Neither visible or near infrared laser light are absorbed by the refractive structures of the eye at low power densities, allowing the light to freely pass into the eye without any surgical cut or effect. At high power densities, the non-linear optical properties of these structures lead to absorption, generating plasma.1'2 The infrared Neodynium-glass femtosecond laser emits a wavelength similar to the Neodynium-YAG laser, which is used widely in ophthalmic laser surgery.1 Each femtosecond laser pulse is approximately ten thousand times shorter in duration, compared to a Q-switched Nd:YAG laser, and lasts only about 10 to 13 seconds.1,4,5
Unlike photothermal lasers, the high peak intensities of the femtosecond laser allows it to create a plasma inside transparent tissues- such as the cornea - without interfering with surface cell layers (Fig 1). Femtosecond laser pulses require significantly less energy to produce photodisruption compared to longer pulsewidth lasers, such as the picosecond and nanosecond laser.6-8 This lower energy threshold translates into smaller cavitation bubble size (microcavitation) (Table 1), allowing nearly contiguous placement of laser pulses. Computer-controlled, high-precision delivery system optics, capable of scanning the focused beam over a 10-mm working diameter with micron-range accuracy have been developed, making these ultrafast lasers ready for biological and medical applications. In cooperation with the University of Michigan at Ann Arbor, MI and the IntraLase Corporation (Irvine, CA), we performed the first clinical studies with the a-prototype of the Pulsion FS equipment to demonstrate the efficacy of this laser in ophthalmic surgery.
Figure 1. Intrastromal surgery with a scanning femtosecond laser places pulses inside the cornea without interfering with the surface layers (courtesy IntraLase Corporation, Irvine, CA).
We also performed ex vivo and in vivo animal studies for potential corneal applications, which led to human clinical trials (Fig 2).8,9 In this report, we summarize our long-term follow-up experience with this Pulsion FS laser prototype in making flaps (Femto-LASIK), creating intrastromal tunnels for intrastromal corneal ring segments (Femto-ICRS), femtosecond laser keratomileusis with lenticule removal (FLK), and intrastromal photorefractive keratectomy (ISPRK) in which corneal tissue is removed without disturbing the epithelium.
Fluence Threshold, Shockwave Range, and Cavitation Bubble Diameter in the Cornea as a Function of Laser Pulse Duration
PATIENTS AND METHODS
The femtosecond laser is an Nd:glass laser that operates at 1.05 µm wavelength, and emits 500 fs pulses at a 3 to 5 kHz repetition rate. The typical pulse energy is between 4 and 6 mJ. Alignment of the system is first verified on a test surface. After placement of topical anesthetic and antibiotic drops, a lid speculum is inserted to achieve sufficient exposure. A suction ring is then applied to the limbus, and a contact lens assembly is used to appianate the cornea. During applanation, the intraocular pressure is elevated to approximately 35 mmHg. The laser pulses are delivered according to preprogrammed patterns for creation of a flap, lenticule, channel, or for volumetric reduction during intrastromal photorefractive keratectomy.
Studies in Pig Eyes: Accuracy and Reproducibility of Femtosecond Laser Resections
Flap creation was tested in fresh porcine eyes for accuracy and reproducibility of resections. Although the system can deliver a wide range of resection parameters, initially flaps of 8.5 mm, 9.0 mm, and 9.5 mm were evaluated at a single depth of 160 µm. A series of resections at varying depths were also evaluated at a single diameter. A digital micrometer (Starrett, model 788, Athol, MA) was used to measure flap thickness with the flap held between two glass slide covers. Bed diameter was measured as the largest distance passing through the corneal center. As seen in Table 2, flap thickness and diameter were highly reproducible and accurate. Flap thickness varied from 6% to 8%, or approximately 12 µm at the intended 160-µm resection thickness. Flap diameter was also reproducible, achieving values in the 1% to 3% range, which means approximately 0.1 to 0.3 mm deviation from the intended diameter.
