Journal of Refractive Surgery

Original Article Supplemental Data

Biological Lenticule Implantation for Correction of Hyperopia: An Ex Vivo Study in Human Corneas

Iben Bach Damgaard, MD; Anders Ivarsen, MD, PhD; Jesper Hjortdal, MD, PhD

Abstract

PURPOSE:

To evaluate changes in corneal tomography after stromal lenticule implantation ex vivo, with respect to the dependency of the lenticule thickness and implantation depth on the corneal curvature and the postoperative biomechanical strength at increased chamber pressure.

METHODS:

Twenty-eight human donor corneas underwent pocket implantation of refractive stromal lenticules. Four groups were created by the combination of two implantation depths (110 and 160 µm) and two lenticule thicknesses (95 µm = 4.00 diopters [D], 150 µm = 8.00 D). Sagittal keratometry and total corneal refractive power (TCRP4mm,apex,zone) were obtained for the front and back curvature with Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany) at chamber pressures of 15 and 40 mm Hg.

RESULTS:

The anterior curvature steepening was comparable between the 4.00 D and 8.00 D groups (P > .141), but more pronounced with 110 µm implantation depth (P < .038). The posterior curvature flattened significantly more after implantation of 8.00 D than 4.00 D lenticules (P < .002), but was similar at 110 and 160 µm implantation depths (P > .071). Average ΔTCRP for the 4.00 D and 8.00 D groups was 3.10 ± 0.60 and 5.30 ± 1.66 diopters (D) at 110-µm depth, respectively (P = .003), but 1.99 ± 0.79 and 3.36 ± 1.45 D at 160-µm depth, respectively (P = .066). The relative correction achieved was 66% to 78% at 110-µm depth and 42% to 50% at 160-µm depth, but similar when using 4.00 D and 8.00 D lenticules. Increased chamber pressure caused significant anterior and posterior curvature steepening after implantation in all four groups (P < .001), but not before implantation (P > .632).

CONCLUSIONS:

The power of the implanted lenticule must be higher than the intended correction, and customized to the chosen implantation depth. Biomechanical strength seems to decrease after lenticule implantation.

[J Refract Surg. 2018;34(4):245–252.]

Abstract

PURPOSE:

To evaluate changes in corneal tomography after stromal lenticule implantation ex vivo, with respect to the dependency of the lenticule thickness and implantation depth on the corneal curvature and the postoperative biomechanical strength at increased chamber pressure.

METHODS:

Twenty-eight human donor corneas underwent pocket implantation of refractive stromal lenticules. Four groups were created by the combination of two implantation depths (110 and 160 µm) and two lenticule thicknesses (95 µm = 4.00 diopters [D], 150 µm = 8.00 D). Sagittal keratometry and total corneal refractive power (TCRP4mm,apex,zone) were obtained for the front and back curvature with Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany) at chamber pressures of 15 and 40 mm Hg.

RESULTS:

The anterior curvature steepening was comparable between the 4.00 D and 8.00 D groups (P > .141), but more pronounced with 110 µm implantation depth (P < .038). The posterior curvature flattened significantly more after implantation of 8.00 D than 4.00 D lenticules (P < .002), but was similar at 110 and 160 µm implantation depths (P > .071). Average ΔTCRP for the 4.00 D and 8.00 D groups was 3.10 ± 0.60 and 5.30 ± 1.66 diopters (D) at 110-µm depth, respectively (P = .003), but 1.99 ± 0.79 and 3.36 ± 1.45 D at 160-µm depth, respectively (P = .066). The relative correction achieved was 66% to 78% at 110-µm depth and 42% to 50% at 160-µm depth, but similar when using 4.00 D and 8.00 D lenticules. Increased chamber pressure caused significant anterior and posterior curvature steepening after implantation in all four groups (P < .001), but not before implantation (P > .632).

CONCLUSIONS:

The power of the implanted lenticule must be higher than the intended correction, and customized to the chosen implantation depth. Biomechanical strength seems to decrease after lenticule implantation.

[J Refract Surg. 2018;34(4):245–252.]

Small incision lenticule extraction (SMILE) performed with femtosecond laser technology has optimized the treatment of refractive errors.1–4 During the flap-free SMILE procedure, an intrastromal lenticule is created with femtosecond laser and mechanically removed through a minor incision. The extracted corneal lenticules are normally discarded after surgery, but could potentially be used for treatment of other refractive conditions such as hyperopia,5,6 aphakia,7 and presbyopia.8

Lenticule implantation was suggested as a tissue additive procedure in 1966 by Jose Barraquer,9 later followed by several studies on synthetic hydrogel inlays for correcting hyperopia. Although the hydrogel inlays were generally tolerated in short-term studies of monkeys10 and humans,11 complications arose due to substantial problems with the nutrition diffusion. Studies reported necrosis of the central anterior layer, opacities, and lipid deposits around the inlays that in some cases had to be removed years after surgery.11,12

The refinement of femtosecond laser technology facilitates new possibilities for tissue additive procedures. The extracted lenticule in SMILE for myopia may now be implanted into a laser-cut intrastromal pocket in a hyperopic patient to induce steepening of the anterior corneal curvature.13 Furthermore, the insertion of a refractive stromal lenticule may also serve as a potential method for stromal volume restoration and stabilization in patients with iatrogenic keratoectasia13 and progressive keratoconus.14

