**3. Femtosecond laser in ophthalmology**

#### **3.1. Characteristic of femtosecond laser**

Femtosecond laser technology was first introduced by Dr. Kurtz in the early 1990s, and it has developed rapidly over the past two decades. "Laser power" is defined as energy delivered per unit time. The laser-related damage will reduce with the decrease of pulse duration. The femtosecond laser for ophthalmology works at 1053-nm wavelength with a very short pulse duration of 10−15 s, minimizing the collateral damage [16]. The accuracy is 5 μm, allowing high precision in ophthalmic operations [17]. The use of the femtosecond laser has revolutionized the modern ophthalmic surgery.

## **3.2. Femtosecond laser in situ keratomileusis (FS-LASIK)**

effectively correct the irregular astigmatism and improve the postoperative contrast sensitiv‐ ity in patients. On the contrary, Trans-PRK simplifies the process, which reduces the poten‐ tial higher order wavefront aberration caused by irregular ablation and decreases postoperative glare and night vision loss. Therefore, increasingly ophthalmologists choose

Trans-PRK is the easiest laser refractive surgery for refractive surgeons to learn, and it is stable in techniques and cost-effective. As a result, it is considered an ideal corneal refractive

Presbyopia is an age-related condition in which accommodation gradually decreases and the eyes are unable to focus and obtain clear near vision. There is one approach to correct presbyopia through laser refractive surgery commonly called PresbyLASIK. Synonymous with LASIK, PresbyLASIK contains the process of making a special ablation profile to either

PresbyLASIK has been described in three different approaches: central PresbyLASIK, peripheral PresbyLASIK, and transitional multifocality. In central PresbyLASIK, the central area is shaped for near vision and the mid-peripheral cornea is shaped for distant vision. On the contrary, in peripheral PresbyLASIK, the central area is shaped for distant vision and the mid-peripheral corneal area for near vision. Both central and peripheral techniques reported‐ ly obtained adequate spectacle independence in both myopia and hyperopia. In addition, a neuroadaptation process is needed in peripheral techniques. The third approach combines depth of field increase and micro-monovision, which induces a certain degree of spherical aberration to each eye to increase the depth of field while making the nondominant eye slightly

Presbyopia remains the biggest challenge to be corrected: the mechanism of accommodation and the cause of presbyopia are complex to understand fully. Therefore, the efficacy of presbyopia correction even with the latest platform is still in dispute. However, there is enough scientific evidence to consider PresbyLASIK as a useful tool in presbyopia correction [14]. Epstein and Gurgos [15] reported that 89% hyperopia (25/28) patients and 91.3% myopia (94/103) patients who underwent peripheral PresbyLASIK were completely spectacle inde‐ pendent and with distance unaided visual acuity of 20/20 in 67.9% (19/28) in hyperopia patients

Femtosecond laser technology was first introduced by Dr. Kurtz in the early 1990s, and it has developed rapidly over the past two decades. "Laser power" is defined as energy delivered per unit time. The laser-related damage will reduce with the decrease of pulse duration. The

perform a multifocal cornea procedure or increase the depth of field.

Trans-PRK to improve postoperative visual quality.

**2.6. Excimer laser in presbyopia correction**

operation for patients.

380 382High Energy and Short Pulse Lasers

myopic [13].

and 70.7% (53/75) in myopia patients.

**3.1. Characteristic of femtosecond laser**

**3. Femtosecond laser in ophthalmology**

The concept of the lamellar refractive procedure was first introduced by Barraquer in the early 1960s. In the 1990s, an excimer laser ablation-assisted lamellar procedure was devel‐ oped, as the foundation of modern laser in situ keratomileusis (LASIK). Compared with photorefractive keratectomy (PRK), visual recovery is faster and visual outcome is rapidly stable after LASIK. Flap-associated complications and increased incidence of dry eye after surgery, however, affect the quality of life. The safety, precision, and predictability of the femtosecond laser have changed LASIK over recent years.

Flap formation is critical to a successful LASIK surgery. Improper flap geometry, decentra‐ tion, irregular cut, and epithelial damage lead to a large number of complications. Over the past decades, mechanical microkeratome has been performed in LASIK because of its reliability and safety. However, complications such as incomplete flap, free flap, and button‐ hole continue to plague surgeons. Furthermore, because of the instability of mechanical microkeratome, corneas may be too steep, too flat, or too thin even after a successful opera‐ tion [18].

