Corneal allogenic intrastromal ring segments, or CAIRS, have been gaining momentum over the years as a minimally invasive procedure for treating keratoconus and corneal ectasia.

"CAIRS is a type of mid-peripheral, mid-stromal additive lamellar keratoplasty. However, unlike other keratoplasties and even unlike all other treatments for keratoconus, CAIRS is a very high-reward, low-risk surgery. Very few procedures have that benefit, and the learning curve is very simple," Soosan Jacob, MS, FRCS, DNB, said.

In 2015, Jacob developed the CAIRS technique and has since introduced several refinements, designed the instruments to perform it and saw it become progressively widespread globally, inspiring colleagues to introduce variations.

"I am very happy about the amount of research and development that is happening because everyone is trying to advance the field, which will ultimately result in everybody's benefit," she said.

Jacob thought of CAIRS as a way to overcome the problems in treating patients with keratoconus, be it the complications of PMMA ring segments, which she had been using previously, or the difficulties associated with deep anterior lamellar keratoplasty.

"In the case of synthetic ring segments, they had an effect, and the patients were happy initially, but quite a few of them came back with complications," she said. "At that time, I was working with allogeneic tissues, and the two ideas I had were presbyopic allogenic refractive lenticule (PEARL) for the treatment of presbyopia and CAIRS for the treatment of keratoconus.'"

Jacob soon developed the instruments to cut and insert the donor tissue, figuring out the channel size and depth, the location, the amount of hydration, as well as the arc, shape, thickness and volume of the segments.

"We soon realized that the mechanism of action was different from synthetic rings that work by stretching the cornea," she said. "CAIRS work by volume expansion and required a completely different nomogram. In 2017, we started by customizing the arc length, the thickness, the optical zone and the depth of implantation. This was good, but there was still something missing. We were using broadly similar rings to treat different types of keratoconus patients. But keratoconus patients vary wildly even within the same phenotype, so how could similar arc lengths and thicknesses work for different types of cones? So, 1 year later, we customized them even further by custom shaping them, looking at individual, small variations within the cone of each eye, even in the same patient."

Custom-shaped CAIRS showed a better ability to regularize the cornea, recenter the cone and improve vision. Jacob uses the Jacob nomogram for custom shaping. She is also working on releasing software that would soon allow custom shaping of CAIRS to be available to all surgeons.

"I am very interested in working with eye banks to allow them to provide custom-shaped CAIRS to their surgeons, ready to implant," she said. "Currently, I partner with Lions World Vision Institute and Beauty of Sight but would love to offer the benefits of this procedure to patients worldwide through more eye banks."

In 2020, when Jacob applied for a patent for CAIRS, she was the only one to use the segments and included in her application all the options she could envisage, including different ways of cutting and preserving the segments, manual and femtosecond dissection, and the use of cross-linking. She tried all these different options, but her conclusion was that the manual technique, with the dedicated trephine she had designed, was still the best for a truly customized procedure.

"In a living eye, you can achieve extreme precision with the laser, but cadaver eyes behave in a different way and may have edema and different levels of hydration. When you use a femtosecond laser on a cadaver eye, you don't have the same level of accuracy, certainly no more as compared to a trephine. This is because of variable hydration, lack of centration guides and often not going full thickness," Jacob said.

The femtosecond laser is also an added cost and is more time-consuming because it requires setting all the parameters, entering them into the machine and applying the suction.

"With the manual procedure, after removing the epithelium and endothelium, I simply press down the trephine to obtain the ring of tissue and then put the customization marks and cut along the marked points with a 15° blade. It takes me about 1 minute to do so," Jacob said.

In addition, the femtosecond laser poses some limitations in terms of the shapes that can be cut, she said.

"It cannot cut all the shapes that I am able to cut manually, exactly tailored to the patient," she said. "There's a lot of calculation involved to be able to get a cut at a certain angle, a certain thickness, and then suddenly change the shape to another angle. It requires a lot of input into the machine. Maybe in the future some of these problems would be overcome, and I am currently also working with a femtosecond laser company trying to do so."

Another problem Jacob sees is that procedures that are the same as CAIRS are being introduced as new procedures and with new names, leading to confusion in terminology among both patients and surgeons alike.

