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1.INTRODUCTIONDuring the last 20 years, the excimer laser has dominated the arena of keratorefractive surgery initially with surface ablation procedures such as photorefractive keratectomy (PRK) and later with the flap-based laser in situ keratomileusis (LASIK). Due to excellent patient satisfaction, high precision, and very good safety1,2, LASIK has become one of the most frequently performed surgical procedures. LASIK is performed as a two-stage procedure, which involves the cutting of a flap in the anterior stroma of the cornea followed by excimer laser photoablation of stromal tissue. Within the last decade, femtosecond lasers have mostly replaced manual microkeratomes for cutting of the LASIK flap (FS-LASIK). Although this may have improved the clinical outcome3, the procedure still has potential disadvantages. First, flap-related complications such as traumatic flap dislocation4, reduced corneal sensitivity due to severed stromal nerves5, and surgically induced ectasia due to loss of biomechanical strength6 remain significant challenges. Second, several factors may influence the precision of the photoablative procedure, including corneal hydration, room humidity, patient age, parallax error, and laser fluency7,8. In surface ablation procedures, postoperative wound healing may cause stromal haze formation and affect the long-term stability of the obtained refractive correction, with myopic regression as a well-known complication of high myopic corrections9. 2.INTRACORNEAL LASER SURGERYWithin the last few years, surgical extraction of a refractive lenticule, ReLEx®, has evolved as a new treatment in the field of keratorefractive surgery. Presently, the VisuMax® femtosecond laser system (Carl Zeiss Meditec, Jena, Germany) is the only platform to offer this treatment. The 500-kHz VisuMax generates very fast pulses (10-15 s) in the near-infrared spectrum. Depending on the specific laser settings, each pulse conveys approximately 150 nJ, which causes localized photodisruption at the focal point. The generated plasma expands, creating a cavitation bubble and, as individual cavitation bubbles fuse, the stroma is cut with a minimum of collateral damage. The VisuMax femtosecond laser uses a high numerical aperture and concave contact glass to focus the laser pulses with very high precision. Thus, laser spots of approximately 1 μm diameter are placed with a defined distance of 2–5 μm in a spiral pattern. To ensure centration on the visual axis, the patient fixates on a blinking light, and suction is applied at the cornea to maintain stability of the eye. Initially, the posterior surface of the lenticule is cut, followed by creation of the anterior surface, which is slightly enlarged in diameter to facilitate surgical manipulation. The present proceeding reviews the current state of the technique, initial clinical results based on a recent review10, and finally presents some of the challenges that need to be addressed by new technologies. Depending on the method used to access the lenticule, ReLEx can be divided into FLEx, in which a LASIK-like flap allows surgical removal of the lenticule, and SMILE, in which a small incision (approximately 2–4 mm in length) is created for manual lenticule extraction, so SMILE opens up the 3rd generation of laser vision correction procedures. A blunt spatula is used to break any remaining tissue bridges after the laser treatment, and the lenticule is removed with a pair of forceps (Figure 1). For further details on the surgical approach, please refer to Sekundo et al.11, Shah et al.12, and Vestergaard et al.13. Figure 1.SMILE procedure. a) Image obtained during femtosecond laser cutting of lenticule. Posterior side of lenticule have been cut and anterior cut have been approximately 50% completed. b) Immediately after completion of femtosecond laser cutting. c) Through a small peripheral incision, remaining tissue-bridges are broken with a blunt spatula. d) Lenticule is removed through the peripheral incision.  In contrast to LASIK, FLEx and SMILE represent a one-laser approach, where the critical laser treatment is performed on the intact cornea rather than on exposed corneal stroma. Consequently, the potential variability associated with the excimer laser photoablation is avoided. In addition, the microinvasive SMILE treatment have several theoretical advantages over flap-based treatments, including very little trauma to the corneal surface, less corneal denervation, and better biomechanical strength due to an almost intact anterior stroma. Since the first introduction of ReLEx, the repetition rate of the VisuMax femtosecond laser has been increased from 200 to 500 kHz, and the settings for laser spot size, energy, and distance have been optimized, changes that may have had a significant impact on the clinical outcome after surgery. Furthermore, the flap-based FLEx represents an evolutionary step before SMILE and is today primarily used as an introductory step for new ReLEx surgeons. Due to these changes, the present review focuses primarily on studies concerning SMILE. At present, the VisuMax allows myopic corrections up to -10 diopters (D) spherical equivalent (SE) correction, with an astigmatic component of up to 5 D. Hyperopic treatments are not available at the moment, although one study has reported on the outcome of hyperopic FLEx14. The VisuMax laser is CE (Conformité Européenne) marked and is currently being evaluated in clinical studies for the approval of SMILE by the FDA (US Food and Drug Administration). 