The femtosecond laser became available for LASIK flap formation approximately 10 years ago. It reduced the risk of the above-mentioned complications. With mechanical microkeratome, the flap is thinner centrally and thicker peripherally (meniscus-shaped flap), which increas‐ es the incidence of buttonhole perforation. The femtosecond laser allows thin and uniform flaps, which improves the stability, safety, and precision of the flaps. It can also create thinner flaps with minimum effects on stromal architecture. Flap centration, diameter, and thickness are also more precise in femtosecond-created flaps. Another advantage of the femtosecond laser is that it allows the surgeon to select the cutting angle, position, and diameter of the hinge, as well as the flap diameter and flap thickness, which may provide better flap stability and reduce clinical epithelial ingrowth.

Though femtosecond lasers reduce the incidence of complications such as buttonhole perforation, incomplete flap, free cap, and irregular cuts, there are still some specific limita‐ tions in FS-LASIK. FS-LASIK requires two laser platforms—one for flap creation (femtosec‐ ond laser) and another for stromal bed ablation (excimer laser)—which increases the time and cost of the laser procedure. Because of the response of corneal keratocytes to the energy and inflammatory responses of adjacent tissues to gas bubbles, patients may encounter photopho‐ bia, called transient light-sensitivity syndrome (TLSS), early after FS-LASIK. With the development of the femtosecond laser, it needs less energy for flap formation, and thus reduces the incidence of TLSS [19]. The presence of cavitation gas bubbles during FS-LASIK, which originate from stray laser pulses into the aqueous humor, can impede the eye tracker of the excimer laser. An increased rate of diffuse lamellar keratitis, a sterile inflammatory reaction, was also observed in FS-LASIK because of the higher flap interface inflammatory response to

laser energy and gas bubbles. Revolution in femtosecond laser energy is expected to reduce the specific complications.

In our previous study, patients treated with a femtosecond laser showed better corneal regeneration than those with a microkeratome did. Because of its precision and predictabili‐ ty, the femtosecond laser makes a smoother flap and causes less damage to the corneal nerve [20]. However, different from others' opinions, our data showed that there were no significant differences in the tear meniscus parameters between the microkeratome and femtosecond laser [21].

#### **3.3. Femtosecond lenticule extraction (FLEx)**

A new approach called femtosecond lenticule extraction (FLEx) was introduced to correct myopia and astigmatism. FLEx does not require a microkeratome or an excimer laser. It uses only the femtosecond laser, which is more convenient than other procedures that require both excimer and femtosecond lasers. Two cuts (posterior and anterior) in the cornea are in‐ volved in the procedure, which thus create a lenticule that is ultimately removed. There is no significant difference between FLEx and conventional LASIK, both in efficacy and safety, which promotes FLEx to be a promising new corneal refractive procedure to correct refrac‐ tive errors.

However, it has been reported that the visual outcome after FLEx was stable early after surgery, but visual recovery was slow [22]. As a corneal flap is necessary before lenticule extraction, associated complications such as dry eye and compromise of corneal biomechanical strength are inevitable. Therefore, the technique evolved into SMILE.

#### **3.4. Small-incision lenticule extraction (SMILE)**

SMILE, passing the Conformite Europeenne (CE) certification in 2009, is a novel technique to correct refractive errors. The procedure involves passing a dissector through a small incision to separate the lenticular interfaces and allow the lenticule to be removed, thus eliminating the need to create a flap [23]. Early or late complications associated with flaps, such as disloca‐ tions and buttonholes are avoided; therefore, patients' experience and visual outcomes improve.

The absence of flap creation minimizes the disruption of the stromal architecture because the corneal lenticule is extracted from the mid-stroma [24]. Fewer corneal nerve branches are disrupted compared with FS-LASIK, which preserves corneal biomechanical strength and maintains sensitivity. Thus, the risk of dry eye and patients' discomfort is reduced after surgery [25]. The minimal disruption of the anterior corneal surface epithelium, Bowman's layer, and anterior stroma is also associated with less risk of dry eye [26]. Laser fluence and difference in stromal hydration, which may affect stromal ablation, are avoidable in SMILE. Prospective and retrospective studies of SMILE have shown that in the terms of efficacy, predictability, and safety SMILE is similar to FS-LASIK.

