Publications by authors named "Jodhbir S Mehta"

349 Publications

Femtosecond laser-assisted stromal keratophakia for keratoconus: A systemic review and meta-analysis.

Int Ophthalmol 2021 Feb 20. Epub 2021 Feb 20.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore.

Purpose: Femtosecond lasers have revived the possibility of stromal keratophakia or tissue additive keratoplasty, a technique originally introduced by Prof. Jose Ignacio Barraquer in the 1960s. The surgical technique offers a unique solution to treat keratoconus. In the current study, we reviewed and performed a meta-analysis of the clinical outcomes of the femtosecond laser-assisted stromal keratophakia in the treatment of keratoconus.

Methods: This is a systematic review and meta-analysis of the estimated outcome difference between pre- and post-lenticule implantations.

Results: A total of related 10 studies were found in the literature. No studies reported adverse events, such as persistent haze or graft rejection, at last patients' visits. We further narrowed down the article selection in accordance to our inclusion criteria to report the composite outcomes (9 studies) and meta-analysis (4 studies). In the composite analysis, we demonstrated that lenticule implantation in keratoconus and post-LASIK ectasia patients appeared to expand the stromal volume of the thin corneas, flattened the cones, and significantly improved uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA) and spherical equivalent (SE). The meta-analysis showed that the random estimated UCVA, BCVA, SE and mean keratometry (K) differences following the lenticule implantation was -0.214 (95% CI: -0.367 to 0.060; p = 0.006), -0.169 (-0.246 to 0.091; p < 0.001), -2.294 D (-3.750 to -0.839 D; p = 0.002), and 2.909 D (0.805 to 5.012 D; p = 0.007), respectively.

Conclusions: Femtosecond laser-assisted stromal keratophakia is a feasible technique to correct the refractive aberrations, expand corneal volume and regularize corneal curvature in patients with keratoconus. However, there is a need to standardize the technique (e.g., whether to crosslink or not or to use convex or concave lenticules) and to formulate a mathematical model that accounts for the long-term epithelial thickness changes and stromal remodeling to determine the shape or profile of the lenticules, in order to improve the efficacy of the keratophakia further.
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http://dx.doi.org/10.1007/s10792-021-01745-wDOI Listing
February 2021

Femtosecond laser-assisted excision of conjunctival melanocytic lesions: Cosmetic and long-term outcomes.

Clin Exp Ophthalmol 2021 Feb 11. Epub 2021 Feb 11.

Department of Cornea and External Diseases, Singapore National Eye Centre, Singapore.

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http://dx.doi.org/10.1111/ceo.13907DOI Listing
February 2021

Inlays and the cornea.

Exp Eye Res 2021 Jan 29;205:108474. Epub 2021 Jan 29.

Singapore National Eye Centre, Singapore; Singapore Eye Research Institute, Singapore; Ophthalmology and Visual Sciences Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Graduate Medical School, Singapore; School of Material Science & Engineering and School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore; Yong Loo Lin School of Medicine, Department of Ophthalmology, National University of Singapore, Singapore. Electronic address:

Presbyopia is a growing problem in view of an aging global population and increasingly patients desire spectacle-free solutions to address this condition. Surgically implanted corneal inlays have been the topic of renewed research efforts in the past several years as a treatment option for presbyopia, with several approaches being used to modify the refractive properties of the cornea and enhance near vision. In this review we discuss historical approaches to corneal inlay surgery, critically appraise the current generation of presbyopia-correcting corneal inlays and their associated complications and consider the future prospects for emerging corneal inlay technologies that aim address the shortcomings of currently available inlays.
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http://dx.doi.org/10.1016/j.exer.2021.108474DOI Listing
January 2021

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes.

Int J Mol Sci 2021 Jan 27;22(3). Epub 2021 Jan 27.

Singapore National Eye Centre, Singapore 168751, Singapore.

