Biological Effects on the Cornea of the Kamra Inlay for Presbyopia

By Linda Roach

Refractive surgeon Marcony R. Santhiago, MD, PhD, was fresh out of medical school in Brazil in 2003 when he traveled to New York City for elective courses at Mount Sinai School of Medicine.

“Mount Sinai is very big in gastroenterology, and I was thinking about specializing in GI,” Dr. Santhiago recalled in a recent interview with Refractive Surgery Outlook.

“But my first rotation was in ophthalmology, and that changed everything. When I saw my first cataract surgery, I knew I needed to do whatever I had to do to be able to perform that surgery,” he said.

It was the first step on a nine-year journey that this year reached a milestone, when he was named the 2012 winner of the ISRS Troutman Prize for a paper he co-authored about corneal inlays and wound healing.¹

Along the way, Dr. Santhiago finished his medical residency, a clinical fellowship and a doctoral program in Brazil, plus a post-doctoral research fellowship in the United States. At age 33, he has co-authored more than 30 peer-reviewed research papers, the majority of which were published during his recently completed research fellowship with Steven E. Wilson, MD, at the Cole Eye Institute of the Cleveland Clinic in Cleveland.

Awarded for a JRS Paper

ISRS awards the Troutman Prize annually to honor a young ophthalmic researcher (under age 45) who published an outstanding paper in the Journal of Refractive Surgery during the preceding year. The award is named for Richard C. Troutman, MD, DSc (Hon), who brought lamellar refractive surgery to the United States.

The 2012 Troutman paper, for which Dr. Santhiago was the lead author, has been praised as a “classic” study of the biological effects on the cornea of the Kamra Inlay for presbyopia (ACI 7000; AcuFocus Inc., Irvine, Calif.). Prior to the study, there was little cellular-level knowledge about the cornea’s initial inflammatory reaction to the Kamra, subsequent cell death and long-term inflammation.

Internationally, refractive surgeons have implanted more than 15,000 of these small-aperture intrastromal inlays outside of clinical trials, and AcuFocus is expected soon to ask the FDA to approve its use in the United States. Dr. Santhiago’s paper reported results of a prospective, controlled study of apoptosis and inflammation after unilateral implantation of the Kamra (depth: 160 µm) in the eyes of 24 New Zealand rabbits. In contralateral control eyes, an equivalent intrastromal pocket was produced by femtosecond laser, dissected with an iris spatula, and then left empty.

At three time points — 24 hours, 48 hours and six weeks after surgery — eight animals were euthanized and their corneoscleral rims removed for controlled immunohistochemical testing. They used the TUNEL assay as an objective test of cell death, as it detects DNA byproducts of apoptosis. Inflammation was monitored with the monoclonal antibody for CD11b, a marker of monocyte inflammatory cells.

Over Time, the Difference Disappears

The tests showed early increases in keratocyte apoptosis and inflammation compared to the controls, which the authors attributed to greater corneal manipulation during inlay insertion. But there were no statistically significant differences in either biomarker at six weeks.

“Despite a perioperative increase in stromal cell death and inflammation, by six weeks after surgery, no significant difference was noted in inflammation or cell death between the inlay group and control pocket only group,” the researchers concluded.

Dr. Santhiago credits Dr. Wilson, his co-author and fellowship program director, for teaching him the essentials of a well-designed and well-presented study.

“Dr. Wilson teaches you how to design the study well, and when everything is done, how to analyze and interpret the results, how to make sure that everything makes sense, and how to put it together in a paper,” Dr. Santhiago said in an interview. “He told me it was important not only to show people what we found, but also to write it well.”

“All the recognition I now have internationally because of this award is more than I even dreamed of,” he said. “And it’s all because of everything Dr. Wilson taught me.”

Dr. Santhiago returned to Brazil earlier this year to become a professor of ophthalmology and head of cataract and refractive surgery at the Federal University of Rio de Janeiro, and a staff member at the University of São Paulo.

