A mechanistic understanding of corneal pathobiology and the development of therapeutic strategies for the treatment of connective tissue disorders

Lead Research Organisation: Cardiff University
Department Name: Optometry and Vision Sciences

Abstract

The cornea is the transparent window at the front of the eye and is its main focussing element. To fulfil its role it has to be transparent, strong and precisely shaped. Transparency and strength are controlled by the collagen fibrils that make up the cornea, and by the small molecules between them. Shape is also controlled by the collagen arrangement, but we have now discovered a complex system of small elastic fibres that we believe helps to restore shape when the cornea is distorted, for example as blood is pumped round the body, during blinking or after eye rubbing. These properties of the cornea are controlled at different structural levels: collagen molecules form fibrils, which in turn form larger structures called lamellae, which are then stacked up to form the tissue itself. Elastic fibres that contain the protein elastin are concentrated around the edge of the cornea in the form of sheets, which we have shown are connected across the human cornea by fine filaments rich in proteins called fibrillins. We want to test our hypothesis that this arrangement allows distortion and recovery mainly at the edge of the cornea, maintaining the shape of the central cornea that controls the focussing of the incoming light. From previous work by us and others, we know a lot about why the cornea is transparent and are beginning to understand the arrangement of collagen lamellae and elastic fibres that gives rise to the cornea's shape and thus its focusing abilities. However, the contribution of different elements of the structure to the overall function is still not known and, until we elucidate this, it will not be possible to understand why, in numerous diseases of the cornea, or after different types of surgery on the cornea, transparency, strength and/or shape are abnormal and vision is lost or very blurred. We have pioneered the use of several sophisticated techniques to study the cornea at every structural level from the molecules upwards: x-ray scattering, serial block face scanning electron microscopy and two photon fluorescence light microscopy. We propose now to build equipment that will allow us to measure which constituents of the structure change when the cornea is distorted by known forces, either during its normal functioning or due to disease and/or surgery. We will also explain how lamellae are arranged to provide form and strength, how the elastic fibres are structured in different parts of the cornea, and what role they play in health and disease. We showed that abnormalities of the elastic fibres occur in corneal diseases such as keratoconus, and we will test our idea that they play a role in other diseases of the eye, such as glaucoma. In addition, we will investigate treatments for corneal disorders, for example by developing new chemical crosslinking methods. To address the world-wide shortage of donor corneas, biological artificial corneas are being developed. However, for corneal replacements to function normally, we must fully understand how nature utilises the constituents of a tissue to achieve its vital properties. This means elucidating the exact relationships between its various components and its function, including how cells communicate with other cells during development, wound healing and tissue regeneration. In the case of the cornea, the knowledge that we will obtain by discovering the exact relationship between its various structural components and its function is crucial for our understanding of corneal transparency and biomechanical stability as related to corneal development, surgical manipulation and implantation, and tissue engineering. Finally, we will demonstrate how cornea is an excellent model system for connective tissues more generally, by collaborating with other groups around the world, using our new techniques to aid our understanding of function/dysfunction in other parts of the body.

Technical Summary

As the primary refractive component of the eye, the well-functioning cornea must be precisely curved, strong and transparent. Our previous studies have shown that these intrinsic qualities are governed by the hierarchical ultrastructure and complex microanatomy of its cells and extracellular matrix. Building on our existing knowledge of healthy corneal function, our main objectives are to (1) understand the structural basis of normal corneal function and dysfunction, and elucidate the role of a previously identified but as yet, uncharacterised corneal elastic fibre system that we believe may help to restore shape when the cornea is distorted; (2) increase our understanding of the role of extracellular vesicle signalling in the development, regeneration and repair of the cornea; (3) develop photochemical therapies for corneal ectasia through laboratory studies and the collection of clinical data into our UK cross-linking consortium audit tool; (4) develop synchrotron x-ray scattering and microscopy techniques to carry out time-resolved biomechanics/structure correlations to study in three-dimensions, at high-resolution, and in an orchestrated, hierarchical manner, the response of the normal and pathological corneas to different loads; (5) collaboratively demonstrate the applicability of these new techniques to other areas of connective tissue research. Most of these will be achieved by combining state-of-the-art imaging techniques, including microfocus synchrotron x-ray scattering, x-ray spectroscopy, optical coherence tomography, multiphoton laser microscopy, high-pressure cryopreservation electron microscopy and volume serial block face scanning electron microscopy, immunofluorescence microscopy, with established biomechanical and biochemical testing procedures (extensometry, interferometry, inflation testing and immunohistochemisty) to study karyotypically normal and abnormal human foetal and adult corneas, pathological corneas and corneal tissue alternatives.