To evaluate the distribution of the transforming growth factor-beta induced (TGFBI) corneal dystrophies in a multi-ethnic population in Singapore, and to present the different phenotypes with the same genotype. This study included 32 patients. Slit lamp biomicroscopy was performed for each patient to determine the disease phenotype. Genomic DNA was extracted from the blood samples and the 17 exons of the TGFBI gene were amplified by PCR and sequenced bi-directionally for genotype analysis. Regarding phenotypes, the study patients comprised 11 (34.4%; 8 with R555W and 3 with R124H mutation) patients with granular corneal dystrophy type 1 (GCD1), 6 (18.8%; 5 with R124H and 1 with R124C mutation) patients with GCD2, 13 (40.6%; 7 with R124C, 2 with H626R, 2 with L550P, 1 with A620D and 1 with H572R) patients with lattice corneal dystrophy (LCD) and 2 (6.3%; 1 with R124L and 1 with R124C) patients with Reis-Bückler corneal dystrophy. Regarding genotype, R124H mutation was associated with GCD2 (5 cases; 62.5%) and GCD1 (3 cases; 37.5%). R124C mutation was associated with LCD (7 cases; 87.5%) and GCD2 (1 case; 12.5%). All the 8 cases (100%) of R555W mutation were associated with GCD1. Although the association between genotype and phenotype was good in most cases (65.7%; 21 of 32 patients), genotype/phenotype discrepancy was observed in a significant number.
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http://dx.doi.org/10.3390/ijms22031230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866065PMC
January 2021

Safety profiles of terahertz scanning in ophthalmology.

Sci Rep 2021 Jan 28;11(1):2448. Epub 2021 Jan 28.

Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Level 12, Singapore, 169856, Singapore.

Terahertz (THz) technology has emerged recently as a potential novel imaging modality in biomedical fields, including ophthalmology. However, the ocular biological responses after THz electromagnetic exposure have not been investigated. We conducted a rabbit study to evaluate the safety profiles of THz scanning on eyes, at a tissue, cellular, structural and functional level. Eight animals (16 eyes) were analysed after excessive THz exposure (control, 1 h, 4 h, and 1 week after continuous 4-h exposure; THz frequency = 0.3 THz with continuous pulse generated at 40 µW). We found that at all the time points, the corneas and lens remained clear with no corneal haze or lens opacity formation clinically and histopathologically. No thermal effect, assessed by thermographer, was observed. The rod and cone cell-mediated electroretinography responses were not significantly altered, and the corneal keratocytes activity as well as endothelial viability, assessed by in-vivo confocal microscopy, was not affected. Post-exposed corneas, lens and retinas exhibited no significant changes in the mRNA expression of heat shock protein (HSP)90AB1), DNA damage inducible transcript 3 (DDIT3), and early growth response (EGR)1. These tissues were also negative for the inflammatory (CD11b), fibrotic (fibronectin and α-smooth muscle actin), stress (HSP-47) and apoptotic (TUNEL assay) responses on the immunohistochemical analyses. The optical transmittance of corneas did not change significantly, and the inter-fibrillar distances of the corneal stroma evaluated with transmission electron microscopy were not significantly altered after THz exposure. These results provide the basis for future research work on the development of THz imaging system for its application in ophthalmology.
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http://dx.doi.org/10.1038/s41598-021-82103-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843699PMC
January 2021

Epithelial and stromal remodelling following femtosecond laser-assisted stromal lenticule addition keratoplasty (SLAK) for keratoconus.

Sci Rep 2021 Jan 27;11(1):2293. Epub 2021 Jan 27.

Department of Medicine and Sciences of Ageing, Ophthalmic Clinic, University "G. D'Annunzio" of Chieti-Pescara, Via dei Vestini, 66100, Chieti, Italy.

The purpose of this study was to evaluate corneal epithelium and stromal remodelling with anterior segment optical coherence tomography in patients who have undergone stromal lenticule addition keratoplasty (SLAK) for advanced keratoconus. This was a prospective non-comparative observational study. Fifteen eyes of 15 patients with advanced keratoconus underwent implantation with a cadaveric, donor negative meniscus-shaped intrastromal lenticule, produced with a femtosecond laser, into a stromal pocket dissected in the recipient cornea at a depth of 120 μm. Simulated keratometry, central corneal thickness (CTT), corneal thinnest point (CTP), central epithelial thickness (CET), central and peripheral lenticule thickness, anterior and posterior stromal thickness were measured. Regional central corneal epithelial thickness (CET) and variations in the inner annular area (IAT) and outer annular area (OAT) were also analysed. All parameters were measured preoperatively and 1, 3, and 6 months postoperatively. The average anterior Sim-k decreased from 59.63 ± 7.58 preoperatively to 57.19 ± 6.33 D 6 months postoperatively. CCT, CTP, CET, and OAT increased and IAT decreased significantly after 1 month. All parameters appeared unchanged at 6-months except that of OAT that further increased. Lenticule thickness was stable. In conclusion we observed that SLAK reshapes the cornea by central flattening with stromal thickening and epithelial thickness restoration.
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http://dx.doi.org/10.1038/s41598-021-81626-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840927PMC
January 2021

The effects of laser displacement on femtosecond laser-assisted conjunctival autograft preparation for pterygium surgery.

