Sometimes they sit just out of sight in the corner of your eye. Other times they waft across your vision, and when you shift your gaze to look at them, they fly out of sight. These pesky obstructions, commonly referred to as floaters, are a visual phenomenon caused by small clumps of collagen in the eye called vitreous opacities. 

While floaters are very common, they are typically unobtrusive enough that people ignore them. Sometimes, however, floaters can be so dark and numerous that they obscure large swaths of a person’s vision. These severe floaters impair people’s ability to drive, work, and simply enjoy their lives, often leading to depression (1).

“There are millions of people in the world suffering from floaters,” said Yannis Paulus, a vitreoretinal surgeon and clinician scientist at the University of Michigan. “Currently, they’re stuck with bad options,” he added. The only available treatments have a significant number of risks.

These treatments include vitrectomy, the surgical removal of the clear gel-like vitreous of the eye that contains the collagen clumps, and laser vitreolysis, shining high-energy light pulses directed at the fibers to break them apart. Vitrectomy is more effective than laser vitreolysis, but patients have experienced retinal tears, detached retinas, and vitreous hemorrhage with both treatments.

While investigating how to make vitrectomy and laser vitreolysis safer and more effective, scientists are also developing new nanobubble-based technologies that may prove even safer and less invasive than the current treatments, improving the quality of life for the many people around the world suffering from disruptive floaters.

Clumps of collagen

The most common cause of floaters is simply getting older. In young eyes, collagen fibers bound to hyaluronan molecules hold together the gel-like structure of the vitreous. As people age, the collagen and hyaluronan begin to dissociate, and the gel becomes more liquid-like, causing the collagen fibers in the vitreous to collapse onto each other and form clumps, which are perceived as floaters.

People over 60 years old often begin to see more floaters due to their vitreous pulling away from the back of the eye in a phenomenon called posterior vitreous detachment. But because this de-gelling process happens faster in people with nearsightedness, nearsighted people in their 20s, 30s, and 40s can also experience floaters.

For people who notice a sudden burst of many new floaters, ophthalmologists first check for any signs of retinal detachments or injuries to the eye. But after ruling out an acute cause, doctors usually suggest that people wait a few weeks or months to see if their floaters seem to fade or become less noticeable. Usually, people experience some neuroadaptation, and the brain tunes out the floaters. But if the floaters don’t get better and they continue to detrimentally affect daily life, people return to their doctors seeking help.

“Unfortunately, the most common form of treatment is to dismiss them and ignore them and send the patient home frustrated and unhappy,” said Jerry Sebag, a vitreoretinal surgeon and floaters researcher at the Vitreous Macula Retina (VMR) Institute. “I started to realize that these patients are being dismissed because we had no way of identifying if they really have a problem, or if they're just overreacting to something that we all experience.”

Sebag and his colleagues developed quantitative assessments to measure how floaters affect people’s vision. They demonstrated that they could use quantitative ultrasound to characterize the density of the entire vitreous with floaters showing up as points and lines of increased density (2). Sebag’s team also reported that floaters decreased a person’s contrast sensitivity, meaning that people with floaters were less able to distinguish between differences in shading and patterns (3).

“With a quantitative component, it enables you to classify conditions as mild, moderate, and severe,” said Sebag. “It enabled me to select patients for treatment.”

Surgical incisions clear out floaters

The most effective way to treat floaters is to physically remove them. By performing a surgery called a vitrectomy, surgeons remove the vitreous from the eye and replace it with a clear gel.

While there are risks of retinal tears and detachments during vitrectomy, “you can usually identify those problems during the surgery. If you see a torn retina, you can laser it during the operation,” said Jason Hsu, a vitreoretinal surgeon and researcher at Thomas Jefferson University.

Vitreoretinal surgeons have recently made improvements to vitrectomies to make these retinal tears less likely. For example, they now use smaller gauge instruments to perform the surgery, meaning that they can make smaller incisions. Sebag has adapted his vitrectomy procedure with this modification and improved the method so that it doesn’t induce a posterior vitreous detachment during the surgery. With these safety modifications, Sebag’s team reported in a clinical study of 195 eyes from 145 patients that vitrectomy led to a 94.1% reduction in vitreous echodensity, indicating successful removal of the vitreous opacities that cause the appearance of floaters (4). The patient’s contrast sensitivity also improved to the level of healthy control eyes after surgery. Out of the 195 eyes operated on, there were three retinal tears and three retinal detachments, but these were successfully repaired during the surgery.

While vitrectomy is relatively safe and effective at treating severe floaters, it does lead to an increased risk for developing cataracts (5). Because of this and because other long-term risks of vitrectomy are unknown, Sebag and other vitreoretinal surgeons hesitate to operate on younger patients.

