Prostate cancer occurs in about one in seven of the male population and is fatal in about 20% of those cases, being the second most common cancer after lung cancer. Surgical intervention seeks to remove sufficient malignant tissue without leaving residuals that can lead to recurrence. At the same time new surgical techniques are emerging to minimise the impact on healthy tissue and preserve nerves and the quality of life. However, currently, the assessment of the success in removing all cancerous tissue depends on evaluation in a pathology lab and means that the surgery will not be curative or needs to be revisited. It is therefore crucial to develop technology that can allow the surgeon to make decisions during surgery that can reduce the chances of recurring disease. One well established indicator of cancerous tissue is the injection of a radioactively labelled tracer that differentiates between malignancy and normal tissue. This tracer can be imaged using positron emission tomography, but this is not a technology that can be utilized within a surgical setting. Recently a new methodology has been developed which allows the radioactive tracer to be imaged using ordinary cameras, by exploiting the emission by radioactive particles of Cerenkov light, in the visible spectrum. This phenomenon opens the possibility to place cameras on endoscopes and combine them with existing methods for robotic assisted surgery. In this project, we will pursue this idea, and make use of techniques for tracking movement of the cameras and the patient, including them in a model of light emission and detection, and realizing a real-time dynamic imaging system assisting the surgeon to excise all cancerous tissue while preserving as much healthy tissue as possible.

The unique properties of light have made it central to our high-tech society. For example, our information-rich world is only enabled by the remarkable capacity of the fibre-optic network, where thin strands of glass are used to carry massive amounts of information around the globe as high-speed optical signals. Light also impacts areas of our society as diverse as laser-based manufacturing, solar energy, space-based remote sensing and even astronomy. One area where the properties of light open up otherwise-impossible capabilities is medicine. In ophthalmology for example, lasers are routinely used to perform surgery on the eye through corneal reshaping. This involves two different lasers. In the first step, a laser producing very short pulses of infrared light cuts a flap in the front surface of the eye to provide access. In the second step, another laser producing longer pulses of ultraviolet (UV) light sculpts the shape of the cornea and correct focusing errors. The flap is then folded back into place so that the cornea can heal. The two very-different laser systems in that example illustrate an important point: the effects of light on human tissues are highly-dependent on the specific properties of both the light and the tissues involved. To sculpt the cornea, the laser wavelength of 193 nm is in the deep UV region of the electromagnetic spectrum, much shorter than the visible range (380 - 740 nm) we are familiar with. This is because (unlike visible light) it is very efficiently absorbed by the cornea, so that essentially all the energy of the light is deposited at the surface. Thus only a very thin layer of tissue (a few microns thick) is removed, or "resected", with each pulse of light, facilitating very-precise shaping of the cornea and accurate adjustment of its focusing properties. 193 nm light can be generated by an ArF excimer gas laser, a >40 year-old technology producing a poor-quality low-brightness beam of light. This is suitable for corneal reshaping, but not for a range of other important therapies requiring higher-quality deep UV beams. Unfortunately, alternative ways to generate such short wavelengths are non-trivial, resulting in complex and expensive laser systems not suitable for widespread clinical uptake. U-care aims to address this gap by exploiting cutting-edge techniques in laser physics. We will develop new sources of deep UV light which will be highly compact, robust and low cost. We will develop ways to deliver this light precisely to tissues, and work to understand in detail the biophysical mechanisms involved. Our efforts will focus on new therapies that target some of the biggest challenges facing medicine: cellular-precision cancer surgery, and the emergence of drug-resistant "super-bugs". Importantly, U-care will involve engineers and physical scientists working in close collaboration with clinicians and biomedical scientists to verify that the therapies we develop are effective and safe. By doing so in an integrated manner, we will drive our deep-UV light therapies towards healthcare impact and widespread use in the clinic by 2050.

This project aims to deliver transformative advances in the development of nanoparticle constructs for use in precision surgery and beyond (e.g. therapeutic drug delivery). This will be achieved by bringing together experts with complimentary expertise in calixarene chemistry, nanochemistry, PET (positron emission tomography) imaging and surgical imaging. By developing the chemistry of calixarenes, we will optimize the galectin receptor binding affinity and demonstrate selective cancer cell targeting. Our preliminary studies reveal that radiolabelled (18F) 'Clicked' calixarenes are readily accessible, with improved HPLC purification (achieved via guest incorporation), which enables in vivo bio-distribution, highlighting ideal (renal) clearance. A major benefit of employing a calixarene-based scaffold is the ability for further functionalization. With this in mind, using standard protocols (Click chemistry), the calixarene will be further modified with the addition of a NOTA motif. The incorporation of such a strongly binding motif will allow us to develop the radiolabelling of this new platform technology, with maximum flexibility i.e. with both 18F and 68Ga radionuclides. The functionalized calixarene scaffold will be immobilized on luminescent conjugated polymer nanoparticles to enhance the imaging capabilities. The biodistribution and tumour uptake of the delivery platform will then be accessed (PET imaging), and results will be fed back into the synthetic programme to allow us to optimize the results. Following successful in vitro studies, in vivo tumour uptake will be assessed; tumour and organ uptake will be quantified to assess biodistribution and tumour targeting. The final phase of the project will explore opportunities for using this technology for the collection of spectra in vivo, by combining with a customizable dual camera head. To evaluate depth sensitivity and multimodal guidance an endoscopic gamma probe will be used for multi-functional probe identification. Such a combined approach will be suitable for pre-clinical imaging with a focus on high resolution and signal quality.