PLoS One 2021 14;16(1):e0245223. Epub 2021 Jan 14.

Singapore National Eye Centre, Singapore, Singapore.

Aims: To evaluate the effects of no-suction femtosecond laser (FSL) stability on conjunctival autograft (CAG) dissection in pterygium surgery.

Methods: Prospective analysis of 35 eyes from 34 subjects who underwent femtosecond laser-assisted pterygium surgery with the Ziemer Z8 laser (Ophthalmic Systems AG, Switzerland). Intraoperative absolute FSL displacements were measured and correlated with the duration and ease of CAG peel, CAG thickness, measured with intraoperative optical coherence tomography, and deviation from intended graft thickness.

Results: The median absolute FSL displacement was 22 μm (interquartile range [IQR] 14.7 to 60.8), while median vertical FSL displacement was 14.7 μm (IQR 7.3 to 44) and median horizontal FSL displacement was 22.0 μm (IQR 14.7 to 44). 65.7% had a grade 1 peel, 11.4% had grade 2 peel, 14.3% had grade 3 peel and 8.6% had grade 4 peel. The median duration of CAG peel was 5.4 seconds (IQR 3 to 21.4). The median CAG thickness was 69 μm (IQR 60.3 to 78.5), and the median deviation from targeted graft thickness was 9 μm (IQR 1 to 16). Eyes with more difficult peels and longer duration of CAG peels had significantly greater vertical FSL displacements (p = 0.04 and 0.02 respectively), but not horizontal displacement, age, ethnicity, CAG thickness or deviation from original thickness, compared to those with better quality and shorter duration peels. 1 eye (2.9%) had an incomplete CAG peel with a buttonhole and 2 eyes had graft tears (5.7%).

Conclusion: Micro-displacements during the suction-free CAG preparation are common but they did not affect the quality of the CAG peel, duration of peel, or CAG thickness. However, vertical globe displacement during FSL-assisted CAG creation was significantly associated with a more difficult and longer CAG peel duration. This highlights the importance of the cornea traction suture fixation to ensure stability of the eye during FSL application.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808670PMC
January 2021

A pilot study investigating anterior segment optical coherence tomography angiography as a non-invasive tool in evaluating corneal vascularisation.

Sci Rep 2021 Jan 13;11(1):1212. Epub 2021 Jan 13.

Singapore Eye Research Institute, Singapore, Singapore.

The current assessment of corneal vascularisation (CV) relies on slit-lamp examination, which may be subjective. Dye-based angiographies, like indocyanine green angiography (ICGA), allows for good visualisation of anterior segment blood vessels. However, ICGA is invasive and can be associated with systemic adverse effects. Anterior segment optical coherence tomography angiography (AS-OCTA) is a non-invasive tool that has been shown to successfully delineate CV. However, there are no previous studies that have reported if AS-OCTA can determine CV stage and activity. We used an established CV model in rabbits to examine serial AS-OCTA scans of CV development and regression following treatment with anti-vascular endothelial growth factor. We compared AS-OCTA derived vascular measurements to that of ICGA determined vessel leakage and CV staging. Our results showed that AS-OCTA vessel densities and vessel branch area significantly correlated with the severity of CV based on ICGA (all p ≤ 0.05). We also found that AS-OCTA vessel densities correlated with ICGA vessel leakage time, following an inverse linear relationship (r = - 0.726, p < 0.01). Changes in aqueous levels of CXCL-12 and PIGF cytokines significantly correlated with AS-OCTA vessel densities (r = 0.736 and r = 0.731 respectively, all p < 0.05). In summary, we found that AS-OCTA derived vessel parameters may be useful for assessing CV severity, while vessel density correlates with CV activity and leakage. Thus, our pilot animal model study suggests that AS-OCTA may be a useful non-invasive imaging tool to provide objective assessment of CV to examine progression or response in treatment, which requires confirmation in clinical studies.
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http://dx.doi.org/10.1038/s41598-020-80099-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807024PMC
January 2021

Evaluation of femtosecond laser-assisted anterior capsulotomy in the presence of ophthalmic viscoelastic devices (OVDs).

Sci Rep 2020 12 9;10(1):21542. Epub 2020 Dec 9.

Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore, Singapore.

