January 2019


Crosslinking playbook
Future directions of CXL

by Chiles Aedam R. Samaniego EyeWorld Asia-Pacific Senior Staff Writer

Crosslinking with Avedro KXL device is the only FDA-approved therapy to slow the progression of ectasia.

Crosslinking has become a new standard of care for patients diagnosed with progressive keratoconus.

At this time, riboflavin is the gold standard for clinical use due to its excellent clinical track record and well-known safety and efficacy properties.
Source (all): Vance Thompson, MD


Ophthalmologists look ahead at the future of crosslinking

According to Vance Thompson, MD, Vance Thompson Vision, Sioux Falls, South Dakota, “Crosslinking [CXL] with the Avedro KXL device [Waltham, Massachusetts] is the only FDA approved therapy to slow the progression of ectasia.
“Progression results in reduction of visual acuity that becomes increasingly difficult to manage with scleral or specialty contact lenses, and if not controlled, it may result in corneal transplantation,” he said.
Despite being first described more than 20 years ago, “crosslinking continues to generate a tremendous amount of research interest around the world,” Dr. Thompson added.
EyeWorld corresponded with Dr. Thompson, as well as Jack Parker, MD, PhD, Parker Cornea, Birmingham, Alabama, and Jorge Alió, MD, professor and chairman of ophthalmology, University of Alicante, Spain, to find out where this research is taking the procedure.

In practice

While Dr. Thompson performs epi-off CXL for patients with progressive keratoconus and corneal ectasia using the Avedro KXL device with the Photrexa riboflavin formulations, the practice is also participating in an Avedro-sponsored Phase 3 clinical trial to evaluate an approach to epithelium-on CXL. “Optimization of epi-on protocols for the treatment of keratoconus is an especially hot topic today,” he said.
Dr. Parker (together with John Parker, MD) operates the Keratoconus Center of Alabama, hence, CXL is “an indispensable part of our practice,” he said. “It’s useful not only for our keratoconic patients with documented progression, but also for individuals with pellucid marginal degeneration and post-LASIK ectasia.”
However, Dr. Parker said that the procedure might only be effective in mild to moderate disease. “In patients with more severe ectasia, other techniques (for example, Intacs [Addition Technology, Lombard, Illinois], DALK, or Bowman’s layer transplantation) may be superior options,” he said.
Dr. Alió, often cited for his research on the topic, detailed his approach to CXL. “I use CXL in my practice in all keratoconus that is suspicious of evolution, either demonstrated by objective methods or if the patient is under 30,” he said. “In patients over 40, I make a follow-up observation of the case, even though more and more I think that we should do crosslinking in these patients, especially if they have a decrease in best corrected visual acuity.”
Dr. Alió follows the Dresden protocol for clearly progressing keratoconus or in the high-risk age group but performs epi-on in patients over 35 in whom progression is doubtful or who may have problems with follow-up. “I perform epi-on crosslinking making [a] few scratches in the epithelium to enhance the penetration of riboflavin,” he added. “This increases the penetration of the riboflavin and increases the effect of the UV light to the superficial 150 microns stroma, which seems to be sufficient in many patients to have the effect.”

Evaluating biomechanics

The clinical evaluation of corneal biomechanics is currently lacking. “Accurate measurement of corneal biomechanics in a real world clinical environment remains a challenge today,” Dr. Thompson said. “We make most of our daily decisions based on topographic and tomographic data from a Pentacam system [Oculus, Wetzlar, Germany].”
While corneal tomographers do not assess true biomechanics, they provide morphologic information on curvature and elevation that can be used to assess disease severity and localization. Meanwhile, devices such as the Corvis ST (Oculus) and Ocular Response Analyzer (Reichert Technologies, Depew, New York) derive additional data on biomechanical strength from the cornea’s dynamic response to an air puff, representing a more comprehensive picture of the state of the cornea.
In terms of research, Dr. Thompson noted that Brillouin spectroscopy and OCT biomechanical assessment may provide better tools for mapping the strength of the cornea in three dimensions.
Dr. Alió emphasized the value of biomechanics measuring devices in research, noting that “the cost benefit of their use is negative for the practical clinician.” This does not devalue their application in clinical research, but in practice, “you do not need them for good treatment of keratoconus.”