"One such example is CTAK, which was started as a circular disc placed into a corneal pocket to treat keratoconus," she said. "It later evolved into CAIRS, which was partly customized for length and thickness alone, was femtosecond cut using a nomogram and was sterilized. These three properties were, however, already widely available with CAIRS at the time, including precise customization and custom shaping because CAIRS was being utilized around the world for many years. CTAK is partially customized CAIRS without the advantages of custom shaping. However, there is widespread confusion that it is a new type of technique to treat keratoconus that is different from CAIRS. Labeling it as something different can cause serious confusion and mislead patients and even surgeons, as already seen happening."

Shady Awwad, MD, was immediately attracted by the CAIRS technique when Jacob presented it in 2017 at the Indian Intraocular Implant & Refractive Surgery meeting.

"A few months later, I had an informal meeting with her and Amar Agarwal and made the decision to introduce CAIRS in my practice," Awwad said. "In Lebanon, keratoconus is highly prevalent, so I treated a lot of patients, and in 2020, I introduced some changes in the technique to make insertion easier."

By dehydrating the segments for a little more than 1 hour before the start of the procedure, Awwad made them rigid enough to be held and inserted without losing shape. He initially called this technique "corneal jerky" and then "extended dehydration."

"They get hard but pliable, like a biopolymer, and a little bit thinner, and we implant them in a normal-sized tunnel where they rehydrate after irrigation of the eye with balanced salt solution," he said.

Another pivotal change he introduced was the development of dedicated software for cutting the segments using a femtosecond laser.

"I had the idea of using the laser right from the start, but at the time, Ziemer was not interested," Awwad said. "Meanwhile, Bader Khayat in Germany and David Gunn in Australia started using the laser, but without dedicated software, the procedure was long and cumbersome, and it was not possible to produce asymmetric, customized segments."

In 2021, Fabian Müller, an engineer at Ziemer, approached Awwad and embraced his project. Together, they developed software for cutting asymmetric allogenic segments using a femtosecond laser, and they fine-tuned the procedure and started scheduling patients, obtaining good outcomes.

"Asymmetric segments were on top of my list to treat certain phenotypes of keratoconus like snowman and duck in which the astigmatism does not align with the coma," Awwad said. "By using the traditional uniform segments, you might flatten the cone and improve coma but at the expense of increasing dramatically the astigmatism. Asymmetrical segments are perfect to treat these phenotypes that we see in 7% to 10% of patients."

The femtosecond laser procedure has an additional cost, and Awwad is not using it in all his patients.

"The femtosecond procedure shines in cutting asymmetrical segments because you need that kind of precision," he said. "If you want to cut just regular segments -- that is 90% of what you do, honestly -- mechanical cutting is still a great choice, and it is cheaper. But femto is there, and we like to continue pushing it because that is how innovation starts."

"When Shady Awwad translated Soosan Jacob's CAIRS to the femtosecond laser, we started introducing the procedure at the ELZA Institute," Farhad Hafezi, MD, PhD, said. "Ziemer is 1 hour away from us, and my colleague Emilio Torres-Netto had previous experience with PMMA rings."

Hafezi introduced yet another variation to the procedure as an alternative to Awwad's extended dehydration. To make insertion easier, and at the same time eliminate any risk for infection and rejection, Hafezi applied a modified cross-linking technique to the donor.

"I was also concerned about the chance of implanting tissue from a donor with keratoconus, and the answer was cross-linking," he said. "My friend Cosimo Mazzotta had the same idea, even before us, but what we developed was a specific nomogram with 10 times the normal energy. Because you are outside the human body, there is nothing you can harm, and the corneal tissue becomes as stiff as a piece of plastic, very easy to implant and sterile."

A further advantage is that the cross-linked segments do not swell during insertion but swell gradually, within a few days after the procedure. This allows for the insertion of whatever amount of volume is needed for the individual cornea.

"OCT elastography measurements showed us that it is the volume to produce the flattening effect, and in some cases, we might need to insert a big volume into a tiny tunnel," he said.

Hafezi called this strategy ECO-CAIRS, short for "extracorporeal optimization of corneal allogenic intrastromal ring segments."

Some years ago, Emilio Torres-Netto, MD, PhD, performed his first elastography studies on PMMA rings to understand their biomechanical effects on the cornea and possibly optimize their performance.