The introduction of femtosecond laser-assisted cataract surgery is an alternative approach to conventional cataract surgery. Our study aimed to determine the effectiveness of femtosecond laser-assisted capsulotomy in the presence of different ophthalmic viscoelastic devices (OVDs) in the anterior chamber. Fresh porcine eyes (n = 96) underwent LDV Z8-assisted anterior capsulotomy, either in the presence of an OVD (Viscoat, Provisc, Healon, Healon GV or HPMC) or without, using 90% and 150% energies respectively. Following that, the capsule circularity, tag's arc-length, tag-length, tag-area and rupture strength (mN) of the residual capsular bag were evaluated. We found that increasing energy from 90 to 150% across the OVD sub-groups improved the studied capsulotomy parameters. Amongst the 90% energy sub-groups, the circularity and tag-parameters were worse with Viscoat and Healon GV, which have higher refractive index and viscosity compared to the aqueous humour. Using 150% energy, Healon GV showed a significantly worse total arc-length (p = 0.01), total tag-length (p = 0.03) and total tag-area (p = 0.05) compared to the control group. We concluded that; an OVD with a refractive index similar to aqueous humour and lower viscosity, such as Healon or Provisc, as well as a higher energy setting, are recommended, to enhance the efficacy of laser capsulotomy.
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http://dx.doi.org/10.1038/s41598-020-78361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726555PMC
December 2020

Diabetic Corneal Neuropathy.

J Clin Med 2020 Dec 6;9(12). Epub 2020 Dec 6.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore.

Diabetic keratopathy (DK) is a common, but underdiagnosed, ocular complication of diabetes mellitus (DM) that has a significant economic burden. It is characterised by progressive damage of corneal nerves, due to DM-induced chronic hyperglycaemia and its associated metabolic changes. With advances in corneal nerve imaging and quantitative analytic tools, studies have shown that the severity of diabetic corneal neuropathy correlates with the status of diabetic peripheral neuropathy. The corneal nerve plexus is, therefore, considered as an important surrogate marker of diabetic peripheral neuropathy and helps in the evaluation of interventional efficacy in the management of DM. The clinical manifestations of DK depend on the disease severity and vary from decreased corneal sensitivity to sight-threatening corneal infections and neurotrophic ulcers. The severity of diabetic corneal neuropathy and resultant DK determines its management plan, and a step-wise approach is generally suggested. Future work would focus on the exploration of biomarkers for diabetic corneal neuropathy, the development of new treatment for corneal nerve protection, and the improvement in the clinical assessment, as well as current imaging technique and analysis, to help clinicians detect diabetic corneal neuropathy earlier and monitor the sub-clinical progression more reliably.
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http://dx.doi.org/10.3390/jcm9123956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762152PMC
December 2020

Regenerative capacity of the corneal transition zone for endothelial cell therapy.

Stem Cell Res Ther 2020 12 4;11(1):523. Epub 2020 Dec 4.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, 20 College Road, The Academia, Discovery Tower Level 6, Singapore, 169856, Singapore.

The corneal endothelium located on the posterior corneal surface is responsible for regulating stromal hydration. This is contributed by a monolayer of corneal endothelial cells (CECs), which are metabolically active in a continuous fluid-coupled efflux of ions from the corneal stroma into the aqueous humor, preventing stromal over-hydration and preserving the orderly arrangement of stromal collagen fibrils, which is essential for corneal transparency. Mature CECs do not have regenerative capacity and cell loss due to aging and diseases results in irreversible stromal edema and a loss of corneal clarity. The current gold standard of treatment for this worldwide blindness caused by corneal endothelial failure is the corneal transplantation using cadaveric donor corneas. The top indication is Fuchs corneal endothelial dystrophy/degeneration, which represents 39% of all corneal transplants performed. However, the global shortage of transplantable donor corneas has restricted the treatment outcomes, hence instigating a need to research for alternative therapies. One such avenue is the CEC regeneration from endothelial progenitors, which have been identified in the peripheral endothelium and the adjacent transition zone. This review examines the evidence supporting the existence of endothelial progenitors in the posterior limbus and summarizes the existing knowledge on the microanatomy of the transitional zone. We give an overview of the isolation and ex vivo propagation of human endothelial progenitors in the transition zone, and their growth and differentiation capacity to the corneal endothelium. Transplanting these bioengineered constructs into in vivo models of corneal endothelial degeneration will prove the efficacy and viability, and the long-term maintenance of functional endothelium. This will develop a novel regenerative therapy for the management of corneal endothelial diseases.
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http://dx.doi.org/10.1186/s13287-020-02046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716425PMC
December 2020

Translational and Regulatory Challenges of Corneal Endothelial Cell Therapy: A Global Perspective.

Tissue Eng Part B Rev 2021 Jan 11. Epub 2021 Jan 11.

