in the 'Pathways to Impact', is expected to be a marked acceleration in the uptake of photoacoustic tomography for small animal, preclinical, imaging. We anticipate that it will become an indispensable imaging modality in every life sciences department and company worldwide involved in understanding pathological or physiological processes, or developing therapeutic drugs or techniques.

The long term implications therefore include not only an impact on the scientists and companies working to understand the basic processes of diseases, and on those scientists supporting this endeavour, eg. researchers developing new targeted contrast agents, or strains of knockout mice, but, more importantly, an impact on patients who will benefit from the new drugs developed with this imaging technology at the heart of the drug development pathway. There will also be an impact in terms of the significant reduction of the number of animals used for research, (www.nc3rs.org.uk) as photoacoustics can image animals in vivo without causing harm.

By translating the optical technology developed in this proposal into clinical photoacoustic-ultrasound scanners, there is significant potential for impact on clinical practice, eg. on radiologists and other medical professionals who will have a real-time imaging tool as easy to use as ultrasound but also providing functional information such as blood oxygenation, but more importantly on patients who receive earlier and more accurate diagnoses. Furthermore, some of the image reconstruction algorithms developed for this preclinical system will be directly applicable to other imaging scenarios, eg. 3D photoacoustic and ultrasound breast imaging for early tumour detection.

This proposal is highly multi-disciplinary, so as well as these clinical and preclinical impacts, there will be beneficial impacts on other areas of science and engineering. For example, both the broadband plane-wave ultrasound generation and the optical detection technology can be used to significantly improve the accuracy of high frequency ultrasound metrology, which is crucial for the safety of therapeutic ultrasound devices. Also, the algorithms and software developed for acoustic modelling and image reconstruction will have an impact on mathematicians and other researchers working on wave-based inverse problems, such as those in seismology or industrial non-destructive evaluation, by providing them with new and efficient tools as well as insights into a related problem.