This column is dedicated to telling the stories of where our field’s great innovations began—sometimes through the voices of the pioneers who introduced them and sometimes through the perspectives of surgeons who are pivotal to their evolution.
Richard L. Lindstrom, MD, has been involved in the development of countless technologies that have become integral to modern ophthalmology. One of his earliest contributions—perhaps overlooked because it is now ubiquitous—is a corneal storage medium. By preserving endothelial cell viability, Optisol (Bausch + Lomb) keeps donor corneas clear and usable for days, greatly improving tissue availability. The impact of effective means of corneal preservation cannot be overstated.
TAL RAVIV, MD
Blindness from corneal damage is a major public health concern worldwide, particularly in low- and middle-income countries. This article briefly discusses the development and impact of corneal preservation strategies and current challenges in addressing corneal blindness.
HISTORICAL CONTEXT
The Austrian ophthalmologist Eduard Zirm performed the first successful human corneal transplant in 1905, when he transferred the cornea of a recently deceased individual directly onto the eye of a living patient.
In the 1930s, Russian surgeon Vladimir Petrovich Filatov developed the moist chamber method—the first means of corneal preservation. Moist gauze was placed in the bottom of a jar. Next, the entire globe of a recently deceased individual was removed, affixed to a metal holder, sealed in the jar, and stored at 4 ºC.
Filatov’s moist chamber method was still the norm when I entered the field of ophthalmology in 1972. It was the duty of my fellow residents at the University of Minnesota and me to visit area morgues, enucleate the eyes of deceased donors, and place the tissue in jars along with saline solution.
These donor corneas remained viable for approximately 24 hours. The waiting list of patients typically ranged from 50 to 100 individuals, and the harvesting and emergency surgery were often performed in the middle of the night. If the patient at the top of the list would not be available within 24 hours of being contacted, we moved on to the next name. The situation was far from ideal.
TECHNICAL DEVELOPMENT
Organ Culture of the Cornea
In 1972, Donald J. Doughman, MD, joined the ophthalmology faculty at the University of Minnesota after completing a 2-year cornea fellowship with Claes Dohlman, MD, PhD, at Harvard University’s Massachusetts Eye and Ear Infirmary. That same year, Dr. Doughman invited me to join him and two brilliant scientists, dermatologist William Summerlin, MD, and world-renowned immunologist Robert Good, MD, PhD, in their work on organ culture preservation in skin. The thought was that some of the same principles could be applied to the cornea.
Our research led to the development of organ culture of the cornea, a method adopted in Europe and still frequently used there. This technique uses a medium supplemented with serum and can preserve corneal tissue at 34 ºC for approximately 30 days.1-3 Tissue matching and blood typing have reduced the risk of graft rejection in Europe but are less successful in the US population.
Intermediate-Term Storage
Our team shifted focus to developing a method by which to preserve corneas at 4 ºC for 7 to 14 days. One challenge was that the tissue thickened during storage as it absorbed fluid. We found that adding dextran to the medium helped address this issue and developed a product called Dexsol. Elsewhere, Herbert Kaufman, MD, PhD, and Bernard McCarey, PhD, were doing similar research that led to the development of MK medium. Both it and Dexsol were meaningful advances, but neither research team was satisfied.
In its first year, 1982, Project Orbis’ founder David Paton, MD, invited me to travel with the organization to Sri Lanka, one of the largest providers of donor corneas in the world. While there, I met Hudson Silva, MBBS, a pioneer in eye banking. He was sending tissue in jars to Japan and had found that surrounding the tissue with culture media helped it last longer. Intrigued, I learned that the media had been developed by Reizo Manabe, MD, who had added chondroitin sulfate. This glycosaminoglycan, derived from shark fins, is an antioxidant, deturgescent, and cell membrane stabilizer.
Back in Minnesota, we found that adding chondroitin sulfate to our Dexsol medium extended corneal preservation times to approximately 2 weeks, even at 4 ºC.4 This research led to our development of a medium containing dextran and chondroitin sulfate that we called Optisol.
At this point, the problem we faced was one of distribution. Only our academic institution and local eye bank had access to Optisol. We created a small company called Aurora Biologicals to make Optisol commercially available. Similar work by Drs. McCarey and Kaufman led to the development of K-Sol with Alcon, but that company ultimately withdrew from the market.
William Link, PhD, then the CEO of Chiron, connected Drs. McCarey and Kaufman with the cell biologist with whom I was working, Debra Skelnik, BS, and me. Together, we developed a form of Optisol containing gentamicin and streptomycin to reduce infection. Chiron distributed the product, and it became the leading medium used by eye banks throughout the world. Bausch + Lomb acquired Chiron and distributes the product, Optisol-GS, to this day. It is also available from some eye banks with amphotericin B, a powerful antifungal agent.
IMPACT AND REMAINING CHALLENGES
The development of effective methods of corneal preservation revolutionized the field. Rather than have their names added to a waiting list, US patients can receive corneal transplants as needed. The tissue is readily available at eye banks across the country, with the Eye Bank Association of America setting accreditation and standards for these organizations. Countries whose eye banks have a surplus of donor corneas, such as the United States and Sri Lanka, are able to export the tissue to a network of eye banks around the world.
Unfortunately, the demand for corneas outstrips the supply, particularly in low- and middle-income countries. Corneal blindness affects 15 to 20 million people outside the United States, yet only approximately 150,000 donor corneas are generated each year worldwide. The challenge today is either to increase the number of donors or to develop an artificial cornea. Many laboratories are currently working on the latter.
Dr. Lindstrom holds six patents on corneal preservation methods.
1. Doughman DJ, Van Horn D, Harris JE, Miller GE, Lindstrom R, Good RA. The ultrastructure of human organ-cultured cornea. I. Endothelium. Arch Ophthalmol. 1974;92(6):516-523.
2. Van Horn DL, Doughman DJ, Harris JE, Miller GE, Lindstrom R, Good RA. Ultrastructure of human organ-cultured cornea. II. Stroma and epithelium. Arch Ophthalmol. 1975;93(4):275-277.
3. Lindstrom RL, Doughman DJ, Van Horn DL, Dancil D, Harris JE. A metabolic and electron microscopic study of human organ-cultured cornea. Am J Ophthalmol. 1976;82(1):72-82.
4. Lindstrom RL, Doughman DJ, Skelnik DL, Mindrup EA. Minnesota system corneal preservation. Br J Ophthalmol. 1986;70(1):47-54.
