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HomemistoryBeating Glaucoma: Australians Lead the Charge

Beating Glaucoma: Australians Lead the Charge

Australian ophthalmologists and researchers have made significant inroads into managing glaucoma. Professor William Morgan from Lions Eye Institute, University of Western Australia, was integral to the development of a microfistula tube, now known as the ‘XEN gelatin’ implant. Professor Minas Coroneo AO, University of New South Wales is the inventor of core patents for the Cypass suprachoroidal drainage device

Professors Morgan and Coroneo tell their stories about the development of these significant products, which are now being used globally to manage glaucoma.

XEN Gelatin: Evolution of a new Glaucoma Surgery

Prof. William Morgan


In 1995, Professor Dao-Yi Yu, a renowned ophthalmologist and researcher, proposed to develop a new form of glaucoma surgery. He led an innovative team at the Physiology and Pharmacology Centre and the McCusker Glaucoma Centre, Lions Eye Institute, the University of Western Australia. At the time, I was a PhD student studying pressure gradients in the optic nerve and Prof. Yu was my main supervisor. He prepared a patent (Yu and Morgan: Biological Microfistula Tube and Implantation Method and Apparatus AU#721915 (1996), PCT/AU97/00811 (1997), US patent #6544249) and invited me to be a co-inventor and join the project.

This project was to develop a minimally invasive surgical technique and a drainage implant that matched physiological conditions as much as possible. To achieve this goal, he developed a bioengineered implant using cross-linked gelatine to make a tiny stent called a microfistula. Additionally, he developed an ab-interno procedure via the anterior chamber avoiding damage to conjunctiva, and built a special implanter. The microfistula was to be injected across the trabecular meshwork, straddling the space between the anterior chamber and the conjunctival regions. Ideally, this would create a drainage bleb without damaging the conjunctiva or requiring scleral incisions.

We have to place this tiny tube in the right location, without damage to cornea or ciliary body and without touching the corneal endothelium or the iris in the angle

Developing the Microfistula and Implanter

The first step was to develop the microfistula and implanter. Developing the microfistula tube was a real challenge because it needed to be bio-compatible and small enough in size to match physiological resistance. It also needed to be semi-rigid when implanting, then soften and swell after implantation. We developed custom-built bench equipment and made thousands of implants using various gelatine cross-linking parameters, and did more than 400 test implantations in animals. Finally, we were able to meet all requirements and worked out how to adjust the cross-linking parameters to control the time of microfistula absorption in the eye.

At same time, Prof. Yu was working with a strong engineering team to build the implanter and manipulation system. We were fully aware that the microfistula had to be precisely placed in the right position, with consistent timing. To avoid possible variations made by the surgeon, we decided to use a motorised implantation and robotic manipulation and only one surgeon (Prof. Yu) did all the implantation surgery in animals. We effectively avoided surgical variations, which provided us an opportunity to identify the key parameters for improving the surgical outcomes. A motorised implanter with a controller and robotic system was specially built (Figure 1A and 1B). The motorised implanter allowed the implantation time to be adjusted to match the swelling of the microfistula tube during implantation.

Figure 1. The robotic manipulation system and motor controllers. A. Insert of a magnified view of the microfistula ready for implantation. B. An early version of the motorised hand held implanter.

To speed up the project, we invited Prof. Xinghuai Sun’s team (Eye & ENT Hospital, Shanghai, China) to join with our Perth team. This allowed extensive animal experiments with follow-up times as long as six years, and provided much new and important knowledge. We obtained valuable information regarding the biological compatibility and longevity of the cross-linked material in the eye. We also demonstrated that our concept and technique could be a safe, effective and minimally invasive surgery for glaucoma.

Overcoming Challenges

An interesting finding from the experimental studies was that even after a trouble free implantation, some blebs failed within two weeks. This led us to think about why there could be different outcomes, even with a good implantation.

It became clear there were some other factors playing an important role… we closely monitored the drainage channel and bleb after surgery and found the failure occurred in the conjunctiva. This meant that filtration surgery could fail, even when a perfect drainage channel was created from the anterior chamber to the conjunctiva. We knew this question had to be addressed because it is critical, not only for our microfistula surgery, but for any glaucoma filtration surgeries including trabeculectomy and other implants. We found that almost all long-term functional blebs had active lymphatic drainage. We attempted to place the microfistula tube in locations rich in lymphatics and achieved functional blebs lasting more than six years in animals, that is the longest longevity reported. The longevity of the functional blebs in animals with active lymphatic drainage is at least six times longer than that without lymphatic drainage. Critically, we had discovered the important roles of the conjunctival lymphatics in the outcome of glaucoma filtration surgery. Our discoveries were published in Progress in Retinal and Eye Research, the highest ranking journal in ophthalmology. All the authors in this paper contributed their best efforts to make a success of this project. We also acknowledge the people from the engineering team who made remarkable contributions. This project could not have succeeded without them!

