Corneal ulcer caused by invading bacteria or fungi (microbial keratitis, MK) is a silent epidemic, disproportionately affecting low-middle income countries (LMICs), and is a major cause of blindness. Despite being a WHO priority disease area it has not explicitly been covered by Vision2020 frameworks and as such, it has garnered little policy, research or development focus over the last 20+ years. In India alone, 1.5-2 million people experience corneal ulcer per year, predominantly affecting the rural-poor. Corneal ulcer is an "ophthalmic emergency" and the longer the delay to seek appropriate treatment, the worse the outcome. Even where gold-standard diagnostics and treatments are available, over 60% of MK patients are still left with visual impairment across India, and >10% of patients require expensive and often unsuccessful surgical interventions such as corneal transplant. These permanent, debilitating outcomes are often attributed to an excessive and uncontrolled inflammatory response, leading to scarring and corneal perforation. Furthermore, these bleak statistics are for the minority of patients who are able to access specialist care in large cities. The rural-poor are, in reality, much worse off. A radical re-development of the entire healthcare pathway, from diagnosis to treatment, is required to improve the prognosis for these patients. Due to the large-scale neglect of corneal ulcer, the fundamental molecular mechanisms driving disease, which are required for developing better diagnostics and new therapeutic strategies have been understudied. These molecular "fingerprints" could hold the key to predicting who will heal or who will suffer long lasting visual impairment and require a different therapeutic strategy. To date, tears (a non-invasive, readily available sample) have proven pivotally important in biomarker discovery for a number of eye disorders such as dry-eye, keratoconus and blepharitis, and non-ocular diseases such as cancer and multiple sclerosis; and have led to the development of commercial diagnostic platforms. Surprisingly, molecular signatures within tears have been relatively understudied in the context of MK, and the translation pipeline is bare. Here, through the development of a series of escalating in vitro and ex vivo models, and through the interrogation of MK patient tears by sophisticated proteomic and metabolomic techniques, the molecular signatures of bacterial and fungal, and resolving and non-resolving MK will be mapped. The key targets identified by the research will feed into diagnostic assay development, which will include the synthesis of novel activatable fluorescent chemistries (SmartProbes), which can be used as a tool to non-invasively capture the molecular "fingerprint" of the infection when coupled with simple optical devices at the point-of-care. Furthermore, targeted approaches to modulate the molecular mechanisms driving "non-resolution" pathways, such as neutrophil activation or clearance, will be investigated to identify novel therapeutic strategies for precision medicine based approaches to treatment. Often translation of such diagnostic technologies and interventional strategies, particularly in low-resource environments, fail or under-perform at the point-of-care. This can partly be attributed to a poor understanding of the intended health-system and lack of end-user engagement during the development process. To mitigate against this, I will work with the world's largest eye-care provider, the Aravind Eye Care System in South India to map MK patient pathways from primary to tertiary care, patient engagement, and how these relate to MK clinical outcomes. Not only will this identify ways to contribute to health-system strengthening, but this insight will feed directly into technology design and provide a route for the clinical evaluation and implementation of the user-appropriate diagnostic and treatment strategies for MK developed within this programme.

The Aravind Eye Care System in Southern India was established as a health care model that could supplement the efforts of the government and also be self-supporting to overcome the problem of avoidable blindness in a developing country. The company Aurolab is an integral part of the Aravind Eye Care System. It manufactures a wide range of high quality ophthalmic consumables. Developing a translational alliance with the Aravind Eye Care System and Aurolab will provide us with the opportunities to gain access to a commercial infra-structure which includes support for polymer technologies and manufacture, product commercialisation in terms of regulatory approvals, IP protection and advertising, as well as distribution and labelling. Aurolab's products are exported to 130 and more countries worldwide and their products meet the regulatory requirements of the USA, EU and WHO. All Aurolab products are manufactured on efficient production lines with strict quality assurance measures. We intend to develop this translational alliance with Aurolab and the Aravind Eye Care System to exploit our novel chemical cross-linking therapy for the treatment of keratoconus. Keratoconus is a progressive condition, often affecting young and working age people, in which the cornea becomes misshapen significantly disrupting the refraction of light into the eye. One of the key features of keratoconus is a loss of corneal mechanical stability. Increasing the stiffness of the cornea can reduce the progression of this debilitating eye disease. Corneal collagen cross-linking focuses on stiffening the cornea in order to preserve corneal integrity due to strong bonds formed within the collagen. Using our understanding of the engineering principles that define the relationship between the structure and mechanical properties of materials we will develop a novel collagen cross-linking therapy using di-carboxylic acids thus this proposal lies clearly at the interface between Engineering and Healthcare Technologies and aligns closely with the Synthetic Biology for Health area. To establish the partnership we will make multiple visits to India regularly over the 2 years of the project. We will also host visits from senior scientists and clinicians from India. In particular we will host a 3 month research exchange for a Product Development Scientist from Aurolab to learn about our research and facilitate a research exchange for our PDRA to spend 3 months at Aurolab to learn about product manufacture and scale up. We will jointly supervise a clinical research fellow at the Aravind Eye Care System and we will establish an in vivo animal model facility in Liverpool which will support this project and future development projects as part of the long term partnership. These other project areas that would benefit greatly from the alliance could lead to translational opportunities and impact to the health and wealth of societies in the UK and globally. By working together to design these projects we will ensure that they address the clinical and commercial requirements for India, the UK and globally. Specific examples could include the extrapolation of the cross-linking therapy to the development of a strategy to increase the mechanical properties of ulcerated cornea to protect against perforation and aid healing and the potential to increase the stiffness of the sclera as a treatment for myopia and/or glaucoma. A further area of particular interest to our project partners is the development of bandage contact lenses with the potential to deliver anti-fungal agents such as voriconazole for the treatment of fungal keratitis which is a major clinical problem in India. In the more longer term there are several projects within the Department of Eye and Vision Science at the University of Liverpool that would benefit from this alliance such as the development of drug delivery devices for the front and back of the eye.