Planned Impact

Our research will have a significant number of non-academic beneficiaries, the principal ones being members of the general public suffering or caring for those with corneal disorders, the practitioners treating them and the charities providing them with advice and support. Corneal problems blind more people worldwide than any other condition apart from cataract. Research into the fundamental structural basis of corneal pathologies and disease mechanisms will have ongoing impact, as it will inform and drive the development of better treatments from which practitioners, and ultimately patients, will benefit. Through public engagement our research will have added societal impact by inspiring interest in STEM subjects and highlighting the importance of organ donation.
Corneal cross-linking has significantly cut costs to the health services by reducing the number of grafts required for keratoconus patients. We predict, that in the short-to-medium term, our cross-linking work will lead to safer treatments, more predictable outcomes, better patient satisfaction and a significant increase in the number of keratoconus patients who can undergo treatment. Our research into new therapies will also offer hope to keratoconus patients with more severe forms of the disease that cannot be treated with conventional cross-linking and if left unchecked, can progress to a devastating corneal perforation. Understanding why the corneas of children and young adults with Down's syndrome are particularly susceptible to developing keratoconus may lead to changes in clinical practice and health care policy, such as advice on how and when to treat. Our research will also be useful to charity and support groups such as the UK Keratoconus Self Help and Support Group, National Keratoconus Foundation and the Down's Syndrome Association, that seek to empower and support sufferers by providing them with the most up-to-date information about their conditions. Our further development of the UK Cross-Linking Consortium and the national keratoconus e-registry will benefit the NHS through the collection of auditable data on cross-linking outcomes, in line with NICE guidelines. It is anticipated that the data set will be used as a resource by governmental bodies to help inform decision-making processes relating to the cost-effectiveness of corneal cross-linking and the provision of cross-linking services.
Corneal surgery has been carried out on millions of people worldwide, not always without post-operative complications. As in the past, where we have helped to improve surgical outcomes in the fields of ex vivo expanded corneal epithelial transplantation and treatments for corneal endothelial dysfunction, our proposed research will benefit public health by driving the development of new and improved surgical approaches. In the same way that our published studies of corneal ultrastructure have been used to develop commercial products (eg. Lumaxis, a device to properly orientate donor corneas prior to surgery), it is anticipated that our newly generated structural and biomechanical data will also be used by commercial entities as a basis for product development. As alluded to above, our research and development of cross-linking therapies continues to generate commercial interest as new products are released into a rapidly evolving market, and as such, it has the potential to stimulate commercial benefit for British medical device companies and economic benefit for the UK.
Finally, due to a world-wide shortage of donor tissue there is a pressing need for the development of artificial corneal replacements. Our research will examine ways of encouraging endogenous regeneration and thus lead to improved corneal-tissue alternatives. This research has high translational potential and will have a lasting impact on quality of life, particularly in developing countries where the shortage of donor tissue is already critical.

