Open Access
Refractive Intervention  |   December 2022
Improvement in Accommodation and Dynamic Range of Focus After Laser Scleral Microporation: A Potential Treatment for Presbyopia
Author Affiliations & Notes
  • Darren S. J. Ting
    Academic Ophthalmology, School of Medicine, University of Nottingham, Nottingham, UK
    Department of Ophthalmology, Queen's Medical Centre, Nottingham, UK
    Singapore Eye Research Institute, Singapore
  • Yu-Chi Liu
    Singapore Eye Research Institute, Singapore
    Singapore National Eye Centre, Singapore
    Duke–NUS Graduate Medical School, Singapore
  • Edwin R. Price
    Ace Vision Group Inc, Newark, CA, USA
  • Tracy S. Swartz
    Ace Vision Group Inc, Newark, CA, USA
  • Nyein Chan Lwin
    Singapore Eye Research Institute, Singapore
  • AnnMarie Hipsley
    Ace Vision Group Inc, Newark, CA, USA
  • Jodhbir S. Mehta
    Singapore Eye Research Institute, Singapore
    Singapore National Eye Centre, Singapore
    Duke–NUS Graduate Medical School, Singapore
  • Correspondence: Jodhbir S. Mehta, Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore. e-mail: jodmehta@gmail.com 
Translational Vision Science & Technology December 2022, Vol.11, 2. doi:https://doi.org/10.1167/tvst.11.12.2
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      Darren S. J. Ting, Yu-Chi Liu, Edwin R. Price, Tracy S. Swartz, Nyein Chan Lwin, AnnMarie Hipsley, Jodhbir S. Mehta; Improvement in Accommodation and Dynamic Range of Focus After Laser Scleral Microporation: A Potential Treatment for Presbyopia. Trans. Vis. Sci. Tech. 2022;11(12):2. doi: https://doi.org/10.1167/tvst.11.12.2.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To examine the ocular changes in accommodation, wavefront aberrations, and dynamic range of focus (DROF) after laser scleral microporation (LSM) for treating presbyopia.

Methods: Four presbyopic aged cynomolgus macaques (>13 years; n = 8 eyes) were included. All eyes received LSM with erbium: yttrium-aluminum-garnet laser. Spherical equivalent, true accommodation, pseudo-accommodation, wavefront aberrations, and extended range of focus (EROF), or collectively known as DROF, were evaluated using a ray tracing aberrometer. True accommodation referred to the difference in spherical equivalent between distance and near vision, whereas EROF (sum of true and pseudo-accommodation) was determined by measuring the difference in diopters (D) between near and distance through-focus curves, at 50% threshold of the visual Strehl ratio of optical transfer function.

Results: From before to seven months after surgery, there was a significant increase in true accommodation from 0.6 ± 1.0 D before surgery to 5.9 ± 2.8 D at seven months after surgery (P < 0.001). EROF increased significantly from 3.4 ± 1.0 D before surgery to 11.1 ± 4.6 D at seven months after surgery (P < 0.001). Ocular aberrations did not vary significantly between preoperative and various postoperative timepoints in either disaccommodated or accommodated states (P > 0.05). No adverse event such as scleral perforation or hypotony was noted.

Conclusions: This non-human primate study demonstrated that LSM serves as a novel therapy for improving accommodation and DROF function biomechanically, with a positive response observed throughout the seven-month postoperative period.

Translational Relevance: This proof-of-concept study highlights the potential of LSM as a novel treatment for vision recovery in presbyopic eyes.