3.CLINICAL RESULTS3.1Refractive outcomeOverall, ReLEx has been reported to have high refractive predictability (Table 1). In the largest report to date on SMILE in 670 myopic eyes 3 months after surgery, the mean error in SE refraction was −0.25 ± 0.44 D, with 80 % of eyes within ± 0.50 D and 94 % within ± 1.0 D 15. We recently extended this evaluation to the first 1,574 eyes 3 months after SMILE and found a similar mean error of -0.15 ± 0.50 D with 77 % of eyes within ± 0.50 D and 95 % within ± 1.0 D32. Other reports on SMILE12, 13, 16, 17 and 500-kHz FLEx18–22 have found very similar refractive outcomes in smaller numbers of patients. The refractive stability after SMILE has not been extensively investigated. However, in one study on 279 eyes with high myopia, refraction was found to be stable from 1 to 3 months after surgery, although a minor regression of -0.15 D was observed during the first month13. One other study on 54 eyes found no regression during the first 6 months after surgery16. Similarly, no regression has been found during the first 3–6 months after 500-kHz FLEx18, 19, 21, 22 or for 1 year after 200-kHz FLEx23, 24. Interestingly, the refractive predictability after SMILE has been found to be unrelated to the degree of the attempted myopic correction15. This is in contrast to excimer-based treatments, which show decreasing precision with increasing myopic correction25. Furthermore, other parameters including preoperative corneal power, patient age, and gender have been found to have very limited impact on the refractive outcome after SMILE15. Correction of high astigmatism has not yet been systematically evaluated after ReLEx. Only one paper on 200-kHz FLEx contains a detailed evaluation of the outcome after cylinder correction26. An undercorrection of approximately 10 % was reported; however, the average preoperative cylinder was only 0.96 ± 0.87 D, and the population skewed toward low corrections, making it difficult to extrapolate to high astigmatisms. Recently, we evaluated correction of myopic astigmatism with SMILE in 775 eyes, of which 106 eyes had astigmatism of 2.50 D or more. On average, 95 % were within ± 1.0 D of the attempted spherical equivalent correction three months after surgery. However, a significant astigmatic undercorrection was observed, with an average error of treatment of 0.17 ± 0.42 D in low astigmatism and 0.59 ± 0.65 D in high astigmatism27. At present, only one study has examined hyperopic treatment (average SE refraction + 2.8 ± 1.3 D) with 200-kHz FLEx14. After 9 months, only 64 % of patients had a postoperative refraction within ± 1.0 D of that attempted, and there was significant regression of the effect during the first 6 months after surgery. Thus, it still remains to be determined whether ReLEx eventually will allow safe and predictable hyperopic treatments. 3.2Visual outcomeIn the first clinical studies, FLEx was reported to have delayed visual recovery in comparison with FS-LASIK12,28. However, later studies suggested that the laser scanning pattern and energy had an impact on the lenticule surface quality and the immediate postoperative outcome 29,30,31. Subsequent changes in the laser scanning trajectory and energy delivery appear to have eliminated the problem with postoperative visual recovery. Three studies have examined the uncorrected distance visual acuity (UDVA) after 500-kHz SMILE for myopia and report 73–100 % of patients as having an UDVA of 20/25 or better 3–6 months after surgery13,15,16. Similar results have been reported for 500-kHz FLEx, and the procedure has been found to be on par with the outcome after FS-LASIK18,22. The efficacy index 3 months after SMILE (postoperative UDVA/preoperative CDVA) has been found to be 0.90 ± 0.25, indicating that a patient on average can expect a postoperative UDVA of 90 % of their preoperative CDVA15. 