The safest floating treatments come with an explosion of nanobubbles (2023)

Sometimes they sit out of sight in the corner of your eye. Other times, they loom over your field of vision, and when you shift your gaze to look at them, they are out of sight. These annoying obstructions, commonly known as floaters, are a visual phenomenon caused by small clumps of collagen in the eye called vitreous opacities.

Although floaters are very common, they are usually so subtle that people ignore them. However, floaters can sometimes be so dark and numerous that they obscure much of a person's vision. These heavy floaters interfere with people's ability to drive, work, and just enjoy life, which often leads to this.Depression(1).

"There are millions of people around the world who suffer from floaters," said Yannis Paulus, a vitreoretinal surgeon and clinical scientist at the University of Michigan. "Right now, they're stuck with bad options," he added. The only available treatments come with a significant number of risks.

These treatments include vitrectomy, the surgical removal of the clear, gelatinous vitreous humor of the eye that contains clumps of collagen, and laser vitreolysis, which uses high-energy light pulses to separate the fibers. Vitrectomy is more effective than laser vitreolysis, but patients have experienced retinal tears, retinal detachments, and vitreous hemorrhage with both treatments.

As scientists investigate how laser vitrectomy and vitreolysis can be made safer and more effective, they are also developing new nanobubble-based technologies that could be even safer and less invasive than current treatments and improve the quality of life for many people in everyone. the world that suffers from annoying floaters.

collagen lumps

The most common cause of floaters is simply aging. In young eyes, collagen fibers attached to hyaluronic acid molecules hold together the gelatinous structure of the vitreous body. As we age, collagen and hyaluronan begin to dissociate and the gel becomes more fluid, causing the collagen fibers in the vitreous to collapse on top of each other, forming clumps that feel like floaters.

People over the age of 60 often begin to see more floaters as the vitreous separates from the back of the eye in a phenomenon called posterior vitreous detachment. However, because this compensation process is faster in people with myopia, nearsighted people in their 20s, 30s, and 40s can also experience floaters.

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In people who notice a sudden rash of many new floaters, ophthalmologists first look for signs of retinal detachment or injury to the eye. But after ruling out an acute cause, doctors usually suggest that patients wait a few weeks or months to see if their floaters seem to go away or become less noticeable. Usually, people undergo some neuroadaptation, and the brain shuts off the floaters. But when floaters don't get better and continue to interfere with daily life, people turn to their doctors for help.

"Unfortunately, the most common form of treatment is to rule them out and ignore them, sending the patient home frustrated and unhappy," said Jerry Sebag, a vitreoretinal surgeon and floater researcher at the Vitreous Macula Retina (VMR) Institute. "I realized that these patients are being discharged because we couldn't determine if they really have a problem or if they're just overreacting to something we're all experiencing."

Sebag and his colleagues developed quantitative assessments to measure how floaters affect people's vision. They showed that they could use itquantitative ultrasoundcharacterize the density of the entire vitreous, with floaters appearing as points and lines of greater density (2). Sebag's team also reported that floaters reduced thecontrast sensitivity, meaning that people with swimmers were less able to distinguish differences in shading and pattern (3).

"With a quantitative component, you can classify conditions as mild, moderate, and severe," Sebag said. "It allowed me to select patients for treatment."

Surgical incisions remove floaters

The most effective way to treat floaters is to physically remove them. In an operation 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 with vitrectomy, “you can usually identify these problems during surgery. If you see a torn retina, you can laser it during surgery," said Jason Hsu, a vitreoretinal surgeon and researcher at Thomas Jefferson University.

Recently, vitreoretinal surgeons have made improvements to vitrectomies to make these retinal tears less likely. For example, they now use smaller instruments to perform surgery, which means they can make smaller incisions. Sebag adapted his vitrectomy procedure with this modification and improved the method so that there is no posterior vitreous detachment during the operation. With these security modifications, the Sebag team reported in aclinical studyof 195 eyes of 145 patients, vitrectomy resulted in a 94.1% reduction in vitreous echodensity, indicating successful removal of the vitreous opacities that cause their appearance (4). The patient's contrast sensitivity also improved postoperatively to the level of healthy control eyes. Of the 195 operated eyes, there were three retinal tears and three retinal detachments, but these were successfully repaired during surgery.