Introduction
Presbyopia is the leading cause of near visual impairment globally, with approximately one billion people aged 35 years and older being affected.1 Conventionally, it is defined as an inevitable, age-related, physiological loss of accommodation where the clarity of vision at near is insufficient to satisfy an individual's near point demand.2 With the improved understanding of the concept, presbyopia is better described as a loss of dynamic range of focus (DROF), where there is a loss of ocular focusing power to adjust for clear vision at various distances, including from far to near (accommodation) and from near to far (disaccommodation). DROF encompasses a collective function of true accommodation (central optical power), pseudoaccommodation, diaphragmatic changes of the pupil, and higher- and lower-order aberrations.3 
The phenomenon of presbyopia is traditionally explained by the Helmholtz theory of accommodation, in which a loss of lens elasticity results in the reduction of accommodative ability.4 Emerging studies have revealed a number of age-related changes such as increased lens thickness and curvature,5 stiffening of ocular tissues,6,7 and changes in the anterior sclera and choroid,8 contributing to the gradual loss of accommodation. The improved diagnostics, as well as the understanding of mechanisms of presbyopia, have provided invaluable guidance to the development and innovation of presbyopic treatment in recent years.2,9 
Dependent on the plane of treatment, presbyopic correction can be broadly divided into pre-corneal, corneal and lens-based treatment. Precorneal or nonsurgical treatment such as spectacle correction and contact lens wear (e.g., monovision and multifocal lens), corneal surgeries including corneal inlays and laser refractive correction (e.g., conductive keratoplasty, INTRACOR, presbyLASIK, etc.), and lens-based treatment using multifocal or accommodating intraocular lens (IOLs) have been attempted with varying success.2,1012 However, the majority of the above-mentioned treatments aim to increase the depth of focus instead of restoring DROF or the true dynamic accommodative ability of the eye. 
The concept of anterior scleral expansion procedure was first proposed by Spencer Thornton13 in 1997, in the form of anterior ciliary sclerotomy (ACS), to improve true ocular accommodation and reverse presbyopia. It was suggested that radial incisions of the anterior sclera overlying the ciliary muscles weaken the biomechanical strength of sclera and expand the space between the ciliary body and lens equator. Theoretically this sequence of events increases the resting tension of the equatorial lens zonule and augments the contraction of ciliary muscles, thereby improving the accommodative ability.14,15 In addition, because the treatment is aimed at the sclera, the visual axis is spared, as opposed to a corneal or lens-based correction. However, some studies have shown that ACS may result in only minimal or no improvement in accommodation in presbyopic eyes, with potential significant sight-threatening complications such as scleral perforation and anterior segment ischemia.14,15 The regression of the effect after ACS has been attributed to postoperative wound healing of the incised areas of scleral tissue. To overcome this issue, insertion of “spacers” into the excised scleral tissues has been proposed to maintain the space, thus the effect of ACS, although long-term efficacy is not retained.16,17 
In view of the highlighted issues of ACS, researchers have explored the option of using lasers as an alternative to modify the biomechanics of the anterior sclera.18 Laser anterior ciliary excision (LaserACE; Ace Vision Group, Newark, CA, USA) is a scleral laser micro-excision procedure with a pore size of 600 µm that uses a handheld fiberoptic erbium:yttrium–aluminum–garnet (Er:YAG) laser to restore accommodative ability, as well as the other components of DROF in presbyopic eyes.18 This is achieved through the creation of micropores in the anterior sclera over key areas of the ciliary muscle. It is well known in material science that porosity confers pliability and elasticity of materials,19 and in a similar fashion, the recent iteration of LaserACE called laser scleral microporation (LSM) creates matrices of even smaller (265 µm) micropores to achieve increased pliability and compliance of the anterior sclera. This newly restored compliance assists contraction of the ciliary muscles during accommodation, which restores the efficiency of the biomechanical functions of the accommodative apparatus.20,21 
LSM used the next-generation laser system (VisioLite Gen I MP; Ace Vision Group), which is designed to provide a touchless, off-axis therapeutic solution to uncrosslink scleral microfibrils to improve compliance in the sclera, to allow for recovery of the DROF functions of the accommodative mechanism. LSM shares the same treatment principle as LaserACE but differs in the delivering method. Both LaserACE and LSM use a diode-pulsed solid-state system, but the latter creates a smaller laser spot size (265 µm instead of 600 µm), reduced laser pulse length, and faster treatment speed. However, the in vivo efficacy and safety of this new laser technique have not been determined. In this preclinical study, we aimed to examine the accommodative changes in non-human primates, the macaque monkeys, which are the ideal animal model for the human eye for accommodation, after LSM for correcting presbyopia. We also evaluated the effects of concurrent subconjunctival collagen treatment on the treatment efficacy because our previous study showed that subconjunctival collagen treatment could improve scleral wound healing after LSM,22 which may have an impact on the treatment efficacy. 
Materials and Methods
Study Animals and Experimental Design
This was an in vivo experimental study using two young (<13 years old [equivalent to <40 years old in humans]; n = 4 eyes) and four old (>13 years old [equivalent to >40 years old in humans]; n = 8 eyes) wild-caught cynomolgus macaques of either sex (weighed 2.7–3.8 kg at study initiation). All macaques underwent comprehensive physical examination to ensure good health before being acclimatized to laboratory conditions and used in the study. After acclimatization, all macaques underwent complete ocular evaluation at baseline. Because this treatment aimed to improve the accommodative ability of the eyes, only the old macaques were followed up during the study period, whereas the young macaques were used only to assess and compare baseline refraction with the old macaques. The protocol was approved by the Institutional Animal Care and Use Committee of SingHealth, Singapore (Ref: 2017/SHS/1286), and adhered to the ARVO statement for the use of animals in research. The study design of using bilateral procedure in the protocol was approved by the Institutional Animal Care and Use Committee because the laser procedure was not considered a visually disabling procedure. 
During surgeries and evaluations, the macaques were tranquilized intramuscularly with ketamine hydrochloride (10 mg/kg) and medetomidine (0.02 mg/kg). Anesthesia was induced with 2% to 3% inhaled isoflurane and maintained with 1% to 2% inhaled isoflurane. All the right eyes were treated with the LSM only (L group), and all the left eyes were treated concurrently with LSM and subconjunctival collagen gel matrix (L+C group). The technique of subconjunctival implantation of collagen matrix was detailed in a previous study.22 The rationale for using the subconjunctival collagen was to determine its modulating effect on postoperative wound healing, which could affect the efficacy of LSM. At the conclusion of procedure, topical TobraDex ointment (Alcon, Fort Worth, TX, USA) was applied to both eyes twice daily for one week. 
Surgical Procedures
The surgical technique of LSM was described in a previous study.22 Briefly, the LSM treatment was performed using an Er:YAG laser (VisioLite Gen I MP) with the following laser parameters: (a) frequency of 100 to 300 hz, (b) fluence of 0.9 to 1.5 W, (c) spot size of 225 µm, and (d) micropore depth of approximately 70% to 90% of sclera. The laser parameters, including the depth of the laser micropores, were previously optimized using an ex vivo porcine model.22 Anterior segment optical coherence tomography was used to measure scleral thickness before surgery. The treatment thickness was 85% of the scleral thickness, and the pulse-per-pore was calculated using the following equation: “Treatment thickness/45.88 = pulse per pore.” The laser depth was subsequently confirmed on histology postmortem. 
The LSM procedure was performed in a 5 mm × 5 mm matrix in four oblique quadrants of the eye (49 micropores/matrix with ∼14 seconds/quadrant) over four of five anatomical and physiological zones of significance (zones 1–4; Fig. 1). The zones were defined as follows: (1) zone 0: 0.0 to 1.3 mm from anatomical limbus; distance from the limbus to the superior boundary of ciliary muscle/scleral spur; (2) zone 1: 1.3 to 2.8 mm from limbus; distance from the sclera spur to the inferior boundary of the circular muscle; (3) zone 2: 2.8 to 4.7 mm from limbus; distance from the inferior boundary of the circular muscle to the inferior boundary of the radial muscle; (4) Zone 3: 4.7 to 6.6 mm from limbus; inferior boundary of the radial muscle to the superior boundary of the posterior vitreous zonule zone; and (5) zone 4: 6.6 to 7.3 mm from limbus; superior boundary of the posterior vitreous zonule zone to the superior boundary of the ora serrata.22 Characteristics of the micropores are demonstrated in Figure 2. All the procedures were performed by an experienced surgeon (J.S.M.). 
Figure 1.
 