Cryopreservation opens up for long-term storage of SMILE lenticules that are viable and with preserved collagen architecture up to 1 month after extraction.6,15 Studies on rabbits16 and non-human primates17 have shown that cryopreserved refractive stromal lenticules were clear and viable with minimal inflammatory response up to 3 months after implantation. The inflammatory response was also stable 6 months after freshly implanted lenticules in rabbits, although collagen rearrangements were observed in the postoperative period.18

The postoperative refractive correction after biological lenticule implantation remains unclear in human subjects. Only a few clinical studies have evaluated lenticule implantation where various lenticule dimesions and implantation depths have been used.5–7 The exact dependency of the implantation depth and lenticule thickness on the postoperative refractive correction still needs to be understood. The strong and resistant anterior corneal layer19 may retain the pressure from an implanted lenticule with less anterior curvature steepening and thereby hyperopic correction. Hence, we hypothesize that implantation of thick SMILE-derived lenticules may induce more posterior curvature surface flattening than anterior curvature steepening compared with thin SMILE-derived lenticules, whereas a stromal lenticule positioned in the more superficial layer will induce more anterior curvature steepening than when implanted in a deeper layer of the cornea.

The current study examined the corneal curvature changes after refractive stromal lenticule implantation ex vivo in human donor corneas deemed unsuitable for patient treatment. We examined the dependency of implantation depth and lenticule thickness on the corneal curvature changes. Furthermore, the postoperative biomechanical strength was assessed with the corneal inflation test by evaluating the corneal curvature changes during low and high simulated chamber pressure.

Materials and Methods

A total of 56 human donor corneas deemed unsuitable for patient treatment were obtained from The Veneto Eye Bank Foundation (Venice, Italy). The included donor corneas were discarded for patient treatment due to low endothelial cell count. Corneal microscopy was performed to ensure that none of the included corneas had evidence of corneal stromal diseases, opacities, irregularities, or severe arcus senilis, which would affect the corneal tomography. The donor corneas were received in a storage medium (CorneaMax; Eurobio, Les Ulis, France) and transferred to a dehydrating 8% dextrancontaining organ culture media for a minimum of 24 hours prior to use. The donor corneas were mounted on a Barron artificial anterior chamber (Katena, Denville, NJ) filled with organ culture medium with 8% dextran. The epithelial layer was removed to the limbus with a blunt spatula. The artificial anterior chamber with the mounted cornea was placed upside-down in the dextran medium for 30 minutes to ensure similar hydration of all corneas before the first measurement.

Twenty-eight donor corneas were allocated for lenticule harvesting and 28 for lenticule implantation. The study consisted of four groups of seven mounted donor corneas with a combination of one of two implantation depths (110 and 160 µm) and one of two thicknesses of the implanted lenticules (95 and 150 µm). If two corneas were received from the same donor, they would be distributed into two separate groups for lenticule harvesting and lenticule implantation.

No ethical approval was needed from the Regional Ethics Committee for the Central Region of Denmark because anonymous donor tissue was used in the experiment (request 186/2015). Written consent that the donor tissue could be used for experimental use was received from the donor's next of kin.

Lenticule Harvesting

SMILE was performed using the 500-kHz VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany) as described previously.20 In brief, the laser cut energy index was set to 34 and the spot/spacing distance to 4.5 µm. After adjusting the contact glass to the center of the artificial anterior chamber, a 7.3-mm cap was cut with a 2.55-mm incision and a cap thickness of 110 and 160 µm, respectively. The mean corneal radius was set to 7.8 mm, with a lenticule diameter of 6.5 mm and a minimum lenticule thickness of 30 µm. Hence, the maximum lenticule thickness was 95 and 150 µm for the 4.00 and 8.00 diopter (D) spherical lenticules, respectively. Remaining tissue bridges were gently broken with a blunt spatula and the lenticule removed with a pair of forceps.

Lenticule Implantation

The stromal pocket was created with the femtosecond laser by cutting a 7.3-mm flap with a 315° hinge, thereby creating a 45° incision. The mean corneal radius was set to 7.8 mm, and the depth of the stromal pocket was 110 and 160 µm, respectively. The lenticule was transferred to the stromal pocket immediately after harvesting, maintaining the same orientation and polarity (Figure AB, available in the online version of this article). An iris spatula was used for lenticule unfolding in the stromal pocket, and the final alignment was performed by surface manipulation with the spatula. Proper alignment was facilitated by measuring the distance from the mounting ring of the artificial anterior chamber to the lenticule edge. The artificial anterior chamber with the implanted lenticule was afterward positioned in a moist chamber for 30 minutes to ensure that all interface air bubbles had dissolved before measurements.

(A) Artificial anterior chamber with a mounted human donor cornea and the pressure monitor connected to the infusion port. (B) After implantation, the incision located in the right side of the image. (C) Optical coherence tomography (OCT) image of a 4.00 diopter (D) lenticule implanted at 160-µm depth. (D) OCT image of an 8.00 D lenticule implanted at 110-µm depth.

Figure A.

(A) Artificial anterior chamber with a mounted human donor cornea and the pressure monitor connected to the infusion port. (B) After implantation, the incision located in the right side of the image. (C) Optical coherence tomography (OCT) image of a 4.00 diopter (D) lenticule implanted at 160-µm depth. (D) OCT image of an 8.00 D lenticule implanted at 110-µm depth.