"We have different nomograms according to the manufacturers, and precision and predictability are not so high as we would like in refractive procedures. We often have surprises after implantation," he said.

In one of these studies, segments with arc length of 120°, 210° or 325° were implanted in model eyes. A relaxation effect was observed inside the area of the rings, increasingly prominent with the longer arc lengths and smaller optical zones.

"We did the same with femto-CAIRS, and we could not observe the same stress distribution and relaxation in the inner part of the corneal rings," Torres-Netto said. "We need more studies, but what we can say is that the rings made of human tissue were very close to the biomechanical behavior of the patient's cornea. They don't induce the unnatural stretching that PMMA rings induce."

These results lead to two important conclusions. First is that the nomograms that have been used so far for synthetic rings cannot be applied to femto-CAIRS.

"The other conclusion is that the changes that we see with femto-CAIRS are probably more related to the addition of volume that the femto-CAIRS provide rather than the biomechanical or stress distribution changes," Torres-Netto said.

Aylin Kiliç, MD, was a pioneer in the use of PMMA rings. They were part of her standard toolbox, and she appreciated the benefits they brought to patients with keratoconus who did not have many options. But she also saw their limitations.

"The rigid nature of PMMA rings simply didn't match the unpredictable, living behavior of the keratoconic cornea," she said. "They lack predictability and carry the risk of stromal melting, extrusion and migration. I remember thinking that there must be a better way. Something more natural. Something that works with the cornea, not against it."

The publication of Jacob's first results with CAIRS was a turning point. At the time, Kiliç was working with VisionGift and Allotex, exploring the use of allogenic corneal tissue for several applications.

"That's when the idea came: What if we could take the concept of intracorneal ring segments in a package?" she said.

Together with VisionGift, Kiliç developed KeraNatural corneal allogenic intrastromal ring segments -- packaged, standardized, designed specifically for keratoconus and with a 2-year shelf life.

"They are ready to use. There's no need to handle or prepare anything in the operating room," she said. "This not only saves time but also dramatically improves sterility and reproducibility. It makes the procedure more streamlined and more accessible for surgeons in different settings."

Over the years, Kiliç and her team developed the Istanbul nomogram, a topography-guided system that allows for personalized treatment while maintaining some critical standards for consistency.

"We always use a femtosecond laser to create a standardized stromal tunnel, 4 mm to 7.5 mm in diameter at a depth of 250 µm. This gives us a stable foundation," she said. "But where the real customization happens is in the choice of the allograft segment. Its thickness, arc length and positioning are all adjusted based on the individual patient's corneal behavior and topographic pattern. That's what makes the nomogram so effective -- it blends structure with flexibility."

The large, superficial channels make it easy to insert the soft tissue of CAIRS and remove them if necessary without the need for drying or cross-linking to create stiffer inserts.

"We changed from PMMA to tissue. Why should we now insert tissue that is as rigid as plastic and stretch the cornea?" Kiliç said. "I want to make surgery more reversible, more adjustable, and I don't want to stretch the cornea. This is my main point. All techniques are working very well, but long-term management is very important."

OSN Cornea/External Disease Board Member David R. Hardten, MD, FACS, was also not fully satisfied with PMMA rings, mainly because they challenged the fitting of contact lenses. When Jacob described CAIRS, he started using them.

"In our practice, we call the procedure anterior lamellar keratoplasty with regional segments (ALKRS), mainly for insurance reasons, but it is essentially the same as CAIRS," he said. "It was a big evolution from PMMA rings. Contact lens fitting was no longer a problem, and the tissue could be customized, thicker or thinner, or broader, longer or shorter."

Cutting, trimming and inserting the soft eye bank tissue by hand was, however, a little challenging. When CorneaGen started producing CTAK femtosecond laser-cut segments, customized on the Oculus Pentacam data of individual patients, Hardten welcomed this novel opportunity and started treating even more patients. CTAK, short for corneal tissue addition keratoplasty, is often used in the United States as an alternative way of naming CAIRS in one of the many iterations aimed at making the procedure easier and more accessible.

"I think of CTAK as an evolution of that technology, as a brand name, so it's like saying Kleenex vs. facial tissues," Hardten said. "We don't actually call it CTAK in our practice. We continue calling it ALKRS because there is not an insurance code for CTAK or CAIRS. And you are adding tissue to the anterior cornea, so it really is an anterior keratoplasty, and it's lamellar because it goes in the lamellar plane."