An illustration demonstrating the five anatomic and physiological zones of significance relevant to the LSM procedure. A series of micropores is created over zones 1–4. This illustration is reproduced from a previous publication by Liu et al.22
Figure 1.
 
An illustration demonstrating the five anatomic and physiological zones of significance relevant to the LSM procedure. A series of micropores is created over zones 1–4. This illustration is reproduced from a previous publication by Liu et al.22
Figure 2.
 
Characteristics and patterns of the micropores created by laser scleral microporation procedure.
Figure 2.
 
Characteristics and patterns of the micropores created by laser scleral microporation procedure.
Clinical Evaluation and Follow-Up
The macaques were examined before surgery and monthly thereafter until 7 months after surgery using slit-lamp biomicroscopy (Nikon FS-3V; Nikon, Tokyo, Japan), tonometry (Tono-Pen AVIA; Reichert Technologies, Buffalo, NY, USA) for measurement of intraocular pressure (IOP), and ray tracing aberrometry (iTrace; Tracey Technologies, Houston, TX, USA) for measurement of wavefront aberrations and DROF. The root mean square values of total wavefront aberration, lower-order aberration (LOA; including astigmatism and defocus), and higher-order aberration (HOA; including spherical aberration, coma, trefoil, and other aberrations) were measured in micrometers (Fig. 3). Baseline and dilated wavefront scans were limited to a 6 mm pupil, whereas scanning after pilocarpine instillation was performed with scans limited to 2 mm pupils. The measurements were taken without any correction of the underlying refractive error. To ensure the accuracy of the measurement of IOP and aberrations, five measurements were obtained for each parameter, and the median value was calculated and used. 
Figure 3.
 
An example of an iTrace image. The VSOTF is computed as a function of defocus using a through-focus curve.
Figure 3.
 