Publications

10 25 50
 
Description Expert reviewer for Health Technology Wales' review of clinical and cost effectiveness of corneal cross-linking
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://healthtechnology.wales/guidance-published-corneal-cross-linking2/
 
Description HEFCW GCRF Fellowship: Corneal photo crosslinking for keratoconus treatment in Malawi
Amount £16,050 (GBP)
Organisation Higher Education Funding Council for Wales (HEFCW) 
Sector Public
Country United Kingdom
Start 01/2020 
End 07/2020
 
Description Imaging BioPro Grant: Hierarchical Effects of Mineralisation on Collagen Structure and Biomechanics
Amount £20,734 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 08/2021 
End 10/2022
 
Description University College London MRC/EPSRC/BBSRC ImagingBioPro grant
Amount £16,108 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 08/2020 
End 04/2021
 
Title A SBF-SEM (Serial block face- scanning electron microscopy) staining method for the study of elastic fibres in connective tissues 
Description A novel SBF-SEM (Serial block face- scanning electron microscopy) staining method was developed to investigate the 3D structure of elastic fibres in cornea. 
Type Of Material Technology assay or reagent 
Year Produced 2021 
Provided To Others? Yes  
Impact This novel method has been successfully used to investigate elastic fibre architecture in the healthy cornea, and in the lung and kidney of a Marfan's syndrome murine animal model, where genetic mutations in fibrillin-1 give rise to defects in the protein components of elastic microfibrils. 
URL https://doi.org/10.3390/mps4030056
 
Title Numerical Simulation of Corneal Fibril Reorientation in Response to External Loading 
Description We published our X-ray scattering data showing changes in fibril orientation and distribution in corneal strips subjected to gradually increasing axial loading. The data was incorporated into a computer model (by our collaborators) to predict fibril re-orientation following tissue removal. 
Type Of Material Computer model/algorithm 
Year Produced 2019 
Provided To Others? Yes  
Impact The model was published by our collaborators in 2019. doi:10.3390/ijerph16183278, with acknowledgement to James Bell for sharing the X-ray experimental information and results. With the ability to simulate fibril reorientation, numerical modelling can have a greater potential in modelling the behaviour following surgery and injury to the cornea. 
 
Description Arie Markovich 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution Ultrastructural analysis of cross-linked tissue
Collaborator Contribution Carried out cross-linking in rabbits
Impact Peer reviewed publication in 2020: doi: 10.1038/s41598-020-66869-y
Start Year 2013
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation Madrid Institute for Advanced Studies
Country Spain 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation Ross University School of Veterinary Medicine
Country Saint Kitts and Nevis 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Portsmouth
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Biomechanics Facility and User Network at Diamond Light Source 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution James Bell is working with Diamond Light Source to develop a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research. To assist in the development of the platform and ensure maximum versatility, James Bell formed a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html).
Collaborator Contribution The multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Impact Tissue stretching and inflation devices have been designed and incorporated into diamond beamlines to enable the synchronous collection of x-ray scattering and mechanical testing data from a range of connective tissues.
Start Year 2020
 
Description Collaboration with Farhad Hafezi (Geneva) 
Organisation Geneva University Hospitals
Country Switzerland 
Sector Hospitals 
PI Contribution We have collected x-ray scattering data from normal and keratoconus corneas that have been previously cross-linked using riboflavin and UVA.
Collaborator Contribution Prof Hafezi has been involved in the concept and design of collagen cross-linking studies involving keratoconus corneas. He also serves as an Honorary Overseas Consultant to the UK Cross-linking Consortium.
Impact Multidisciplinary publication (Ophthalmology, Biophysics, Biology): doi.org/10.1371/journal.pone.0022405 Farhad Hafezi is a confirmed guest speaker at our 2020 UK-Cross-linking Consortium meeting which will be held in May 2020, as part of the Royal College of Ophthalmology Annual Congress.
Start Year 2010
 