Although vitrectomy is relatively safe and effective in treating severe floaters, it increases the risk of developing them.waterfalls(5). For this reason, and because other long-term risks of vitrectomy are unknown, Sebag and other vitreoretinal surgeons are reluctant to operate on younger patients.

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

An explosion in the eye

Rather than physically remove the vitreous opacities that floaters cause, some optometrists have attempted to destroy them with pulses from a yttrium aluminum garnet (YAG) laser.

"It's not like a typical laser beam that we think of in Star Wars or anything where it burns tissue. The YAG laser is like a little explosion in the eye," Hsu said. "It's almost like vaporizing a piece of tissue with this highly concentrated energy." This process breaks large collagen aggregates into smaller pieces, reducing the occurrence of floaters.

Ophthalmologists have used YAG lasers for decades to remove cloudy layers of scar tissue that form after cataract surgery and when treating certain types of glaucoma, but their use to treat floaters is relatively new and somewhat controversial.

in the onlyclinical studySo far, the efficacy of YAG laser vitreolysis in floaters has been studied. 54% of patients who received the YAG treatment reported an improvement in the appearance of floaters (6). None of the study patients experienced side effects.

However, YAG laser treatment carries significant risks. The laser energies required to destroy the fibers that cause floaters are double or triple the energies used for the other, more routine applications of YAG lasers. Even with the highest energy laser pulses, a person may need to go through several YAG laser treatment sessions to effectively remove a problem floater. In some cases, surgeons have focused the laser too close to the front or back of the eye, directly damaging the lens or retina.

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

"Not all floaters are good candidates for YAG laser vitreolysis," he said, but if, for example, "the floaters are in the middle of the vitreous, where signs and symptoms can be correlated well, it may be a fantastic opportunity to avoid something like a vitrectomy and not let [the patient] suffer if they live with it.”

While Singh has been very successful in treating floaters with YAG vitreolysis in his practice, many other physicians have not.

"There is no protocol for using the YAG laser, either in terms of patient selection or in terms of how to actually deliver the treatment in a scientifically reproducible way," Sebag said. She is organizing a study on how to make YAG vitreolysis more reproducible and safe by using quantitative ultrasound to measure results, among other methods.

Singh agreed that proper training on how to perform YAG vitreolysis is an essential part of successful floater treatment.

“The laser is not unsafe. We as clinicians can feel insecure," she said. "It's important for clinicians to understand where they are in the vitreous and learn how to maximize that view."

He and others are investigating the use of systems to more accurately track floaters in the vitreous and the use of the more efficient femtosecond laser instead of a YAG laser to treat floaters, which would reduce the number of laser sessions. needed to destroy floaters.

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

Nanobubbles explode floats

Before Stefaan De Smedt, a drug delivery researcher at Ghent University, presented his research years ago at the Belgian Academy of Medicine, he had never considered nanobubbles as the next frontier in eye blister treatment. He and his team were interested in using vapor nanobubbles, generated by aiming a laser at nanoparticles, as a method of delivering nucleic acids into cells.

When scientists shine a laser at a specific frequency at closely spaced nanoparticles, the nanoparticles absorb the energy from the laser, which heats the solution surrounding the nanoparticles, causing the liquid to vaporize and nanobubbles to form. These nanobubbles expand and then burst into dozens or hundreds.nanoseconds after they are formed (7), resulting in the generation of a mechanical force that can puncture a hole in a cell membrane.

"I spoke to an ophthalmologist, [and] he said it might also be useful to see if these types of nanobubbles might be of value in disrupting aggregates," De Smedt said.

Intrigued by this possibility, De Smedt and his postdoc Félix Sauvage began testing the ability of nanobubbles of vapor generated by different types of nanoparticles to destroy the collagen aggregations that cause floaters. in a new onelearnPublished innature's nanotechnology, De Smedt, and Sauvage, in collaboration with Sebag, Paulus, and others, reported the success of nanobubbles made of gold nanoparticles and an ophthalmic dye in breaking up collagen aggregates.livefor the first time (8).

