Indocyanine green had a glamorous start. Initially, the dye was used to create the cyan layer in Technicolor movies in Hollywood after World War II. It wasn’t until 1957 that ICG was considered for medical use when the Mayo Clinic used ICG primarily for evaluating hepatic function. Soon after realizing that ICG would be useful for evaluating blood flow, it found its way into ophthalmology. Enter Bob Flower, Dr.h.c.

The field of ophthalmic imaging owes much of what we understand about ocular hemodynamics to Dr. Flower’s research. He was director of Collaborative Biomedical Programs at the Johns Hopkins University’s Applied Physics Laboratory, and full professor at New York University. He has published over 100 articles and has presented over 250 papers and abstracts. At almost 80 years old, he holds 35 patents, all in the fields of hemodynamics and microvasculature innovation, and is still a much sought-after consultant.

Recently, I had the distinct honor of sitting down for a discussion with Dr. Flower (via Zoom) from his home on Southport Island, ME.

Darrin Landry: Your introduction to ophthalmology is an interesting story.

Bob Flower: Yes. I think it was 1966. I was at Moffett Field, a NASA research center in the suburbs of San Francisco. At the time, I was the Applied Physics Lab’s (APL) representative of Johns Hopkins University for a joint research project being done at Moffett Field. I had been there for about six weeks, and wanted to return home for a week. It coincided with a visit by luminaries from the Department of Ophthalmology at Hopkins School of Medicine. This included Drs. Ed Maumenee, Arnall Patz, David Robinson and Maurice Langham.

Now, APL’s work was all classified—mostly military research—and they wanted to incorporate some of the lab’s technology into solving problems of public health concern by matching five senior APL researchers with five investigators from the School of Medicine. In particular, Arnall Patz was working on the problem of retrolental fibroplasia, now known as retinopathy of prematurity. I made a few comments on his thoughts, not thinking more about it.

I then received a call from Arnall Patz; how he found me, I have no idea. He told me he had already spoken to the overall director of APL, and if it were agreeable to me, I could take an immediate leave of absence from APL and work with him. It kind of came out of the blue. I was flattered, but had no real interest. I told him I would have to think it over.

About 45 minutes later, my boss called. I was involved in a project called ELF—electromagnetic flash blindness. There was concern that military pilots would be blinded by nuclear explosion light. We had developed transparent shields that would become instantly opaque if an electromagnetic pulse hit it, protecting the pilot’s eyes.

DL: So, it was truly the first polarizing sunglasses!

BF: Yes! So, my boss told me that I was to fly with a military pilot to Hawaii, where I would be flying in a B-52 Stratofortress over the area where the French were performing nuclear tests. The idea was that I would be testing these ELF shields. I thought to myself, “Bob doesn’t need to be there.” My response was, “Oh, haven’t you heard? I’ve already been approved to take a leave of absence to work with Dr. Patz in the Ophthalmology Department, so I am afraid you’ll have to find another man for the job.”

And I tell you, I sweated bullets trying to track down Arnall Patz. When I finally found him, I said, “you know, Arnall, I’ve been thinking about your offer…blah, blah, blah.” And I stayed there for 18 years.

DL: Would it be fair to say that the research you’ve done over the past 50 years essentially boils down to the study of microvascular systems and hemodynamics?

BF: That’s correct. And in ophthalmology, you have every vascular type, including plexus, in the back of the eye and they are easy to access. Now, back then, the choroid was considered just a huge plexus that mattered little compared to the retina.

I started looking at the movies we were making with fluorescein angiography in animals, and noticed the choroidal blood flow wasn’t staying constant at all—there were changes in it. That’s what caught me. I was told that ICG might have a weak fluorescence in ethanol, and might not be useful for anything. I happened to be looking through infrared goggles in my lab, and saw test tubes glowing in the dark. It turns out that they contained samples of monkey blood that had ICG in it. It took me until 1974 to publish the first ICG angiogram of a human eye.

DL: By demonstrating the fluorescent properties of ICG, you then changed the course of ICG use.

BF: Yes. Up until then, everyone was just looking at the absorption of light by ICG, not the fluorescence. Now, we had a use for it by visualizing dynamic blood flow in the choroid. For a number of years, ICG was primarily used in ophthalmology. Now, it is primarily used to evaluate vascular flow in skin, lymphatic circulation, and in reconstructive surgery.

So that means that ICG has come full circle in its use—back to its first medical application in cardiology, only this time because of its fluorescence, rather than its light absorbency.

DL: Initially, ophthalmic imaging was film based. Now, of course, we capture angiography with digital video. Given the incredible flow rate of blood in the choroid, how were you able to capture ICG fluorescence?

BF: You know, everyone back then was so interested in the highest possible resolution. Some of the cameras were capable of much more resolution than you could possibly get out of the optics of the eye. I told them we could go with much smaller cameras with higher speed. You get your maximum resolution, but you get the advantage of a higher speed, or frames per second. In fact, the first ICG angiograms I made were done at 30 frames per second. And that was on infrared film!

The camera I used was the same one they sent up on rockets. It weighed about 35 pounds, and it had a variable shutter on it, so I could set it for 30 frames a second. It frustrates me that people are still more concerned with higher spatial resolution, and not higher speed.

DL: Even after all these years, it seems you are still trying to convince people that the dynamic flow is more important than some pathology in ophthalmic diseases.

BF: In my opinion, ophthalmology should not get stuck on using pattern recognition to diagnose, using descriptive terms to identify pathology. And some of those things took on physiological meaning, which should have never happened.

To this day, angiogram interpretation still can be influenced by how technical staff determine what is a good image, and what is presented to the clinician to determine a diagnosis. That clinician may have no idea how difficult those images may have been to acquire, because of this or that, and how that may have affected the images. And there may be no opportunity to convey that to the clinician.

(Giovanni) Staurenghi, who is an ophthalmologist in Italy, always would have conversations with the person who captured the images, in depth, to get that information. That’s extremely helpful, because, you know, angiography is a dynamic test. Yet we are looking at static images.

DL: It’s important that people know the history and understand the foundation of these diagnostic tests they perform. Yet, I find I am hard-pressed to speak to anyone who really knows it.

BF: It doesn’t matter how good, bad or indifferent your work is: within 10 to 15 years, it will be forgotten. And that’s true for the most part. If you look at all the papers written now about ICG in cardiology or any other field, there’s almost no indication about how the technique originated in ophthalmology.

Ophthalmology borrows from many disciplines, especially oncology, but ICG angiography may be the one thing that came out of ophthalmology and went into a whole panorama of other disciplines. OP