The excimer laser provides a precise surgical instrument for the treatment of corneal disease. 1,2 The laser emits ultraviolet radiation at a wavelength of 193 nm, and can remove microns of corneal tissue with minimal heat damage to the adjacent tissue. 3,4 Phototherapeutic keratectomy (PTK) with the excimer laser has been shown to be effective in removing corneal lesions and smoothing surface irregularities. 5,6 The excimer laser frequently obviates the need for more invasive procedures such as lamellar or penetrating keratoplasty. 7 The excimer is effective at removing superficial corneal irregularities, but often induces a new irregular surface topography, regardless of the surface smoothing agent used during the procedure. Often the patient is left with a hyperopic shift when current scar removal protocols are followed. 8 We propose the BioMask as an ideal corneal modulator because it can be shaped before ablation, thereby reducing unwanted hyperopic shifts and irregularities. The material is applied as a heated liquid and transforms into a solid material within 3 minutes as it cools. The material can be shaped using a customized applanator lens with a known radius of curvature. This new surface works as a template for the prescribed corneal topography. The lens is removed after the material has cooled, and the newly molded surface is then ready for excimer laser ablation. The laser effectively removes the BioMask while it reshapes the surface topography. After ablation, the central topography of the cornea closely matches the base curve of the lens used to shape the BioMask. 9
MATERIALS AND METHODS
The BioMask is derived from porcine type I collagen and closely matches the ablation characteristics of a human cornea. 10 This material and its use have been described and characterized in previous publications. 9 For the purposes of this nonrandomized, prospective clinical trial we used the BioMask system, which comprises a computer-controlled heating block unit, a set of applanator lenses ranging from 35 to 44.5 diopters in curvature, customized lens forceps used to hold the applanator during the procedure, a custom-made cannula for delivery of the material onto the cornea, and the BioMask material itself.
An Institutional Review Board/Ethics Committee approval was obtained for this study, and a patient consent form was signed by all subjects before participation in this clinical trial. Inclusion criteria included age at least 18 years, and decreased functional vision attributable to corneal scars in the anterior one third of the stroma, resulting in a reduction in potential best visual acuity secondary to one or more of the following conditions: (1) corneal scars as a result of herpes simplex or herpes zoster known to be nonactive for 6 months before enrollment in this study; (2) corneal scars and opacities located in the anterior 150 μm that may be the result of trauma (mechanical or chemical); (3) corneal dystrophies, including map dot, lattice, Reis-Buckler's, granular, macular, and others as may be indicated; (4) Salzmann's nodular degeneration; (5) recurrent corneal erosions unresponsive to conventional therapy; (6) band keratopathy, calcific or spheroidal; and (7) status post-pterygium resection with residual corneal scarring.
Exclusion criteria fell under two separate groups: ocular and systemic. Ocular exclusion criteria included severe blepharitis, lagophthalmos, severe dry eye, uncontrolled uveitis, corneal neovascularization within the 9-mm central optical zone, keratoconus, active ocular infections, and patients who had undergone a laser-assisted in situ keratomileusis (LASIK) procedure. Systemic exclusion criteria included any disease compromising the immune system; diabetes mellitus; collagen vascular diseases; pretreatment corneal thickness such that posttreatment pachymetry could be ≤250 μm; a patient in a situation or having a condition that, in the opinion of the investigator, may confound the results of the study or may interfere with optimal participation in it, or may produce a significant risk for the patient; any patient using antimetabolites; history of glaucoma or suspected glaucoma; clinically significant atopic disease; patients at risk for development of angle closure glaucoma/strabismus; pregnant/lactating women or women planning a pregnancy during the study; anyone participating in another clinical study; and anyone with a known sensitivity to study medications. Patients of the Kremer Laser Eye Center were enrolled prospectively into the BioMask clinical study in a consecutive fashion starting in January 1997, with enrollment still ongoing.