Singapore Eye Research Institute, Singapore, Singapore.

Cell therapies are emerging as a unique class of clinical therapeutics in medicine. In 2015, Holoclar ( expanded autologous human corneal epithelial cells containing stem cells) gained the regulatory approval for treating limbal stem cell deficiency after chemical eye burn. This has set a precedent in ophthalmology and in medicine, reinforcing the therapeutic promise of cell therapy. However, to generalize and commercialize cell therapies on a global scale, stringent translational and regulatory requirements need to be fulfilled at both local and international levels. Over the past decade, the Singapore group has taken significant steps in developing human corneal endothelial cell (HCEnC) therapy for treating corneal endothelial diseases, which are currently the leading indication for corneal transplantation in many countries. Successful development of HCEnC therapy may serve as a novel solution to the current global shortage of donor corneas. Based on the experience in Singapore, this review aims to provide a global perspective on the translational and regulatory challenges for bench-to-bedside translation of cell therapy. Specifically, we discussed about the characterization of the critical quality attributes (CQA), the challenges that can affect the CQA, and the variations in the regulatory framework embedded within different regions, including Singapore, Europe, and the United States. Impact statement Functional corneal endothelium is critical to normal vision. Corneal endothelial disease-secondary to trauma, surgery, or pathology-represents an important cause of visual impairment and blindness in both developed and developing countries. Currently, corneal transplantation serves as the current gold standard for treating visually significant corneal endothelial diseases, although limited by the shortage of donor corneas. Over the past decade, human corneal endothelial cell therapy has emerged as a promising treatment option for treating corneal endothelial diseases. To allow widespread application of this therapy, significant regulatory challenges will need to be systematically overcome.
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http://dx.doi.org/10.1089/ten.TEB.2020.0319DOI Listing
January 2021

Lamellar Keratoplasty for Advanced Keratoconus.

Asia Pac J Ophthalmol (Phila) 2020 Dec;9(6):580-588

Singapore National Eye Centre, Singapore.

Ectatic corneal diseases are a group of disorders resulting in progressive corneal steepening and thinning. Keratoconus, keratoglobus, pellucid marginal degeneration, post-keratorefractive ectasia, and corneal graft ectasia are the types of corneal ectasia. Early diagnosis with appropriate diagnostic tools can help prevent progression, eliminating the need for corneal transplantation. Lamellar or full thickness corneal transplantation are the treatment options for advanced diseases. Although the visual outcomes of penetrating keratoplasty are comparable to anterior lamellar keratoplasty (ALK) especially in keratoconus, ALK is the preferred treatment of choice considering benefits including reduced graft rejection, less long-term complications, and better graft survival. This article reviews the various surgical techniques in ALK with its clinical outcomes in advanced keratoconus.
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http://dx.doi.org/10.1097/APO.0000000000000338DOI Listing
December 2020

Biomimetic vs. Direct Approach to Deposit Hydroxyapatite on the Surface of Low Melting Point Polymers for Tissue Engineering.

Nanomaterials (Basel) 2020 Oct 29;10(11). Epub 2020 Oct 29.

Tissue Engineering and Cell Therapy, Singapore Eye Research Institute, Singapore 169856, Singapore.

Polymers are widely used in many applications in the field of biomedical engineering. Among eclectic selections of polymers, those with low melting temperature (T < 200 °C), such as poly(methyl methacrylate), poly(lactic-co-glycolic acid), or polyethylene, are often used in bone, dental, maxillofacial, and corneal tissue engineering as substrates or scaffolds. These polymers, however, are bioinert, have a lack of reactive surface functional groups, and have poor wettability, affecting their ability to promote cellular functions and biointegration with the surrounding tissue. Improving the biointegration can be achieved by depositing hydroxyapatite (HAp) on the polymeric substrates. Conventional thermal spray and vapor phase coating, including the Food and Drug Administration (FDA)-approved plasma spray technique, is not suitable for application on the low T polymers due to the high processing temperature, reaching more than 1000 °C. Two non-thermal HAp coating approaches have been described in the literature, namely, the biomimetic deposition and direct nanoparticle immobilization techniques. In the current review, we elaborate on the unique features of each technique, followed by discussing the advantages and disadvantages of each technique to help readers decide on which method is more suitable for their intended applications. Finally, the future perspectives of the non-thermal HAp coating are given in the conclusion.
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http://dx.doi.org/10.3390/nano10112162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693928PMC
October 2020

Nanotechnology for the Treatment of Allergic Conjunctival Diseases.

