ReLEx Studies

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Innovative SMILE procedure from ZEISS successfully performed on more than 100,000 eyes

Micro-invasive refractive surgery becomes an established laser vision procedure for the correction of myopia. Clinical trial in the USA expanded.

JENA / Germany, 04.02.2014.

Two years after its international launch, the SMILE procedure developed by ZEISS has become the third generation of laser vision correction. More than 80,000 eyes worldwide have now been successfully treated using the micro-invasive method which offers improved predictability of the vision correction outcome without the need to create a corneal flap. The US FDA has approved expansion of the US clinical trial.

The SMILE procedure developed by ZEISS for refractive surgery stands for Small Incision Lenticule Extraction and combines state-of-the-art femtosecond laser technology and precise lenticule extraction providing a micro-invasive laser vision correction method. Unlike LASIK (Laser-Assisted in situ Keratomileusis), in which an excimer laser ablates tissue inside the cornea after opening the corneal surface by cutting a corneal flap, the SMILE procedure is performed without a flap. The ZEISS femtosecond laser VisuMax® is used to create a very thin disc of tissue (lenticule) inside the intact cornea, which can then be extracted through a small incision. An excimer laser is not required.

“With SMILE ophthalmic surgeons now for the first time have a refractive surgery procedure that provides great benefits for their patients with the least possible intervention: the cornea of the eye remains intact as much as possible; the predictability of the correction is very good. The results are convincing more and more physicians and patients around the world,” says Dr. Ludwin Monz, President and CEO of Carl Zeiss Meditec AG.

One of those physicians is Detlev R.H. Breyer, MD from the eye surgery clinic “Breyer & Kaymak” located in Düsseldorf. “SMILE is a very valuable addition to our clinic’s portfolio of procedures, as we can now treat patients on an even more individual basis, and less invasively. Our practice is happy about the increasing demand we are receiving for this procedure, thanks to many recommendations from satisfied SMILE patients.”

The SMILE procedure has also been documented in scientific publications as “predictable, effective and safe”, regardless of the patient’s age. Jesper Hjortdal, MD, DrMedSci, PhD from Aarhus University Hospital in Denmark concludes in one of his studies, on 670 eyes of 335 patients with myopia, that SMILE is not inferior in any way to the LASIK procedure in these three aspects,1 and was awarded the Waring Medal for outstanding contributions by the Journal of Refractive Surgery.

In the period after the surgery SMILE proves to be superior to the LASIK method: According to recent studies, inflammation was less common after SMILE procedures, and healing of the cornea was better2. The problem of dry eye syndrome often described following laser vision correction has also shown to be reduced after a SMILE procedure, as reported by Prof. Dan Z. Reinstein, MD from the London Vision Clinic, in several publications3: “As the nerve tracts of the cornea remain largely intact, the SMILE procedure is the least invasive of all refractive procedures. Various studies show that dry eye syndrome is a much rarer side-effect compared with LASIK.”

The refractive correction of vision defects using laser technology has established itself as a method to enable eligible patients to have a life without glasses. Over the past few years development has focused on making the treatment less risky. The micro-invasive SMILE can now be considered a third-generation procedure, after methods such as PRK (Photorefractive Keratectomy) and LASIK – it involves the least possible intervention with the cornea remaining as intact as possible.

The procedure was launched internationally in September 2011 and is established in key markets such as Europe, China and India. A clinical trial is currently underway in the USA. The first results were presented in April 2013 by Jon Dishler, MD, US Medical Monitor for the VisuMax IDE Study and the FDA approved expansion of the clinical trial in July 2013. “Based on the excellent safety and effectiveness of data submitted to the FDA on the first 79 subjects treated with the SMILE procedure and followed for at least three months, the FDA granted approval to expand the study to the full cohort of 360 subjects. This is an important milestone for the study,” said Dr. Dishler at the Annual Meeting of the American Academy of Ophthalmology (AAO) in New Orleans at the beginning of November. In December 2013 the FDA granted approval to extend the trial further to include myopia of up to –10.00 diopters. The clinical trial in the USA began in June 2012; Dr. Dishler presented the first results in April 2013.To date, a total of 255 patients have been treated within the scope of the trial, at five centers in the USA. Outside the USA there are more than 150 centers in 38 countries with more than 300 surgeons performing the SMILE procedure.

2014-5-15

INTERNATIONAL

Scientific rationale for why femtosecond laser intrastromal keratomileusis is the future of corneal refractive surgeryby Dan Z. Reinstein, M.D.