An example of an iTrace image. The VSOTF is computed as a function of defocus using a through-focus curve.
Based on wavefront aberrations data, the iTrace computed the visual Strehl ratio of the optical transfer function (VSOTF) as a function of defocus using a through-focus curve, as described previously (Fig. 3).23 VSOTF has been shown to be a good predictor for measuring visual performance and range (or depth) of focus.23 Extended range of focus (EROF) or the range of focus measured on the iTrace aberrometer is a combination of two depth of focus curves. The EROF was determined by measuring the difference in diopters between the near and distance through-focus curves at the 50% threshold of VSOTF (Fig. 4). EROF thus includes true accommodation plus a range of focus with acceptable blur, called “pseudo-accommodation.” True accommodation was defined as the difference in the spherical equivalent (SE) refraction between distance (unstimulated eyes) and near vision (pilocarpine-stimulated eyes). Pseudo-accommodation was then calculated by subtracting true accommodation from EROF. Examination of near vision was performed using pharmacological stimulation with 0.5% pilocarpine (an accommodation-stimulating drop). Distance vision was examined in both unstimulated and pharmacologically stimulated states using 1.0% tropicamide (a cycloplegic drop). The aberrometry measurement was obtained 45 minutes after the instillation of pilocarpine or tropicamide, and both measurements were obtained on two separate days to avoid any interference of the residual effect of the instilled drop. 
Figure 4.
 
Calculation of the DROF by measuring the difference in diopters between the near and distance through-focus curves, at the 50% threshold of VSOTF. True accommodation is calculated by the difference in the SE refraction between distance and near vision.
Figure 4.
 
Calculation of the DROF by measuring the difference in diopters between the near and distance through-focus curves, at the 50% threshold of VSOTF. True accommodation is calculated by the difference in the SE refraction between distance and near vision.
The use of pharmacological pilocarpine-stimulated method has been previously established and used in human studies for measuring the accommodative amplitude.24,25 It has been shown to correspond well with the measurement of voluntary accommodation (although some degree of overestimation may occur with pilocarpine-stimulated eyes, mainly in the younger eyes).24 The minimal change in the accommodation of the old monkeys observed in our study after pilocarpine stimulation suggested that overestimation of the accommodation measured after topical pilocarpine was unlikely.24 Baseline or unstimulated eyes have been used for measurement of SE during the disaccommodated state in previous studies.26,27 We had performed measurements in both unstimulated and tropicamide-stimulated states and found no significant differences in various measurements between the two conditions; therefore measurement of the unstimulated eyes (similar to previous studies) was used as the disaccommodated state for distance vision in our analysis. 
Statistical Analysis
Statistical analyses were performed using R software, v3.6.0. All continuous values are presented as mean ± standard deviation. Baseline measurements were compared between young and old macaques using Student's t-tests. Because of difficulties with the clinical measurement of the macaques, which resulted in missing data at certain postoperative time points, we tested for treatment effects by using a linear mixed effects analysis using the “lmer” function in the R package “lme4,”28 with month as a fixed effect and eye as a random effect, to test for changes in variables over time while simultaneously accounting for repeated measures. Significance of the fixed effect was determined with a likelihood ratio test comparing the full model against a reduced model without month as a factor. We then conducted post hoc analysis with the “glht” function of the “multcomp” package,29 comparing postoperative timepoints with the preoperative timepoint. P values < 0.05 were considered statistically significant. 
Results
Baseline Characteristics
A total of 12 eyes from two young macaques (n = 4 eyes) and four old macaques (n = 8 eyes) were included in this study at baseline. Before surgery, as expected, there was a significant difference in the true accommodative ability between the young and old macaques (7.2 ± 7.0 vs. 0.6 ± 0.9; P = 0.24; Table). There was also a considerable difference in the EROF between young and old macaques (11.5 vs. 3.4 ± 1.0), but statistical significance could not be determined because of the availability of only a single datum in the “young macaques” group due to inadequate iTrace quality (Table). There was no significant difference in the magnitude of total wavefront aberration, HOA, LOA, and IOP (all P > 0.05; Table). In young macaques, SE shifted from 2.9 to −4.4 D when accommodated. The LOA was slightly (but non-significantly) higher in accommodated state (0.9 µm) than in disaccommodation state (0.8 µm), which was likely attributed to the considerable effect of induced myopia during accommodation with counterbalance from the effect of pharmacologically induced pupil constriction. On the other hand, in older macaques, there was an insignificantly higher LOA in disaccommodated state than accommodated state, which was likely due to the effect of pharmacologically induced pupil constriction and slightly improvement in the SE during accommodation (Table). 
Table.
 