Pharmaceuticals (Basel) 2020 Oct 29;13(11). Epub 2020 Oct 29.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore.

Allergic conjunctivitis is one of the most common external eye diseases and the prevalence has been increasing. The mainstay of treatment is topical eye drops. However, low bioavailability, low ocular drug penetration, transient resident time on the ocular surface due to tear turnover, frequent topical applications and dependence on patient compliance, are the main drawbacks associated with topical administration. Nanotechnology-based medicine has emerged to circumvent these limitations, by encapsulating the drugs and preventing them from degradation and therefore providing sustained and controlled release. Using a nanotechnology-based approach to load the drug is particularly useful for the delivery of hydrophobic drugs such as immunomodulatory agents, which are commonly used in allergic conjunctival diseases. In this review, different nanotechnology-based drug delivery systems, including nanoemulsions, liposomes, nanomicelles, nanosuspension, polymeric and lipid nanoparticles, and their potential ophthalmic applications, as well as advantages and disadvantages, are discussed. We also summarize the results of present studies on the loading of immunomodulators or nonsteroidal anti-inflammatory drugs to nano-scaled drug delivery systems. For future potential clinical use, research should focus on the optimization of drug delivery designs that provide adequate and effective doses with safe and satisfactory pharmacokinetic and pharmaco-toxic profiles.
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http://dx.doi.org/10.3390/ph13110351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694068PMC
October 2020

Endothelial keratoplasty with anterior chamber intraocular lens versus secondary posterior chamber intraocular lens.

Br J Ophthalmol 2020 Oct 28. Epub 2020 Oct 28.

Singapore National Eye Centre, Singapore.

Aim: To describe the long-term outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) with an anterior chamber intraocular lens (ACIOL) compared to secondary posterior chamber (PC) IOL.

Methods: This was a retrospective comparative cohort study. The clinical data of 82 eyes from 82 consecutive patients with pseudophakic (PBK) or aphakic bullous keratopathy (ABK) who either underwent DSAEK with retained or secondary ACIOL (n=23) or DSAEK with IOL exchange and/or secondary PCIOL (retropupillary iris-claw IOL, n=25; intrascleral-fixated IOL, n=29; or sulcus IOL, n=5) were analysed. The main outcome measures were graft survival and complications up to 5 years.

Results: The graft survival in the secondary PCIOL group was superior than the ACIOL group over 5 years (year 1, 100.0% vs 100.0%; year 3, 94.7% vs 75.0%; year 5, 91.1% vs 60.6%, p=0.022). The presence of an ACIOL was a significant risk factor associated with graft failure (HR, 4.801; 95% CI, 1.406 to 16.396, p=0.012) compared to a secondary PCIOL. There was no significant difference in the rate of graft detachment and elevated intraocular pressure between the groups. There were five cases (9.3%) of IOL subluxation or dislocation in the retropupillary iris-claw and intrascleral-fixated IOL groups.

Conclusions: Eyes that underwent DSAEK with ACIOL in situ had poorer long-term graft survival compared with those with secondary PCIOL. Intraocular lens exchange was not associated with a higher complication rate. In ABK or PBK eyes with ACIOL, we recommend performing IOL exchange and/or secondary PCIOL implantation combined with endothelial keratoplasty.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316711DOI Listing
October 2020

Nrf2: A unifying transcription factor in the pathogenesis of Fuchs' endothelial corneal dystrophy.

Redox Biol 2020 10 16;37:101763. Epub 2020 Oct 16.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore; Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore. Electronic address:

Nuclear factor, erythroid 2 like 2 (Nrf2), is an oxidative stress induced transcription factor that regulates cytoprotective gene expression. Thus, Nrf2 is essential for cellular redox homeostasis. Loss or dysregulation of Nrf2 expression has been implicated in the pathogenesis of degenerative diseases, including diseases of the cornea. One of the most common diseases of the cornea in which Nrf2 is implicated is Fuchs' endothelial cornea dystrophy (FECD). FECD is the leading indication for corneal transplantation; and is associated with a loss of corneal endothelial cell (CEC) function. In this review, we propose that Nrf2 is an essential regulator of CEC function. Furthermore, we demonstrate that deficiency of Nrf2 function is a hallmark of FECD. In addition, we advocate that pharmacological targeting of Nrf2 as a possible therapy for FECD.
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http://dx.doi.org/10.1016/j.redox.2020.101763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578533PMC
October 2020

Corneal transplantation after failed grafts: Options and outcomes.

Surv Ophthalmol 2021 Jan - Feb;66(1):20-40. Epub 2020 Oct 14.

