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Recently, we have pioneered a portfolio of revolutionary optical technologies in the area of laser spectroscopy, namely deep Raman spectroscopy, for non-invasive molecular probing of biological tissue. The developments have the potential of making a step-change in many fields of medicine including cancer diagnosis. The techniques comprise spatially offset Raman spectroscopy (SORS) and Transmission Raman (both patented by the applicants). The methods are described in detail in a tutorial review: http://www.rsc.org/Publishing/Journals/CS/article.asp?doi=b614777c . There is an urgent clinical need for early objective diagnosis and prediction of likely treatment outcomes for many types of subsurface cancers. This is not addressed by existing technologies. There are numerous steps along the cancer clinical pathway where real-time, in vivo, molecular specific disease analysis would have a major impact. This would allow for more accurate and immediate diagnosis at first presentation, by improving screening or surveillance techniques, leading to earlier diagnosis and better treatment outcomes. Secondly it would allow surgical margin assessment and treatment monitoring in real-time and thirdly identification of metastatic invasion in the lymphatic system during routine surgery. There are numerous other areas where a rapid molecular analysis of a tissue sample in the clinic or theatre environment would allow improved clinical decision-making. Clearly these approaches would be beneficial to the patient by reducing cancer recurrence rates; but also by minimising the numbers of invasive procedures required, thus reducing costs and patient anxiety. Raman spectroscopy is a highly molecular-specific method, which itself has proven to be a useful tool in early epithelial cancer diagnostics, although it has been restricted to sampling the tissue surface of less than 1 mm deep. Our new technology unlocks unique access to tissue abnormalities of up to several cm's deep, i.e. at depths one to two orders of magnitude higher than those previously possible with conventional Raman. We propose to make major breakthroughs in this area and advance diagnostics (including cancer margin assessment and staging) particularly focussed on breast cancer and lymph node metastasis initially as focused case studies and then potentially applied to prostate cancers (not included directly in this proposal). This will be explored as a joint cross-disciplinary venture between Profs Stone and Matousek, the two key researchers in this area, who between them have pioneered the concepts and have established a team of cross-disciplinary scientists and clinicians to advance this field. To fully capitalise on our international lead, we now seek funding to progress this work in a timely manner by developing a novel medical diagnostic platform. We propose to bring together key players from multidisciplinary areas covering physical sciences, spectroscopy, radiology, cancer diagnostic and therapeutic surgery, and histopathology to exploit all of the relevant skills and develop a critical mass of researchers. The principal collaborating teams at the heart of the programme will include: 1) Matousek group in Central Laser Facility at Rutherford Appleton Laboratory focussing on maximising the potential of the technique by implementing further technological developments. 2) Stone group with 17 years experience of applied clinical spectroscopy to develop and evaluate the technology applied to human tissues and undertake complex multivariate analysis to distil the data into relevant diagnostic outputs.

Recently, we have pioneered a portfolio of revolutionary optical technologies in the area of laser spectroscopy, namely deep Raman spectroscopy, for non-invasive molecular probing of biological tissue. The developments have the potential of making a step-change in many fields of medicine including cancer diagnosis. The techniques comprise spatially offset Raman spectroscopy (SORS) and Transmission Raman (both patented by the applicants). The methods are described in detail in a tutorial review: http://pubs.rsc.org/en/content/articlelanding/2016/cs/c5cs00466g. There is an urgent clinical need for early objective diagnosis and prediction of likely treatment outcomes for many types of subsurface cancers. This is not addressed by existing technologies. There are numerous steps along the cancer clinical pathway where real-time, in vivo, molecular specific disease analysis would have a major impact. This would significantly reduce needle biopsy, in around 80% of those recalled following mammographic screening this step is unnecessarily - ie leading to the diagnosis of benign lesions. Our novel approach would allow for more accurate and immediate diagnosis in conjunction with mammography at first presentation by improving screening or surveillance techniques, leading to earlier diagnosis and better treatment outcomes. Secondly it would allow surgical margin assessment and treatment monitoring in real-time and thirdly identification of metastatic invasion in the lymphatic system during routine surgery. There are numerous other areas where a rapid molecular analysis of a tissue sample in the clinic or theatre environment would allow improved clinical decision-making, for example when pre- operatively staging the disease and particularly when non-invasively monitoring tumour response during chemo/radiotherapy. Clearly these approaches would be beneficial to the patient by reducing cancer recurrence rates; but also by minimising the numbers of invasive procedures required, thus reducing costs and patient anxiety. Raman spectroscopy is a highly molecular-specific method, which itself has proven to be a useful tool in early epithelial cancer diagnostics, although in its conventional form it has been restricted to sampling the tissue surface of much less than 1 mm deep. The new technology unlocks unique access to tissue abnormalities of up to several cm's deep, i.e. at depths one to two orders of magnitude higher than those previously possible with Raman. Following on from our previous project, where we were able to demonstrate conceptually a ~100x improvement in signal recovery compared to our early feasibility work, we are now able to rapidly develop a platform for real-clinical tools using this approach. We propose to make major breakthroughs in this area and advance diagnostics particularly focussed on breast cancer and lymph node metastasis initially as focused case studies and then potentially applied to prostate cancers (outside the scope of this proposal). This will be explored as a joint cross-disciplinary research venture between Profs Stone and Matousek, the two key researchers in this area. We now seek funding to progress this work in a timely manner by developing a novel medical diagnostic platform of major societal impact. We propose to bring together key players from multidisciplinary areas covering physical sciences, spectroscopy, radiology, cancer diagnostic and therapeutic surgery, and histopathology to exploit all of the relevant skills and develop a critical mass of expertise to tackle these challenging issues.

