Source: Healio Interviews
Disclosures: De Smet reports he is chief medical officer and co-founder of Preceyes. Edwards, Hubschman, Kapetanovic and Tsao report no relevant financial disclosures. Yeu reports she is an advisory board member for ForSight Robotics.
April 15, 2021
11 min read

‘Enormous’ potential of robotics opens door to next revolution in eye surgery

Source: Healio Interviews
Disclosures: De Smet reports he is chief medical officer and co-founder of Preceyes. Edwards, Hubschman, Kapetanovic and Tsao report no relevant financial disclosures. Yeu reports she is an advisory board member for ForSight Robotics.
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Ophthalmology is one of the most technology-driven branches of medicine, and most key advances in the field have relied on devices rather than drugs. Now, robots and artificial intelligence are poised to be part of an impending revolution.

“For various reasons, robotics is entering our field with some delay as compared with other surgical specialties, but it is going to play a major role in the future. The time has come because retinal genetic therapies including gene replacement therapy and optogenetics are making rapid progress, and translating them to the clinic strictly depends on precision of delivery,” Jasmina Kapetanovic, MD, PhD, said.

Jasmina Kapetanovic, MD, PhD
According to Jasmina Kapetanovic, MD, PhD, robotics has come with some delay in eye surgery but will play a major role in the future.

Source: Jasmina Kapetanovic, MD, PhD

“The potential is enormous, actually. Any surgical treatment or technique can gain precision and accuracy, leading to unprecedented levels of safety and efficacy as compared with traditional surgery. The delicate maneuvers in the retina and surroundings that require micrometric precision, but also more standardized surgical procedures such as cataract, will be revolutionized by robots,” Jean-Pierre Hubschman, MD, said.

Kapetanovic, a clinician scientist at the University of Oxford, and Hubschman, associate professor of ophthalmology and director of the Advanced Robotic Eye Surgery Laboratory at UCLA, are involved in the two most advanced and promising projects involving robotics in eye surgery today.

The first, the Preceyes surgical system, was born from the original idea of Marc de Smet, MDCM, PhD, retina specialist, co-founder and chief medical officer of Preceyes BV. Fifteen years ago, he sought the collaboration of engineering at Eindhoven University of Technology in the Netherlands to create a microrobot prototype for vitreoretinal surgery. The Preceyes surgical system, which was successfully validated following preclinical and clinical trials, obtained a CE mark in 2019 and is now commercially available for use.

The second project, the intraocular robotic interventional surgical system (IRISS), was developed at UCLA through a collaboration between the Mechatronics and Controls Laboratory and the Stein Eye Institute. Hubschman and Tsu-Chin Tsao, PhD, professor of mechanical and aerospace engineering at UCLA, have been working together on this project for more than 10 years. IRISS is at an advanced prototype stage, awaiting funds to move to human trials.

Preceyes surgical system for retina

The Preceyes surgical system is a master-slave telemanipulation system. A joystick held by the surgeon is remotely connected to a robotic arm that holds the instruments and performs the surgical maneuvers inside the eye.

Marc de Smet, MDCM, PhD
Marc de Smet

“The surgeon looks through the surgical microscope and guides the motion of the instruments. The system allows for a high degree of precision, better than 20 µm, with 4° of freedom, ie, rotation, entry and exit, and two rotations around the point of entry, much like a manually operated instrument. In addition, it can open and close instruments inside the eye and activate a light source or a laser,” de Smet said.

A computer controls the speed at which translation through the eye occurs, so that movements can be faster when instruments are away from delicate structures and gradually scale down to almost no motion while approaching, for example, the retinal surface. It also builds a memory of location at each time point, so that surgeons can stop and restart maneuvers from exactly the same location. It can be programmed to place virtual boundaries to prevent the arm from going too far or to advance in preset steps, of 50 µm or 10 µm, for instance, to reach a specific location.

“When you want to pull out an instrument, you just press on a button. You can also switch instruments, such as from blade to forceps, never losing the site of where you are operating. At any time during surgery, you can reprogram your maneuvers on the touch screen,” de Smet said.

First-in-human achievements

The first clinical trial with the Preceyes surgical system was performed at the University of Oxford. The first stage of the study involved 12 patients randomly assigned to robot-assisted surgery or standard manual surgery for either epiretinal membrane or internal limiting membrane removal.

Thomas L. Edwards, MD, PhD, first author of the study, was one of the surgeons who performed the robotic-assisted procedures and recalls it as an extraordinary experience of close collaboration between the clinical team led by Prof. Robert MacLaren and the engineers who worked on the system.