3.3Safety and complicationsThe induced change in corrected distance visual acuity (CDVA) may be used as an indicator for the overall safety of a refractive surgical procedure. In general, loss or gain of two or more lines on the Snellen visual acuity card is considered significant and noticeable for the patient. Most studies on FLEx or SMILE are too small to properly evaluate the safety of the procedure, and the frequency of a two-line loss in CDVA has been reported to lie between 0 and 8 % 11,12,16–22. In one study on 279 eyes after SMILE, 0.4 % of eyes were reported to have a loss of two or more lines12. In contrast, a 2.4 % risk of a two-line loss was found in 670 eyes by Hjortdal et al.15. However, in the same study, a safety index (CDVA before/CDVA after surgery) of 1.07 ± 0.22 was found, indicating that CDVA on average increased after surgery, as would be expected because of the image magnification of myopic keratorefractive procedures. In a recent single-center study, the safety and complications of 1,574 SMILE procedures were evaluated after 3 months32. CDVA was found to have improved with two or more lines in 3.4 % of eyes, whereas 1.5 % of eyes had experienced a loss of two or more lines. Yet, at a late follow-up visit, all patients with a loss in visual acuity had recovered to within one line of the preoperative value. The surgeon learning curve and the laser settings were found to be important parameters for the postoperative visual recovery. Overall, safety after SMILE appears to be comparable with that reported after FS-LASIK1,3, although recovery may be prolonged in a few cases. Endothelial changes after FLEx and SMILE have not been systematically evaluated. Only one study on 38 eyes has reported endothelial cell counts and found that FLEx induced no significant changes in endothelial cell density19. A variety of peri- and postoperative complications have been reported after SMILE. The most frequently reported perioperative complications include tears at the incision and minor abrasions, whereas decentration, suction loss, difficulties removing the lenticule, and cap perforation may rarely occur12,13,17,18,26. Frequent postoperative complications include dry eye, microstriae, and increased interface scatter, whereas rare complications include keratitis, interface inflammation, epithelial ingrowth, and monocular ghost images18,19,26. Recently, we found irregular postoperative topography in 18 of 1,574 eyes, giving rise to ghost images in six cases32. Topography-guided PRK was performed in four of these eyes, ameliorating the symptoms in three cases. In another recent paper, a lenticule remnant was documented to be the cause of postoperative monocular double vision33. Postoperative ectasia has not been reported after SMILE; however, one case has been documented after a flap-based FLEx treatment23. Overall, SMILE appears to be a technically more demanding surgical procedure than LASIK, introducing specific potential complications related to the extraction of the refractive lenticule while eliminating some typical LASIK complications. Still, despite a relatively high frequency of peri- and postoperative complications, the visual outcome is reported to be good, with minimal risk of loss in CDVA on the long term. 3.4Higher order aberrations (HOAs) and contrast acuityFew studies have compared the induced HOAs after FLEx and LASIK20 or FS-LASIK18,24. In these studies, both FLEx and LASIK were found to increase the total corneal or whole-eye HOAs; however, FLEx induced less spherical aberration than FS-LASIK. Furthermore, in LASIK the induced HOAs were found to increase with the degree of attempted refractive correction, whereas in FLEx no such correlation was found20. Parallax error during excimer laser photoablation has been suggested as an explanation for the observed differences in induced spherical aberration after LASIK and FLEx20. As of yet, no studies have reported changes in HOAs after SMILE with the 500-kHz VisuMax laser. Contrast sensitivity after ReLEx has been examined in a retrospective, comparative study on 200-kHz FLEx and FS-LASIK. Both procedures showed a similar increase in photopic contrast sensitivity after 1 year; however, FLEx also showed an improvement in mesopic contrast that was not found after FS-LASIK24. Presently, changes in contrast sensitivity have not been evaluated after SMILE. Based on the few comparative studies on HOAs and contrast sensitivity, ReLEx appears to be similar or better than LASIK; however, studies on SMILE are lacking. 3.5Corneal sensitivity and tear secretionThree studies have examined the corneal sensitivity after SMILE in comparison with a flap-based treatment34,35,36. In a randomized paired-eye study, Demirok et al. demonstrated less reduction in corneal sensitivity after SMILE than after FS-LASIK, although sensitivity had fully normalized in both groups by 6 months35. In another randomized paired-eye study, the corneal nerve density and number of long nerve fibers were higher after SMILE than after FLEx34; accordingly, sensitivity was better after SMILE. Finally, in a comparative study on SMILE, FLEx, and FSLASIK, better sensitivity was found at all time points for up to 3 months after SMILE36. Studies based on a paired-eye evaluation of the postoperative tear secretion after SMILE in comparison with a flap-based treatment34,35 were not able to document significant differences in tear osmolarity, tear secretion rate, and tear meniscus height. However, one study found a slight difference in the postoperative tear-film break-up time in favor of SMILE34. Overall, the minimally invasive SMILE causes less damage to corneal nerves than flap-based treatments, resulting in better postoperative sensitivity. However, these changes appear to have only minimal measurable impact on the postoperative tear secretion. 