“I just haven't followed people for 30 years, so I can't answer that question,” said Sebag. As an alternative to vitrectomy, some ophthalmologists turned to a risky and somewhat controversial treatment: laser vitreolysis.

An explosion in the eye

Rather than physically removing the vitreous opacities that cause floaters, some ophthalmologists have tried blasting them apart with pulses of a yttrium-aluminum-garnet (YAG) laser.

“It's not like a typical laser beam that we think of like in Star Wars or something where it's burning tissue. The YAG laser is like a little explosion in the eye,” said Hsu. “It’s almost like evaporating some of the tissue with this high concentrated energy.” This process breaks up large aggregates of collagen into smaller pieces, reducing the appearance of floaters.

Ophthalmologists have used YAG lasers for decades to remove cloudy layers of scar tissue that form after cataract surgery and in the treatment of specific kinds of glaucoma, but their use to treat floaters is relatively new and somewhat controversial.

In the only clinical trial so far investigating the effectiveness of YAG laser vitreolysis for floaters, 54% of the patients who received the YAG treatment reported improvement in the appearance of floaters (6). None of the patients in the trial experienced any adverse effects.

There are, however, substantial risks associated with YAG laser treatment. The laser energies needed to blast apart the fibers that cause floaters are double or triple that of the energies used for the other more routine uses of YAG lasers. Even with the higher energy laser pulses, a person may need to sit through multiple sessions of YAG laser treatment to effectively break up a bothersome floater. In some instances, surgeons have focused the laser too close to the front or back of the eye, causing direct damage to the lens or the retina.

Citing these concerns, Inder Paul Singh, an ophthalmologist at the Eye Centers of Racine and Kenosha, explained that newer YAG lasers allow for better illumination of the vitreous, which helps ophthalmologists more easily orient themselves in the eye, decreasing the risks of damaging vital structures.

“Not every floater is a good candidate for YAG laser vitreolysis,” he said, but for example, if “the floater is in the middle of the vitreous where you can correlate signs and symptoms well, this can be a fantastic opportunity to avoid something like a vitrectomy and not to make [the patient] suffer living with it.”

While Singh has had much success treating floaters with YAG vitreolysis in his practice, that has not been the case for many other doctors.

“There is no protocol to guide the use of YAG laser, either in terms of which patients to select or in terms of how to really do the treatment in a reproducible scientific fashion,” Sebag said. He is organizing a study on how to make YAG vitreolysis more reproducible and safer using quantitative ultrasonography, among other methods, to measure outcomes.

Singh agreed that proper training on how to perform YAG vitreolysis is integral to successful floater treatment.

“The laser is not unsafe. It’s we as doctors who can be unsafe,” he said. “It's important for doctors to feel comfortable understanding where they are in the vitreous and learning how to maximize that view.”

He and others are investigating the use of systems to track floaters more accurately in the vitreous and the use of the more efficient femtosecond laser rather than a YAG laser for floater treatment, which would decrease the number of laser sessions needed to destroy floaters.

With the current risks associated with both vitrectomy and laser vitreolysis, researchers are looking for new strategies to treat floaters.

Nanobubbles bust up floaters

Before presenting his research at the Academy of Medicine in Belgium years ago, Stefaan De Smedt, a drug delivery researcher at Ghent University, had never considered nanobubbles as the next frontier in eye floater treatment. He and his team were interested in using vapor nanobubbles, which are produced by shining a laser at nanoparticles, as a method to deliver nucleic acids into cells.

When scientists shine a laser of a certain frequency at nanoparticles that are close together, the nanoparticles absorb the energy from the laser, which heats up the solution surrounding the nanoparticles, causing the liquid to evaporate and create nanobubbles. These nanobubbles expand and then pop tens to hundreds of nanoseconds after they form (7), leading to the creation of a mechanical force that can poke a hole in a cell membrane.

“I was talking to an ophthalmologist, [and] he said maybe it could be useful as well to see whether this kind of nanobubbles could be valuable to destroy aggregates,” De Smedt said.

Intrigued by the possibility, De Smedt and his postdoctoral fellow Félix Sauvage began testing the ability of vapor nanobubbles produced by different kinds of nanoparticles to destroy the collagen aggregates that cause floaters. In a new study published in Nature Nanotechnology, De Smedt and Sauvage, working in collaboration with Sebag, Paulus, and others, reported the success of nanobubbles produced by gold nanoparticles and an ophthalmologic dye to destroy collagen aggregates in vivo for the first time (8).