Research on epi-on protocols highlights the role of oxygen in CXL. “Recent studies have shown that oxygen plays a key role in regulating the amount of crosslinking that we can induce, particularly when accelerated protocols are applied in epi-on treatments,” Dr. Thompson said. “Avedro is currently enrolling patients in a multicenter, sham-controlled Phase 3 clinical study in the United States to evaluate the use of supplemental oxygen, pulsed high irradiance light, and a transepithelial riboflavin formulation in progressive keratoconus patients.”
Dr. Alió thinks these “accelerated” or “fast protocols” will be used more in the future, making the procedure more effective and reducing treatment time.
Meanwhile, Dr. Parker noted, “Modifications and alternatives to the original Dresden protocol are pouring in.”
“If some method for enabling ‘epi-on’ crosslinking to achieve the same effect as the standard ‘epi-off’ technique could be found, that would decisively change the way the procedure is performed,” he said.


Research is also currently underway to find alternatives to different components of the current procedure.
“Crosslinking will benefit in the future from the advances that will substitute the ultraviolet light, with its proven toxic effects, for other types of energies or biochemical products or nanosubstances,” Dr. Alió said. “We have been working for several years in the application of nanotechnology to the treatment of keratoconus,1 which seems to be, in my opinion, a very promising technique. Other non-light dependent systems are being developed worldwide.”
The substitution of riboflavin, however, while possible, seems unlikely. “Several other photoactive compounds have been described in the literature as alternatives to riboflavin,” Dr. Thompson said. “Some of these agents absorb light at different wavelengths, such as rose bengal, which mainly absorbs green light. This is interesting but may present a different challenge for retinal safety compared to riboflavin. The ability of any crosslinking compound to effectively cross the epithelium is a very important property that remains to be evaluated with these new molecules.”
None of these alternative compounds have been evaluated in large enough studies to give a clear idea of their potential advantages and disadvantages. “For the time being, riboflavin is the gold standard for clinical use due to its excellent clinical track record and well-known safety and efficacy properties,” Dr. Thompson said.
Dr. Alió doesn’t see riboflavin being replaced in the near future. “Probably in the future new CXL substances will appear when a total change in paradigm in the treatment of keratoconus appears, knowing better how to deal with the collagen fibers to strengthen them in a different way,” he said.
“Riboflavin is so effective, and so well studied, there may be little motivation to find an alternative chemical solution, aside from the price of the riboflavin itself, which is more a function of corporate pricing decisions than ‘production cost’ of the solution,” Dr. Parker said.

Expanding indications

Experience with CXL has also led to some expanding indications. “I have been following the development of refractive applications of CXL with interest, particularly the PiXL procedure,” Dr. Thompson said. “Preliminary studies from international colleagues have demonstrated that crosslinking can induce predictable refractive change in normal corneas, and we are eagerly anticipating larger scale trials to evaluate this noninvasive refractive technology.”
The stroma is loaded with riboflavin and a zonal UV pattern is applied, creating regional differences in corneal biomechanics. Combined with advanced epi-on treatment strategies, the cornea can thus be reshaped without adding or removing tissue.
“The noninvasive nature of this procedure could make it particularly appealing to early presbyopes, and we can also envision potential applications for patients who have undergone prior refractive surgery and have ‘aged out,’ now requiring add power for near and not wanting to return to spectacle wear,” Dr. Thompson said.
Dr. Alió sees the indications of CXL expanding to include a supplemental role in corneal infections. “We have important and good experience in using CXL for corneal infection but always associated with the topical treatment, which is very much enhanced in its effectivity thanks to CXL,” he said. “I do not think that CXL alone will be the way to treat corneal infections.”
Dr. Alió cited scleral CXL as another potential application, while Dr. Parker went even further, wondering if the technology might not expand to tissues outside the eye. “What other stressed connective tissues in the body could use some non-invasive strengthening?” he asked.