The BioMask surgical procedure was performed as follows. The patients were brought into the operating room and prepared and draped in the usual sterile manner for ophthalmic surgery. One drop of tetracaine was given two times, spaced approximately 1 minute apart. The operative eye was irrigated with balanced salt solution and the cornea was then dried with filtered oxygen. The center of the cornea was marked with gentian violet to allow for better centration of the applanator. One to two drops of the BioMask material was then placed on the cornea and covered with an applanator lens of a predetermined base curve. The base curve was chosen based on corneal topography, keratometry, the patient's refraction, and the desired refractive outcome. Corneal topography was determined before and after surgery using the Humphrey topography system (Division of Carl Zeiss, Inc., Dublin, CA, U.S.A.) or the PAR system (PAR Inc., New Hartford, NY, U.S.A.). The applanator lens was cooled for 3 minutes with filtered oxygen. The rim of excess BioMask material was removed from the eye. The eye was dried for another minute. Pressure was applied around the contact lens to free it from the BioMask material. The lens was then removed from the eye. All of the lights in the room and on the laser were turned off so the surgeon could dark adapt. The Kremer broad-beam excimer laser (model KEA940202 under U.S. Food and Drug Administration Investigational Device Exemption #G970278/A1) was used for each patient. The Kremer laser is a 193-nm ArF laser with a fluence at the operating plane of 134 mJ/cm 2 and 37.9 mJ of energy/pulse, with a 6-mm diameter aperture. The treatment pulse frequency is 10 Hz. The pulse frequency was not adjusted during the treatment. The patient was instructed to fixate on the aiming beam and the ablation was started. Increased fluorescence was seen as the BioMask was eroded and the epithelium became visible at the highest topographic point of the cornea. This point generally coincided with the preoperative corneal topography and slit lamp biomicroscopy. Ablation was continued until the fluorescence was no longer visible in the elevated areas and disappearing rapidly in the areas of the most depressed epithelium. The eye was irrigated with balanced salt solution and a bandage soft contact lens was applied. The eye was then given one drop of the following: prednisolone acetate 1%, ciprofloxacin, and ketorolac tromethamine (Acular; Allergan, Inc., Irvine, CA, U.S.A.). The patient was then brought to the recovery room and discharged home. Patients were examined on postoperative days 1, 7, and 30. They were examined again at months 3, 6, 9, and 12. Postoperative medications usually included the following regimen for every patient: antibiotic eye drops four times a day for 2 weeks or until complete epithelial healing occurred; bandage contact lens for 7 days during epithelial healing (if the epithelium was not healed, the old lens was replaced with a fresh one for another 7 days, repeated as needed until the epithelium was completely healed); diclofenac sodium (Voltaren; Novartis Pharmaceuticals, East Hanover, NJ, U.S.A.), one drop four times a day for 1 week, or until epithelial healing was complete; tobramycin with 0.1% dexamethasone (Tobradex; Alcon Laboratories, Fort Worth, TX, U.S.A.) four times a day until epithelial healing was complete; fluorometholone (FML; Allergan) 0.1% four times a day on a tapering dose schedule (four, three, and two times a day until the 6-month examination); and oral analgesics given as needed. Patients were encouraged to make all follow-up visits. Patients who missed visits were rescheduled within 1–2 days for the initial follow-up visits and within 1 week at the required monthly visits. Patients were aware at the beginning of the study that the follow-up visits were essential to ensure a good outcome and obtain good data. Patients were always free to drop out of the study with no ramifications to their future eye care.