3.6Corneal biomechanics and sublayer thicknessIn SMILE, most of the anterior stroma remains intact after surgery. Since the cornea is biomechanically strongest in the anterior part37, it would theoretically be more robust after SMILE than after a flap-based treatment where most of the anterior lamellae are severed. Thus, SMILE-treated corneas may be more resistant to trauma and less prone to developing postoperative keratectasia, and they have been suggested to be even stronger than PRK-treated corneas37. Furthermore, it has recently been speculated that the refractive lenticule should be removed deeper within the stroma to increase the postoperative corneal strength38. Although this might be advantageous from a biomechanical point of view, many factors could affect the outcome, including endothelial safety, the quality of the laser cut in deeper stroma, and the relative front- and back-surface changes. Thus, the optimal depth of the refractive lenticule still remains to be determined. At present, only one study has been published on the biomechanical properties after SMILE in comparison with FS-LASIK using the Ocular Response Analyzer39. This paired-eye, randomized study found no differences in corneal hysteresis (CH) or corneal resistance factor (CRF) 6 months after surgery. In a comparable study on SMILE and FLEx, we similarly found no difference between the methods regarding CH and CRF40. However, in a small comparative study on SMILE, FLEx, and FS-LASIK, we recently found the biomechanical response, as measured with the Corvis ST, to be more abnormal after a flap-based treatment than after SMILE41. Overall, the biomechanical changes after SMILE are still unclear, and there is a considerable need for further studies. A planar and uniform flap is generally considered important in flap-based keratorefrative surgery, and three studies have found the cap to be of nearly uniform thickness and similar to the flap after FLEx or FS-LASIK16,42,43. Furthermore, in one study, no significant changes were observed in central cap or stromal bed thickness for 6 months after surgery43. We recently evaluated corneal sublayer thicknesses after SMILE and FLEx40 and found no significant difference in cap or stromal bed thickness 6 months after surgery. As seen after other myopic keratorefractive procedures44,45, a compensatory epithelial hyperplasia was observed. 4.EXPERIMENTAL STUDIESIn excimer laser keratorefractive surgery, the energy delivered to the cornea may promote subsequent inflammation and wound repair49. In contrast to the excimer laser, femtosecond lasers deliver only minimal amounts of energy to surrounding tissue50, suggesting that the femtosecond laser may induce less postoperative wound repair. In accordance, a recent study in rabbits has demonstrated FLEx to induce less wound healing and inflammation than FS-LASIK, particularly after high myopic corrections50. Whether this observation has any clinical relevance remains to be determined; wound repair after LASIK and, in particular, PRK has been extensively investigated and is known to influence the postoperative outcome49,51,52. Extracting an intact stromal lenticule from the cornea opens new interesting possibilities in keratorefractive surgery. First, if the extracted tissue can be successfully preserved, the surgical procedure may in theory be reversed at a later time point by re-implantation of the lenticule. Second, the lenticule can be used to change the refraction in another individual, for example, by implanting a myopic lenticule in the stromal pocket of a hyperopic patient53. Such a procedure would in Europe require permission from national authorities, as this would be considered a corneal transplantation. In a recent study, refractive lenticules from rabbit eyes were demonstrated to have an intact collagen structure and viable keratocytes after 1-month cryopreservation54. Other studies in rabbits and primates have shown successful cryopreservation and later re-implantation of a stromal lenticule55–57. Furthermore, in primates, the procedure was shown to induce little postoperative wound repair, and keratocyte repopulation could be observed after 16 weeks47. Thus, although further studies are needed, lenticule re-implantation or transplantation from one patient to another may become reality in the near future. 5.NEEDS FOR TECHNOLOGY IMPROVEMENTAlthough intrastromal refractive surgery as performed with the SMILE technique seems to be predictable, efficient and safe, there are issues that could be improved. 