Thomas L. Edwards, MD, PhD
Thomas L. Edwards

“It was exciting having a robot and the Preceyes engineers in the operating theater. The precision and superhuman abilities that the machine granted us were like nothing ever used before in the eye. Being able to position the tip of a needle extremely close to the retina and then let go of the controller and see the needle remain perfectly still — you would never dream of doing that. It was hard to believe,” he said.

The extreme precision of the robot opened their eyes to a new universe of fine details, normally unnoticed.

“We noticed imperfections in some of the instruments. Needles, for example, that we thought to be straight, when rotated round the long axis showed a slight deviation of the tip. We even noticed how the eye moves with pulses of the heartbeat and jokingly asked the anesthetist if he could do something about it,” Edwards said.

Edwards is now back in his home country, Australia, and is exploring opportunities to use the Preceyes system in future collaborative research once COVID restrictions are loosened.

Human hands cannot compete

In the second stage of the study, Preceyes was used to perform subretinal injection of recombinant tissue plasminogen activator, a clot buster agent, in 12 patients with vision loss due to subretinal hemorrhage. Kapetanovic was introduced to the technology at this stage in 2018.

“I was trained to use the robot and then operated on patients myself. I was lucky. It was a privilege given to very few people,” she said. “The trial went very well and is now completed and about to be published.”

She continues to collaborate with Preceyes to upgrade the system and has organized training sessions for OR staff to implement a specific protocol for robot-assisted surgery.

“Introducing a new procedure requires not only the surgeons to be trained, but the whole team to set up the machine and to know which parts need to be sterilized, dressed and draped,” Kapetanovic said.

Subretinal injection is a procedure in which no human hand could compete with a robot. The physiological tremor of surgeons is on average around 100 µm, ranging between 80 µm and 250 µm, and increases during static tasks.

“Preceyes allows you to go into the subretinal space very precisely. Your hand movements are translated into micromovements by the robot, and when you reach the exact location you are aiming at in the retina, the needle is held very still, allowing you to perform the infusion slowly and steadily. When we perform the same procedure manually, hand tremor tends to enlarge the little hole in the retina, and at that point, the drug refluxes back into the vitreous, causing inflammation. That’s why we usually want to quickly inject and come out of the eye. With Preceyes, you can keep the needle still for a longer time, performing a slow, controlled infusion in minutes rather than seconds, while the retinotomy space remains very tight,” Kapetanovic said.

The study also proved that the procedure can be performed in this way using a local anesthetic, “a very important improvement,” she said.

In the pipeline

In the pipeline, there is now the idea of a clinical trial for cannulation for central retinal vein occlusion involving several centers across Europe.

“We have no cure for CRVO. Cardiologists and neurosurgeons burst the clots with anticoagulants after a heart attack or a stroke, but eye surgeons do not as the retinal vein is so small that it would be too dangerous to perform the localized procedure manually. We treat the complications of CRVO, but if we could treat the cause, the clot, with precise cannulation and infusion using the robot, we would prevent many cases of vision loss,” Kapetanovic said.

Preceyes was also used at Rotterdam Eye Hospital in the Netherlands to perform specific stages of surgery in 10 patients with macular pucker, and in June 2020, it was installed at New York Eye and Ear Infirmary (NYEE) to perform laboratory research.

“NYEE is planning to collaborate with us to further develop the technology for existing procedures and novel treatments and eventually launch the first clinical trials in the United States,” de Smet said.

Innovative therapies, such as gene therapy, will greatly benefit from this option, according to de Smet.

“Injecting gene therapeutic products exactly in the subretinal space while minimizing reflux is difficult. In some ways, today we have accepted that reflux may happen and are fairly satisfied if we lose ‘only’ 50% of the vectors in the vitreous cavity, but if we were able to retain 95% of the virus particles or more in the subretinal space, we could minimize the immune response and even titrate the results,” he said.

In his opinion, robotics in ophthalmology should not be looked at from the standpoint of necessarily carrying out full surgery, but rather as a way of performing or enhancing specific tasks during the surgery.

“A hybrid approach for ophthalmology makes more sense, in part because we are limited by the instrumentation that exists today and partly because there are relatively easy procedures that surgeons can excellently perform manually. Vitrectomy, for instance, is repetitive and relatively easy, while membrane peeling is a more complicated task, and here is where robots are going to make a difference,” de Smet said.

IRISS for cataract

“Before getting involved in the IRISS project, I did a lot of industrial type of research such as metal cutting and material removal, so I was intrigued by the idea of creating a robot to cut and remove the crystalline lens,” Tsao said.