Description Diamond 
Organisation Diamond Light Source
Country United Kingdom 
Sector Private 
PI Contribution Data collection at the Diamond Light Source and equipment development . In partnership with Diamond Light Source, Dr James Bell is leading the development of a biomechanical testing platform that will allow a wide-range of scientists to perform simultaneous x-ray scattering/biomechanical testing on a range of connective tissues.
Collaborator Contribution Assisting with data collection and equipment development. Administration and publicity of the Biomechanics Facility User Network
Impact Our ongoing collaboration with DLS has resulted in a large number of publications, the most recent of which are: doi: 10.1016/j.actbio.2017.11.015 doi: 10.1098/rsif.2017.0062. doi: 10.1167/iovs.16-21358. The formation of a Biomechanics Facility and User Network at Diamond Light Source (https://www.diamond.ac.uk/Instruments/Soft-Condensed-Matter/small-angle/I22.html). Led by James Bell, the multi-disciplinary user network (comprising ~20 connective tissue researchers, physicists and engineers) are contributing to the design of a general purpose miromechanical testing platform that will be made freely available to scientists during their beamtime at Diamond Light Source to enhance connective tissue and materials-based research.
Start Year 2007
 
Description Fibrillin knock-out mouse 
Organisation Universidade de São Paulo
Country Brazil 
Sector Academic/University 
PI Contribution We instigated a collaboration with Prof Lygia Pereira, Department of genetics, Sao Paulo University, Brazil who developed a mouse model for Marfans syndrome, where FBN1 gene is knocked out. We undertook biophysical studies of corneas from these mice which have helped us to understand the role of fibrillin microfibrils in maintaining corneal shape and have led to multiple publications. In 2020, we hosted a researcher from Sao Paulo visiting Cardiff University for 1-month to receive training in electron microscopy techniques (from Dr Phil Lewis) and to work on a joint research project (with Dr Phil Lewis), examining the ultrastructure of multiple connective tissues in the Marfans syndrome mouse model. The work is currently being written up for publication.
Collaborator Contribution Developed the mouse model for Marfan's syndrome and supplied mouse eyes for ultrastructural studies. Sent a researcher to Cardiff University to work on a joint research project exploring the ultrastructure of other connective tissues in the Marfan's mouse model. Provide expertise in Marfan's Syndrome and its impact on other connective tissues
Impact Multiple scientific papers published: doi:10.1016/j.exer.2020.108001; doi: 10.1167/iovs.16-21358. Several other papers under review and in preparation. Phil Lewis and Keith Meek hosted a visiting scientist from Sao Paulo for 1-month in 2020, providing them with training in advanced electron microscopy data collection and image techniques. Electron microscopy data was collected from multiple connective tissues in the Marfans syndrome mouse model and the work is currently being written up for publication (Title: Changes of Extracellular Matrix and Vascular Dynamics in Kidney in Marfan syndrome model).
Start Year 2016
 
Description Prof Jinhai Huang - Fudan University 
Organisation Fudan University
Country China 
Sector Academic/University 
PI Contribution Keith Meek and Sally Hayes are co-authors on two draft publications with Prof Jinhai Huang, having both provided critical appraisal of the laboratory research and assisted in the drafting of the manuscripts. Keith Meek has been made a Guest Professor at Fudan University.
Collaborator Contribution Dr Jinhai Huang's research team have performed laboratory investigations into novel corneal therapeutics and have drafted two manuscripts on which Sally Hayes and Keith Meek are co-authors.
Impact Keith Meek appointed Honorary Guest Professor at Fudan University Jinhai Huang appointed as an Honorary International Advisor to the UK-Corneal Crosslinking Consortium on the subject of rose bengal cross-linking.
Start Year 2021
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation Moorfields Eye Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation NHS Bristol
Department Bristol Eye Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation Royal Liverpool University Hospital
Department St. Paul's Eye Unit
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation Singleton Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation St Thomas' Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description UK Cross-linking (UK-CXL) Consortium 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution We set up the consortium in 2013 and Sally Hayes continue to manage it.
Collaborator Contribution The aims of the consortium are: (1) to provide a forum for ophthalmologists and vision scientists to develop research collaborations and co-ordinated multi-centre studies, (2) establish a code of best practice for corneal cross-linking in order to standardise the treatment and its measurement outcomes and (3) provide information and advice to national bodies about developments in corneal cross-linking. The consortium currently comprises 63 UK-based ophthalmologists, optometrists and vision scientist members committed to achieving these aims. The founders of the cross-linking treatment also serve as honorary international advisors to the Consortium.
Impact 1. Hosted the UK Cross-linking conference, Birmingham, 2016 2. Developed a National Keratoconus Database for the recording of cross-linking outcomes 3. Collaborative multidisciplinary publications (biophysics and ophthalmology): doi: 10.1167/iovs.17-22994.; doi: 10.1016/j.exer.2016.10.014. 4. 4. Sally Hayes submitted a letter to Health Technology Wales on behalf of the UK Cross-linking Consortium, providing evidence of the cost-effectiveness of corneal cross-linking. Sally was subsequently invited to serve as an independent, external expert reviewer for the Health Technology Wales (HTW) Evidence Appraisal Review of 'Clinical and cost effectiveness of epithelium-off corneal crosslinking to treat adults and children with keratoconus' to provide feedback on their report. She was also invited to attend the HTW Appraisal Panel Meeting (March 2021) to assist the panel in reaching an informed decision. In May 2021 HTW announced their decision to support the provision of corneal cross-linking on the NHS in Wales. The support of the UK-CXL Consortium was also acknowledged in HTW report.
Start Year 2013
 
