Bio-synthetic corneal endothelial grafts for transplantation
Lead Research Organisation:
University of Liverpool
Department Name: Eye and Vision Sciences
Abstract
Corneal transplantation is the most frequent type of transplantation with over 180,000 performed each year. There is a global shortage of corneas with only one available for every 70 required and more than 12 million people on a waiting list for a transplant. Researchers are developing ways to increase the number of patients that can be treated from just one donor. This project aims to do that by combining corneal cells with an innovative biomaterial to create a biosynthetic corneal graft. The major advantage being that one donor cornea could potentially create more than 30 grafts.
Diseases of the corneal endothelium, such as Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK), result in significant loss of vision and are the commonest reasons for corneal transplantation. Damage to this endothelial layer of the cornea leads to swelling and thus loss of transparency. Replacement of the endothelial layer with a corneal transplant reduces the swelling and restores transparency. Although corneal transplantation is more than 80% successful at 1 year, after 5 years 30% of people with FECD and 48% of people with PBK may require a second transplant due to failure of their first graft.
We have developed a peptide based hydrogel with excellent optical and physical properties that can be tuned depending on the particular application. We have data that show corneal endothelial cells adhere and divide, increasing in number on the surface of the hydrogel to produce a layer of cells that look and behave very similarly to those in a healthy cornea. This graft also has the physical strength to be manipulated for transplantation using surgical tools that a corneal surgeon would use on a patient. This graft also functions to reduce corneal swelling and restores transparency in a rabbit model of endothelial failure.
This project will develop our new bio-synthetic graft along the translational pathway towards the clinic. We aim to do this by changing the hydrogel manufacture method to allow production of thinner hydrogels, optimising the method to culture the cells for clinical use and evaluating the safety and efficacy of these optimised grafts in a rabbit model.
Diseases of the corneal endothelium, such as Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK), result in significant loss of vision and are the commonest reasons for corneal transplantation. Damage to this endothelial layer of the cornea leads to swelling and thus loss of transparency. Replacement of the endothelial layer with a corneal transplant reduces the swelling and restores transparency. Although corneal transplantation is more than 80% successful at 1 year, after 5 years 30% of people with FECD and 48% of people with PBK may require a second transplant due to failure of their first graft.
We have developed a peptide based hydrogel with excellent optical and physical properties that can be tuned depending on the particular application. We have data that show corneal endothelial cells adhere and divide, increasing in number on the surface of the hydrogel to produce a layer of cells that look and behave very similarly to those in a healthy cornea. This graft also has the physical strength to be manipulated for transplantation using surgical tools that a corneal surgeon would use on a patient. This graft also functions to reduce corneal swelling and restores transparency in a rabbit model of endothelial failure.
This project will develop our new bio-synthetic graft along the translational pathway towards the clinic. We aim to do this by changing the hydrogel manufacture method to allow production of thinner hydrogels, optimising the method to culture the cells for clinical use and evaluating the safety and efficacy of these optimised grafts in a rabbit model.
Technical Summary
Diseases of the corneal endothelium, such as Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK), result in significant loss of vision and are the commonest reasons for corneal transplantation. Damage to this endothelial layer leads to oedema and thus loss of transparency. Replacement of the endothelial layer with a corneal transplant reduces the oedema and restores transparency. Although corneal transplantation is more than 80% successful at 1 year, five-year graft survival rates are significantly reduced to 70% for FECD and 52% for PBK, meaning that patients often require a second transplant. There is a global shortage of corneas with only one available for every 70 required, therefore, there is an opportunity to combine biomaterials with in vitro expanded corneal endothelial cells (CECs) to produce multiple bioengineered grafts from each donor cornea. These biomaterials not only serve as a carrier for CEC transplantation but may also enhance cell function to increase the long-term success of transplanted grafts.
We have developed a poly-epsilon-lysine based hydrogel with excellent optical and mechanical properties that can be controlled by the nature and percentage of the cross-links and the density of the peptide. We have data that show primary CECs adhere and proliferate on the surface of the gel to produce a confluent monolayer and that this graft has the physical integrity to be manipulated for transplantation using a clinical delivery device. Furthermore, the graft functions to restore corneal thickness and transparency in an in vivo rabbit model of endothelial failure.