The ability to look at small numbers of molecules in a sea of others has appealed to scientists for years. On the fundamental side we want to watch in real time how molecules undergo chemical reactions directly, how they explore the different ways they can come together, interact and eventually form a bond, and ideally we would like to influence this so that we can select just a single product of interest. We also want to understand how molecules react at surfaces since this forms the basis of catalysis in industrially relevant processes and is thus at the heart of almost every product in our lives. However, most scientific studies take place in precise conditions achieved in the laboratory, such as high vacuum, to select the cleanest possible conditions, but which look nothing like the real world applications they simulate. Hence most knowledge is empirical and pragmatically optimised. We have been working on a completely new way to watch chemistry in an incredibly tiny test tube, itself a molecule. We use a barrel-shaped molecule called a 'CB' that can selectively suck in all sorts of different molecules. Recently, we have found a way to combine these barrel containers with tiny chunks of gold a few hundred atoms across, in such a way that shining light onto this gold-barrel mixture focuses and enhances the light waves into tiny volumes of space exactly where the molecules are located. By looking at the colours of the scattered light, we can work out what molecules are present and what they are doing, with enough sensitivity to resolve tiny numbers. Our aim in this grant is to explore our promising start (that was seeded by EU funding). We aim to develop all sorts of ways to make useful structures that sense neurotransmitters from the brain, protein incompatibilities between mother and foetus, watch hydrogenation of molecules take place, find trace gases that are dangerous, and many others. At the same time we want to understand much more deeply and carefully how we can go further with such ideas, from controlling chemical reactions happening inside the container, to making captured molecules inside flex which can result in colour-changing switches. To make all this happen we take research groups spanning physics and chemistry and completely mix them up, so that they can work together on these very interdisciplinary aspects. We have found this works extremely well. We also involve a number of companies and potential end users (including the NHS) who know the real problems when trying to exploit these technologies in important areas including diagnostics, imaging and catalysis.

We can use intricately controlled assemblies of metals carved into structures on the scale of a billionth of a metre, to funnel and concentrate light into tiny volumes of space. This 'nano-optics' allows us to access for the first time small numbers of molecules and atoms moving around in real time. Even more interesting we can start to use light to control the movement of molecules and atoms, since it can produce strong forces directly at the nanoscale. In this research, we plan to use our new-found ability to concentrate on a whole range of physical phenomena that underlie devices at the heart of healthcare, information technology, and energy production. For instance we can watch how lithium ions move into and out of a small fragment of battery, and how the deformations of the atomic lattice are produced, which is what determines how long batteries last and how much energy they can store. Another project uses light to move gold atoms around inside larger carbon-based molecules, to control what colour they absorb at, and what molecules they can sense. Further projects build wallpapers constructed from tiny flipping components that produce colour changes on demand, the precursor to walls that change colour at the flick of a switch or display images or text on the side of lorries. Underpinning all this are serious advances in learning how to build such structures reliably, so anyone can make use of our new ideas. We understand very little about what happens when we put molecules inside such compressed nano-cavities for light, and these fundamentals will open up new areas. This research also crucially helps us understand what new properties we can create, and predicts how to improve them best. This will lay open many of the new technologies of the next century.