Corneal Tomography and OCT

Tomographic measurements were performed with the Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany). A custom-made device ensured the exact same orientation of the artificial anterior chamber before and after surgery (Figure AA). The hydration level of the mounted cornea was controlled by monitoring the central corneal thickness (CCT). The first Pentacam HR measurement was used as the reference CCT, and hydration was kept stable by moistening with isotonic saline. Pressure in the artificial anterior chamber was adjusted with an attached column containing organ media and monitored with a pressure monitor (Compass Compartment Pressure; Centurion, Williamston, MI). Measurements before and after implantation were performed with a chamber pressure of 15 and 40 mm Hg (Figure AA). Post-implantation cap and lenticule thicknesses were assessed with optical coherence tomography (OCT) (Heidelberg Engineering GmbH, Heidelberg, Germany) as shown in Figures AC–AD.

The median of three consecutive measurements before and after implantation was used for comparison. Primary outcome measurements were the average sagittal keratometry readings of the central 3-mm radius described as the radius (r) for the front and back curvature, and Δr was calculated as rpost − rpre. Secondary outcome measurements were cap and lenticule thicknesses after implantation and the total corneal refractive power (TCRP) in the 4-mm apex zone. The TCRP4mm, apex, zone was chosen for statistical analysis because previous studies have shown that it accurately assesses the manifest refraction following laser refractive surgery.21

Statistical Analysis

Statistical analysis was performed with STATA (version 13; STATACorp, College Station, TX) and Graph-Pad Prism for MAC OS X (v6.0; GraphPad Software, Inc., La Jolla, CA) software. A two-factor mixed analysis of variance (ANOVA) was performed to take into account the within-subject factors (measurements before and after implantation, using two different pressure levels), and the between-subject factors (four groups, based on two implantation depths and two lenticule thicknesses). The following statistical comparisons were made for the keratometry readings and TCRP: time point (preimplantation vs post-implantation), implantation depth (110 vs 160 µm), lenticule thickness (4.00 vs 8.00 D), and chamber pressure (15 vs 40 mm Hg).

To describe the results after lenticule implantation, we defined the term “intended correction” as 4.00 and 8.00 D, which corresponds to the refractive power of the lenticules when removed during a SMILE procedure for myopia. Analysis of the preoperative characteristics was performed with one-way ANOVA. A P value of less than .05 was considered statistically significant.

Results

Characteristics before and after implantation are shown in Table A (available in the online version of this article). There were no statistical differences in donor age, recipient age, time in dextran prior to mounting, or CCT before implantation (P > .872, oneway ANOVA). The average lenticule thicknesses after implantation were 93 ± 4.2 and 97 ± 5.0 µm for the 4.00 D lenticule groups and 156 ± 11 and 155 ± 11 µm for the 8.00 D lenticule groups, respectively.

Implantation Characteristicsa

Table A:

Implantation Characteristics

Corneal Tomography

Table B (available in the online version of this article) shows the mean change in sagittal keratometry after surgery for the front and back curvature, whereas Figure 1 illustrates Δr for the front and back curvature under various lenticule thicknesses (4.00 and 8.00 D), implantation depths (110 and 160 µm), and chamber pressure levels (15 and 40 mm Hg). Average Δr for all combinations of thicknesses, depths, and pressure levels were significantly different from zero (P < .008), with the exception of Δr4.00 D,160µm,15mmHg and Δr4.00 D,160µm,40mmHg (P > .103).

Changes in Corneal Sagittal Curvature (Δr = rpost − rpre) for the Front and Back Surface With a Chamber Pressure of 15 and 40 mm Hga

Table B:

Changes in Corneal Sagittal Curvature (Δr = rpost − rpre) for the Front and Back Surface With a Chamber Pressure of 15 and 40 mm Hg

Mean Δr for the (A) front and (B) back corneal curvature after implantation of a 4.00 D and 8.00 D lenticule. Bars represents standard deviations. The x-axis shows the chamber pressure of 15 and 40 mm Hg, using a 110-µm (black) and 160-µm (gray) implantation depth. a markings: Significant difference in Δr between 4.00 D and 8.00 D lenticule implantation. b markings: Significant difference in Δr between 110- and 160-µm implantation depths.

Figure 1.

Mean Δr for the (A) front and (B) back corneal curvature after implantation of a 4.00 D and 8.00 D lenticule. Bars represents standard deviations. The x-axis shows the chamber pressure of 15 and 40 mm Hg, using a 110-µm (black) and 160-µm (gray) implantation depth. a markings: Significant difference in Δr between 4.00 D and 8.00 D lenticule implantation. b markings: Significant difference in Δr between 110- and 160-µm implantation depths.

For the front curvature, a 110-µm implantation depth induced significantly more steepening than a 160-µm implantation depth in all groups (P < .038, Figure 1A, b markings), with the exception of the 4.00 D groups at a chamber pressure of 15 mm Hg (P = .208). Furthermore, Δr for the anterior curvature did not differ after implantation of 4.00 D and 8.00 D lenticules when compared under identical implantation depths and pressure levels (P > .141).

For the back curvature, the induced flattening was similar when using an implantation depth of 110 and 160 µm (P > .069). The implantation of an 8.00 D lenticule gave rise to significantly more posterior curvature flattening than the 4.00 D lenticule for all combinations of implantation depths and chamber pressure levels (Figure 1B, a markings, P < .001).

