Press Releases & Archive

SINGAPORE EYE RESEARCH INSTITUTE OCULAR STEM CELL RESEARCH

The human eye contains adult stem cells which are essential to vision. Over the last few years, research efforts have been made to identify the exact location of these stem cells in order to treat corneal and retinal diseases which arise from damage or loss of these stem cells due to injury or ageing.

The Surface of the Eye contains Corneal and Conjunctival Stem Cells
The major advances have been in corneal stem cells, and we now know that stem cells are located around the edges of the human cornea, an area known as the Limbus. These Limbal Stem Cells (LSCs) are responsible for constantly producing the outermost layer of cells of the cornea, a layer known as the corneal epithelium, throughout life, and the layer is a vital structure keeping the cornea clear and transparent, thus allowing us to see. This corneal epithelial layer is only one of 2 epithelial layers on the surface of the eyeball, the other epithelial layer being the Conjunctiva, which is a cell surface covering the sclera, or white part of the eye. We now know that the Conjunctiva is equally important in keeping the cornea clear, as it provides support and lubrication (in the form of tears) to the cornea, and the presence of Conjunctival Stem Cells (CSCs) has also been recently discovered - these exist high up under the eyelid.

Diseases affecting the Ocular Surface cause corneal blindness
Many conditions of corneal blindness are due to damage or loss of the corneal epithelium, and/or the conjunctival epithelium, both of which are considered as the Ocular Surface. These diseases are termed Ocular Surface Diseases (OSD), and blindness occurs due to limbal or conjunctival stem cell deficiency. These include acute chemical and thermal injuries to the eye, which occur in burns victims and industrial chemical accidents (usually acid or alkali splashed into the eye). Chemical injuries also occur in acid attacks, and also in various forms of chemical weapons, such as mustard gas. Other forms of ocular surface injury occur include severe eye corneal infections (e.g. related to contact lens ulcers, or trachoma) and severe eye and skin conditions such as Stevens Johnson syndrome, in which an allergy causes extensive skin and eye blisters, leading to blindness.

Treating Ocular Surface Diseases
Previously, treating these diseases with conventional corneal transplants had a very high failure rate, because we were not transplanting stem cells at the time of the transplant. Over the last few years, we, and others in the field have pioneered the surgical technique of transplanting both Limbal, and Conjunctival Stem Cells, and these stem cell transplants are now routine procedures within our corneal transplantation program. However, there are often problems in obtaining adequate stem cells, either from the opposite eye, or from corneal donors.

SERI is growing Ocular Surface Stem Cells
In 2000, in collaboration with the Burns Unit, Dept of Plastic Surgery, SGH, and Pennsylvannia School of Medicine, SERI scientists and clinicians embarked on an ocular stem cell research project, with the aim to grow and culture both Limbal and Conjunctival Stem Cells for clinical transplantation. From a small biopsy of about 2mm2 in size, we are now able to culture and grow an entire sheet of either conjunctival or corneal epithelial cells, measuring up to 25mm by 25mm, which can cover the entire surface of the cornea, or conjunctiva.

Note that there are no major Ethical Issues in our stem cell research. Firstly, we are concentrating only on culturing Adult Stem Cells at present, so there are no ethical issues regarding the use of embryonic stem cells and embryos. Secondly, therapeutic cloning is at present not a viable option for Adult Stem Cells.

SNEC Clinical Trials on Cultured Stem Cell Transplants
Singapore National Eye Centre (SNEC) has successfully performed its first series of Cultured Conjunctival Stem Cell Transplants, and Cultured Limbal Stem Cell Transplants.

1. Cultured Conjunctival Stem Cell Transplants
In October of 2001, SNEC surgeons performed the first Cultured Conjunctival Stem Cell Transplant in a patient suffering from a common local conjunctival disorder known as pterygium. To our knowledge, this was the first of its kind in the world, as no one else was growing conjunctiva at that time.