This study will develop our technology along the translational pathway by improving the crosslinking method to reproducibly allow production of thinner hydrogels, optimising the manufacture to allow scale up and culture of human CECs in a GMP aligned protocol and evaluating the safety and efficacy of these optimised grafts in an in vivo rabbit model.
We have developed a poly-epsilon-lysine based hydrogel with excellent optical and mechanical properties that can be controlled by the nature and percentage of the cross-links and the density of the peptide. We have data that show primary CECs adhere and proliferate on the surface of the gel to produce a confluent monolayer and that this graft has the physical integrity to be manipulated for transplantation using a clinical delivery device. Furthermore, the graft functions to restore corneal thickness and transparency in an in vivo rabbit model of endothelial failure.
This study will develop our technology along the translational pathway by improving the crosslinking method to reproducibly allow production of thinner hydrogels, optimising the manufacture to allow scale up and culture of human CECs in a GMP aligned protocol and evaluating the safety and efficacy of these optimised grafts in an in vivo rabbit model.
Publications
Parekh M
(2022)
Delivering Endothelial Keratoplasty Grafts: Modern Day Transplant Devices.
in Current eye research
Description | HLS Capital Equipment Fund |
Amount | £55,888 (GBP) |
Organisation | University of Liverpool |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2023 |
End | 01/2023 |
Description | Good manufacturing practice protocol development |
Organisation | NHS Blood and Transplant (NHSBT) |
Country | United Kingdom |
Sector | Public |
PI Contribution | We have been engaging in knowledge transfer with the NHSBT at their research site in Barnsley. They are developing a GMP protocol for the culture of our human corneal endothelial cells for our clinical product. We have been sharing protocols that we have developed together with our partners at Singapore Research Eye Institute for the culture of the cells. |
Collaborator Contribution | NHSBT have been developing the protocols based on UK and EU legislation for ATMP manufacture. They have used their expertise in Cell therapy manufacture to create our Batch manufcaturing record and refined our protocol to make it suitable for manufacture in grade B clean rooms. |
Impact | No outcomes currently but we will aim to publish a protocol for teh manufacture of cells in the UK. |
Start Year | 2021 |
Description | UK Regenerative Medicine Platform Network (UKRMP) |
Organisation | UK Regenerative Medicine Platform |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We were invited to join the UKRMP2 Aceullar/Smart materials hub in 2022 after I received my MRC DPFS grant. We contributed to the eye workpackage by sharing our work on our biosynthetic corneal endothelial graft. I presented an update on our work at the UKRMP Materials hub meeting at Imperial in London in 2021 and my PDRA David Robinson presnted at the Univeristy of Nottingham in 2022. In 2023 I presented at the UKRMP final Showcase (all 3 hubs) in Edinburgh. We contributed data to the biannual progress reports. We hosted several students from other groups within the hub that came to our lab to learn techniques such as primary ocular cell culture. |
Collaborator Contribution | Through the UKRMP hub we were able to connect with another group that had a supercritical CO2 steriliser. One of our PDRAs was able to visit the lab and learn how to use this equipment. We have subsequenty purchased the same kit and are optimising it for the sterlisiation of our biomaterials. |
Impact | We contributed to the bi- annual progress reports which were submitted to the UKRMP2 funders for continued support for the relevamt workpackages. |
Start Year | 2022 |
Title | PEKMA Materials |
Description | The present invention relates to hydrogels, methods of making them, their use in the treatment of eye disorders and as bandage contact lenses. The present invention also provides modified poly-e-lysine polymers and methods of making them. |
IP Reference | GB2205071.0 |
Protection | Patent / Patent application |
Year Protection Granted | |
Licensed | No |
Impact | N/A Patent filed in April 2022 |
Description | Potential end users survey and video |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Explainer video and survey created and distributed to potential end user of the product (biosynthetic corneal endothelial graft) to guage their interest in using the graft as a surgeon for the patients or receiving it as a patient themselves. Provided useful information on what data we would need to provide before surgeons and patients would be on board. Highlighted thatour assumptions about long waiting times due to lack of tissue were correct. |
Year(s) Of Engagement Activity | 2022 |