We are in the age of the femtosecond laser. Having first found
utility in creating a flap for LASIK procedures, it became clear that the
potential for other uses in eye surgery was significant. Most recently, cataract surgery femtosecond applications have been the focus of development for laser companies. Now with the clinical trial of the
VisuMax laser under way, a true refractive platform may be possible with only the use of a femtosecond laser. As with all new technology, there will no doubt be continued improvement, and we can expect that the results will improve. Is intrastromal keratomileusis the future of corneal refractive surgery? Dan Reinstein, M.D., makes a compelling case in this month’s “International outlook” column. One thing is certain: Refractive surgeons around the world will be watching this carefully. Read for yourself and form your own opinion.John Vukich, M.D.,
international editor

Figure 1: Diagrams of the intact stromal lamellae after LASIK (top) and SMILE (bottom) highlighting the anterior lamellae that remain intact after SMILE. The RST calculations are shown for a 500 μm cornea with a 100 μm ablation/lenticule and 120 μm flap/cap thickness. The LASIK RST of 280 μm consists only of posterior stroma. The SMILE RST has the same 280 μm of posterior stroma, but also has 70 μm of anterior stroma, for a total of 350 μm of stroma. However, since the anterior stroma is 50% stronger than posterior stroma, a further 35 μm can be added to make an effective total of 385 μmFigure 2: Diagrams demonstrating the
difference between SMILE (top) and LASIK (bottom) in how the two procedures affect the anterior corneal nerve plexusFigure 3: Mean corneal sensation for 39 eyes after SMILE compared with the corneal sensation after LASIK averaged over nine published studiesSource (all): Dan Z. Reinstein, M.D.

Ever since femtosecond lasers were first introduced into refractive surgery, the ultimate goal has been to create an intrastromal lenticule that can be manually removed in one piece, thereby circumventing the need for incremental photoablation by an excimer laser. Following the introduction of the VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany) in 2007, the intrastromal lenticule method was introduced in a procedure called femtosecond lenticule extraction (FLEx) in which a flap was created and lifted to allow the lenticule to be removed.
Following the successful implementation of FLEx, a new procedure called small incision lenticule extraction (SMILE) was developed. This procedure involves passing a dissector through a small 2-3 mm incision to separate the lenticular interfaces and allow the lenticule to be removed, thus eliminating the need to create a flap. The results of the first prospective trials of SMILE have been reported,^{1, 2} and there are now more than 50 surgeons routinely performing this procedure worldwide.
A number of femtosecond lasers are commercially available, but the VisuMax is the only one being used for an intrastromal lenticular cut. There are six distinct design elements of the VisuMax that represent how the device was conceived from the ground up as a high precision intracorneal lenticular cutting tool. Central to the VisuMax mode of operation is the extremely light-touch coupling system that minimizes corneal distortion and a rapid, high precision femtosecond pulse placement to achieve sufficient 3D geometric cutting precision such that refractive lenticules can be created accurately within the body of the stroma. The main elements are (1) the curved coupling contact glass, which results in minimal corneal distortion, (2) coupling suction applied to the peripheral cornea (not the conjunctiva/sclera) allowing for a low suction force to immobilize the cornea, again reducing tissue distortion, (3) individual calibration of each contact glass based on confocal detection of radiation, (4) the combination of an optical beam path that is suspended on a fulcrum with force-feedback servo control of the height of the patient bed and headrest in order to maintain a consistent contact glass force onto the cornea (again minimizing tissue distortion), (5) a high numerical aperture of the beam designed to deliver a tight concentration of femtosecond energy with low per-pulse energy load, and (6) a high pulse repetition rate of 500 kHz in order to minimize treatment time.