Preoperative Characteristics of Young and Old Macaques Before Laser Scleral Microporation Treatment
Table.
 
Preoperative Characteristics of Young and Old Macaques Before Laser Scleral Microporation Treatment
Changes in SE After LSM
In the disaccommodated state, SE remained relatively stable at each monthly postoperative time point over seven months (P = 0.14). However, in the accommodated state, SE became more myopic during the postoperative period (P < 0.001), highlighting a continual improvement in the accommodative ability (Fig. 5). From the preoperative mean of 0.0 ± 1.5 D, the SE in the accommodated state was significantly lower at one month after surgery (−2.3 ± 2.6 D, P = 0.049), five months after surgery (−4.4 ± 1.8 D, P < 0.001), and seven months after surgery (−6.9 ± 1.7 D, P < 0.001). 
Figure 5.
 
Preoperative and postoperative measurements of the mean SE in the disaccommodated and accommodated states following laser scleral microporation treatment in old macaques. *SE significantly decreased at one, five, and seven months after operation. The sample sizes were eight, seven, five, six, six, four, and four eyes (months 0-7, respectively) for the disaccommodated state, and eight, eight, five, six, six, four, and four eyes in the accommodated state. Data are presented as mean ± standard deviation.
Figure 5.
 
Preoperative and postoperative measurements of the mean SE in the disaccommodated and accommodated states following laser scleral microporation treatment in old macaques. *SE significantly decreased at one, five, and seven months after operation. The sample sizes were eight, seven, five, six, six, four, and four eyes (months 0-7, respectively) for the disaccommodated state, and eight, eight, five, six, six, four, and four eyes in the accommodated state. Data are presented as mean ± standard deviation.
Changes in Postoperative Accommodation and EROF
From before to seven months after surgery, there was a steady and significant increase in true accommodation after the treatment (P = 0.003; Fig. 6), with an increase from 0.6 ± 0.9 D before surgery to 4.8 ± 2.8 D at six months after surgery (P = 0.017) and 5.9 ± 2.8 D at seven months after surgery (P < 0.001). Pseudo-accommodation also increased significantly over time (P = 0.013), which was primarily driven by a significant increase from 2.8 ± 1.0 D before to 5.3 ± 2.3 D at seven months after surgery (P = 0.019). Furthermore, EROF, as measured with iTrace, increased significantly over time (P = 0.022; Fig. 6), with an increase from 3.4 ± 1.0 D before surgery to 11.1 ± 4.6 D at seven months after (P < 0.001). There was no significant difference in true accommodation (P = 0.29), pseudo-accommodation (P = 0.54), and EROF (P = 0.20) between both eyes, suggesting that subconjunctival collagen application did not significantly influence the accommodative effect of LSM. 
Figure 6.
 
Preoperative and postoperative measurements of DROF, true accommodation, and pseudo-accommodation in old macaques after laser scleral microporation treatment. *All three variables increased by seven months after operation. Sample sizes were five, two, five, four, six, two, and four eyes for DROF and Pseudo-accommodation, and eight, seven, five, six, six, four, and four eyes for true accommodation. Data are presented in mean ± standard deviation.
Figure 6.
 
Preoperative and postoperative measurements of DROF, true accommodation, and pseudo-accommodation in old macaques after laser scleral microporation treatment. *All three variables increased by seven months after operation. Sample sizes were five, two, five, four, six, two, and four eyes for DROF and Pseudo-accommodation, and eight, seven, five, six, six, four, and four eyes for true accommodation. Data are presented in mean ± standard deviation.
Changes in Ocular Wavefront Aberrations
Wavefront aberrations did not vary significantly between preoperative and postoperative timepoints in terms of total aberrations (in either the disaccommodated [P = 0.23] or accommodated states [P = 0.07]), LOA (in either the disaccommodated [P = 0.17] or accommodated states [P = 0.13]), and HOA in the disaccommodated state (P = 0.44). HOA in the accommodated state was found to vary significantly (P = 0.010) but not between the preoperative and any postoperative timepoints (P > 0.05 for all comparisons; Fig. 7). Smaller pupils in the accommodative state did cause some variabilities in the results. 
Figure 7.
 
Preoperative and postoperative measurements of total aberrations, LOA, and HOA in the disaccommodated state after the laser scleral microporation procedure. Aberrations were measured and quantitated in root mean square (RMS), in micrometers, for a given pupil radius. The measurements did not vary between the preoperative and any postoperative timepoints. N = 8, 8, 7, 5, 6, 6, 4, and 4 eyes (at months 0–7 after surgery) for all aberration variables.
Figure 7.
 
