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Advances in treating corneal disease

Advances in corneal research and development are shifting the landscape, potentially making transplantation of donor corneas – and even corneal surgeons – obsolete in future. RHIANNON BOWMAN investigates the homegrown projects leading the way.

Disease and damage to the cornea is a leading cause of blindness globally but remarkably only one donor cornea is available for every 70 needed.

Transplantation with corneal graft tissue has been the mainstay for treating corneal blindness, but a global shortage and rejection issues continue to expose the need for more advanced treatment options, even in developed countries like Australia.

Studies show corneas are procured in approximately 82 countries, with only a few exporting them in large numbers. About 53% of the world’s population have no access to corneal transplantation.

Australia is at the forefront of improving surgical techniques and developing innovations that might quell current demands on eye banks and offer more reliable, personalised and affordable solutions to a greater number of patients.

These include intricate devices that enable more ophthalmologists to perform the most complex procedures, new bioengineered corneas and materials that mend corneal wounds otherwise destined for transplant surgery.

Four leading experts share their perspectives on advances in this field, including the director of one of Australia’s largest providers of donated eye tissue who provides an update on the current donation landscape and new pressures caused by COVID-19.

Simplifying complex procedures

Ophthalmic surgeon Professor Mark Daniell is head of corneal services at the Royal Victorian Eye and Ear Hospital and leads the Centre for Eye Research Australia’s (CERA) corneal research unit.

With Daniell at the helm, CERA has begun engineering corneal tissue in the laboratory for transplantation, which could help millions of people regain their sight.

While transplantation of donor tissue is common in Australia and the US, there is a major shortage of donor tissue elsewhere, leaving an estimated 6.5 million people without access to a transplant operation.

In response to the global shortage, the team has successfully grown cells from donated corneal tissue and is now working on creating corneal cells out of stem cells taken from blood or skin. Daniell says with the development of tissue-engineered cornea, the next stage will be using the patient’s own cells to amplify them.

In addition to gene and cell therapy solutions, CERA’s corneal unit recently received half a million dollars in medical research funding to fast-track development of CorGel, an ultra-thin hydrogel film that is used to insert donor corneal tissue to restore vision.

The grant will support 18 months of preclinical work to refine and test CorGel before progressing to a clinical trial and the first human study.

Daniell says the device was borne out of a challenge associated with Descemet’s Membrane Endothelial Keratoplasty (DMEK) surgical technique, which replaces only the endothelium layer. DMEK procedures have better patient outcomes but is surgically more complex because the graft membrane tends to scroll up when inserted into the eye. CorGel overcomes this by acting like a ‘scaffold’ which is attached to the transplant to keep the donor corneal tissue flat when it is inserted into the eye.

“We’re looking at endothelial transplants and the best way to do those. Japanese researchers are transferring endothelial cells from the lab into the eye by injecting cells into the eye. We’ve found it’s better to attach endothelial transplant cells to a scaffold. Trials indicate the scaffold has nice properties and handling during surgery,” he says.

The CorGel device has the potential to make DMEK surgery the default endothelial corneal transplant method globally due to being more efficient and with better outcomes.

The CorGel device also aims to simplify the surgery so any anterior segment surgeon can perform it.

Last year a study of a new wet lab model of DMEK using human corneas mounted on an artificial anterior chamber with an artificial iris aimed to compare the performance time and scores between beginners and experienced anterior segment surgeons.

It found the DMEK wet lab model offers a close to reality, feasible, resource-sparing and valid teaching technique that allows all DMEK surgical steps to be performed. It also offers the possibility of varying the surgical difficulty by changing the anterior chamber depth.

Endothelial keratoplasty is a hotbed of research activity, Daniell says, and some developments could change the need for a corneal transplant altogether.

Promising research shows Descemet’s stripping only – or Descemetorhexis without endothelial keratoplasty (DWEK) – can improve visual acuity in early to intermediate stage Fuchs’ endothelial corneal dystrophy, without corneal transplantation.

“DWEK strips the diseased endothelium, allowing it to heal with healthy cells re-growing over that area. This procedure could change the need for corneal transplant,” Daniell says.