TCRP

The TCRPs before and after implantation are listed in Table 1, whereas ΔTCRPs are shown in Figure 2. There was a significant increase in the TCRP after implantation in all four groups at 15 and 40 mm Hg (P < .001), although the intended correction was not achieved. The TCRP increased significantly more using the thicker lenticules, with an average ΔTCRP of 5.30 ± 1.66 D after 8.00 D lenticule implantation and 3.10 ± 0.60 D after 4.00 D lenticule implantation at 110-µm depth (15 mm Hg, P = .003, Table 1 and Figure 3). Likewise, the average ΔTCRP was 3.36 ± 1.45 and 1.99 ± 0.79 D after 8.00 D and 4.00 D lenticule implantation at 160-µm depth, respectively (15 mm Hg, P = .066). The implantation depth had a significant impact on ΔTCRP; 66% to 78% of the intended correction was achieved with a 110-µm implantation depth, whereas 42% to 50% of the intended correction was achieved with a 160-µm implantation depth. The relative correction was similar when using 4.00 and 8.00 D lenticules for implantation (Table 1).

TCRP for the 4-mm Apex Zone Before and After Implantationa

Table 1:

TCRP for the 4-mm Apex Zone Before and After Implantation

Change in total corneal refractive power after implantation (ΔTCRP). Bars represents standard deviations (SD). The x-axis shows the fixed chamber pressure for lenticules with 110-µm (black) and 160-µm (gray) implantation depth. a markings: Significant difference in ΔTCRP between 4.00 and 8.00 diopter (D) (4D and 8D) lenticule implantation. b markings: Significant difference in ΔTCRP between 110- and 160-µm implantation depths.

Figure 2.

Change in total corneal refractive power after implantation (ΔTCRP). Bars represents standard deviations (SD). The x-axis shows the fixed chamber pressure for lenticules with 110-µm (black) and 160-µm (gray) implantation depth. a markings: Significant difference in ΔTCRP between 4.00 and 8.00 diopter (D) (4D and 8D) lenticule implantation. b markings: Significant difference in ΔTCRP between 110- and 160-µm implantation depths.

Total corneal refractive power before and after implantation of a 4.00 and 8.00 diopter (D) lenticule at 110-µm depth.

Figure 3.

Total corneal refractive power before and after implantation of a 4.00 and 8.00 diopter (D) lenticule at 110-µm depth.

Biomechanical Strength

The pressure-induced changes in sagittal radius and TCRP before and after surgery are shown in Table C (available in the online version of this article). Before implantation, there were no significant differences in sagittal rpre,15mmHg and rpre,40mmHg for the front and back curvature in any of the four groups (P > .632). After implantation, rpost,15mmHg was significantly larger than rpost,40mmHg in all four groups for the front and back curvature, indicating a significant curvature steepening with increased chamber pressure (P < .001). Also, more anterior steepening during pressure elevation was observed if the 4.00 D lenticules were positioned in the superficial corneal layer (110 vs 160 µm, P = .005), whereas no difference was observed for the 8.00 D lenticules (P = .201).

Pressure-Induced Changes in Sagittal Radius (rsag3mm), and TCRP Before and After Lenticule Implantationa

Table C:

Pressure-Induced Changes in Sagittal Radius (rsag3mm), and TCRP Before and After Lenticule Implantation

For the pressure-induced change in TCRP, the average TCRPpre,15mmHg and TCRPpre,40mmHg were comparable in all evaluated groups (P > .680, Table C). After implantation, the increased chamber pressure caused a significant increase in TCRP in all four groups due to the steepening of the front curvature, although the steepening of the back curvature decreased the TCRP (P < .001). During pressure elevation, the difference in TCRP was more pronounced if the 4.00 D lenticules were positioned in the superficial layer of the cornea (110 vs 160 µm, P = .001), whereas no significant difference was seen for the 8.00 D lenticules (P = .159).

Discussion

The current study examined the corneal tomography after lenticule implantation in ex vivo human donor corneas. We found that the achieved correction after lenticule implantation does not correspond to the refractive power of the lenticule when it is removed during SMILE. Approximately 78% and 50% of the intended correction was reached with an implantation depth of 110 and 160 µm, respectively. The achieved percentage of correction was independent of the refractive power of the lenticule. However, implantation of higher powered lenticules seemed to induce more posterior curvature flattening than anterior curvature steepening, where the posterior curvature alteration contributes less to the refractive correction.

Lenticule implantation and re-implantation has previously been examined in rabbits22–24 and non-human primates17,25 to evaluate the refractive correction and viability of the implanted tissue. A previous study in monkeys found that 83% of the intended correction was reached 6 months after autologous 4.00 D lenticule implantation at 100-µm depth.25 However, the lenticule implantation was performed under a partially dissected corneal flap, where the laser cutting may have weakened the anterior stroma and Bowman's membrane. For lenticule re-implantation, a previously extracted lenticule may not cause the same tension in the cap as when a lenticule is implanted into a newly created stromal pocket.26 Consequently, the biomechanical and tomographic responses may not be comparable when lenticule implantation is used for stromal tissue addition or restoration.