Preoperative and postoperative measurements of total aberrations, LOA, and HOA in the disaccommodated state after the laser scleral microporation procedure. Aberrations were measured and quantitated in root mean square (RMS), in micrometers, for a given pupil radius. The measurements did not vary between the preoperative and any postoperative timepoints. N = 8, 8, 7, 5, 6, 6, 4, and 4 eyes (at months 0–7 after surgery) for all aberration variables.
Safety
Compared to preoperative, the IOP was shown to be significantly lower following LSM at all postoperative timepoints (P < 0.013 for all comparisons; Fig. 8). There was no adverse event, including scleral perforation or hypotony, observed throughout the study. 
Figure 8.
 
Preoperative and postoperative measurements of the IOP after laser scleral microporation procedure. *IOP at all postoperative timepoints was significantly lower compared to the preoperative measurement. N = 8, 8, 8, 6, 6, 6, 4, and 4 eyes (at months 0–7). Data are presented as mean ± SD.
Figure 8.
 
Preoperative and postoperative measurements of the IOP after laser scleral microporation procedure. *IOP at all postoperative timepoints was significantly lower compared to the preoperative measurement. N = 8, 8, 8, 6, 6, 6, 4, and 4 eyes (at months 0–7). Data are presented as mean ± SD.
Discussion
With the continual improved understanding of the pathogenesis and pathophysiology of presbyopia, as well as the advancement in lens technology, the therapeutic armamentarium for presbyopia has expanded considerably over recent decades. Among all these, treatments that aim to restore the DROF function of the eye, including true accommodative ability of the eye (e.g., anterior scleral procedure therapies, accommodating IOLs, or both), are still considered the holy grail of presbyopic corrective treatment.2 Unlike corneal laser refractive procedure and multifocal IOLs, which work by splitting of the light into two or more foci resulting in compromise of other focal points, LSM recovers the natural ocular biomechanical ability to adjust the eye via a physiological and dynamic optic shift mechanism for resolving presbyopia.30 Therefore, theoretically, LSM is able to improve accommodative ability and DROF without affecting the visual quality, which is often decreased in other types of presbyopia-corrective surgeries that affect the visual axis. Hence, this is a treatment of vision recovery rather than vision correction.3134 
In this non-human primate study, we demonstrated the ability of LSM to significantly improve physiological accommodative ability and total DROF. A significant improvement in the mean EROF by 7.7 D was observed, with an increase from 3.4 D before surgery to 11.1 D at seven months after surgery. The increase was largely attributable to the improvement in true accommodation (by 5.3 D) and, to a smaller extent, in pseudo-accommodation (by 2.4 D), although this latter improvement in pseudo-accommodation may merely represent measurement error given the variability of this measurement observed across timepoints. The extent of improvement in the EROF (by 7.7 D) provides an accommodative ability that is equivalent to a human eye of ≤40 years old.35 In addition, the presbyopic correction for human usually only requires 2 to 3 D. Therefore these findings suggest that the LSM can provide sufficient DROF recovery that is functionally useful, even if only the improvement in true accommodation is considered. Moreover, SE in the disaccommodated state remained similar between preoperative and various postoperative timepoints, suggesting that LSM was able to improve the accommodative ability without affecting the resting tension of the ciliary muscle and the primary lens position. 
LSM, a newer iteration of the LaserACE procedure, was previously published by Hipsley et al. 20 and was reported to demonstrate favorable visual outcomes at 24 months after operation. The mean binocular uncorrected near visual acuity (at 40 cm) was shown to improve significantly from 0.20 logMAR to 0.12 logMAR. The treated patients reported less difficulty in areas which require near vision (e.g., reading newspaper, seeing price list during shopping, etc.) and the overall patient satisfaction was good. However, two patients developed scleral microperforation with transient hypotony (IOP of 5 mm Hg and 8 mm Hg, respectively), although this was successfully resolved with collagen matrix application and a bandage contact lens, with IOP normalization by postoperative day 3. A more recent study observed that three patients who were treated with LaserACE procedure were able to achieve distance-corrected near visual acuity of 20/20 or better at eight to 13 years after surgery, highlighting the long-term efficacy and stability of the treatment.21 
However, it is noteworthy to highlight that the LaserACE procedure requires the delivery of the laser via a fiberoptic handheld probe that could only laser one spot at a time, rendering the procedure less standardized and efficient. In contrast, the LSM procedure uses the next-generation laser system (VisioLite Gen I MP) and can deliver 49 laser micropores/matrix with ∼14 seconds/quadrant, with a smaller laser spot size, faster treatment speed, and reduced laser pulse length which has been shown to induce less damage and result in faster wound healing).36 Moreover, the regularly spaced matrix of micropores created by the LSM may confer a more controlled and standardized modification of the biomechanical properties of the anterior sclera, as compared to the previous LaserACE procedure (1 spot/laser at a time). Further safety improvements have been added by using optical coherence tomography to measure and predict depth control using the new Gen I MP system. 