5.1Laser cut qualityThe femtosecond laser used in ReLEx is a 1,043 nm solid-state Nd:Glass laser. At the laser focus point, the laser energy increases above a critical level and plasma formation and cavitation takes place. The actual point of focus is associated with some degree of imprecision that is determined by lateral and axial beam scanning imprecision. However the axial point of interaction between laser pulse and corneal tissue may fluctuate du to non-linear effects within a certain range that is approx. given be the Rayleigh length (zR) (Figure 2): Figure 2.The actual point of focus of the femtosecond laser is associated with some degree of imprecision and is characterized by the Rayleigh length (zR). The Rayleigh length is dependent on the wavelength (λ) and the beam waist (w0). (Courtesy: Dirk Mühlhoff, Carl Zeiss Meditec, Jena, Germany).  The VisuMax femtosecond laser operates with a wavelength of 1043 nm (λ) and a beam waist (w0) of 1 μm. The beam waist is dependent on a number of optical factors related to the femtosecond laser system. From the known parameters the Rayleigh length can be calculated to be about 3 μm. This shows that the axial position of individual points of interaction is stable within a range of about 3μm. One can see why the VisuMax technology fulfills the applicative requirements if one takes into account that a cut surface is defined by millions of adjacent points of interaction. Electron microscopy pictures of the lenticule show that the cut quality is high58. Similarly, clinical investigations document that the cap thickness in SMILE can be created accurate and reproducible59. Sometimes the Rayleigh length is discussed in relation to the central profile thickness for a 1-diopter correction that is approximately 13 μm. This is misleading because not the central profile thickness but the corresponding overall corneal curvature change is the relevant parameter. This again is supported by the high predictability of the SMILE procedure15. Further optimization of the femtosecond laser with respect to wavelength and beam waist is discussed today. If the wavelength could be reduced to one-third and/or the beam waist could be lowered further, the Rayleigh length would be reduced. However, it seems questionable whether such technological modifications actually are useful and possible, especially considering laser safety. Extractability is another aspect of cut quality that is clinically interesting. This parameter is closely related to the number of laser spots that are used to separate the lenticule from its surrounding tissue with only a reasonably low number of tissue bridges. With its 500 kHz laser pulse repetition rate the VisuMax is able to produce a well-separated lenticule within about 30 seconds. The current level of speed and extractability is acceptable but still keeps room for future improvements. 5.2Centration and cyclotorsionThe optimal exact centration of laser refractive procedures with respect to the various lines and axes that can be defined in the human eye has been debated for years60. Some authors argue that refractive procedures should be centered at the pupil center, other argues that centration should be at the corneal vertex, and other that the correct centering is somewhere between these fairly easily identifiable landmarks, as this will correspond to the visual axis. In femtosecond lasers, the eye is fixed by suction to an applicator attached to the laser in order to keep the cornea stable during laser cutting. The operating surgeon has to put on suction and fixate the eye manually. After the eye is stabilized, it is not possible to translate the center of laser cutting into a more ideal position. Similarly, the eye may undergo cyclotorsion from the upright to the supine position. As refraction is performed when patients are upright, but surgery is performed with patients supine, this may induce errors when astigmatism is treated. Modern excimer lasers are equipped with very fast image tracking and processing software, which allows the laser to compensate for cyclotorsion automatically. Excimer lasers also allows the surgeon to adjust the center of the treatment to the position best corresponding to the visual axis. Development of similar tracking solutions and capabilities for automatic adjustment of centration and cyclotorsion possibly would improve the outcome of femtosecond based intrastromal procedures. 5.3Astigmatic and hyperopic treatmentGeometrically, correction of myopia is fairly simple and the necessary lenticule shape to be removed was calculated many years ago by Munnerlyn et al.61. Although this calculation ignores aspects related to the aspheric shape of the cornea, the formula has been widely used, also as a basis for intrastromal refractive surgery. In correction of astigmatism and hyperopia, the actual correcting tissue removal will end abruptly. For astigmatic corrections, the ends of the removed toric cylinder will give rise to symmetric discontinuities in the meridian of the cylinder, and in hyperopic corrections, the doughnut shaped tissue will end with a rotational symmetric discontinuity. Although such discontinuities may seem dramatic, the overlying corneal stroma and epithelium will act as smoothing factors, but at the expense of less refractive effect. In