Stem cells

“At first blush, it’s not obvious how stem cells would help. In patients with keratoconus, the cornea is mechanically stretched into some distorted conformation, and there’s scarring, and it’s not entirely clear what stem cells would do about either of those problems,” Dr. Parker said. “On the other hand, the cornea may possess a surprising ability to rebound back to normal shape and strength, given the right stimulus. For example, rarely, pregnancy may trigger the development of keratoconus. Nevertheless, after delivery, the cornea almost always returns to its previous configuration. To my knowledge, no one currently understands how that happens, but it suggests that there is some chemical pathway for flattening and stabilizing ectasia.”
Dr. Alió is actively researching stem cells and CXL, with published results for Phase 2 and 3 clinical trials.2,3 Preliminary results suggest that adipose-derived stem cells implanted into a stromal pocket differentiate into keratocytes and may produce new extracellular matrix.
Their 1-year data is currently under peer review.
Dr. Alió thinks that the corneal stromal regeneration that stem cells may facilitate will change the paradigm of CXL. “I am sure that in the future corneal transplantation will be avoided in most cases thanks to the use of stem cells,” he said.

Bowman’s layer transplantation

Physicians are divided on Bowman’s layer transplantation. While Dr. Thompson considers the technique experimental, citing the advantages as an acellular graft and a sutureless procedure, Dr. Alió is skeptical. “I do not think the use of Bowman’s layer will solve the problem of keratoconus but rather the therapy of the diseased cells, the keratocytes, which are those responsible for keratoconus,” he said. “Bowman’s layer transplantation is too complicated and not clear in its outcomes, which are complicated and only partially consistent.”
On the other hand, the procedure is Dr. Parker’s preferred option for patients with advanced, progressive keratoconus. “By supplementing the keratoconic cornea with the strongest layer from a healthy donor cornea (the Bowman’s layer), the progression of the patient’s ectasia is almost always arrested,” he said. “In addition, a significant flattening of the patient’s cornea is usually achieved, on average, ~9 D. This amount of flattening frequently enables patients to comfortably wear their contact lenses and achieve satisfactory vision. At the same time, it spares them the more invasive alternatives of full or nearly full thickness keratoplasty.”
Whichever way research ultimately takes CXL, Dr. Thompson highlighted the importance of catching patients who would benefit from the procedure as early as possible. “Our goal is to slow the progression of ectasia before we lose the ability to bring patients to their full visual potential, and therefore, we think it is of great benefit to catch these patients early, watch them closely for progression, and to treat with CXL as soon as it is indicated,” he said. “Hopefully, we are getting better at catching more of our keratoconus patients earlier and stabilizing progression with CXL before more extreme measures are needed.”


1. Vega-Estrada A, et al. Biocompatibility and biomechanical effect of single wall carbon nanotubes implanted in the corneal stroma: a proof of concept investigation. J Ophthalmol. 2016;2016:4041767.
2. Alió Del Barrio JL, et al. Cellular therapy with human autologous adipose-derived adult stem cells for advanced keratoconus. Cornea. 2017;36:952–960.
3. Alió Del Barrio JL, et al. Corneal stroma enhancement with decellularized stromal laminas with or without stem cell recellularization for advanced keratoconus. Am J Ophthalmol. 2018;186:47–58.

Editors’ note: Dr. Thompson has financial interests with Avedro. Dr. Alió and Dr. Parker have no financial interests related to their comments.

Contact information

: jlalio@vissum.com
Parker: jack.parker@gmail.com
Thompson: vance.thompson@vancethompsonvision.com

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