Cultured human corneal endothelial cells as a tissue engineered endothelial graft (TEEK), human corneal endothelial cells (hCECs) injection therapy, iPSC converted to CEC, and bioengineered corneal stroma to treat keratoconus, stromal scarring and stromal dystrophies are amid the troves of research taking place into corneal disease, he says.

Bowman layer transplantation and artificial intelligence to treat keratoconus are also among the corneal disease research Daniell is interested in.

“Artificial intelligence is being utilised in patients with keratoconus for early diagnoses, prediction of progression, and corneal topography with Pentacam, in corneal cross-linking,” Daniell says.

Gene therapy is another area of growing interest, he says, unlocking its potential to treat Fuch’s endothelial dystrophy and corneal stromal dystrophies without a transplant.

The I-CAN study in 2014 showed that aganirsen eye drops significantly inhibited corneal neovascularisation in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularisation.

The possibilities seem endless.

Corneal biopen rewrites conventional treatment

Vision Eye Institute consultant Professor Gerard Sutton is one of Australia’s leading ophthalmic surgeons and is internationally recognised as an expert in corneal transplantation.

Sutton’s affiliations include Professor of Clinical Ophthalmology and Eye Health at The University of Sydney, Save Sight Institute; Medical Director at NSW Eye & Tissue Banks, Australian Ocular Biobank; Professorial Fellow Australian Institute for Innovative Materials, University of Wollongong; and Sydney Eye Hospital Foundation Board Member.

He was the first Australian surgeon to perform corneal transplantation with the femtosecond laser, and the first to successfully use an artificial cornea in New South Wales.

With a strong research interest in corneal bioengineering, Sutton is currently involved in a number of projects that have the potential to make a significant difference in corneal disease and reliance on donor corneas.

“My research is part of a well-organised collaboration with Lions NSW Eye Bank, the Save Sight Institute at the University of Sydney, and the Intelligent Polymer Research Institute at the University of Wollongong. This structure joins together scientists, surgeons and eye bankers. Undertaking research can be a challenging, torturous regulatory pathway, so this set up means a pipeline is already established,” Sutton says.

The collaboration has close ties with iFix Medical, an Australian medical device company commercialising innovative technology and products for ophthalmologists to better manage and treat corneal disease, corneal repair and corneal transplantation.

One of their most advanced projects which Sutton is working on is the development of a corneal biopen, known as the iFix System, to treat corneal ulceration. The device won Sydney’s Big Idea Innovation Award in 2017, receiving seed funding to reach the next stage of commercialising the device. Further funding followed when the device was awarded $1.15 million in the 2018 NSW Medical Devices Fund.

The iFixPen is a hand-held device that delivers a 3D-printed structure directly onto corneal defects.

According to the product website, the iFix System has two components: iFixPen and the iFixInk. The iFixPen is a hand-held device that delivers a 3D-printed structure directly onto corneal defects. The patent-pending iFixInk creates a completely transparent and biodegradable structure to seal the wound, better preventing infection, relieving pain and accelerating healing.

Sutton says the team has completed animal trials and is preparing to conduct human trials.

He is also involved in developing a bioengineered cornea and supporting collagen fibres with the University of Wollongong’s ARC Centre of Excellence for Electromaterials Science. This cornea overcomes common issues like durability by using an electro-compaction technique that maintains excellent and critical optical properties.

“Millions of people don’t have access to donor corneas. The donor system is flawed internationally. A bioengineered cornea made or modified from a patient’s own cells would be superior to our current options,” Sutton says.

“The whole concept of bioengineering is taking off around the world. Cell-based therapy and growing cells in the lab is also an area of research moving along,” Sutton says.

The Australian and New Zealand Corneal Bioengineering working group (ANZCorBio), which Sutton and Professor Daniell are both members of, held their first face-to-face meeting in Sydney last year and were due to meet again in November.

Sutton says among the key speakers were a New Zealand group led by Associate Professor Trevor Sherwin and his colleagues at The University of Auckland who have been trying to determine if an eye drop can permanently stabilise and reshape the cornea, and thus provide treatment for condiitons like keratoconus.