Description Veni Vidi 
Organisation Veni Vidi
Country United Kingdom 
Sector Private 
PI Contribution Corneal cross-linking research and the writing of scientific publications
Collaborator Contribution no charge supply of multiple vials of riboflavin and the donation of one travel grant
Impact multiple publications on cross-linking: doi: 10.1016/j.exer.2016.10.014. doi: 10.1167/iovs.15-18769. doi: 10.1016/j.jcrs.2015.10.004.
Start Year 2012
 
Description 'Science in the Kitchen - Eyeball Biscuits' for Cardiff Science Festival 2022 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Sally Hayes and Sian Morgan developed and recorded an engagement activity for Cardiff Science Festival 2022 (19-22 Feb) called 'Crafty Eyes' which featured 'Science in the Kitchen - Eyeball Biscuits' and 'Origami Eyes'. The recording consisted of a step-by-step demonstration for making eyeball biscuits and contained educational content about the important structures of the eye and how damage to these important structures can lead to vision loss. It was followed by a demonstartion of how to make origami eyes with a focus on the role of the cornea in good eye sight. The video was released as a YouTube premier on the Cardiff Science Festival YouTube channel on 21st Feb and was later made available to all via their youtube channel: https://www.youtube.com/watch?v=g9pZjyNJBOk
The video received over 475 views in the first 3 weeks after release and received positive feedback from viewers saying that it was engaing and informative.
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=g9pZjyNJBOk
 
Description Contribution to Vision Bridge (Julian Jackson) 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Keith Meek contributed to the "Eye research - an equal partner" report (published in 2019) with a section named 'Latest developments in sight-saving corneal therapies'. The report attracts thousands of views via www.visionbridge.org.uk and has helped to spread the word about eye research across membership organisations, trade media, patient support groups, social networks and associations across the UK.
Year(s) Of Engagement Activity 2019
URL http://www.visionbridge.org.uk
 
Description Demonstration of ocular defects activity to A-level students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Sally Hayes demonstrated the 'Ocular defects activity' to 500 A-level students attending Science Health Live (Cardiff University). The students were encouraged to try on a range of spectacles that simulate different ocular pathologies and were told about the corneal research programme at Cardiff University.
Year(s) Of Engagement Activity 2020
 
Description Eye dissection you tube video 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Sian Morgan and Sally Hayes recorded a demonstration of an eye dissection and used it to describe the important structures of the eye, what can go wrong in various conditions and the ongoing work at Cardiff University to try and cure sight problems. The video is available on the Cardiff University Centre for Education and Innovation Youtube Channel. The video has received 20 views in the last 2 weeks since its release.
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=gY1TmhxGxjk
 