Cornea, Cataract and Refractive Surgery Unit, Vissum (Miranza Group), Alicante, Spain; Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain.

Corneal transplantation is the most commonly performed human tissue transplantation procedure worldwide. Because of the large number of transplants, corneal graft failure has become one of the most common indications for corneal transplantation. The relatively recently developed lamellar transplant techniques have brought about specific potential complications leading to graft failure that may require different approaches to repeat transplantation other than penetrating keratoplasty. On the other hand, these new lamellar techniques also provide novel ways of rescuing failed penetrating grafts, with potential advantages over successive penetrating keratoplasties, such as reduced intraoperative risks and faster visual rehabilitation. We summarize the incidence and risk factors of graft failure for penetrating and lamellar (stromal and endothelial) corneal transplants and discuss the various surgical alternatives currently available to rescue such failed grafts, with a focus on the reported outcomes and limitations.
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http://dx.doi.org/10.1016/j.survophthal.2020.10.003DOI Listing
October 2020

Analysis of corneal nerve plexus in corneal confocal microscopy images.

Neural Regen Res 2021 Apr;16(4):690-691

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute; Department of Cornea and External Eye Disease, Singapore National Eye Centre; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore.

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http://dx.doi.org/10.4103/1673-5374.289435DOI Listing
April 2021

Cross-sectional Study on Corneal Denervation in Contralateral Eyes Following SMILE Versus LASIK.

J Refract Surg 2020 Oct;36(10):653-660

Purpose: To compare long-term corneal nerve status following small incision lenticule extraction (SMILE) versus laser in situ keratomileusis (LASIK).

Methods: Twenty-four patients were randomized to receive SMILE in one eye and LASIK in the other eye. In vivo confocal microscopy examination and dry eye assessments were performed at a mean of 4.1 years postoperatively. The patients were further divided into two groups based on the mean assessment time: 2.7 years postoperatively (2.7 years group) and 5.5 years postoperatively (5.5 years group). Another 6 age-matched normal patients were recruited.

Results: At 4.1 years, LASIK eyes had significantly less corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and corneal total branch density and significantly more nerves with beading than SMILE eyes. The CNFD, CNBD, CNFL, and number of nerves with sprouting were significantly higher in the 5.5 years group than in the 2.7 years group, in both types of surgery, suggesting persistent nerve regeneration. The CNBD and CNFD in the 5.5 years group, regardless of surgical types, were significantly lower than those in the control group, indicating the nerve status had not recovered to normal ranges even at 5.5 years. High myopic treatment resulted in significantly reduced CNFD with LASIK but not with SMILE. There were no significant differences in the dry eye parameters between the two procedures at 4.1 years postoperatively.

Conclusions: The impact on corneal nerves following refractive surgery is long-lasting. SMILE had better nerve preservation and regeneration than LASIK, but neither procedure had recovered nerve status to normal levels even at 5.5 years. [J Refract Surg. 2020;36(10):653-660.].
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http://dx.doi.org/10.3928/1081597X-20200730-01DOI Listing
October 2020

Corneal endothelial dysfunction: Evolving understanding and treatment options.

Prog Retin Eye Res 2020 Sep 22:100904. Epub 2020 Sep 22.

Price Vision Group, 9002 N. Meridian St., Suite 100, Indianapolis, IN, USA.

The cornea is exquisitely designed to protect the eye while transmitting and focusing incoming light. Precise control of corneal hydration by the endothelial cell layer that lines the inner surface of the cornea is required for optimal transparency, and endothelial dysfunction or damage can result in corneal edema and visual impairment. Advances in corneal transplantation now allow selective replacement of dysfunctional corneal endothelium, providing rapid visual rehabilitation. A series of technique improvements have minimized complications and various adaptations allow use even in eyes with complicated anatomy. While selective endothelial keratoplasty sets a very high standard for safety and efficacy, a shortage of donor corneas in many parts of the world restricts access, prompting a search for alternatives. Clinical trials are underway to evaluate the potential for self-recovery after removal of dysfunctional central endothelium in patients with healthy peripheral endothelium. Various approaches to using cultured human corneal endothelial cells are also in clinical trials; these aim to multiply cells from a single donor cornea for use in potentially hundreds of patients. Pre-clinical studies are underway with induced pluripotent stem cells, endothelial stem cell regeneration, gene therapy, anti-sense oligonucleotides, and various biologic/pharmacologic approaches designed to treat, prevent, or retard corneal endothelial dysfunction. The availability of more therapeutic options will hopefully expand access around the world while also allowing treatment to be more precisely tailored to each individual patient.
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http://dx.doi.org/10.1016/j.preteyeres.2020.100904DOI Listing
September 2020

Conjunctival sparing femtosecond laser-assisted conjunctival autografts for double-headed pterygium surgery.