Having completed animal trials, Sutton says the eye drop is yet to go in front of an ethics committee to be approved for human trials but it is hoped ingredients of the formulation – which have previously been used in other clinical trials – will speed up the approval process.

The next step after human trials would be to treat end-stage keratoconus patients in order to help them avoid a corneal graft. Following that, the treatment could be applied to patients with earlier disease, to help reshape and ‘freeze’ the cornea in the new shape.

“Corneal cross-linking has been around for a while, and although it’s terrific, it’s not perfect. Newer versions of cornea endothelial transplant, such as treatments devised by Professor Noriko Koizumi from Doshisha University in Japan, mean more options for patients, and an eye drop treatment means less surgery. With these new developments, it’s possible that in my working lifetime corneal surgeons will become extinct and we can prevent corneal disease developing and reduce the need for corneal transplant,” Sutton says.

“For patients, that means more accessible treatment, less expense and quicker recovery.”

Corneal adhesive to reduce demand on donor system 

Associate Professor Chameen Samarawickrama, from the University of Sydney’s Faculty of Medicine and Health and The Westmead Institute for Medical Research, has helped develop and perform preclinical testing of LiQD Cornea, an adhesive liquid that mends damaged corneas.

Currently, corneal perforation from infection or inflammation is sealed with cyanoacrylate glue. However, the resulting cytotoxicity means that without follow-up corneal transplantation, sight could be lost.

“Corneal perforation from trauma or infection is painful. The current treatment strategy is to seal the wound using glue to buy time to treat the infection and inflammation, but the glue is not a perfect solution. It causes scarring, and often blood vessels grow in, decreasing vision. If the hole is in the periphery, it may not affect vision, but if the hole is in their central vision, they need a transplant to restore vision” Samarawickrama says.

He says Australia is a powerhouse of corneal research, meaning funding applications are a highly-competitive process.

“Funding can be difficult to secure and it’s a time-consuming task. Last year I was fortunate to secure National Health and Medical Research Council funding for LiQD Cornea but a common response I receive from funding bodies is that although the device is both interesting and fundable, there is a limited amount of funding to go around,” Samarawickrama says.

He was the only successful applicant in Australia to secure a NHMRC Investigator Grant for funding commencing in 2020 for cornea research, valued at $366,925.

Samarawickrama says one reason why there’s so much corneal research activity is because surgeons don’t yet have an adequate treatment option for corneal perforations that doesn’t rely on transplantation, a problem exacerbated by the current shortage of donor corneas.

“There are about 4,300 corneal perforations on average in Australia each year. There isn’t any global data on perforations but approximately 1 in 70 who need a transplant get one. The other 69 have no choice but to endure poor vision,” Samarawickrama says.

“If we can treat corneal perforations so patients don’t need a transplant, those who need a transplant for other corneal diseases can get one. Our aim with LiQD Cornea is therefore two-fold: offer a better treatment for a problem that already exists, and eliminate the need for a transplant so that limited resources [donor corneas] can be diverted to others who genuinely need it.”

LiQD Cornea is a cell-free, liquid hydrogel matrix for corneal regeneration. It comprises short collagen-like peptides conjugated with polyethylene glycol and mixed with fibrinogen to promote adhesion within tissue defects.

“Cornea surgeons have a specific skill set but with LiQD Cornea we wanted to develop a device that could be used by a general ophthalmologist. You don’t need advanced surgical skills to squeeze a syringe onto the eye. It is purposefully designed so any ophthalmologist can use it safely.”

Five years into development, LiQD Cornea has been successfully tested in animal models, with developers now looking towards next steps to get approval for human trial.

“LiQD Cornea is a collagen-based glue because the cornea is predominantly collagen. Collagen is the native ingredient. Animal-testing demonstrated the cornea maintained clarity and didn’t become inflamed, with no scarring or vascularisation. LiQD Cornea bio-integrates into the eye; simplistically this means that we are achieving corneal regeneration,” Samarawickrama says.