Previous studies in humans of lenticule implantation for hyperopia have reported a tendency toward undercorrection when the refractive powers of the implanted lenticules were similar to the intended correction.5,6 Thus, one of the first case studies by Pradhan et al.7 reported a 5.18 D increase in refractive power after implantation of a 10.50 D spherical lenticule under a 180-µm cap. Another recent study examined lenticule implantation in four presbyopic patients where a 1-mm corneal button was trephined from a 2.50 to 2.75 D spherical lenticule and inserted under a 120-µm cap in the non-dominant eye.8 They reported promising near distance visual acuity with a central hyperprolate area on the keratometry readings, but the average steepening in keratometry was unfortunately not reported.

To our knowledge, only one study has examined lenticule implantation ex vivo in human donor corneas.27 Using hyperopic-shaped lenticules from SMILE with the thinnest point centrally positioned, they found an average correction of 7.31 ± 1.52 D after implantation of 8.00 D lenticules at a 115-µm stromal depth. Although the biconcave lenticule shape may have caused more hyperopic shift than observed in the current study, the authors did not report the average CCT after implantation as a measure for the hydration of the recipient corneas. Because the corneal topography is known to depend on the corneal hydration level,28 we monitored the CCT continuously before and after implantation and kept the hydration stable with frequent moistening.

In the current study, we demonstrated that lenticule implantation of higher powered lenticules caused more posterior curvature flattening than anterior steepening. Although both curvature alterations increase the corneal refractive power, the posterior flattening only provides a minor refractive change due to the small difference in refractive index between cornea and aqueous humor. A possible explanation of the inward flattening lies in the strength of the anterior corneal stroma and Bowman's membrane.19 Also, a previous study used finite analysis to assess the postoperative stress strain distribution after lenticule implantation and found 159.94% increased stress in the central 3-mm anterior stroma after implantation of a 10.50 D lenticule under a 180-µm cap.26 We did not perform relaxing incisions in the edge of the cap, but this technique has been suggested by some surgeons to increase the effect when implanting high powered lenticules. Another suggestion is to implant the lenticule under a corneal flap, but with a risk of postoperative flap and lenticule dislocation if exposed for eye trauma. Furthermore, this approach would weaken the anterior stroma due to cutting of the anterior collagen lamellae. The optical quality after implantation may depend on the arrangement of Bowman's layer and the corneal collagen fibers. Thus, implantation of a thick lenticule under a flap may cause more microfolds in Bowman's layer than seen after implantation under a cap. However, it may be more difficult to flatten and align the lenticules in the pocket than under a flap, and may consequently cause more disarrangements of the collagen layer in the stromal lenticule.

Surprisingly, we did observe a significant posterior and anterior curvature steepening when the chamber pressure was raised from 15 to 40 mm Hg after surgery. The increase in TCRP from anterior curvature steepening exceeds the decrease in TCRP from the posterior curvature steepening because of the refractive index of air, cornea, and aqueous humor. Consequently, the TCRP increased significantly from 3.10 ± 0.60 D at 15 mm Hg to 4.27 ± 1.12 D at 40 mm Hg (4.00 D lenticule, 110 µm depth). Due to the unexpected results, we repeated the protocol without laser cutting and implantation to ensure that hydration regulation and storage in the moist chamber were not potential confounders. We found that the keratometry values and TCRP did not differ at a chamber pressure level of 15 and 40 mm Hg when stored under the same conditions as the remaining donor corneas. The femtosecond pocket creation spares the integrity of the anterior stroma, but the minor incision and the lamellar cut still damage collagen fibers and weaken the corneal biomechanical strength.29 Both the lamellar dissection and the minor incision may weaken the corneal biomechanical strength to a certain degree and subsequently cause the increased curvature steepening with increased chamber pressure. Furthermore, the change in anterior curvature and TCRP with increased pressure was more severe after implantation of lenticules in the superficial layer (110 vs 160 µm), possibly explained by the position of the lamellar cut in the biomechanically stronger layer of the cornea.19

Multiple adjustments of the set-up were tried to ensure acceptable tracking of the anterior and posterior corneal curvature. We determined that the Barron artificial anterior chamber was suitable for this purpose because it was possible to see the bottom on the chamber during measurements. By marking the center of the artificial anterior chamber with a 1.5-mm diameter hole, we ensured that the measurements before and after implantation were taken at the exact same point. The high reflection from the artificial anterior chamber and mounting ring was dramatically reduced by black non-reflective spray paint. However, even though the donor corneas were well hydrated, the surface tracking was approximately 70% to 90% and 50% to 70% for the front and back curvature, respectively. Therefore, we ensured that there were no larger areas missing in the central 4-mm diameter zone for each measurement. We experienced that moisturizing of the surface with a semi-wet spear (isotonic saline) 30 seconds before measurements gave the most optimal image quality. We also tried with 8% dextran and artificial eye drops, but they seemed to cause a hyperreflective surface that led to inaccurate tracking of the anterior curvature.

We used an ex vivo model of human donor corneas to examine the dependency of implantation depth and lenticule thickness on the increase in refractive power. Although a major strength of this model is the use of human donor tissue, we acknowledge its limitations. It would be preferable to use whole globe eyes rather than donor corneas mounted in an artificial anterior chamber. The fixation of the corneoscleral rim may affect the biomechanical response following implantation and thereby the refractive outcome.30 Furthermore, using an ex vivo model, we were not able to evaluate whether there was any regression over time due to potential remodeling of the stroma and epithelial layer and changes in the hydration level of the lenticule and/or the recipient cornea. However, we maintained a stable hydration for both the recipient cornea and the implanted lenticule before and after implantation to avoid inadequate hydration that would affect the corneal tomography. It would be preferable to use paired donor corneas to compare the implantation depth, but this was not practically possible due to limited supply of tissue. However, a few paired corneas were included in the study, which was taken into consideration in the statistical analysis.