One of the main advantages of LSM lies in its ability to improve the physiological DROF ability of the accommodative apparatus without operating on the visual axis. It is well established that laser corneal refractive surgeries and multifocal IOLs to correct for myopia, hyperopia, astigmatism, or presbyopia can induce considerable high- and low-order aberrations, which can negatively affect visual quality (particularly in eyes with a larger pupil) and result in undesired positive symptoms such as glare, haloes, and ghosting.32,37,38 Interestingly, we observed a continual improvement in the DROF and accommodative ability over the seven-month post-LSM period. This phenomenon may be related to the neuroadaptive ability of the muscles related to neuromuscular rehabilitation (in this case, the ciliary muscles), which typically occurs with continuous exercise and training.39 However, we expect this effect to stabilize over time because there will be a limit to the extent of physiological improvement and restoration of the ciliary muscle contraction and the scleral pliability after LSM. 
Finally, LSM is an extraocular, noncorneal procedure that obviates the potential risk of severe corneal complications such as infectious keratitis and flap complications (observed in corneal refractive surgeries), as well as sight-threatening intraocular complications such as retinal detachment and endophthalmitis that are associated with lens-based surgeries. We observed a significant but small decrease in the IOP by around 3 mm Hg, but without the occurrence of any adverse event such as hypotony or scleral perforation. Furthermore, LSM does not complicate any future corneal or cataract surgery, and further cornea- or lens-based refractive surgeries can be performed to augment the effect of LSM-corrected presbyopia, especially if there is any regression of the treatment effect after LSM. We do not expect that the procedure-induced biomechanical scleral changes or neuroadaptive improvement will pose any impact on the biometry calculation (for monofocal or multifocal lens) or the cataract surgery intraoperatively as operating on LSM-treated eyes will be similar to operating on younger eyes, which have preserved scleral pliability and compliance, and good accommodative ability. In addition, our study showed that the disaccommodated SE remained similar in LSM-treated eyes between preoperative and postoperative periods, suggesting that the resting tone of the ciliary muscle and the lens position did not change after LSM. 
We have recently reported the favorable, self-limiting tissue responses and safety after LSM treatment in macaques.22 In addition, it was shown that concurrent subconjunctival collagen impact was able to suppress the inflammatory responses and wound contraction at the treated scleral site. In this study, there was no significant difference in true accommodation, pseudo-accommodation and DRoF between the right and the left eyes, suggesting that concurrent subconjunctival collagen implants can be performed during LSM to reduce the laser-induced inflammation without affecting the efficacy of presbyopic correction. 
To our knowledge, this study represents the first macaque preclinical study examining the efficacy of this new scleral laser technique, LSM, in improving DROF (including true accommodative ability). The macaque eye has been shown as the closest approximation to the human eye when it comes to evaluating accommodative ability. However, in view of the stringent regulation on conducting non-human primate studies, the sample size of our study was limited to 12 eyes only (four eyes from two young macaques [only used for baseline measurement in this study] and eight eyes from four old macaques). Although a smaller sample size is known to increase the risk of a type 2 error (i.e., failing to reject an incorrect null hypothesis), we were still able to observe significant improvement in the accommodative ability after LSM. Another limitation lies in the difficulties with using iTrace in macaques, because the long noses of these animals presented considerable challenges to the optical alignment of the iTrace, potentially affecting the results. Additionally, it is noteworthy that the iTrace software was calibrated for human axial length, which was longer than the axial length of the monkey eyes in this study, although appropriate modification was made to account for the difference. 
In conclusion, this proof-of-concept study provides a first-hand examination of the in vivo efficacy and safety of LSM for presbyopic correction. Further human clinical trials will help validate our findings and potentially pave the way for a new treatment for presbyopia. 
Acknowledgments
Supported by the SingHealth Foundation Grant, Singapore (SHF/FG624S/2014). 
Disclosure: D.S.J. Ting, None; Y.-C. Liu, None; E.R. Price, Ace Vision Group Inc. (F); T.S. Swartz, Ace Vision Group Inc. (F); N.C. Lwin, None; A. Hipsley, Ace Vision Group Inc. (F, S), Ace Vision Group Inc. (P); J.S. Mehta, None 
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Figure 1.
 