Moving to Commercialisation

After 10 years of hard and successful work, we wished to translate our experimental study to clinical application through commercialisation. In 2006, the Lions Eye Institute, who owned the patents, negotiated with The Innovation Factory, a US based incubator to setup a start-up company, AqueSys in California to purchase exclusive rights to the patents in agreement for certain milestones in terms of the development of the system. Prof. Yu’s team has transferred all their techniques, information and knowledge to AqueSys, and helped them to get substantial funding from venture capitalists. His team was also a part of the subsequent international clinical trial across seven countries.

A significant achievement by AqueSys was to convert the lab-based microfistula manufacturing procedure to an industrial scale, machine based procedure, that allowed the finished product to be standardised. Prof. Yu provided Aquesys with details of the step-by-step procedures and cross-linking protocols for making a long lasting microfistula in the living eye. His team tested the important parameters in lab bench and animal studies to ensure quality standards. Aquesys named the microfistula tube the ‘XEN gelatin’ implant. The company improved the hand held motorised implanter and ran international multiple centre clinical trials, then made continuous improvements to the implanter systems, finally arriving at a hand operated disposable product.

We wish to acknowledge all the ophthalmologists who contributed their clinical experience and knowledge, particularly in providing valuable suggestions throughout this project. Prof. Yu analysed all patients from the clinical trial and determined the optimum procedures to achieve the best outcomes. We learned that although this procedure appears ‘simple’, in reality it is far more complex. We have to place this tiny tube in the right location, without damage to cornea or ciliary body and without touching the corneal endothelium or the iris in the angle. The distal end of the microfistula needed to be placed in the superficial layer of Tenon’s capsule at a certain distance from the limbus.

First Human Procedure

We performed our first human microfistula procedure in 2007. I was particularly nervous about doing a novel procedure using novel material on a living patient of mine. Both Dao-Yi Yu and I wanted to watch this particular patient very closely for quite a few months before we embarked on more procedures in case there were problems. Fortunately, this particular patient, who had failed trabeculectomy before, did extremely well with a pre-operative pressure of 25 mmHg coming down to 8 mmHg and virtually remaining at 8 mmHg for the entirety of the follow-up period, which was three years. However unfortunately, that particular patient died of cardiovascular disease three years after surgery.

All of our early patients, bar one, had undergone previous glaucoma surgery, either trabeculectomy and/or Molteno tube surgery: and all bar two had undergone prior cataract extraction surgery. The rationale was that trabeculectomy was still the gold standard procedure and that patients who had not previously had trabeculectomy should be offered that primarily. Only when it had failed did we feel justified in offering this novel procedure.

We began to do more patients under a sponsored FDA Phase 1 and Phase 2 Study between 2009 and 2010, performing 23 procedures on 21 subjects (Figure 2). Following the success of the early studies, Aquesys enlarged the multicentre study to various centres in Europe and North America and concentrated on the major ophthalmic markets. The trial data was later accepted by the United States Food and Drug Administration. Full European CE certification was granted in 2014 and since then, more than ten thousand XEN implants have been performed in Europe. Full FDA approval was granted in the United States in 2016 followed by Canadian and New Zealand approval. In 2016, Allergan Inc. took over the manufacture, sales and distribution of the XEN gelatin microfistula. Recently, two-year data from a randomised multicentre study suggested that there is comparability in intraocular pressure outcomes between trabeculectomy and XEN microfistula insertion.

Figure 2. An implanted microfistula tube in the first human eye surgery, two years postoperatively. A. The conjunctiva shows a shallow bleb and looks healthy. B. The microfistula entering the angle of the eye.

Further Developments

To achieve the optimum outcome from each patient, we have to work to improve XEN-Microfistula surgery. Obviously, we urgently need to develop a non-invasive and label free imaging technique to help the surgeon find the optimum location for the XEN-Microfistula to be implanted, and then monitor the interaction between aqueous humour and lymphatic capillaries in the conjunctiva. Prof. Yu’s team is currently working with engineering teams to develop the required non-invasive conjunctival lymphatics imaging techniques.