Advantages of ReLEx SMILE over LASIK

These new femtosecond intrastromal lenticule procedures offer a number of potential advantages.
1. More accurate and repeatable tissue removal: Intrastromal lenticule procedures may have
advantages over LASIK as all of the potential errors associated with excimer laser ablation are avoided, such as stromal hydration, laser fluence projection and reflection losses, and other environmental factors. In ReLEx, the tissue removal is defined only by the accuracy of the optomechanics of the femtosecond laser, none of which is affected by environmental conditions. Therefore, it is likely that there will be less need for personalized nomograms to be used for different machines, locations, or surgeons. In addition, the accuracy remains similar for low and high corrections as the only variable is the distance between the upper and lower lenticular cuts.
2. Increased biomechanical stability and reduced biomechanical variability: Potential benefits of SMILE are the relatively higher biomechanical strength of the remaining cornea as well as a reduction in the variability of the biomechanical effects produced by refractive tissue removal.
Randleman et al³ published a study in 2008 in which they measured the tensile strength of strips of stromal lamellae cut from different depths within the cornea. They found a strong negative correlation between stromal depth and tensile strength. The anterior 40% of the central corneal stroma was found to be the strongest region of the cornea, whereas the posterior 60% of the stroma was at least 50% weaker.
We are accustomed to calculating the residual stromal thickness in LASIK as the amount of stromal tissue left under the flap, so the first instinct is to apply this rule to SMILE. However, because there is no flap created in SMILE, the anterior stromal lamellae remain intact everywhere except for the small 2-3 mm incision. Therefore, the actual residual stromal thickness in SMILE is calculated as the stromal thickness below the posterior lenticule interface plus the stromal component of the overlying cap—between the anterior lenticule interface and the epithelium. Moreover, because anterior stroma is 50% stronger than posterior stroma, a further 50% of the untouched anterior stromal thickness can be added to get a residual stromal thickness value that can be compared to a LASIK residual stromal thickness.
If this concept is applied to an example case (Figure 1), the significant improvement in biomechanics can be appreciated. Consider an eye with a spherical equivalent refraction of –8.00 D and a central corneal pachymetry of 500 μm. We will assume that the epithelial thickness is 50 μm, that the LASIK excimer laser ablation depth and SMILE lenticule thickness are 100 μm, and that both procedures were performed under a 120 μm LASIK flap and with a 120 μm SMILE cap (depth of the anterior lenticule interface). The LASIK RST would be 280 μm, but the SMILE RST would be 385 μm after adding 1.5 times the 70 μm of intact anterior stroma.
Recently, Knox Cartwright et al⁴ performed a study on human cadaver eyes and found that creating a sidecut only resulted in a similar
increase in strain to that found after creating a whole flap, with a significantly greater increase when the depth was increased from 90 to 160 μm. On the other hand, the increase in strain was the same at both depths when a delamination cut only was performed.
Applying this finding to SMILE, since no anterior corneal sidecut is created, there will be slightly less increase in corneal strain in SMILE compared to thin flap LASIK and a significant difference in corneal strain compared to LASIK with a thicker flap.
Also, given the finding that the increase in corneal strain with a delamination cut only is independent of depth, this means that the SMILE lenticule can be created at any depth within the stroma. Therefore, putting this finding together in context of the varying tensile strength of stroma at different depths as described above, the effective post-op corneal biomechanical strength will increase as the lenticule is moved deeper. Therefore, it is possible that SMILE might be used to extend the range of myopia that can be corrected by corneal excimer laser surgery.
3. Reduction in post-op dry eye: The other major potential advantage of the flapless ReLEx SMILE procedure is the reduction in post-op dry eye compared with that observed after PRK and LASIK.
The cornea is one of the most densely innervated peripheral tissues in humans. Nerve bundles within the anterior stroma grow radially in from the periphery toward the central cornea. The nerves then penetrate Bowman’s layer and create a network of nerve fibers, known as the sub-basal nerve plexus, by branching both vertically and horizontally between Bowman’s layer and basal epithelial cells.
In LASIK (as shown in Figure 2), sub-basal nerve bundles and superficial stromal nerve bundles in the flap interface are cut by the microkeratome or femtosecond laser, with only nerves entering the flap through the hinge region being spared. Subsequent excimer laser
ablation severs stromal nerve fiber bundles. Post-op, this means that the patient may have dry eye symptoms and decreased corneal sensitivity while the nerves regenerate. A number of studies have reported the recovery of corneal sensation after LASIK and show that recovery to normal levels takes on average 6 months. Figure 3 shows the average corneal sensation across these nine studies.
In SMILE on the other hand, the anterior corneal anatomy is preserved and the anterior stromal nerve plexus is disrupted significantly less since there are no sidecuts created—no flap is created; this should result in fewer dry eye symptoms and a faster recovery of post-op patient comfort. Early results seem to support this hypothesis. We have measured corneal sensation in 39 eyes after SMILE and the results compare favorably with the average data taken from similar published LASIK studies. Corneal sensation had recovered to the baseline level by 3 months after SMILE compared with 6-12 months after LASIK. Also, corneal sensation was only slightly depressed in the majority of eyes after SMILE at the day 1 post-op visit, whereas corneal sensation was found to be generally 0 in published LASIK studies reporting 1-day data.
In summary, with the introduction of the VisuMax femtosecond laser technology it has become clinically feasible to now create refractive lenticules of proper regularity with sufficient accuracy to meet and
possibly exceed the accuracy of excimer laser tissue ablation for corneal refractive corrections. This enables Jose Ignacio Barraquer’s original concept of keratomileusis to be effectuated through a minimally invasive pocket incision with maximal retention of anterior corneal innervational and structural integrity. It is the final frontier in the realization of the perfect refractive surgical technique for both patients and surgeons.

References

1. Sekundo W, Kunert KS, Blum M. Small
incision corneal refractive surgery using the small incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol. 2011;95:335-339.
2. Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: All-in-one femtosecond laser refractive surgery. J Cataract Refract Surg. 2011;37:127-137.
3. Randleman JB, Dawson DG, Grossniklaus HE, McCarey BE, Edelhauser HF. Depth-dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24:S85-89.
4. Knox Cartwright NE, Tyrer JR, Jaycock P, Marshall J. The effects of variation in depth and side cut angulation in sub-Bowman’s keratomileusis and LASIK using a femtosecond laser: a biomechanical study. J Refract Surg. 2012 Jun;28(6):419-25.

Editors’ note: Dr. Reinstein practices at the London Vision Clinic, London, and is affiliated with the Department of Ophthalmology, Columbia University Medical College, New York, and the Centre Hospitalier National d’Ophtalmologie, Paris. He has financial interests with Carl Zeiss Meditec and ArcScan Inc. (Morrison, Colo.).