The first data on CTAK were published by the group of Steven Greenstein and Peter Hersh, and Hardten's group was one of the first to collect new data, recently presented at the American Society of Cataract and Refractive Surgery meeting, on both keratoconus and post-LASIK ectasia.

"CTAK segments are the corneal allogenic tissue segments that most of us use in the U.S., partly because they are cut with the femtosecond laser, so the thickness and length are very accurate," Hardten said.

He praised the "amazing intuition" of Jacob in her surgery; her ability to size the segments according to corneal shape, "some sections slightly wider, some slightly narrower, thinner or thicker to get the best results"; and her confidence in moving them to different areas, twisting them 20°, pulling them more central, more peripheral and even doing enhancements.

"We don't have the same experience," he said. "Most of our patients are really looking to get some improvement, stop their progression and be able to get back into contact lenses. Right now, I am happy to have something that can achieve those goals, and we don't want to create expectations we would not be able to meet."

CAIRS surgery, in all its deviations, is easy, fast, adjustable, augmentable and reversible, and it can be combined with other procedures.

"If you don't achieve the outcomes you expected, you can remove the segments, you can adjust them, and you can enlarge the channel and insert additional tissue," Jacob said.

She almost always combines CAIRS with corneal cross-linking, which she performs just after the insertion.

"I believe it firms up the cornea in the best possible shape," she said. "Visual rehabilitation is faster, and it also avoids these generally bilaterally affected patients from taking time off from work multiple times."

"CAIRS is also a very adjustable procedure," Jacob said. "If for any reason the patient progresses -- because of rubbing the eyes, for instance, or because of not cross-linking the patient's cornea -- I may put in a little bit of additional tissue to get it back to the original amount of flattening and then do cross-linking again. When done with the right technique, the rate of intraoperative complications is close to zero, and the rate of postoperative complications is also very low."

CAIRS can be combined with IOLs and phakic IOLs, with wavefront-guided or topography-guided PRK.

"I don't combine it with laser because I don't like a subtractive procedure in keratoconus, but there are people who are doing it," Jacob said. "My point is that it's very compatible with all other surgeries"

Combining CAIRS with other keratoconus treatments, especially cross-linking, is something Kiliç considers carefully, always aiming to tailor the approach to each patient's disease stage and biomechanical profile.

"In some patients, I perform CAIRS first, followed by CXL in a staged manner to stabilize the biomechanical changes achieved with the ring," she said. "In others who have already had CXL, we perform CAIRS secondarily to further improve their corneal shape and vision."

In a study, Kiliç analyzed 67 eyes with or without prior cross-linking and found that the group without prior cross-linking achieved greater improvement in vision and a stronger flattening effect on keratometric values.

"This suggests that while CXL stabilizes the cornea, it may also make it more resistant to reshaping. So, the biomechanical stiffness from prior CXL may dampen the remodeling response we often see with CAIRS alone," she said.

Hafezi and Torres-Netto have also been combining ECO-CAIRS with phototherapeutic keratectomy-assisted customized epi-on corneal cross-linking (ELZA-PACE-CXL), in which customized map-driven PTK is performed over the cone to remove the epithelium only in that region. Epi-on cross-linking is then performed on the cornea, with an epi-off window just over the cone.

The timing of cross-linking in relation to CAIRS is decided on an individual basis.

"It depends on the patient's visual acuity, on whether keratoconus is progressing or not, and on whether the patient has already had CXL before and when. All those factors play a role," Torres-Netto said.

Hardten performs cross-linking at the same time as he does ALKRS in all his patients.

"We don't want these patients to continue to progress over time," he said. "ALKRS improves the shape, and cross-linking keeps them from continuing to progress. And most of them have improvement in best corrected vision with glasses. Most of them have improvement in uncorrected vision. They can still wear a contact lens."

In practice, CAIRS can be used flexibly as a stand-alone refractive and reshaping treatment, particularly in clear, soft, non-cross-linked corneas, or in combination with cross-linking, either simultaneously or sequentially, when long-term stabilization is the priority, Kiliç said.

"Ultimately, the decision is individualized. But what's clear is that CAIRS remains effective in both contexts, offering a safe and adaptive tool in our keratoconus armamentarium," Kiliç said.