The current study showed that the achieved correction was generally lower than the power of the implanted lenticule. Higher powered lenticules tended to induce more posterior flattening than anterior curvature steepening. Also, increased chamber pressure after implantation caused significant steepening of the anterior surface due to weakening of the corneal tissue, and consequently higher TCRP values. However, further studies are needed to confirm these findings. Moreover, it would be interesting to evaluate the to-mographical effect of lenticule implantation in corneas with abnormal biomechanical properties, as seen in keratoconus.

References

  1. Vestergaard AH, Grauslund J, Ivarsen AR, Hjortdal JO. Efficacy, safety, predictability, contrast sensitivity, and aberrations after femtosecond laser lenticule extraction. J Cataract Refract Surg. 2014;40:403–411. doi:10.1016/j.jcrs.2013.07.053 [CrossRef]
  2. Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: all-in-one femtosecond laser refractive surgery. J Cataract Refract Surg. 2011;37:127–137. doi:10.1016/j.jcrs.2010.07.033 [CrossRef]
  3. Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the small incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol. 2011;95:335–339. doi:10.1136/bjo.2009.174284 [CrossRef]
  4. Ivarsen A, Asp S, Hjortdal J. Safety and complications of more than 1500 small-incision lenticule extraction procedures. Ophthalmology. 2014;121:822–828. doi:10.1016/j.ophtha.2013.11.006 [CrossRef]
  5. Sun L, Yao P, Li M, Shen Y, Zhao J, Zhou X. The safety and predictability of implanting autologous lenticule obtained by SMILE for hyperopia. J Refract Surg. 2015;31:374–379. doi:10.3928/1081597X-20150521-03 [CrossRef]
  6. Ganesh S, Brar S, Rao PA. Cryopreservation of extracted corneal lenticules after small incision lenticule extraction for potential use in human subjects. Cornea. 2014;33:1355–1362. doi:10.1097/ICO.0000000000000276 [CrossRef]
  7. Pradhan KR, Reinstein DZ, Carp GI, Archer TJ, Gobbe M, Gurung R. Femtosecond laser-assisted keyhole endokeratophakia: correction of hyperopia by implantation of an allogeneic lenticule obtained by SMILE from a myopic donor. J Refract Surg. 2013;29:777–782. Erratum in: J Refract Surg. 2015;31:60. doi:10.3928/1081597X-20131021-07 [CrossRef]
  8. Jacob S, Kumar DA, Agarwal AA, Agarwal AA, Aravind R, Saijimol AI. Preliminary evidence of successful near vision enhancement with a new technique: PrEsbyopic Allogenic Refractive Lenticule (PEARL) corneal inlay using a SMILE lenticule. J Refract Surg. 2017;33:224–229. doi:10.3928/1081597X-20170111-03 [CrossRef]
  9. Barraquer JI. Modification of refraction by means of intracorneal inclusions. Int Ophthalmol Clin. 1966;6:53–78. doi:10.1097/00004397-196606010-00004 [CrossRef]
  10. McDonald MB, McCarey BE, Storie B, et al. Assessment of the long-term corneal response to hydrogel intrastromal lenses implanted in monkey eyes for up to five years. J Cataract Refract Surg. 1993;19:213–222. doi:10.1016/S0886-3350(13)80945-5 [CrossRef]
  11. Ismail MM. Correction of hyperopia by intracorneal lenses: two-year follow-up. J Cataract Refract Surg. 2006;32:1657–1660. doi:10.1016/j.jcrs.2005.08.057 [CrossRef]
  12. Mulet ME, Alió JL, Knorz MC. Hydrogel intracorneal inlays for the correction of hyperopia. outcomes and complications after 5 years of follow-up. Ophthalmology. 2009;116:1455–1460.e1. doi:10.1016/j.ophtha.2009.05.019 [CrossRef]
  13. Lazaridis A, Reinstein DZ, Archer TJ, Schulze S, Sekundo W. Refractive lenticule transplantation for correction of iatrogenic hyperopia and high astigmatism after LASIK. J Refract Surg. 2016;32:780–786. doi:10.3928/1081597X-20160726-01 [CrossRef]