Time for Research, Despite a Busy Practice

Although he is a busy refractive surgeon, Dr. Santhiago sets aside two afternoons a week to design and conduct research studies, guided by what he learned from Dr. Wilson.

It was gratifying to spend “every single little moment” during the fellowship learning, he added. “I used to say that I felt like I was in Disney World all the time,” he said.

In turn, Dr. Wilson praises Dr. Santhiago and his predecessors for having the intellectual curiosity, the ambition and the work ethic to make the most of their time working in the lab where he studies the cornea’s cellular and molecular biology. “They’ve made my career as much as I’ve made theirs,” he said.

This was the third Troutman Prize given to a research fellow from Dr. Wilson’s program — an accomplishment that spotlights not just Dr. Santhiago but also the success of the Cleveland program in nurturing the next generation of ophthalmic clinician scientists.

“Steve is to be commended for producing these extraordinary young people,” said refractive surgeon Marguerite McDonald, MD, who herself mentored Dr. Wilson when she was chief of the cornea service at Louisiana State University. [Dr. McDonald is medical editor of Refractive Surgery Outlook.]

“Steve has had a string of hits. His research fellows have gone on to do good work in the refractive surgery field and have produced some classic papers,” she said.

Two-Year Commitment Makes a Difference

Dr. Wilson said he believes the productivity of his former fellows stems from his decision requiring them to commit to staying at least two years. A third year is optional.

“One year is just not enough time. You’re just kind of getting rolling when you’re leaving. So I won’t take them for less than two years,” Dr. Wilson said. “My experience is that if they stay a second year, they accomplish at least 200 percent more work than they would if they had stayed just one year. If they stay two or even three years they can accomplish an amazing amount.”

The two-year requirement has brought more international fellows into the program than U.S. trained ophthalmologists, he said. “Most American fellows are in a hurry. They want to do that one-year clinical fellowship and get on with the rest of their life,” he explained.

Fellows Can Build a Long Publication List

Fellows who join him often are newly minted international ophthalmologists eager to start a career in academia. But he urges them to make the most of their fellowship.

“I tell them, if you really want to be an academic ophthalmologist, first of all, don’t be in a hurry to be done with your fellowship. Get as much exposure and opportunities to broaden your horizons as possible. You have the rest of your life to be in your final job. Don’t shortchange yourself by being in a hurry,” he said.

“And if you produce 20 papers during your fellowship years, you’ll have a leg up on other people when you’re competing for the best positions at top institutions.”

Planting Seeds for Tomorrow

Dr. Wilson said his ultimate goal goes beyond the interpersonal. It is to plant the seeds of ophthalmology’s research future; to grow a new generation of clinician scientists capable of clarifying the mysteries of how corneal cells communicate and differentiate.

“There always will be new treatments and new refractive surgeries, and we need to understand what their effects are on the cornea’s cellular and molecular processes. It’s good for corneal and refractive surgery to have people who can study these things. But there are very few individuals trained in the world to do so,” Dr. Wilson said.

“That’s why I do this research fellowship program. Not only do I enjoy it and love it, but it also helps to build the next generation of clinician scientists,” he said.

Now back in Brazil teaching, performing refractive surgery in a multispecialty practice with his wife and his father-in-law, and planning more research, Dr. Santhiago has set himself one more goal.

“When I found out I had won the Troutman, I talked to a previous winner and told him he had been a great example to follow,” Dr. Santhiago said. “And I really hope that I, too, can be an example someday to young guys who want to go into ophthalmology.”

¹ Santhiago MR, Barbosa FL, Agrawal V, Binder PS, Christie B, Wilson SE. Short-term cell death and inflammation after intracorneal inlay implantation in rabbits. J Refract Surg. 2012 Feb;28(2):144-149. Epub 2011 Dec. PubMed PMID: 22149664.

Dr. Santhiago has no financial conflicts to disclose.