Description Health Technology Wales External Expert 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Corneal cross-linking remains unavailable on the NHS in Wales, despite it having been available in England, Scotland and North Ireland for many years. On behalf of the Welsh Government, Health Technology Wales are currently undertaking a review of corneal cross-linking cost-effectiveness on the NHS in Wales. Sally Hayes was invited by Health Technology Wales to be an external expert on corneal cross-linking, providing input into their report and discussions. The decision-making meeting to decide whether or not HTW recommend CXL provision on the NHS in Wales was due to take place in Jan 2021 but has been postponed due to COVID.
Year(s) Of Engagement Activity 2020,2021
 
Description More than meets the eye - Cardiff Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Sally Hayes and Sian Morgan ran two x 30-minute 'live' and interactive public engagement sessions titled 'More than Meets the Eye' at the Cardiff Science Festival on Thursday 18th and Saturday 20th Feb 2021. The activity featured fun facts about the eye (in particular the cornea and disorders of the cornea), optical illusions and provided an opportunity for the public to have their eye related questions answered. https://www.cardiffsciencefestival.co.uk
69 people signed up for the event and it was attended by 50, mostly young families. The session prompted a lot of positive feedback which was evidenced in a mentimeter survey, with participants scoring the session as follows: 4.7/5 for fun, 4.9/5 for interesting and 4.1/5 for 'I know more about the eye than I did before'.
Following on from the success of this event, we have had more requests from local primary schools to deliver the activity virtually during term time.
Year(s) Of Engagement Activity 2021
URL https://www.cardiffsciencefestival.co.uk/en/events
 
Description More than meets the eye - Primary school event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Sally Hayes and Sian Morgan delivered a live lesson/engagement activity titled 'More than Meets the Eye and Eye Origami' to two local primary school in Feb/March 2021 (audience of 30 at each event). A competition was held for the creation of the most realistic origami eye and the most fantastical origami eye.
Year(s) Of Engagement Activity 2021
 
Description Q and A for secondary school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Dr Hayes was asked to do a Q and A session with a secondary school student (13 years-old) from Bristol to talk about her life as a scientist and her current research on the cornea. The student was enthused by session and felt inspired to become a scientist! The student presented the Q and A session to her 60-pupil year group as part of a presentation on Women in STEM for British Science Week.
Year(s) Of Engagement Activity 2021
 
Description STEM for Britain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Sian Morgan particpated in Stem for Britain 2021 and presented her research on 'enhanced drug delivery methods to target corneal disease' to the Houses of Parliament. She was announced winner of the Bronze Award. STEM for Britain is a major scientific poster competition which has been held in Parliament since 1997 and is organised by the Parliamentary and Scientific Committee to provide both Houses of Parliament with an insight into the outstanding research being undertaken in UK universities by early-career researchers.
Year(s) Of Engagement Activity 2021
URL https://stemforbritain.org.uk/stem-for-britain-biological-and-biomedical-sciences-exhibition/
 
Description Sight Cymru Megafocus meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Third sector organisations
Results and Impact Sight Cymru is an independent charity that aims to help people with sight loss in Wales, prevent unnecessary sight loss, support Welsh authorities and health boards in providing excellent rehabilitation services, train professionals, carers, service users, friends and family, provide advice to develop the eye-care sector throughout Wales. Sally Hayes was invited to present at the Sight Cymru Megafocus (Minority Ethnic Group Association for Ophthalmic Care Uptake and Service Improvement in Wales) virtual meeting on 27th November 2020 to provide the committee with an update on the status of corneal cross-linking in Wales and our current research into keratoconus and corneal cross-linking. The 9 attendees at the meeting comprised optometrists, an ophthalmologist, charity and lay members.
Year(s) Of Engagement Activity 2020
 
Description work experience for A-level student 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Keith Meek and Sally Hayes arranged a days work experience for an A-level student from a local school. The student was taken to Diamond Light Source for a tour of the synchrotron light source and the neutron scattering facility (ISIS). The student was introduced to several beamline scientists and gained first-hand experience of x-ray scattering data collection from corneal tissue.
Year(s) Of Engagement Activity 2019