Bacterial and fungal infections are responsible for significant death, disability and poor outcomes and are a major financial burden on the health service. Infections resulting from invasive procedures or injuries whereby the body's own defences are breached are common and are now increasing in incidence and severity due to the rise of antimicrobial resistance. In the past, antibiotics were readily able to treat such infections. This research thus addresses, arguably, the biggest challenge facing modern healthcare, the rise of antimicrobial resistance. The post antibiotic era is looming and novel strategies that do not rely upon conventional antibiotics and antifungals are urgently required. This research proposal will develop to near-clinical readiness, novel classes of therapeutic molecules that will bind specifically to microbes for subsequent activation with low energy light to augment microbial killing. Work on the different elements needed to create this technology platform will be undertaken by investigators at Edinburgh and Liverpool Universities in collaboration with partners in India and in a global surgical network. This project will be based in the Proteus interdisciplinary "hub" to ensure rapid product development. The researchers will spend time in each others labs as well as arranging an open network meeting once a year to ensure broader engagement. The scientists (researcher co-investigators) in the proposal who are all early career researchers will benefit significantly from networking and establishing the area of targeted therapeutic delivery for microbial photodynamic therapy. The research will involve Chemists, Production Engineers, NHS Medical Physics, Bioengineers, industrial collaborators and a committed team of senior clinicians (Respiratory and Critical Care Physicians, Surgeons and Ophthalmologists) to co-develop and test the technology in a variety of model systems to demonstrate the widespread applicability in applications that involve surfaces such as the skin, wounds, eyes and in the lung. A key ambition of the research will be to pave the way for subsequent clinical development and as such user (clinical and regulatory) input will be paramount at the inception and development of the technology. The research will develop and foster global links with an ethos of "safe, affordable and scalable" solutions that will then have the highest likelihood of clinical adoption in a variety of healthcare settings. The team will leverage existing capability and expertise in manufacturing, regulatory and commercialisation support to expedite development. In summary, this project will generate; 1) A cutting-edge point of care technology platform which will help patients, doctors and health care workers throughout the world 2) Career development of the early stage researchers 3) Sustainability for the Proteus IRC by launching into targeted therapy of infection 4) Create a sustainable network to disseminate the technology

India is home to over 15 million blind people. Diabetes is a global epidemic but India is one of the top 3 countries most affected with 69 million people diagnosed with diabetes. Diabetic retinopathy is the most common complication of diabetes, whereby blood vessels in the retina leak or die and, if left untreated, this leads to visual loss. Sight threatening diabetic retinopathy (STDR) is the leading cause of blindness in the working age group causing loss of productivity, affecting individual households and the national economy. Despite a fast growing economy, a billion people in India live below the poverty line. Diabetes may result in poverty and poverty is associated with diabetes. Therefore, unless the complications of diabetes are identified early and treated, the impact of blindness on the quality of life and productivity of the Indian population will continue to have a negative impact on the nation's economy. Annual screening of all people with diabetes with retinal photography and prompt treatment of STDR has been shown to decrease the rate of blindness in the UK. However, the technology involved is costly, requires trained manpower and is impractical as a method for screening 69 million people in India annually, when the major proportion of health expenses have to borne by the patients. By increasing research capacity and capability through this programme, we aim to initiate systematic diabetic retinopathy screening in India through research and evaluate innovative technologies that can accurately identify patients at risk of blindness due to STDR close to home. These technologies can be applied in all DAC listed countries with prospects of reverse innovation in the UK. The range of research capability activities (SDG Goal 4) and capacity building in India is aimed at better patient outcomes (SDG Goal 3), developing a workforce with quality education (SDG 4), enhancing sustainable livelihoods (SDG Goal 8) and contributing to India's and the UK's work towards an efficient value based healthcare. Firstly, we will introduce population based diabetic retinopathy screening in India and evaluate whether a hand-held camera with smartphone technology and automated grading is feasible in both India and the UK instead of the standard costly cameras and trained manpower employed in the UK currently. We expect more population coverage of retinal screening with this technology and more patients to be referred for treatment. The research capability at the referral hospitals will also improve from this programme with new quality standards being set for treatment. Secondly, we will develop and validate a blood test of a panel of established markers that can detect STDR and other complications of diabetes with the aim to translate into clinical practice. This will allow patients to monitor their own blood tests for STDR. This has the potential to revolutionise the way people with diabetes are monitored for STDR and other complications globally, empower patients and health care workers with new knowledge, improve research capability in India and the UK, improve research capacity in India and improve the global economy in terms of sustained health, industry and innovation and decreasing inequality in terms of access to healthcare. The programme has the potential to change the landscape of diagnosing and triaging STDR globally. In addition, development of a diabetic retinopathy research network of researchers in India will ensure scalability and sustainability of world-class research in India. These research projects will have secondary benefits to the UK in terms of increasing research capability and reverse innovation. Moreover, the programme will also provide comparative cost-effectiveness data of current standard of care versus these newer technologies to inform national guidelines committees and policy makers globally.

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.