This project aims to deliver transformative advances in the development of nanoparticle constructs for use in precision surgery and beyond (e.g. therapeutic drug delivery). This will be achieved by bringing together experts with complimentary expertise in calixarene chemistry, nanochemistry, PET (positron emission tomography) imaging and surgical imaging. By developing the chemistry of calixarenes, we will optimize the galectin receptor binding affinity and demonstrate selective cancer cell targeting. Our preliminary studies reveal that radiolabelled (18F) 'Clicked' calixarenes are readily accessible, with improved HPLC purification (achieved via guest incorporation), which enables in vivo bio-distribution, highlighting ideal (renal) clearance. A major benefit of employing a calixarene-based scaffold is the ability for further functionalization. With this in mind, using standard protocols (Click chemistry), the calixarene will be further modified with the addition of a NOTA motif. The incorporation of such a strongly binding motif will allow us to develop the radiolabelling of this new platform technology, with maximum flexibility i.e. with both 18F and 68Ga radionuclides. The functionalized calixarene scaffold will be immobilized on luminescent conjugated polymer nanoparticles to enhance the imaging capabilities. The biodistribution and tumour uptake of the delivery platform will then be accessed (PET imaging), and results will be fed back into the synthetic programme to allow us to optimize the results. Following successful in vitro studies, in vivo tumour uptake will be assessed; tumour and organ uptake will be quantified to assess biodistribution and tumour targeting. The final phase of the project will explore opportunities for using this technology for the collection of spectra in vivo, by combining with a customizable dual camera head. To evaluate depth sensitivity and multimodal guidance an endoscopic gamma probe will be used for multi-functional probe identification. Such a combined approach will be suitable for pre-clinical imaging with a focus on high resolution and signal quality.

Medical imaging has transformed clinical medicine in the last 40 years. Diagnostic imaging provides the means to probe the structure and function of the human body without having to cut open the body to see disease or injury. Imaging is sensitive to changes associated with the early stages of cancer allowing detection of disease at a sufficient early stage to have a major impact on long-term survival. Combining imaging with therapy delivery and surgery enables 3D imaging to be used for guidance, i.e. minimising harm to surrounding tissue and increasing the likelihood of a successful outcome. The UK has consistently been at the forefront of many of these developments. Despite these advances we still do not know the most basic mechanisms and aetiology of many of the most disabling and dangerous diseases. Cancer survival remains stubbornly low for many of the most common cancers such as lung, head and neck, liver, pancreas. Some of the most distressing neurological disorders such as the dementias, multiple sclerosis, epilepsy and some of the more common brain cancers, still have woefully poor long term cure rates. Imaging is the primary means of diagnosis and for studying disease progression and response to treatment. To fully achieve its potential imaging needs to be coupled with computational modelling of biological function and its relationship to tissue structure at multiple scales. The advent of powerful computing has opened up exciting opportunities to better understand disease initiation and progression and to guide and assess the effectiveness of therapies. Meanwhile novel imaging methods, such as photoacoustics, and combinations of technologies such as simultaneous PET and MRI, have created entirely new ways of looking at healthy function and disturbances to normal function associated with early and late disease progression. It is becoming increasingly clear that a multi-parameter, multi-scale and multi-sensor approach combining advanced sensor design with advanced computational methods in image formation and biological systems modelling is the way forward. The EPSRC Centre for Doctoral Training in Medical Imaging will provide comprehensive and integrative doctoral training in imaging sciences and methods. The programme has a strong focus on new image acquisition technologies, novel data analysis methods and integration with computational modelling. This will be a 4-year PhD programme designed to prepare students for successful careers in academia, industry and the healthcare sector. It comprises an MRes year in which the student will gain core competencies in this rapidly developing field, plus the skills to innovate both with imaging devices and with computational methods. During the PhD (years 2 to 4) the student will undertake an in-depth study of an aspect of medical imaging and its application to healthcare and will seek innovative solutions to challenging problems. Most projects will be strongly multi-disciplinary with a principle supervisor being a computer scientist, physicist, mathematician or engineer, a second supervisor from a clinical or life science background, and an industrial supervisor when required. Each project will lie in the EPSRC's remit. The Centre will comprise 72 students at its peak after 4 years and will be obtaining dedicated space and facilities. The participating departments are strongly supportive of this initiative and will encourage new academic appointees to actively participate in its delivery. The Centre will fill a significant skills gap that has been identified and our graduates will have a major impact in academic research in his area, industrial developments including attracting inward investment and driving forward start-ups, and in advocacy of this important and expanding area of medical engineering.