However, there are still some difficulties in SMILE. Similar to a flap in FS-LASIK, a cap whose uniform regularity is essential to optimal visual outcome is created using a femtosecond laser.

In addition, the surface quality of the corneal lenticule can be irregular, causing tissue bridges, cavitation bubbles, scratches, or incomplete extraction of stromal lenticules [27]. At present, SMILE is mainly applied in mild myopia. It still needs more attempts and experience to be used in hyperopic eyes.

Complications such as epithelial erosion, suction loss, cap perforation, and lenticule extrac‐ tion difficulty can all occur. Corneal haze, dry eye syndrome, keratitis, and interface inflam‐ mation have also been reported.

SMILE is a promising new technique for refractive error correction. With further develop‐ ment of the femtosecond laser, SMILE may gain greater acceptance in the future. However, we still have to pay more attention to its complications to verify its safety.

### **3.5. Femtosecond laser in presbyopia correction**

### *3.5.1. Corneal inlay implantation*

laser energy and gas bubbles. Revolution in femtosecond laser energy is expected to reduce

In our previous study, patients treated with a femtosecond laser showed better corneal regeneration than those with a microkeratome did. Because of its precision and predictabili‐ ty, the femtosecond laser makes a smoother flap and causes less damage to the corneal nerve [20]. However, different from others' opinions, our data showed that there were no significant differences in the tear meniscus parameters between the microkeratome and

A new approach called femtosecond lenticule extraction (FLEx) was introduced to correct myopia and astigmatism. FLEx does not require a microkeratome or an excimer laser. It uses only the femtosecond laser, which is more convenient than other procedures that require both excimer and femtosecond lasers. Two cuts (posterior and anterior) in the cornea are in‐ volved in the procedure, which thus create a lenticule that is ultimately removed. There is no significant difference between FLEx and conventional LASIK, both in efficacy and safety, which promotes FLEx to be a promising new corneal refractive procedure to correct refrac‐

However, it has been reported that the visual outcome after FLEx was stable early after surgery, but visual recovery was slow [22]. As a corneal flap is necessary before lenticule extraction, associated complications such as dry eye and compromise of corneal biomechanical strength

SMILE, passing the Conformite Europeenne (CE) certification in 2009, is a novel technique to correct refractive errors. The procedure involves passing a dissector through a small incision to separate the lenticular interfaces and allow the lenticule to be removed, thus eliminating the need to create a flap [23]. Early or late complications associated with flaps, such as disloca‐ tions and buttonholes are avoided; therefore, patients' experience and visual outcomes

The absence of flap creation minimizes the disruption of the stromal architecture because the corneal lenticule is extracted from the mid-stroma [24]. Fewer corneal nerve branches are disrupted compared with FS-LASIK, which preserves corneal biomechanical strength and maintains sensitivity. Thus, the risk of dry eye and patients' discomfort is reduced after surgery [25]. The minimal disruption of the anterior corneal surface epithelium, Bowman's layer, and anterior stroma is also associated with less risk of dry eye [26]. Laser fluence and difference in stromal hydration, which may affect stromal ablation, are avoidable in SMILE. Prospective and retrospective studies of SMILE have shown that in the terms of efficacy,

However, there are still some difficulties in SMILE. Similar to a flap in FS-LASIK, a cap whose uniform regularity is essential to optimal visual outcome is created using a femtosecond laser.

the specific complications.

382 384High Energy and Short Pulse Lasers

femtosecond laser [21].

tive errors.

improve.

**3.3. Femtosecond lenticule extraction (FLEx)**

are inevitable. Therefore, the technique evolved into SMILE.

**3.4. Small-incision lenticule extraction (SMILE)**

predictability, and safety SMILE is similar to FS-LASIK.

Corneal inlay implantation is performed for presbyopic correction. It changes the anterior corneal surface curvature, cornea refractive index, and depth of focus by placing a small inlay of suitable biocompatible material within the stroma. The benefits of inlays are the reversibil‐ ity of the procedure by removal of the implant, implantation simplicity, and implant reposi‐ tioning. The ability to perform ad hoc refractive procedures allows the simultaneous correction of ametropia. The most common complications after the surgery are glare and dry eye. The femtosecond laser advances flaps and tunnel creation to implant the inlays accurately on the line of sight, and thus result in remarkable improvements in uncorrected visual acuity (near and intermediate) and minimal change in uncorrected distance visual acuity. This procedure also provides good nonspectacle-corrected near vision for average daily activities [18, 28].