The primary outcomes for this clinical study were best spectacle-corrected visual acuity (BSCVA) and uncorrected visual acuity (UVA). The data were collected at appropriate follow-up gates and recorded on data forms by M.A. The last follow-up visit for each patient was used for the analyses. The outcome data were analyzed using the Statistical Analysis Systems Univariate Procedure (SAS, Cary, NC, U.S.A.), which produces descriptive statistics as well as probabilities. A Wilcoxon signed-ranks test statistic was used to test for significant differences between preoperative and postoperative visual acuity scores. The scores were converted from Snellen acuity scores to log of minimum angle of resolution scores (logMAR) so that the true geometric mean could be computed. The logMAR scores are derived using the equation [logMAR = −log (decimal acuity)]. 11
The following represents the percentage of patients who made it through to a specific follow-up period; 1 month, 100% (22/22); 3 months, 90% (20/22); 6 months, 82% (18/22); 9 months, 45% (10/22); and 12 months, 32% (6/19) of patients enrolled. Table 1 summarizes the best-corrected acuity outcomes with patients stratified by their treatment indications. When ranked in order of BSCVA outcome, patient's with Salzmann's nodular degeneration did the best, followed by prior refractive surgery, corneal dystrophies, and, last, corneal scars. Even though BSCVA did not improve as much in the corneal scar group, 50% of the patients reported an improvement in the symptoms they experienced before surgery, based on questionnaires. Table 2 summarizes the descriptive statistics regarding visual acuity measures. Tables 3 and 4 list each patient's visual acuity before and after surgery, as well as when the measurement was taken and how the visual outcome changed. UVA averaged 20/180 before surgery and 20/123 after surgery, with the change being nonsignificant statistically. However, the mean change in BSCVA before versus after surgery did result in a statistically significant outcome (p = 0.0356). Before surgery, the mean Snellen visual acuity was 20/90, whereas after surgery the visual acuity was increased to 20/60. The average follow-up time was 8 months for both UVA and BSCVA (Table 2). When examining changes in each patient's BSCVA, 65% improved, with an average gain of 3.7 lines per patient (range, +2 to +10). Fifteen percent of the patients lost an average of 3.0 lines (range, −2 to −6), and 20% had no change (Table 3). With respect to UVA, 63% improved by an average of 4.25 lines per patient (range, +2 to +9). Twenty-six percent lost an average of 5.6 lines (range, −2 to −8), and 10% had no change (Table 4). The average hyperopic shift induced was 3.44 ± 3.35 diopters. Figure 1 shows the topography picture for a patient with an irregular surface after an aborted LASIK with loss of corneal tissue. The patient's BSCVA was 20/200 after the aborted LASIK. Figure 2 shows the topography for the same patient 9 months after surgery, after the surface was smoothed with BioMask. The patient's BSCVA improved to 20/40 with a more regular surface contour.
Many disorders that limit vision, including band keratopathy, Salzmann's nodular degeneration, and various postinfectious and traumatic corneal scars, are characterized by irregular corneal surfaces. Patients with iatrogenic irregular astigmatism from prior refractive surgery, either incision or laser related, have become a treatment group that is extremely difficult to repair with current methods. The excimer laser is capable of producing a relatively smooth corneal surface, but the surface must be fairly smooth initially. 3,12 A direct excimer laser treatment to a rough corneal surface, however, will not result in smoothing. Instead, the rough surface contour will be duplicated deeper into the corneal tissue. Therefore, the production of a smooth surface requires the use of a substance during ablation that blocks low areas so that high points are ablated preferentially. 13 Past publications have presented techniques aimed at developing reproducible methods for modeling corneal surface irregularities. These methods have been used to facilitate the study and comparison of BioMask and other possible smoothing agents. 13–15 Based on our studies, the ideal agent should (1) be nontoxic and biocompatible; (2) be distinguishable from corneal tissue to facilitate monitoring of the ablation; (3) have an excimer laser ablation rate similar to the ablation rate of the cornea; (4) when applied, have a viscosity adequate to fill corneal irregularities homogeneously; (5) have excellent corneal adherence with no movement caused by beam pressure; (6) be capable of being molded to any desired curvature (7) have a short solidification time (preferably within minutes of application); and (8) be easy to manipulate and remove. In this study, BioMask exhibits the properties needed to fulfill the requirements of an ideal smoothing agent. Multiple formulations of the BioMask have been studied. Ablation rates from 0.24 to 0.32 μm/pulse have been established for the different formulations. 