Figure 2. Scanning electron micrographs of the corneal flap interface created with A) mechanical keratome (Chiron Hansatome), and B) femtosecond laser keratome in ex vivo porcine corneas. The surface quality of the corneal bed produced by the laser is at least equivalent or slightly smoother than that of the mechanical keratome. Magnification x200.
Flap Thickness and Diameter Reproducibility at 160-pm Setting With the Femtosecond Laser
For corneal flaps, an outwardly expanding spiral pattern consisting of approximately 500,000 to 800,000 pulses was scanned at 160, 180, or 200 µt? depth for a total diameter of 8 to 10 mm. This was followed by a side cut to the surface, with creation of a hinge by partially blocking the beam. After completion of the laser procedure, suction was released and the contact lens delivery system was elevated, allowing access to the resected corneal flap. Excimer laser photoablation (VISX 20/20B, Santa Clara, CA) was then performed under the elevated flap. The flap was then repositioned, as with conventional LASIK, and the edges were aligned easily due to the cone-shaped edge cut made at 45° relative to the surface.
For a channel, a spiral was used to create an expanding annular pattern using approximately 200,000 pulses at a depth of 400 µm (approximately two-thirds corneal depth) with an inner ring diameter of 6.6 mm and an outer diameter of 8.2 mm. Intrastromal corneal ring segments (ICRS, KeraVision, Fremont, CA) were then introduced into the laser-created channels, after dissection of the interface with a blunt instrument.
Femtosecond Laser Keratomileusis
For a lenticule, a plano-convex lens-shaped volume of corneal stroma was laser resected by first introducing an expanding spiral in a concave pattern, relative to the corneal surface, to a diameter of 4.5 mm. A central depth of 60 µm more than the intended flap thickness and a peripheral depth at the level of the flap thickness allowed for an 8.50-diopter (D) myopic refractive correction. A corneal flap was then created, as with FemtoLASIK, after which the lenticule was identified and removed manually from below the flap. Finally, the flap was repositioned easily, as with Femto-LASIK.
Intrastromal Photorefractive Keratectomy
For intrastromal volume reduction, leaving the epithelium intact, the suction ring and contact lens delivery system were once again applied. In these early experiments, we used a truncated cone-shaped pattern for myopia and a ring-shaped pattern for hyperopia treatment, in order to examine refraction changes without disturbing the central part of the cornea. For correction of myopia, a total of 7 to 10 lamellar layers of laser pulses were focused starting at a corneal depth of 170 to 200 µm and ending 100 µm from the surface. The most posterior layer of pulses was applied to a diameter of 3.5 mm. With each successive layer placed 10 µm more anterior to the next, the diameter was enlarged an additional 0.3 to 0.42 mm, so that the final most anterior layer had a diameter of 6.5 mm. For correction of hyperopia, 7 to 10 ring layers were applied with an inner diameter of 6.0 mm and an outer diameter of 8.0 mm. Since an individual femtosecond laser pulse is estimated to remove a volume of 27 to 125 µmp 3 by converting collagen to a gas through plasma mediated ablation, the total depth of tissue removed should correspond to the pulse volume times the number of layers and take on a profile dependent on the diameter of each layer.
After the procedures, eyes received a combined topical antibiotic/anti-inflammatory agent (TobraDex, Alcon, Ft Worth, TX) and a holed patch for 1 day. Postoperatively, these drops were used five times per day for 1 week, and then three times per day for 1 month. Topical artificial tears were also used five times per day for 1 to 3 months. Follow-up examinations were performed 1 day, 1 week, and 1, 3, 6, 12, and 18 months after femtosecond laser refractive surgery.
Both fully sighted and partially sighted eyes were enrolled for this initial clinical evaluation of femtosecond laser refractive surgery. The procedures were performed in only one eye of each patient, except in the Femto-LASIK and Femto-ICRS groups, where several patients had both eyes (sighted) done 1 to 3 months apart.
For Femto-LASIK, surgery was performed on 46 eyes (24 OD, 22 OS) for myopia up to -14.00 D. Patient age range was 23 to 55 years (mean 36.93 ± 10.3 yr); there were 30 females and 16 males.
