October 2018


Research highlight
New noninvasive refractive treatment on the horizon

by Liz Hillman EyeWorld Senior Staff Writer

New, noninvasive surgeries, such as epi-on PiXL (Avedro) shown here, hope to capitalize on corneal collagen crosslinking to correct refractive error.
Source: Anders Behndig, MD

“We are very confident in
our animal models. They are
—Sinisa Vukelic, PhD

Animal model tests of femtosecond laser crosslinking showed positive induction of steepening and flattening effects

Surgery in all specialties is continuing to move toward the least invasive modes possible, and refractive surgery is no exception.
Two methods are making headway based on the concept of collagen crosslinking to stiffen and change corneal shape, inducing a refractive change. Avedro (Waltham, Massachusetts) has been pioneering photorefractive intrastromal crosslinking (PiXL) for the last few years as a noninvasive method of topography-guided, accelerated crosslinking using riboflavin and UVA light for correction of low myopia. Another technique that had recently published results in an animal model, though clinical trials have not yet been conducted, is femtosecond laser crosslinking.
The research on the latter front, led by Sinisa Vukelic, PhD, Fu Foundation School of Engineering and Applied Science, Columbia University, New York, uses a femtosecond laser at low-energy pulses at a high-pulse rate to produce a low-density plasma that interacts with water molecules that are then broken, creating reactive oxygen species (ROS), or oxygen radicals, Dr. Vukelic explained to EyeWorld. These radicals interact with the collagen fibrils and form crosslinks, which leads to the known phenomenon of stiffening.
Dr. Vukelic thinks this technique could be used to induce customized myopic and hyperopic correction even to the depth of the posterior stroma, without having to remove the epithelium.
Dr. Vukelic and coinvestigators published their results of this technique on ex vivo and in vivo animal models in Nature Photonics.1 Fifteen ex vivo porcine eyes received a flattening treatment, which would be used to correct myopia, and 13 porcine eyes received a steepening treatment, as would correct hyperopia. Both groups were paired with control eyes, and a separate control study was conducted to evaluate the experimental setup. According to the paper, the depth of the treatment was about 220 µm.
In terms of the flattening effect, a 12% change in effective refractive power was seen within 8 hours after treatment. This lessened afterward as the cornea stabilized to a refractive power that was about 92% of the initial level, which Wang et al. equated to a 3.45 D shift. With the corneal steepening treatment, Wang et al. observed a steepening effect that increased gradually over 12 hours before stabilizing at a significantly higher effective power than baseline.
Histological examinations showed no laser-induced damage, and the crosslinking density after 1 week appeared stable, the researchers stated in the paper.
In vivo experiments on a rabbit model assessed effective refractive power at 24 hours, 7 days, and out to 3 months postop, using a similar treatment protocol as that performed on porcine eyes. At 48 hours postop, the myopic treatment group saw a mean 1.74 D change in effective refractive power, and a mean 1.64 D change in effective refractive power was observed by 7 days in the hyperopic treatment group. The study authors wrote that these changes remained stable out to 3 months postop and that there was “no wound or wound-healing response resembling that observed after other refractive surgery … and no collagen disorganization, epithelial cell and stromal [edema], intrastromal vacuole formation or endothelial cell detachment.”
“[A]ll these features are associated with thermal damage to stromal tissue, so we can thus conclude that no such damage occurred,” Wang et al. continued, adding later that confocal microscopy revealed endothelial cell shape and density appeared unchanged between the treated group and controls.
“We are very confident in our animal models. They are conclusive,” Dr. Vukelic said, adding that even in samples that weren’t ideal, the method of treatment proved successful every time.
At this point, he and coinvestigators are researching how to reduce treatment time from about 35 minutes to 5–6 minutes, Dr. Vukelic said, adding that he hopes to start a clinical trial sometime in the next year.
Research on PiXL, which is already available as a refractive treatment in Europe and Asia but not yet approved for use in the U.S., continues to progress as well. A paper session at the 2018 ASCRS•ASOA Annual Meeting included several presentations about photorefractive intrastromal crosslinking. One evaluated the safety and efficacy of PiXL with supplemental oxygen in 40 eyes of patients who were unwilling to have laser vision correction.2 The mean change in manifest refraction from baseline was 1.18 +/–0.5 D at 3 months postop and UDVA change was logMAR 0.526. According to this research, 78.3% of eyes were UCDVA 20/25 or better at 3 months without significant regression, hyperopic shift, endothelial cell loss, or loss of best corrected visual acuity due to haze. Another paper looked at the safety and efficacy of PiXL with supplemental oxygen with targeted, high-dose, pulsed, accelerated application. At 6 months, the mean change in manifest refraction of the 21 eyes in 11 patients was 1.6 D from baseline; there was a 1.8 D shift in spherical equivalent from baseline. UCVA improved by a mean of four lines, and there was no significant change in endothelial cell density or number of cells.3 Lim et al. published results in 2017 showing the efficacy and stability of PiXL out to 12 months for treatment of low myopia.4


1. Wang C, et al. Femtosecond laser crosslinking of the cornea for non-invasive vision correction. Nature Photonics. 2018;12:416–422.
2. Sachdev GS, Ramamurthy S. Photorefractive intrastromal crosslinking for the treatment of low myopia. 2018 ASCRS•ASOA Annual Meeting.
3. Elling Em, Dick HB. Epithelium-on photorefractive intrastromal CXL with supplemental oxygen for low myopic refractive error: six-month results. 2018 ASCRS•ASOA Annual Meeting.
4. Lim WK, et al. Epithelium-on photorefractive intrastromal crosslinking (PiXL) for reduction of low myopia. Clin Ophthalmol. 2017;11:1205–1211.
Editors’ note: Dr. Vukelic has no financial interests related to his comments.

Contact information

Vukelic: sv2147@columbia.edu

New noninvasive refractive treatment on the horizon New noninvasive refractive treatment on the horizon
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