Professor William Morgan is a consultant ophthalmologist at Royal Perth Hospital, consultant ophthalmologist at Princess Margaret Hospital, Professor at UWA and also Co-Director of LEI’s McCusker Glaucoma Centre. He has completed a doctorate in philosophy studying the response of the optic nerve to pressure, particularly in relation to glaucoma. He sees patients with glaucoma and other ocular conditions such as cataracts. Professor Morgan maintains an active research interest in glaucoma as well as in the epidemiology of blinding eye disease.


Development of the Cypass Micro-Stent

Prof. Minas Coroneo

My development of the world’s first supraciliary Minimally Invasive Glaucoma Surgery (MIGS), was triggered by two events in the early stages of my ophthalmology training.

These occurred back in the 1980s when, as a junior trainee in Sydney, I often worked weekends, night-shifts, and on-call.

At that time, indoor cricket had become popular, and it led to many eye trauma cases. One case of traumatic cyclodialysis in particular, made an impression; the low pressure was difficult to manage at a time when treatment options for glaucoma were relatively limited. I noted that cyclodialysis and the suprachoroidal space are a low-resistance pathway – if only it could be controlled. One of the cases in the cricket eye injury literature had been described by Australian ophthalmologist Arthur D’Ombrain,1 who had been the first to recognise traumatic glaucoma.2 I also attended a basic science course in New Zealand where I met Professor A.C. Molteno, the inventor of the Molteno glaucoma drainage devices and subsequently learned to implant these devices.

Recognising that the trabecular meshwork was likely to be the most sophisticated biological valve that had ever evolved, I went on to complete my doctorate on the electrophysiology of trabecular meshwork cells,3 confirming that there was more than one cell type in the angle, and that a population of trabecular meshwork cells was excitable and likely contractile.

I saw glaucoma as a ‘dismal’ subspecialty; despite technically perfect surgery, operations failed, patients’ vision often deteriorated, and the well-known treatment limitations and paradoxes led me to realise that I did not wish to be a glaucoma subspecialist. I continued research on central issues in glaucoma and developed an in vitro model for pressure-induced apoptotic cell death and means by which it could be blocked via TRAAK channels, which are pressure-sensitive cell membrane channels.4,5

Trypan Blue

Carrying out challenging cataract surgery in the Australian outback provided the stimulus for my first invention in ophthalmology—the use of trypan blue as a capsular and ocular dye. The first United States patents for VisionBlue were issued in 2002,6,7 and the product entered the market.8 This invention steered me toward cataract and refractive surgery and I became interested in how surgical techniques like phacoemulsifcation had revolutionised anterior segment surgery and how it even provided a safe intervention for narrowangle glaucoma.9 It dawned on me that glaucoma needed an equivalent to ‘phaco’ to create a similar revolution for glaucoma management. The case of traumatic hypotony resurfaced just at the time when the first intraocular lens that could be rolled into a cylinder less than 1mm in diameter, the ThinOptX (Abingdon, VA) intraocular lens (IOL),
was developed in 2002.10

My interest in ultraviolet light and the focusing of peripheral light by the anterior eye11 resulted in the development of a dysphotopsia-free intraocular lens12,13 and so I had a keen interest in intraocular lens technology. Whereas most people saw an IOL, all I could think of was that the optic could be ‘repurposed’, that is, connected to a tube and inserted atraumatically through a small side-port incision, transcamerally, into the suprachoroidal space. I obtained ThinOptX lenses, glued fine tubing to them (Fig. 3), and performed a series of experiments in perfused porcine eyes. A U.S patent was issued14 in 2007.

Figure 3. The Cypass Micro-Stent

In reviewing this area of research, it was apparent that following Leopold Heine’s15 landmark paper in 1905, describing cyclodialysis as a new operation for treating elevated intraocular pressure in uncontrolled glaucoma, many attempts have been made to take advantage of the suprachoroidal pathway to treat glaucoma.

The combination of improved biomaterials and surgical implant techniques, which largely evolved from advances in cataract surgery, has resulted in relatively minimally invasive, atraumatic implantation of micro-stents into both the angle and the suprachoroidal space. I termed this technique a minimally invasive glaucoma procedure.14

The technology was licensed to Transcend Medical (Menlo Park, CA) in September 2006, and the Cypass (‘ciliary bypass’) micro-stent was developed. I was employed by this company as a consultant and contributed to both the design evolution and the development of the surgical technique.