For Femto-ICRS, 16 eyes (7 OD, 9 OS; 8 male, 8 female) received the channel-forming treatment with implantation of intrastromal corneal ring segments. Patient age range was 31 to 50 years (mean 39.8 ± 6.5 yr).
For femtosecond laser keratomileusis, five eyes of five patients, each with one highly myopic, anisometropic and amblyopic eye, were sculpted by the femtosecond laser to create and remove a corneal lenticule from the amblyopic eye. Patient age range was 20 to 43 years (mean 29 ± 11.1 yr).
For intrastromal photorefractive keratectomy, the procedure was performed in 13 patients, each with an amblyopic eye (4 myopic, 9 hyperopic). Patient age range was 21 to 54 years (mean 35 ± 11.1 yr).
Four patients in the Femto-LASIK group and one in the Femto-ICRS group were selected as controls, with no secondary refractive procedure (excimer ablation or ring insertion). These were selected in order to evaluate potential refractive effects of the femtosecond laser procedure itself.
Preoperative and postoperative examinations included slit-lamp microscopy, Schirmer strip, tear break-up time, corneal topography, ultrasonic biometry and pachymetry, direct and indirect ophthalmoscopy, uncorrected (UCVA) and best spectaclecorrected Snellen visual acuity (BSCVA) and manifest and cycloplegic refraction; follow-up time was at least 1 year.
In the 43 patients who had flap creation with the femtosecond laser (Fig 3) followed by excimer laser treatment, refractive results achieved were comparable to those of the conventional LASIK procedure, performed by the same surgeon.
Figure 4 shows BSCVA change over 1.5 years of follow-up after the femtosecond-LASIK treatment. We treated amblyopic eyes, so the average BSCVA was just slightly above 20/40. This figure suggests that the wound healing process was slower compared to conventional LASIK, and may be explained by difficulties encountered in flap elevation; in a few eyes separation of the flap from the stromal bed was not optimum. Figure 5 shows change in BSCVA at 6 months compared to before surgery. No patient lost two or more lines of BSCVA and most, patients (36 of 43; 83.7%) attained a postoperative uncorrected visual acuity equal to their preoperative BSCVA.
Figure 3. A) Steps of corneal flap creation with a femtosecond laser keratome (courtesy IntraLase Corporation, Irvine, CA). B) Postoperative slit-lamp photomicrographs at 12 hours after surgery, and C) at 1 week after surgery show no loss of corneal clarity and excellent flap stability.
Figure 4. Change in best spectacle-corrected visual acuity (BSCVA) over time after Femto-LASIK in 46 eyes.
Figure 5. Change in Snellen lines of BSCVA 6 months after FemtoLASIK compared to before treatment in 46 eyes.
Achieved (6 mo after surgery) versus intended refractive correction is presented in Figure 6. The highly myopic eyes show undercorrection, but none of the eyes were overcorrected by more than 1.00 D. The slope of the fitted line is 0.856 shows good correlation (correlation coefficient, R=O. 9855) compared to our conventional LASIK-treated eyes performed with a Hansatome microkeratome (Chiron/Bausch & Lomb, Rochester, NY) and VISX 20/20 B excimer laser. In six eyes with high myopia, the full excimer laser ablation was not performed in order to leave a sufficient residual corneal stromal bed. In three eyes, the flap was cut but not lifted; no change was seen in manifest refraction or corneal topopgraphy. Figure 7 shows change in average manifest refraction during the same follow-up period.
Figure 6. Achieved versus intended correction at 6 months follow-up after Femto-LASIK in 46 eyes.