Since then, within a rigorous and ethically-approved clinical trial, a total of 22 patients with pterygium have received cultured stem cell transplants. In all cases, these transplants have been successful in resurfacing the eye after excision of the pterygium. The procedure first involves removing a small 2mm2 biopsy of stem cells from under the patient's upper eyelid (a painless 5-minute procedure). These stem cells are then grown in the SERI Stem Cell Laboratory for about 2 weeks, until an entire sheet of conjunctival epithelium is grown. At this point, the patient comes for excision of the pterygium, and we then use his cultured epithelial sheet to cover the defect left behind. This reduces pain and discomfort, and the risk of infection, as compared to not covering up the skin defect, and also serves to reduce regrowth or recurrence of the pterygium.

We have also used Conjunctival Stem Cell Transplants in 2 other patients. One was a 9 year old Indian girl who suffered from extensive disfigurement in one eye due to the presence of an extensive and growing conjunctival nevus (or mole), affecting over 3/4 of her eye surface. Ordinarily, we cannot adequately treat this, as extensive removal of the nevus will bare most of the surface of the eye, and cause major scarring and damage. We successfully performed a Cultured Stem Cell Transplant to replace 3/4 of her eye surface with no scarring or loss of vision. It is now 8 months after surgery, and no recurrence of the nevus has occurred. The last patient was a 73 year old Malay man who suffered from glaucoma. Glaucoma surgery involves creating a closed valve within the eye to allow for release of pressure, and this is sited over the conjunctiva. In this case, there was a leaking wound of the overlying conjunctiva which failed to heal for several months, with internal eye fluid constantly leaking out. With a Cultured Stem Cell Transplant, we were able to close this hole and resurface the filtration site.

2. Cultured Limbal (Corneal) Stem Cell Transplants
Cultured limbal stem cell transplants are performed in only handful of eye centres around the world. We have also performed Cultured Limbal (Corneal) Stem Cell Transplants in 4 patients blinded by stem cell corneal diseases. Two patients suffered from chemical injuries, one patient suffered from an extensive ocular surface cancer damaging the cornea, and the last patient suffered from corneal blindness due to generalized stem cell deficiency. Although the period of follow-up after surgery is still short (ranging from 4 to 7 months) the cultured grafts so far have been successful, and all patients have improved vision to a varying degree. We foresee that cultured limbal stem cell transplants will be an invaluable procedure which will boost our success with conventional corneal transplants in these patients.

Summary
SERI has been successful in initiating an Ocular Surface Stem Cell Research Program, and will continue to pursue this important line of research which demonstrates the ability to perform cutting edge basic laboratory research with direct clinical applications to our patients to restore vision, a practical "bench to bedside approach". Granting agencies which have provided significant funding include the NMRC, BMRC and the NUS. In addition to continuation of our clinical trials, our group's focus over the next few months will be to perform pivotal laboratory studies to add to our fundamental understanding of ocular surface stem cell biology, thus contributing to the scientific knowledge of adult stem cells, and refine laboratory culture techniques, with the integration of artificial substrates and polymers to expand and grow these stem cells. This leads us to the next stage of Tissue Bioengineering of the Ocular Surface.

SERI Ocular Stem Cell Research Group

A/Prof Donald Tan Principal Investigator Prof Roger Beuerman Co-Principal Investigator Dr Li Jing Stem Cell Biologist Dr Leonard Ang Lead Investigator, Conjunctival Stem Cells Dr Ti Seng Ei Lead Investigator, Limbal Stem Cells Dr Howard Cajucom-Uy Clinical Investigator Dr Jessica Abano Corneal Fellow Cheyenne Seah Research Assistant David Wong Research Assistant Audrey Khoo Research Assistant

Collaborators

Dr Phan Toan Thong Co-investigator Dr Bob Lavker Scientific Advisor

Participating Institutions

Singapore Eye Research Institute Singapore National Eye Centre Stem Cell Research Group, Outram Campus Dept of Ophthalmology, National University of Singapore Burns Unit, Dept of Plastic Surgery, SGH Dept of Dermatology, Pennyslvannia School of Medicine