An illustration demonstrating the five anatomic and physiological zones of significance relevant to the LSM procedure. A series of micropores is created over zones 1–4. This illustration is reproduced from a previous publication by Liu et al.22
Figure 1.
 
An illustration demonstrating the five anatomic and physiological zones of significance relevant to the LSM procedure. A series of micropores is created over zones 1–4. This illustration is reproduced from a previous publication by Liu et al.22
Figure 2.
 
Characteristics and patterns of the micropores created by laser scleral microporation procedure.
Figure 2.
 
Characteristics and patterns of the micropores created by laser scleral microporation procedure.
Figure 3.
 
An example of an iTrace image. The VSOTF is computed as a function of defocus using a through-focus curve.
Figure 3.
 
An example of an iTrace image. The VSOTF is computed as a function of defocus using a through-focus curve.
Figure 4.
 
Calculation of the DROF by measuring the difference in diopters between the near and distance through-focus curves, at the 50% threshold of VSOTF. True accommodation is calculated by the difference in the SE refraction between distance and near vision.
Figure 4.
 
Calculation of the DROF by measuring the difference in diopters between the near and distance through-focus curves, at the 50% threshold of VSOTF. True accommodation is calculated by the difference in the SE refraction between distance and near vision.
Figure 5.
 
Preoperative and postoperative measurements of the mean SE in the disaccommodated and accommodated states following laser scleral microporation treatment in old macaques. *SE significantly decreased at one, five, and seven months after operation. The sample sizes were eight, seven, five, six, six, four, and four eyes (months 0-7, respectively) for the disaccommodated state, and eight, eight, five, six, six, four, and four eyes in the accommodated state. Data are presented as mean ± standard deviation.
Figure 5.
 
Preoperative and postoperative measurements of the mean SE in the disaccommodated and accommodated states following laser scleral microporation treatment in old macaques. *SE significantly decreased at one, five, and seven months after operation. The sample sizes were eight, seven, five, six, six, four, and four eyes (months 0-7, respectively) for the disaccommodated state, and eight, eight, five, six, six, four, and four eyes in the accommodated state. Data are presented as mean ± standard deviation.
Figure 6.
 
Preoperative and postoperative measurements of DROF, true accommodation, and pseudo-accommodation in old macaques after laser scleral microporation treatment. *All three variables increased by seven months after operation. Sample sizes were five, two, five, four, six, two, and four eyes for DROF and Pseudo-accommodation, and eight, seven, five, six, six, four, and four eyes for true accommodation. Data are presented in mean ± standard deviation.
Figure 6.
 
Preoperative and postoperative measurements of DROF, true accommodation, and pseudo-accommodation in old macaques after laser scleral microporation treatment. *All three variables increased by seven months after operation. Sample sizes were five, two, five, four, six, two, and four eyes for DROF and Pseudo-accommodation, and eight, seven, five, six, six, four, and four eyes for true accommodation. Data are presented in mean ± standard deviation.
Figure 7.
 
Preoperative and postoperative measurements of total aberrations, LOA, and HOA in the disaccommodated state after the laser scleral microporation procedure. Aberrations were measured and quantitated in root mean square (RMS), in micrometers, for a given pupil radius. The measurements did not vary between the preoperative and any postoperative timepoints. N = 8, 8, 7, 5, 6, 6, 4, and 4 eyes (at months 0–7 after surgery) for all aberration variables.
Figure 7.
 
Preoperative and postoperative measurements of total aberrations, LOA, and HOA in the disaccommodated state after the laser scleral microporation procedure. Aberrations were measured and quantitated in root mean square (RMS), in micrometers, for a given pupil radius. The measurements did not vary between the preoperative and any postoperative timepoints. N = 8, 8, 7, 5, 6, 6, 4, and 4 eyes (at months 0–7 after surgery) for all aberration variables.
Figure 8.
 
Preoperative and postoperative measurements of the IOP after laser scleral microporation procedure. *IOP at all postoperative timepoints was significantly lower compared to the preoperative measurement. N = 8, 8, 8, 6, 6, 6, 4, and 4 eyes (at months 0–7). Data are presented as mean ± SD.
Figure 8.
 
Preoperative and postoperative measurements of the IOP after laser scleral microporation procedure. *IOP at all postoperative timepoints was significantly lower compared to the preoperative measurement. N = 8, 8, 8, 6, 6, 6, 4, and 4 eyes (at months 0–7). Data are presented as mean ± SD.
Table.
 
Preoperative Characteristics of Young and Old Macaques Before Laser Scleral Microporation Treatment
Table.
 
Preoperative Characteristics of Young and Old Macaques Before Laser Scleral Microporation Treatment
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