The researchers demonstrated that both hyaluronan-coated gold nanoparticles and indocyanine green (ICG) ophthalmic dye preferentially bind to and disrupt human vitreous opacities isolated from vitrectomy patients in Sebag's practice. Because the particles are specifically bound to the collagen aggregates, nanobubble formation occurred only in the aggregates. This means that even if the laser shines on a spot in the eye without nanoparticles or dyes, it does not create nanobubbles that could damage other structures in the eye.

"The threshold for creating bubbles is very high," Sauvage explains. "We have a selective method to trigger bubble generation."

Emboldened by how well their technology worked on oneex vivosystem, De Smedt's team searched for the best animal model to test it.live. This proved challenging because, as Paul quipped, "you don't have a mouse telling you he has floaters in his vision."

The team ultimately ended up with rabbits, with their relatively large eyes that are more human-like, making them ideal models.

De Smedt, Sauvage and their colleagues injected collagen fibers into the rabbits' eyes to give them vitreous opacities, then injected gold nanoparticles, or ICGs, and shined laser pulses into the rabbits' eyes. They found that they only had to use an average of five laser pulses to completely remove the collagen aggregates.

"When we saw these data on its efficacy, I was pretty stunned," Paulus said. When the team tested the safety of his technique, he found that it had no adverse effects on the rabbits' retinas.

Because the nanoparticles and dye bind directly to collagen fibers, the researchers were able to remove vitreous opacities in places in the eye that would not be possible with a YAG laser, such as near the retina. Similarly, aggregating the particles allowed the researchers to use a lower energy laser to induce nanobubbles than would be needed for a YAG laser to disrupt the fibers, greatly improving safety.

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

"It's about taking two things that we essentially do almost independently, these ocular injections and the laser, and combining them," he said.

In the future, De Smedt and his team are interested in studying the pharmacokinetics of their gold nanoparticles and ICG in humans. While both gold nanoparticles and ICG are biocompatible, only ICG is biodegradable, making it more likely to progress to future human clinical trials.

"Certainly we still need to do more clinical trials before this is available to everyone, but I think it would really be a game changer in terms of the ability to treat these floaters in a low-risk, minimally invasive way." And I think it would really transform our patient care," Paulus said.

Although De Smedt did not initially plan 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 released theirsfirst roleOn nanoparticles and buoyancy aids (9), he and Sauvage received hundreds of questions from people around the world about the potential of technology to treat buoyancy aids.

"I try to imagine how it feels to open your eyes and always be depressed because you can't really see," De Smedt said. "It can help people get their sight back, which means giving them back their quality of life."

references

1. Kim, Y-K.et al.Psychological distress in patients with symptomatic vitreous opacities.Journal of Ophthalmology2017, 3191576 (2017).
2. Mamu, Jet al.Ultrasound-based quantification of vitreous floaters correlates with contrast sensitivity and quality of life.Research Ophthalmology and Visual Science 56, 1611-1617 (2015).
3. García, G.A.et al.Impaired contrast sensitivity function after a 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 visual impairment of vitreopathy secondary to vitreous floaters.retinal ophthalmology 2, 881–887 (2018).
5. Yo, K.M.P.et al.Incidence of cataract surgery after vitrectomy for vitreous opacities.retinal ophthalmology 1, 154-157 (2017).
6. Schah, CP and Heier, JS Laser-YAG vitreolysis versus sham-YAG vitreolysis in symptomatic vitreous swimmers: a randomized clinical trial.JAMA Oftalmol135, 918–923 (2017).
7. Xiong, R.et al.Comparison of gold nanoparticle-mediated photoporation: vapor nanobubbles overcome direct heating to deliver macromolecules into living cells.ACS-Nano 8, 6288-6296 (2014).
8. save, f.et al.Laser-induced nanobubbles safely remove vitreous opacities in vivo.natural nanotechnology(2022).
9. save, f.et al.Photoablation of human vitreous opacities by light-induced vapor nanobubbles.ACS-Nano 13, 8401-8416 (2019).