  14. Ganesh S, Brar S. Femtosecond intrastromal lenticular implantation combined with accelerated collagen cross-linking for the treatment of keratoconus: initial clinical result in 6 eyes. Cornea. 2015;34:1331–1339. doi:10.1097/ICO.0000000000000539 [CrossRef]
  15. Mohamed-Noriegaarim K, Toh K-P, Poh R, et al. Cornea lenticule viability and structural integrity after refractive lenticule extraction (ReLEx) and cryopreservation. Mol Vis. 2011;17:3437–3449.
  16. Lim CHL, Riau AK, Lwin NC, Chaurasia SS, Tan DT, Mehta JS. LASIK following small incision lenticule extraction (SMILE) lenticule re-implantation: a feasibility study of a novel method for treatment of presbyopia. PLoS One. 2013;8:1–12. doi:10.1371/journal.pone.0083046 [CrossRef]
  17. Riau AK, Angunawela RI, Chaurasia SS, Lee WS, Tan DT, Mehta JS. Reversible femtosecond laser-assisted myopia correction: a non-human primate study of lenticule re-implantation after refractive lenticule extraction. PLoS One.2013;8:e6758. doi:10.1371/journal.pone.0067058 [CrossRef]
  18. Zhao J, Shen Y, Tian M, et al. Corneal lenticule allotransplantation after femtosecond laser small incision lenticule extraction in rabbits. Cornea. 2017;36:222–228. doi:10.1097/ICO.0000000000001076 [CrossRef]
  19. Randleman JB, Dawson DG, Grossniklaus HE, McCarey BE, Edelhauser HF. Depth-dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24:S85–S89.
  20. Hjortdal JØ, Vestergaard AH, Ivarsen A, Ragunathan S, Asp S. Predictors for the outcome of small-incision lenticule extraction for myopia. J Refract Surg. 2012;28:865–871. doi:10.3928/1081597X-20121115-01 [CrossRef]
  21. Gyldenkerne A, Ivarsen A, Hjortdal JØ. Assessing the corneal power change after refractive surgery using Scheimpflug imaging. Ophthalmic Physiol Opt. 2015;35:299–307. doi:10.1111/opo.12202 [CrossRef]
  22. Zhang T, Sun Y, Liu M, et al. Femtosecond laser-assisted endokeratophakia using allogeneic corneal lenticule in a rabbit model. J Refract Surg. 2015;31:775–782. doi:10.3928/1081597X-20151021-07 [CrossRef]
  23. Sun Y, Zhang T, Zhou Y, et al. Reversible femtosecond laser-assisted endokeratophakia using cryopreserved allogeneic corneal lenticule. J Refract Surg. 2016;32:569–576. doi:10.3928/1081597X-20160523-02 [CrossRef]
  24. Angunawela RI, Riau AK, Chaurasia SS, Tan DT, Mehta JS. Refractive lenticule re-implantation after myopic ReLEx: a feasibility study of stromal restoration after refractive surgery in a rabbit model. Invest Ophthalmol Vis Sci. 2012;53:4975–4985. doi:10.1167/iovs.12-10170 [CrossRef]
  25. Liu R, Zhao J, Xu Y, et al. Femtosecond laser-assisted cor-neal small incision allogenic intrastromal lenticule implantation in monkeys: a pilot study. Invest Ophthalmol Vis Sci. 2015;56:3715–3720. doi:10.1167/iovs.14-15296 [CrossRef]
  26. Studer HP, Pradhan KR, Reinstein DZ, et al. Biomechanical modeling of femtosecond laser keyhole endokeratophakia surgery. J Refract Surg. 2015;31:480–486. doi:10.3928/1081597X-20150623-07 [CrossRef]
  27. Mastropasqua L, Nubile M. Corneal thickening and central flattening induced by femtosecond laser hyperopic-shaped intrastromal lenticule implantation. Int Ophthalmol. 2017;37:893–904. doi:10.1007/s10792-016-0349-6 [CrossRef]
  28. Ousley P, Terry M. Hydration effects on corneal topography. Arch Ophthalmol. 1996;114:181–185. doi:10.1001/archopht.1996.01100130175011 [CrossRef]
  29. Knox Cartwright NE, Tyrer JR, Jaycock PD, Marshall J. Effects of variation in depth and side cut angulations in LASIK and thin-flap LASIK using a femtosecond laser: a biomechanical study. J Refract Surg. 2012;28:419–425. doi:10.3928/1081597X-20120518-07 [CrossRef]
  30. Metzler KM, Mahmoud AM, Liu J, Roberts CJ. Deformation response of paired donor corneas to an air puff: intact whole globe versus mounted corneoscleral rim. J Cataract Refract Surg. 2014;40:888–896. doi:10.1016/j.jcrs.2014.02.032 [CrossRef]