Tsu-Chin Tsao, PhD
Tsu-Chin Tsao

The IRISS is aimed at performing anterior and posterior intraocular surgical procedures, but the latest developments have focused on cataract surgery, precisely on the stage of lens removal while other stages are performed by femtosecond laser. IOL implantation is another task that will eventually be assigned to the robot.

The two arms of IRISS can simultaneously manipulate two surgical instruments through ocular incisions spaced millimeters apart and can automatically alternate between multiple surgical instruments on each arm. An OCT system integrated into the platform is used for preoperative planning and intraoperative guidance.

“Based on OCT scans, the system models the eye anatomy, plans a trajectory and performs precise lens extraction. The ultrasound tool is then switched to an I/A tool to thoroughly clean the capsule. This is now performed in about 4 to 5 minutes, but we are aiming for 2 to 3 minutes. Initially, precision was in the range of 0.2 mm, and now it is 5 µm to 10 µm in our new design, approximately 10 times better than a human surgeon,” Tsao said.

The surgeon is like a high-level conductor who pushes the start button, and while the robot does all the scanning and maneuvers in a fully automated way, the surgeon can always intervene at specific points with a mouse click, assign a task, or modify or override the procedure, he said.

“Our robot has all three components that make a fully automated robotic system: sensing, image guidance, and decision and control capabilities,” he said.

Hubschman said that the robotic system can also provide “tactile feedback” in addition to visual feedback. Augmented feedback capabilities can be useful during certain surgical tasks, in particular delicate retinal procedures.

Jean-Pierre Hubschman, MD
Jean-Pierre Hubschman

“When you play video games, in the joystick you can feel vibration, or resistance. When the car during the game goes off the road, you can feel some resistance. Same thing with the robotic manipulators — we can translate critical information into tactile feedback,” he said.

During manual surgery, much of what could theoretically be sensed through the forceps is below the human threshold, and surgeons can rely only on visual feedback. With IRISS, both the visual and tactile feedback are provided and potentiated, leading to a degree of precision and accuracy that humans cannot achieve.

“The OCT will detect precisely where the pieces of the lens are and would guide the robotic arm to fish those pieces very delicately and precisely, with no risk of causing capsule rupture. During traditional cataract surgery, there is a trade-off between cleaning the bag thoroughly with the risk of causing capsule rupture or leaving some material in the bag and getting posterior capsule opacification. Thanks to the combination of perfect visualization and sensing capabilities of the IRISS system, we can clean the capsule thoroughly and very safely,” Hubschman said.

Autonomous like self-driving cars

Autonomous and intelligent technology is better and faster than humans also in preventing or responding to intraoperative complications.

“The human time of reaction is around 300 milliseconds, while the system would react within 20 milliseconds to 30 milliseconds. The robot also detects and adjusts immediately to any eye movement. I like the analogy with autonomous cars. Statistics tell us that about 97% of collisions are human error-related. With an autonomous car, the risk of collision is drastically reduced thanks to more precise evaluation of the situation, better control and a faster reaction than humans. Machine learning makes the system even better at each surgery in the same way autonomous cars learn from each mile driven, making the system more and more reliable,” Hubschman said.

Because it is a complex system, IRISS has a way to go to obtain clinical validation and marketing authorization.

“A lot depends on resources,” Tsao said. “Now we have some funding from the U.S. National Institutes of Health, and with this support, we should be able to test the system on animal models in the next 2 to 3 years and then on cadaver eyes. If we get interest from external investors, we could start a company and go on very fast to human studies. Technology-wise we are ready, but the approval process is a long process with a very high cost.”

Democratize eye surgeries worldwide

Over the past two decades, several robotic projects were started in ophthalmology but have come to a standstill for various reasons. Recently, ForSight Robotics, a company based in Israel, announced the ongoing development of “a surgical robotic platform that will transform the future of ophthalmic surgery.” According to a press release, the creation of automated, machine learning-based solutions for eye surgery is presented as a way of meeting the challenges posed by increasing demand and shortfall of workforce for eye care, particularly surgery. The goal of the project is to democratize ophthalmic microsurgery, enabling more patients around the world to access sight-saving treatments.

Elizabeth Yeu, MD, an advisory board member for ForSight on this project, sees great potential in this evolving technology.

“As a clinician, I am excited about the potential that advanced robotics can do for eye surgery. There is the upside of simultaneously incorporating AI or machine learning and live imaging to create more accuracy, safety and less endothelial cell density loss with ocular surgeries,” she said.

Click here to read the Point/Counter to this Cover Story.