“The next step is meeting the TGA’s Good Manufacturing Practice (GMP) codes for the authority to proceed with human trials. We’ve completed one animal trial but we need to complete a second one, although with COVID affecting research, it might end up being next year.”

Australian eye bank update

Qualified in pathology and holding a PhD in surgical medicine, Dr Graeme Pollock established the Lions Eye Donation Service (LEDS) in 1991 and has never left. Now director, he has more than 30 years’ knowledge of the statistics and science behind corneal transplant. He works closely with Professor Daniell who is medical director of LEDS.

LEDS is one of Australia’s largest providers of donated eye tissue for transplant and medical research. It is a collaboration between CERA, The Royal Victorian Eye and Ear Hospital, the University of Melbourne, and supported by the Lions Clubs.

“[In 2019] there were 1,498 eye donors in Australia and surgeons performed 2,385 transplants. Australia is one of the few countries that supplies donor corneas to other counties; for instance, LEDS supplies donor corneas to New Zealand, so the number of corneas provided by Australia eye banks is even larger than just the Australian figures,” Pollock says.

The 2020 statistics will look markedly different with coronavirus making those who tested positive unable to donate.

“[In 2020] we’ve had a decrease in donations but this is not due to ruling out a large percentage of the population because they have had COVID-19. Lockdowns have put pressure on donor referral systems out of hospitals, and those referral systems rely on staff having donation front-of-mind.”

Pollock says the organ donor consent rate has also decreased.

“Bereavement is complicated and difficult at the best of times, but more so during COVID-19 with restrictions on travel and funeral numbers making it even more difficult for families to make a decision on donating organs and tissues.”

Although there has been a marked drop in cornea donations, there have also been fewer transplant surgeries.

“A large percentage of corneal transplants are elective. There has been less demand for donor corneas than usual, but it varies depending on which state you’re in. For example, elective surgery in Victoria is operating at about 75% of normal demand (at the time of writing), so any increase in donations is not reflected in transplants not being done,” Pollock says.

Donor corneas can be stored for up to 30 days.

Donor corneas can be stored for up to 30 days using an organ culture storage technique LEDS adopted in 2005, extending the previous seven-day storage life using refrigeration. Pollock says the time between LEDS receiving a donated cornea and releasing it for transplant is 14 or 15 days on average.

While the storage window has increased, prolonging opportunities, other developments are shaping the future of eye banks.

“We’re seeing the number of patients needing a transplant for keratoconus reducing, and cross-linking is playing its part in that,” Pollock says.

“Simultaneously, we’re seeing a growing number of transplants for other reasons; Keratoconus used to be the most common reason for requiring a donor cornea in Australia – but now it’s Fuch’s dystrophy.”

He says different corneal transplant techniques that have emerged in the past 10 to 15 years, such as DMEK and DSEK, have changed the donor landscape.

“Since doing that type of transplant for Fuch’s Dystrophy, patient recovery is much better, compared to recovery from a full thickness transplant. Because patient recovery and visual outcomes have improved with endothelial keratoplasty techniques, more patients with Fuch’s dystrophy are undergoing corneal transplant,” Pollock says.

“Over the last 10 years the demand for corneas for transplantation has more than doubled. This is largely driven by newer techniques which provide added benefit.”

Pollock predicts there won’t be significant change to corneal transplants in the next five years and expects current trends to continue with more endothelial keratoplasty. He says almost 75% of all transplants are now DSEK or DMEK.

Looking further ahead, he believes stem cell therapy is the next big thing.

“Successfully growing endothelial cells could negate the need for donor corneas,” he says. “There is limited ability to culture those endothelial cells other than injecting into the anterior chamber.”

A pilot clinical examination recently conducted in Japan researched the viability of a cell‐infusion treatment for patients with bullous keratopathy.

“That’s the direction it’s going in. Evidence-based literature is coming out from that technique but those studies haven’t involved large numbers,” Pollock says.

“It’s still some way off being a routine type of therapy, but I suspect eye banks will evolve from being transplant tissue service providers into cell therapy service providers.”