TCRP for the 4-mm Apex Zone Before and After Implantationa

TCRP (D)4.00 D Lenticule8.00 D LenticuleP (110 vs 160 µm)P (4.00 D vs 8.00 D)




110 µm (n = 7)160 µm (n = 7)110 µm (n = 7)160 µm (n = 7)4.00 D8.00 D110 µm160 µm
TCRPpre,15mmHg43.89 ± 1.3744.25 ± 1.3043.13 ± 1.8244.22 ± 1.25
TCRPpost,15mmHg46.99 ± 1.4646.24 ± 1.3448.42 ± 2.6147.58 ± 1.72
TCRPpre,40mmHg43.92 ± 1.5244.22 ± 1.2743.25 ± 1.9544.29 ± 1.37
TCRPpost,40mmHg48.20 ± 1.0846.63 ± 1.1249.64 ± 2.8448.49 ± 1.97
ΔTCRP15mmHg3.10 ± 0.601.99 ± 0.795.30 ± 1.663.36 ± 1.45.138.009b.003b.066
ΔTCRP40mmHg4.27 ± 1.122.40 ± 0.816.39 ± 1.604.20 ± 1.73.012b.003b.004b.016b
% relative correction, 15 mm Hgc78%50%66%42%

Implantation Characteristicsa

Characteristic4.00 D Lenticule8.00 D Lenticule


110 µm (n = 7)160 µm (n = 7)110 µm (n = 7)160 µm (n = 7)
Lenticule donor
  Age (y)59 ± 6.6 (47 to 69)67 ± 12 (45 to 78)64 ± 13 (46 to 78)62 ± 13 (41 to 77)
  Time in dextran (hours)37 ± 17 (24 to 63)41 ± 12 (25 to 63)36 ± 11 (24 to 48)34 ± 10 (24 to 46)
  CCT before extraction (µm)b466 ± 12 (449 to 482)456 ± 10 (441 to 470)461 ± 10 (444 to 473)458 ± 12 (432 to 477)
Lenticule recipient
  Age (y)66 ± 13 (45 to 78)64 ± 6.3 (57 to 73)63 ± 14 (41 to 79)61 ± 15 (40 to 78)
  Time in dextran (hours)39 ± 11 (24 to 48)42 ± 13 (25 to 63)39 ± 13 (24 to 50)36 ± 11 (24 to 50)
CCT before implantation (µm)b463 ± 14 (450 to 484)459 ± 20 (442 to 501)459 ± 11 (438 to 472)462 ± 7.2 (454 to 476)
  CCT after implantation (µm)560 ± 11 (546 to 576)554 ± 20 (533 to 592)607 ± 11 (585 to 616)611 ± 7.9 (596 to 621)
  OCT cap thickness (µm)112 ± 5.0 (105 to 116)158 ± 12 (137 to 169)114 ± 4.2 (105 to 117)161 ± 5.3 (157 to 169)
  OCT lenticule thickness (µm)93 ± 4.2 (84 to 96)97 ± 5.0 (92 to 105)156 ± 11 (138 to 168)155 ± 11 (147 to 178)

Changes in Corneal Sagittal Curvature (Δr = rpost − rpre) for the Front and Back Surface With a Chamber Pressure of 15 and 40 mm Hga

Variable4.00 D Lenticule8.00 D LenticuleP (110 vs 160 µm)P (4.00 vs 8.00 D)




110 µm (n = 7)160 µm (n = 7)110 µm (n = 7)160 µm (n = 7)4.00 D8.00 D110 µm160 µm
Anterior curvature, rsag3mm (mm)
  Δr15mmHg−0.29 ± 0.12−0.10 ± 0.12−0.51 ± 0.29−0.19 ± 0.20.208.025b.142.609
  Δr40mmHg−0.48 ± 0.25−0.17 ± 0.13−0.66 ± 0.29−0.30 ± 0.26.037b.013b.210.376
Posterior curvature, rsag3mm (mm)
  Δr15mmHg0.43 ± 0.100.40 ± 0.171.13 ± 0.571.33 ± 0.60.084.172< .001b< .001b
  Δr40mmHg0.27 ± 0.080.28 ± 0.130.84 ± 0.461.10 ± 0.29.969.070.001b< .001b

Pressure-Induced Changes in Sagittal Radius (rsag3mm), and TCRP Before and After Lenticule Implantationa

Variable4.00 D Lenticule8.00 D LenticuleP (110 vs 160 µm)



110 µm (n = 7)160 µm (n = 7)110 µm (n = 7)160 µm (n = 7)4.00 D8.00 D
Anterior curvature, rsag3mm (mm)
  rpre,40mmHg–rpre,15mmHg0.00 ± 0.070.00 ± 0.04−0.02 ± 0.060.00 ± 0.041.000.677
  rpost,40mmHg–rpost,15mmHg−0.18 ± 0.13b−0.06 ± 0.06b−0.18 ± 0.08b−0.12 ± 0.07b.005c.201
Posterior curvature, rsag3mm (mm)
  rpre,40mmHg–rpre,15mmHg0.02 ± 0.04−0.01 ± 0.03−0.02 ± 0.010.00 ± 0.04.587.565
  rpost,40mmHg–rpost,15mmHg−0.14 ± 0.08b−0.12 ± 0.07b−0.31 ± 0.21b−0.22 ± 0.10b.798.071
TCRP (D)
  TCRPpre,40mmHg–TCRPpre,15mmHg0.03 ± 0.23−0.02 ± 0.230.12 ± 0.260.07 ± 0.19.805.810
  TCRPpost,40mmHg–TCRPpost,15mmHg1.20 ± 0.69b0.39 ± 0.30b1.21 ± 0.43b0.91 ± 0.36b.001c.159
Authors

From the Department of Ophthalmology, Aarhus University Hospital, Aarhus C, Denmark.

Supported by Carl Zeiss Meditec, Fight for Sight Denmark, Einar Willumsens Foundation, August Frederik Wedell Erichsens Foundation, and Aase and Ejnar Daniselsens Foundation. The Pentacam HR was donated by Bagenkop-Nielsens Myopia Foundation and Fonden til lægevidenskabens fremme.

The authors have no financial or proprietary interest in the materials presented herein.

The authors thank Simon Bang Kristensen, statistician at the Department of Biomedicine, Aarhus University, for his statistical assistance for this study.

AUTHOR CONTRIBUTIONS

Study concept and design (AI, JH); data collection (IBD); analysis and interpretation of data (IBD, JH); writing the manuscript (IBD); critical revision of the manuscript (AI, JH); administrative, technical, or material support (JH); supervision (AI, JH)

Correspondence: Iben Bach Damgaard, MD, Department of Ophthalmology, Aarhus University Hospital, Nørrebrogade 44, Building 10, 2nd Floor, 8000 Aarhus C, Denmark. E-mail: iben.b.pedersen@gmail.com

Received: September 11, 2017
Accepted: January 02, 2018

10.3928/1081597X-20180206-01

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