Minor complications included decentration of the flap (two eyes) because of imperfections in the applanation device (patient interface). The magnitude of the decentrations was less then 2 mm, thus excimer laser photoablations were performed. In these cases we were not able to maintain the centration of the vacuum ring that holds the patient's eye during treatment. On the basis of these experiences, the patient interface has been improved. Three early patients also developed epithelial inclusion cysts between the flap edge and adjacent stroma, when the edge was perpendicular to the corneal surface. This was due to mild retraction of the edge from the adjacent stroma; this improved after changing the vertical flap edge to an edge with an angle 45° from the surface. Free caps or buttonholed flaps, which are occasionally seen when using a traditional microkeratome, were not observed. There was no epithelial ingrowth in the interface and no further epithelial inclusion cysts after changing the flap edge orientation. The flaps created with the femtosecond laser were more uniform in thickness than traditional flaps. We measured flap thickness in vivo in 15 eyes with the Advent ultrasound pachymeter (Mentor, Norwell, MA). Flap thickness was evaluated by subtracting the thickness of the residual stromal bed from preoperative corneal thickness. Mean thickness value was 159 ±8.5 µm intended value was 160 µm. This result correlates strongly with a more detailed in vitro study (Table 2). The percentage of difference from the average in the in vitro study is 1.9%. The resected flaps showed excellent stability immediately after repositioning (Fig 3), without loss of corneal clarity. As multiple procedures were performed, we were able to optimize dissection and surface quality, side cut, hinge architecture, and centration techniques.
Figure 7. Change in spherical equivalent refraction during follow-up after Femto-LASIK in 46 eyes.
In the 16 patients where intrastromal corneal ring segments were implanted into tunnels made with the femtosecond laser (Fig 8), refractive results were the same as with the standard ICRS procedure. However, unlike conventional ICRS, there were practically no operative complications. We found only minimal deposits in the tunnels in two eyes in the first postoperative month, and these deposits did not get more prominent over the following year. Visual acuity improved immediately after surgery (Fig 8).
Femtosecond Laser Keratomileusis
In five patients (five eyes) who had femtosecond laser keratomileusis, mild corneal edema occurred during the first 2 postoperative days. Centration of the procedures was excellent and the high amount of myopia in these amblyopic eyes was corrected following removal of the lenticule (Fig 9). Corneal transparency was maintained, and refractive stability was good (Fig 9). Uncorrected visual acuity was better than preoperative BSCVA in all patients.
Figure 8. Pre-cut channels and entry cuts made by the femtosecond laser for corneal implants. A) Pulses are scanned in a circular pattern below the surface to create the channel, followed by an entry cut for inserting the implants. Slit-lamp photomicrographs (courtesy IntraLase Corporation, Irvine, CA) B) immediately after intracorneal ring implantation, and C) 1 day postoperatively.
Intrastromal Photorefractive Keratectomy
Intrastromal photorefractive keratectomy of the cornea was performed in five moderately myopicamblyopic, and eight hyperopic-amblyopic eyes. The bubbles created during surgery in the stroma disappeared within 1 to 2 hours after surgery (Fig 10), after which the corneas became highly transparent. Figure 11 shows the pattern of pulse placement and topographic change for both myopic and hyperopic eyes. Refractive results for the hyperopic patients were stable by the first month; they achieved a mean correction of +2.00 D postoperatively (Fig 12). Visual acuity (with and without correcton) in every eye was better at 1 week after surgery compared to preoperative BSCVA. For the high myopic and amblyopic patients, refractive results improved more slowly; they achieved a stable mean correction of -1.00 D at 3 months, -1.25 D at 6 months, and -2.25 D at 12 months postoperatively (Fig 13). There was no haze detected throughout the 18 months of follow-up; fluoromethalone eye drops were used during the first postoperative month.
Laser in situ keratomileusis using a microkeratome to create a corneal flap10·11 has been the most commonly performed surgical procedure worldwide for correcting refractive errors.1214 Although LASIK has a high success rate, complications have been reported in approximately 2% to Qc/< of eyes1510 with visually significant consequences in about 10%. The majority of these are linked to deficiencies in microkeratome performance.
Our initial experience with the femtosecond laser surgical system reveals a number of clinical advantages over traditional techniques. For example, corneal flap creation with a mechanical microkeratome can lead to the unique disadvantage of thin, thick, irregular, button-holed, or partial flaps, as well as metal fragment deposits.15,16 The reproducibility and ability to vary laser-created parameters (such as thickness, diameter, hinge location, hinge angle, and side-cut architecture), as well as maintain normal intraocular pressure, can facilitate greater clinical safety and flexibility.1,20
The flaps we created in animal experiments and in the human clinical trials displayed excellent stability immediately after repositioning, without loss of corneal clarity. Pulse spacing and refinement can optimize the dissection, surface quality, side cut and hinge architecture, as well as centration techniques.