COMPASS Trial Data

In 2016 Alcon acquired Transcend Medical and its CyPass Micro-Stent platform. On 9 October 2017, Alcon presented data from the COMPASS clinical trial; the largest MIGS study to date with a two-year follow-up for more than 500 mild-to-moderate glaucoma patients undergoing cataract surgery. One new analysis shows that best-corrected visual acuity (BCVA) outcomes were similar between the control group and CyPass group at all time points through 24 months. Additionally, of those patients who achieved the primary endpoint (unmedicated mean diurnal IOP reductions ≥ 20 per cent), 93 per cent were not using ocular hypotensive medication at 24 months, as compared to 72.4 per cent of patients in the control group.

The device was developed and initially trialled to treat patients with mild to moderate primary open-angle glaucoma, in conjunction with cataract surgery. Three-year results from the CyCLE Study for Supraciliary Micro-Stent Implantation Combined with Cataract revealed that at three years postoperative, subgroups with controlled and uncontrolled IOP at baseline (<21 mmHg and ≥21 mmHg, respectively) had a higher proportion of subjects using no medications and a lower proportion of subjects using three or more medications compared to baseline. Additionally, at the 36-month postoperative examination, mean medicated IOP decreased by 8.1 mmHg in subjects with uncontrolled IOP at BL.16

In cases of suprachoroidal implantation, it appears that finally, a century after Heine’s work, a controlled cyclodialysis had been achieved. In a small way, with my contribution to the potential ‘phaco-like’ transformation of glaucoma surgery, it is hoped the outlook and practice in this area will be less dismal.

Minas Coroneo BSc(Med), MBBS, MSc, MD, MS, FRACS, FRANZCO, FARVO is Professor and Chairman, Department of Ophthalmology, University of New South Wales at Prince of Wales Hospital, New South Wales. Professor Coroneo is Chairman of the Look For Life Foundation and has an interest in the development of new technologies and ophthalmic devices. In 2016 Prof. Coroneo was appointed a Member in the General Division of the Order of Australia (AO) for his distinguished service to ophthalmology, research and development of innovative surgical technologies and devices, and commitment to eye health in regional and indigenous communities.

This article was adapted with permission, from chapter 11, Minimally Invasive Glaucoma Surgery (Thieme, www.thieme.com/books-main/ophthalmology/product/3947-minimally-invasive-glaucoma-surgery)


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2. Tumbocon JA, Latina MA. Angle recession glaucoma. Int Ophthalmol Clin 2002;42:69–78

3. Coroneo MT, Korbmacher C, Flügel C, Stiemer B,
Lütjen-Drecoll E, Wiederholt M. Electrical and morphological evidence for heterogeneous populations
of cultured bovine trabecular meshwork cells. Exp Eye Res 1991; 52:375–388

4. Agar A, Li S, Agarwal N, Coroneo MT, Hill MA. Retinal ganglion cell line apoptosis induced by hydrostatic pressure. Brain Res 2006;1086:191– 200

5. Coroneo MT, inventor. Methods for preventing pressure induced apoptotic neural cell death. Australian patent 2006236018. October 1, 2009

6. Coroneo MT, inventor. Methods for visualizing the anterior lens capsule of the human eye. US patent 6 367 480. April 9, 2002

7. Coroneo MT, inventor. Ophthalmic methods and uses. US patient 6 372 449. April 16, 2002

8. Coroneo M. Retrospective on staining with trypan blue. Cataract & Refractive Surgery Today. 2005;5:49–51

9. Roberts TV, Francis IC, Lertusumitkul S, Kappagoda MB, Coroneo MT. Primary phacoemulsifcation for uncontrolled angle-closure glaucoma. J Cataract Refract Surg 2000;26:1012–1016

10. Callahan WB, Callahan JS, inventors. Deformable intraocular corrective lens. US patent 6 096 077. August 1, 2000

11. Coroneo M. Ultraviolet radiation and the anterior eye. Eye Contact Lens 2011;37:214–224

12. Coroneo MT, Pham T, Kwok LS. Off-axis edge glare in pseudophakic dysphotopsia. J Cataract Refract Surg 2003;29:1969–1973

13. Coroneo MT, inventor. Treatment of photic disturbances in the eye. US patent 7 217 289. May 15, 2007

14. Coroneo MT, inventor. Ocular pressure regulation. US patent 7 291 125. November 6, 2007

15. Heine L. Die Cyclodialyse, eine neue glaukomoperation. Dtsch Med Wochenschr 1905;3:824–826

16. www.alcon.com/news/media-releases/alcon-presents-new-data-cypass-micro-stent-patients-mild-moderate-primary-open