excimer laser surgery, transition zones have been used to smoothen these gaps, and similar transitions have been used in femtosecond laser surgery. Further research is needed to explore the optimum size of these transition zones, and also to optimize the cutting sequence between the refractive deep cut, cap cut, and transition zones, and side cuts. 5.4Topography and wave-front guided treatmentsLaser refractive treatments are normally based on standard sphero-cylindrical treatments defined by meticulous refraction of the patient before surgery. As the optics of the eye is not perfect, all eyes have some degree of higher-order optical aberrations of which spherical aberrations and coma are the dominant. Aberrations can be measured in individual eyes by whole-eye aberrometry62. Some eyes have very large aberrations caused by imperfections in the shape of the cornea; this is typically called irregular astigmatism and can be measured by corneal topography. Topographic as well as whole-eye aberrations may be corrected by excimer laser surgery, and successful correction of such aberrations result in better visual acuity62. At present, femtosecond laser based surgery of the cornea cannot correct higher-order aberrations or irregular astigmatism. Development of interfaces from aberrometers and topographers into individualized lenticule cutting patterns will possibly improve the outcome of intrastromal procedures in patients with high levels of such optical imperfections. 5.5RetreatmentsAlthough ReLEx has been found to have a high refractive predictability, some patients have a postoperative residual refractive error due to over- or undercorrection15. In flap-based treatments, an excimer-based enhancement procedure can be performed after lifting the flap46. Retreatment after SMILE is, however, more complicated. Possible approaches may include PRK or LASIK, whereas a new ReLEx procedure may be more unpredictable due to multiple dissection planes within the cornea. Presently, no systematic clinical evaluation of SMILE enhancements has been published. One study has reported on successful topography-guided PRK in SMILE patients with postoperative irregular astigmatism32, and another has reported on successful FS-LASIK in a patient with perioperative suction loss47. In a rabbit model, the conversion of a SMILE cap to a flap has been demonstrated, allowing subsequent intrastromal photoablation48. Still, the optimal approach for SMILE enhancements needs to be established. Performing a new conventional SMILE procedure is typically referred from, as most surgeons are afraid to interfere with the original incision plane that may result in difficult or incomplete lenticule removal. A possible option would be to perform a new SMILE procedure in a different plane, either deeper in the cornea, or more superficial, in the cap. In both situations, further development and clinical testing of this variation of the technique is necessary. 5.6Corneal biomechanics testOne considerable advantage of SMILE is that no corneal flap is created. Intuitively, this would leave the cornea considerably stronger than after a LASIK procedure. Mathematical modeling suggests that this feature is the case38. Real clinical documentation for the biomechanical advantage of SMILE compared with LASIK is, however, not available. Our knowledge on the biomechanical properties of the human cornea comes from in vitro testing of corneal strips or whole globes63. During the last 10 years, devices based on pneumatic force application have been introduced. Unfortunately, neither Corneal Hysteresis as measured by the Ocular Response Analyzer40 or more recently, techniques based on dynamic Scheimpflug visualization of corneal deformation have be able to document fundamental differences between flap-based and cap-based laser surgery41. As a spin-off conclusion, it is clear that there is considerable need for technological development of clinically usable devices that more precisely can evaluate biomechanical properties of the cornea. Such devices would also have significant interest as a diagnostic tool to identify patients with sub-clinical keratoconus. 6.CONCLUSIONSeveral studies have shown that the refractive and visual outcomes after SMILE and FLEx are as good as after FS-LASIK, and ReLEx has even been indicated to induce fewer HOAs. Furthermore, SMILE has been shown to be as safe as LASIK, although the procedure may be technically more demanding and have a different variety of complications. The minimal impact on the anterior stroma in SMILE represents the most interesting aspect of the new procedure. Thus, stromal nerves are spared, and SMILE has been convincingly demonstrated to cause less denervation and have better sensitivity than flap-based treatments. Yet, the impact on postoperative tear secretion and dry-eye symptoms remains unclear. Due to the intact anterior stromal lamellae, the cornea may be stronger after SMILE than after a flap-based treatment. 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