We have demonstrated that a femtosecond laser can be used for implanting intrastromal corneal rings with similar results to those of traditional ICRS.17
In the case of femtosecond laser keratomileusis, the anterior curvature of the cornea flattens due to the removal of an intrastromal lenticule, resulting in a refractive change analogous to current LASIK techniques. Compared to LASIK, femtosecond laser keratomileusis is a single-step procedure. It is performed on a low vacuum fixated eye, which makes centration both accurate and easy to maintain. For clinical use of femtosecond laser keratomileusis, a surgical nomogram describing the shape, size, and position of the lenticule has been designed on the basis of an accurate analytical model of the human cornea.18 The accuracy, reproducibility, stability, and safety of this procedure must be determined in a larger series of patients.
Figure 9. A) Conceptual illustration of femtosecond laser keratomileusis (courtesy IntraLase Corporation, Irvine, CA), and B) corneal elevation topography (Orbscan) at 3 months after femtosecond laser keratomileusis reveals improvement of about 10 diopters.
Femtosecond laser intrastromal photorefractive keratectomy is a new method for correcting low myopia and hyperopia without any cuts on the corneal surface. The epithelium and Bowman's layer remain intact, hence patients do not have pain or discomfort following the procedure. Since the refractive results are of significant magnitude and remain stable, resulting in excellent patient satisfaction, this treatment has a promising future after clinical validation in a large number of patients. The 3.00 D of myopic (or hyperopic) change corresponds to 7 to 10 layers of pulses, which remove a depth of 3 to 5 µm each, resulting in a maximum central (or peripheral) depth of 20 to 50 µm. The mean of this range corresponds to the depth of 3.00 D with conventional laser vision correction.
Figure 10. Slit-lamp photomicrographs after intrastomal photorefractive keratectomy for myopia: A) immediately after surgery, B) after 1 hour, and C) after 1 .5 hours; D) immediately after intrastomal photorefractive keratectomy for hyperopia; and E) one-half hour after intrastomal photorefractive keratectomy for hyperopia.
Figure 11. Diagram of pulse placement for volume reduction with intrastomal photorefractive keratectomy; A) for myopia, and B) for hyperopia. Six-month postoperative corneal topography of intrastomal photorefractive keratectomy C) for myopia, and D) for hyperopia. Corneal topography demonstrates an approximate 3.00-D change for each condition.
The potential advantages of the femtosecond laser keratome include the ability to vary multiple parameters, maintain normal intraocular pressure, and increase postoperative stability of the flap. Femtosecond lasers may also have significant potential for improving corneal transplantation (anterior, or posterior lamellar and full-thickness transplantation), as well as surgical manipulation of other ocular tissues, such as the sclera (glaucoma surgery) and the lens (cataract surgery or presbyopia correction). Continuous improvements in ultrafast laser technology and the increasing demands from ophthalmologists to improve available surgical techniques suggest that the femtosecond laser in refractive surgery will evoke further investigation.
Figure 12. Average achieved hyperopic correction during follow-up after ISPRK in nine eyes.
Figure 13. Average achieved myopic correction during follow-up after ISPRK in four eyes.
1. Spooner GJR. Juhasz T, Ratkay-Traub 1. Djotyan G, Horvath C. Sacks Z, Marre G, Miller D, Williams AR, Kurtz R. New development in ophthalmic applications of ultrafast lasers. Commercial and Biomedical Applications of Ultrafast Lasers II, Proceedings of SPIE 2000;3934:62-72.
2. Juhasz T, Djotyan G, Loesel FH, Kurtz RM, Horvath C. Bille JF. Mourou G. Applications of femtosecond lasers in corneal surgery. Laser Physics 2000;10:1-6.
3. Puliafito CA, Steinert RR Deutsch TR Excimer laser ablation of the comea and lens. Ophthalmology 1985;92:741-748.
4. Vogel A, Capon MRC. Asiyo-Vogel MN. Birngruber R. Intraocular photodisruption with picosecond and nanosecond laser pulses: tissue effects in cornea, lens, and retina. Invest Ophthalmol Vis Sci 1994;35:3032-3044.