## *3.5.2. IntraCor surgery*

IntraCor surgery is a new technique applicable for ametropic or low-degree hyperopic eyes (+0.5 to +1.5 D). It changes the topographic and refractive characteristics of the central portion of the cornea selectively with femtosecond laser. The procedure involves concentric intrastro‐ mal ring creation in the central portion of the cornea at different corneal depths (between the Bowman's and Descemet's boundaries). Other than the treatment failure in presbyopic correction, no major complications have been reported. IntraCor surgery is promising in the field of presbyopia correction [18].

#### **3.6. Astigmatic keratotomy (AK)**

To correct low to high astigmatism, astigmatic keratotomy (AK) is performed. The accuracy of length, optical zone, and incision depth are crucial in visual outcomes. However, the limitation of AK is the unpredictability of manual corneal incision. The application of femtosecond laser in AK provides accuracy and precision in corneal incision manufacturing and thus improves significantly in uncorrected and best-corrected visual acuity. The femto‐ second laser can also be applied in case of high degrees of post-keratoplasty astigmatism. The

incisions within the graft button present precise geometry and reliable depth of incision. Specific complications associated with femtosecond laser-assisted AK such as self-healing micro-corneal perforations and low-grade inflammation at the incision site appeared [18, 29].

#### **3.7. Intracorneal ring segments**

Intracorneal ring segments were small and curved when first proposed in 1978. Clear ring segments made of polymethylmethacrylate are implanted in the deep corneal stroma with the aim of generating modifications of corneal curvature and refractive changes. Peripheral intracorneal implantation has been permitted to correct low to moderate astigmatism and myopia and keratoconus by Food and Drug Administration (FDA). Complications such as incomplete tunnel formation, corneal perforation, endothelial perforation, corneal melting, and uneven implant placement may occur with the traditional technique. The femtosecond laser can be programmed to create corneal channels at a specific depth and orientation with high predictability and precision to allow safer insertion of Intacs segments. In patients with keratoconus, the femtosecond laser can be programmed to cut tunnels for the implantation of intracorneal ring segments, and it results in better safety owing to greater consistency of depth and uniformity [29, 30].

#### **3.8. Penetrating keratoplasty (PKP)**

Penetrating keratoplasty (PKP) developed rapidly after first being introduced in the early 1900s. The surgical outcomes rely on a centered and perpendicular cut of cornea, a wellmatched donor button, and a recipient bed [18]. Manual PKP requires a long learning curve and a lengthy procedure time, which can be optimize using the femtosecond laser. The femtosecond laser can also achieve a higher precision in surgical steps, such as the donor cornea cutting. Moreover, the choice of shapes and diameters in femtosecond laser-assisted PKP is dependent on individualized clinical requirement. It enables advanced shaped corneal cuts creation, eliminates manual dissection, thus minimizing misalignments, and increases the stability of the wound. Some pattern of incisions that are not compassable with conventional technique can be achieved by femtosecond laser. However, postoperative regular and irregular astigmatism remain a major challenge in full-thickness keratoplasty.

#### **3.9. Anterior lamellar keratoplasty (ALK)**

Anterior lamellar keratoplasty (ALK) is a partial thickness corneal transplantation indicated for management of anterior corneal dystrophies degenerations, ulcers, and scars. The advantages of ALK over PKP include being less invasive and having a decreased rate of rejection. Femtosecond laser-assisted suture less anterior lamellar keratoplasty (FALK), first described in 2008, has been reported to be safe, effective, and stable. The femtosecond laser has reduced irregular astigmatism and accelerated visual recovery by its precision of pre‐ programmed corneal dissections at a variety of depths and orientations. As the corneal incision is well shaped, it can be converted to full-thickness keratoplasty in case of Descemet mem‐ brane perforation. The donor and recipient tissue are better positioned because of highly precise cuts assisted by the femtosecond laser, and thus sutures are typically removed earlier. Limitations of ALK include the high cost and the slow growth of the epithelium over the graft [18, 30].

### **3.10. Femtosecond laser-assisted endothelial keratoplasty**