9 The current formulation, which has an ablation rate of 0.28 μm/pulse, was chosen because this is the reported ablation rate of corneal stroma. 10 At 45°C, the material is like a viscous syrup, but at body temperature (<37°C) it becomes a firm gel. The transition from liquid to gel takes approximately 2 to 3 minutes at room temperature. This transition time can be reduced by cooling the applanator surface with a stream of cold, purified gas. The applanator lens is used as a template, and the single application of the BioMask simplifies the current method of multiple applications of methylcellulose or other smoothing agents. The latter method was explored by several researchers and the findings indicated that multiple applications of a masking fluid can increase the risk of an irregular surface, and may lengthen the time needed to perform the treatment. The materials also were difficult to apply and were susceptible to rippling and drying effects caused by airflow from the effluent remover of the laser system. 15–17 In our clinical trial, we did not encounter these technical problems because the BioMask has the advantage of being applied once with no intermittent applications needed during the ablation. It also sets up as a firm gel within 2–3 minutes, and therefore is not affected by airflow. Another method, the photoablative lenticular modulator (PALM) technique, mimics the use of the BioMask and is used in Greece by Pallikaris et al. 18
We performed the BioMask procedure with two different goals: (1) to increase BSCVA, and (2) to obtain emmetropia, if possible. The BSCVA results in this study seem to indicate that the more corneal scarring present in the stroma, the more difficult it is to obtain a good result. This is evidenced by the fact that the group of patients with corneal scarring did not show the gain in BSCVA that was observed in the other three groups (Salzmann's nodular degeneration, prior refractive surgery, or corneal dystrophies). Even though the corneal scar group did not show as much improvement in BSCVA, these patients also did not show any increased loss of BSCVA compared with the other groups.
Three patients in this study lost BSCVA. Patient #5 had a mild hyperopic shift, a slight worsening of his irregular cylinder, and a two-line loss of BSCVA. Patient #14 had a slight myopic shift and a one-line loss of BSCVA. However, this patient felt that his visual acuity had actually improved. Finally, patient #12 developed a nonhealing epithelial defect for the first month. The most likely etiology is that the patient had inadvertently been using frequent corticosteroid drops. Unfortunately, when he reepithelialized, he had a resulting dense central corneal scar and a six-line loss of BSCVA, and subsequently underwent a penetrating keratoplasty. Although many patients had a gain in BSCVA, most patients still were ametropic. Five patients had a decrease in UVA. These included the three patients who lost BSCVA and patients #9 and #15. Patient #9 had a slight myopic shift and a gain in BSCVA. Patient #15 had a 4-diopter myopic shift but an increase in BSCVA. As more patients undergo the BioMask procedure, the calculations to determine which base curve to choose for the rigid, gas-permeable contact lens will be more accurate and, it is hoped, will make emmetropia a more common outcome.
Further clinical trials with the BioMask, especially when used as a refractive adjuvant, are essential. The applanator mold, which is used to replace the rigid, gas-permeable contact lens, has been significantly improved to reduce the incidence of canting. Canting of the applanator lens can result in irregular astigmatism and also may influence wound healing. Even though improvements in the application of the BioMask have been made, there is still a fairly steep learning curve associated with the use of this material. For instance, the surgical field must be dried continuously during the procedure because the material is hygroscopic and excess tears delay or prevent solidification of the mask if those tears are drawn into the mask material. The amount of material used also is of concern because a thick mask requires considerably more pulses to be ablated and may unnecessarily lengthen the time needed to perform the procedure. Expert training on the use of this material and practice are necessary to obtain a good clinical result. In the future, as corneal topography becomes more precise with regard to measuring irregular corneal surfaces and we are able to link topography more effectively to scanning excimer laser systems, then perhaps we will be able to smooth an irregular surface with reasonable precision. Until then, the BioMask remains a promising adjunct to the excimer laser for use in treating these corneal surface irregularities.
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