The researchers demonstrated that both gold nanoparticles coated in hyaluronan and the ophthalmologic dye indocyanine green (ICG) preferentially bound to and destroyed human vitreous opacities that had been isolated from vitrectomy patients in Sebag’s practice. Because the particles specifically bound to the collagen aggregates, the creation of nanobubbles only occurred at the aggregates. This means that even if the laser shines on a place in the eye with no nanoparticles or dye, no nanobubbles will be created to potentially damage other structures in the eye.

“The threshold to generate bubbles is very high,” explained Sauvage. “We have a selective manner to trigger the generation of bubbles.”

Encouraged by how well their technology worked in an ex vivo system, De Smedt’s team searched for the best animal model to test it in vivo. This proved to be somewhat of a challenge, because, as Paulus quipped, “you don't have a mouse telling you that it has floaters in its vision.”

The team finally landed on rabbits with their relatively large eyes, which are closer in size to those of humans, making them ideal models.

De Smedt, Sauvage, and their colleagues injected rabbit eyes with collagen fibers to give the rabbits vitreous opacities, then they either injected the gold nanoparticles or ICG and shined laser pulses into the rabbits’ eyes. They found that they only needed to use an average of five laser pulses to completely remove the collagen aggregates.

“When we saw that data about how effective it was, it was pretty stunning to me,” said Paulus. When the team assessed the safety of their technique, they found that it had no adverse effects on the rabbits’ retinas.

Because the nanoparticles and dye bind directly to the collagen fibers, the researchers could remove the vitreous opacities from locations in the eye that would be impossible using a YAG laser, such as close to the retina. Similarly, the aggregation of the particles allowed the researchers to use a lower energy laser to induce nanobubbles than that required for a YAG laser to break up fibers, vastly improving safety. 

This technology also improves on vitrectomy because it does not require a risky surgery, rather simply an injection of nanoparticles or dye into the eye. Eye injections are a common procedure for vitreoretinal surgeons, Paulus added.

“It's taking two things that we do in essence almost independently — these eye injections and the laser — and combining them,” he said.

Moving forward, De Smedt and his team are interested in investigating the pharmacokinetics of their gold nanoparticles and ICG in humans. While both gold nanoparticles and ICG are biocompatible, only ICG is biodegradable, making it the more likely of the two to move forward into future human clinical trials.

“Certainly, there's additional work in terms of clinical trials that we need to do before this is readily available for everyone, but I think it would really be a game changer in terms of the ability to treat these floaters in a manner that's minimally invasive with low risk. And I think it would really transform our care for patients,” said Paulus.

Although De Smedt did not initially set out to develop new treatments for floaters, he now understands what a non-invasive and effective treatment would mean for people suffering from floaters. After his team published their first paper on nanoparticles and floaters (9), he and Sauvage received hundreds of questions from people all over the world asking about the potential of the technology to treat floaters.

“I try to imagine how it feels to open your eyes and to feel always depressed about the fact that you cannot really see,” De Smedt said. “It can contribute to giving vision back to people, which means to give quality of life.”

References

1. Kim, Y-K. et al. Psychological Distress in Patients with Symptomatic Vitreous Floaters. Journal of Ophthalmology  2017, 3191576 (2017).
2. Mamou, J. et al. Ultrasound-Based Quantification of Vitreous Floaters Correlates with Contrast Sensitivity and Quality of Life. Investigative Ophthalmology & Visual Science  56, 1611-1617 (2015).
3. Garcia, G.A. et al. Degradation of Contrast Sensitivity Function Following Posterior Vitreous Detachment. American Journal of Ophthalmology  172, 7-12 (2016).
4. Sebag, J. et al. Long-Term Safety and Efficacy of Limited Vitrectomy for Vision Degrading Vitreopathy Resulting from Vitreous Floaters. Ophthalmology Retina  2, 881-887 (2018).
5. Yee, K.M.P. et al. Incidence of Cataract Surgery after Vitrectomy for Vitreous Opacities. Ophthalmology Retina  1, 154-157 (2017).
6. Shah, C.P. & Heier, J.S. YAG Laser Vitreolysis vs Sham YAG Vitreolysis for Symptomatic Vitreous Floaters: A Randomized Clinical Trial. JAMA Ophthalmol  135, 918-923 (2017).
7. Xiong, R. et al. Comparison of gold nanoparticle mediated photoporation: vapor nanobubbles outperform direct heating for delivering macromolecules in live cells. ACS Nano  8, 6288-6296 (2014). 
8. Sauvage, F. et al. Laser-induced nanobubbles safely ablate vitreous opacities in vivo. Nat Nanotechnol (2022).
9. Sauvage, F. et al. Photoablation of Human Vitreous Opacities by Light-Induced Vapor Nanobubbles. ACS Nano  13, 8401-8416 (2019).