5. Juhasz T. Kastis GA. Suárez C, Bor Z, Bron WE. Timeresolved observations of shock waves and cavitation hubbies generated by femtosecond laser pulses in corneal tissue and water. Lasers Surg Med 1996:19:23-31.
6. Krueger RR. Marchi V, Gualano A, Juhasz T, Speaker M. Suárez C. Clinical analysis of the Nd:YLF picosecond laser as a microkeratome for laser in situ keratomileusis. J Cataract Refract Surg 1998;24:1-7.
7. Kurtz RM, Liu X. Einer V7M. Squier JF. Du D, Mourou GA. Photodisruption in the human cornea as a function of laser pulse width. J Refract Surg 1997;13:643-658.
8. Kurtz RM, Horvath C, Liu HH. Krueger R, Juhasz T. Lamellar refractive surgery with scanned picosecond and femtosecond laser pulses. J Refract Surg 1998;14:541-548.
9. Yen KG, Sachs Z, Einer VE, Traub IR, Juhasz T, Kurtz RM. Histopathology of femtosecond laser intrastromal refractive surgery in rabbits !abstract]. Invest Ophthalmol Vis Sci 1999;40(suppl)621.
10. Pallikaris IG, Papatzanaki ME, Síganos DS, Tsilimbaris MK. Corneal flap technique for laser in situ keratomileusis; human studies. Arch Ophthalmol 1991;109:1699-1702.
11. Pallikaris IG. Síganos DS. Laser in situ keratomileusis to treat myopia: early experience. J Cataract Refract Surg 1997;23:39-49.
12. Binder PS, Moore M. Lambert RW, Seagrist DM. Comparison of two microkeratome systems. J Refract Surg 1997;13:142-153.
13. Buratto L, Ferrari M. Rama P. Excimer laser intrastromal keratomileusis. Am J Ophthalmol 1992;113:291-295.
14. Knorz MC, Liermann A, Seiberth V, Steiner H, Wiesinger B. Laser in situ keratomileusis to correct myopia from -6.00 to -29.00 diopters. J Refract Surg 1996;12:575-584.
15. Seiler T. Koufala K, Richter G. Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg 1998; 14: 312-317.
16. Alio JL, Perez-Santonja JJ, Tervo T Tabbara KF. Vesaluoma M, Smith RJ, Maddox B, Maloney RK. Postoperative inflammation, microbial complications, and wound healing following laser in situ keratomileusis. J Refract Surg 2000:16: 523-538.
17. Schanzlin DJ. Abbott RL, Asbell PA, Assil KK. Burns TE, Durrie DS. Fouraker BD, Lindstrom RL, McDonald II JE. Verity SM, Waring III GO. Two-year outcomes of intrastromal corneal ring segments for the correction of myopia. Ophthalmology 2001; 108:1688-1694.
18. Djotyan GP, Kurtz RM, Fernandez DC. Juhasz T An analytically solvable model for biomechanical response of the cornea to refractive surgery. J Biomech Eng-T ASME 2001;123:440-445.
19. Juhasz T, Loesel F, Kurtz RM, Horvath C, Mourou G. Femtosecond laser refractive corneal surgery. IEEE Journal of Special Topics in Quantum Electronics 1999;5:902-910.
20. Ratkay-Traub I, Juhasz T. Horvath C, Suarez C, Kiss K, Ferincz I, Kurtz R. LTltra-short pulse (femtosecond) laser surgery: Initial use in LASIK flap creation. Ophthalmol Clin N Am 2001;14:347-355.
21. Vogel A, Hentschel W, Holzfuss J, Lauterborn W. Cavitation bubble dynamics and acoustic transient generation in ocular surgery with pulsed neodynium:YAG laser. Ophthalmology 1986:93:1259-1269.
Fluence Threshold, Shockwave Range, and Cavitation Bubble Diameter in the Cornea as a Function of Laser Pulse Duration