Clin Exp Ophthalmol 2020 Nov 29;48(8):1115-1118. Epub 2020 Sep 29.

Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore.

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http://dx.doi.org/10.1111/ceo.13860DOI Listing
November 2020

Tissue Responses and Wound Healing following Laser Scleral Microporation for Presbyopia Therapy.

Transl Vis Sci Technol 2020 03 9;9(4). Epub 2020 Mar 9.

Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore.

Purpose: To investigate the postoperative inflammatory and wound-healing responses after laser scleral microporation for presbyopia.

Methods: Thirty porcine eyes were used for the optimization of laser intensities first. Six monkeys (12 eyes) received scleral microporation with an erbium yttrium aluminum garnet (Er:YAG) laser, and half of the eyes received concurrent subconjunctival collagen gel to modulate wound-healing response. The intraocular pressure (IOP) and the laser ablation depth were evaluated. The animals were euthanized at 1, 6, and 9 months postoperatively. The limbal areas and scleras were harvested for histologic analysis and immunofluorescence of markers for inflammation (CD11b and CD45), wound healing (CD90, tenascin-C, fibronectin, and HSP47), wound contraction (α-smooth muscle actin [α-SMA]), vascular response (CD31), nerve injury (GAP43), and limbal stem cells (P63 and telomerase).

Results: In the nonhuman primate study, there was a significant reduction in IOP after the procedure. Overall, the ablation depth was 76.6% to 81.2% at 1 month and slightly decreased to 71.5% to 72.7% at 9 months. Coagulative necrosis around the micropores, as well as expression of CD11b, CD45, tenascin, fibronectin, HSP47, and GAP43, was distinct at 1 month but subsided with time. Collagen gel treatment significantly suppressed the upregulation of CD11b, CD45, fibronectin, and tenascin-C. The expression of CD90, α-SMA, and CD31 was minimal in all eyes.

Conclusions: The study demonstrated the course of inflammatory and wound-healing responses following laser scleral microporation. The tissue responses were small and self-limited, resolved with time, and were suppressed by concurrent collagen treatment. It provides a useful understanding of this new procedure.

Translational Relevance: The results would be helpful in the laser parameter modification to improve the long-term treatment stability.
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http://dx.doi.org/10.1167/tvst.9.4.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396200PMC
March 2020

Proposal and validation of a new grading system for pterygium (SLIT2).

Br J Ophthalmol 2020 Aug 11. Epub 2020 Aug 11.

Singapore Eye Research Institute, Singapore, Singapore

Background/aims: To propose and validate a new pterygium grading system based on slit-lamp evaluation.

Methods: This prospective cross-sectional study included 217 patients with pterygium. All patients underwent slit-lamp examination, and slit-lamp photographs were independently graded by two graders twice. A total of eight parameters were evaluated and all parameters were assigned with a score of 1-4 (normal-severe). Intra-rater and inter-rater reliability as determined by weighted Cohen's kappa analysis.

Results: A total of 868 independent assessment, based on 217 slit-lamp images, were performed by two graders. For conjunctival assessment, the intra-rater reliability was excellent for body thickness (κ=0.81-0.89) and size at limbus (κ=0.87-0.92), substantial-to-excellent for body vascularity (κ=0.72-0.86), and moderate-to-excellent for body length (κ=0.57-0.81), whereas the inter-rater reliability was excellent for size at limbus (κ=0.86), substantial for body thickness (κ=0.72-0.73) and body vascularity (κ=0.66-0.75), and moderate for body length (κ=0.54-0.57). For corneal assessment, the intra-rater reliability was excellent for all four parameters (κ=0.84-0.90) whereas the inter-rater reliability was excellent for head length (κ=0.86-0.87), substantial-to-excellent for head vascularity (κ=0.78-0.82), substantial for Stocker's line (κ=0.79-0.80) and head thickness (κ=0.67-0.69). The grading system was named SLIT2, which included tocker's line, ize at limbus, ength of head/body, njection/vascularity of body/head, and hickness of body/head.

Conclusion: The proposed SLIT2 grading system, consisting of eight components, may serve as a reliable tool to standardise the reporting of pterygium severity and disease recurrence for clinical and research applications.
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http://dx.doi.org/10.1136/bjophthalmol-2020-315831DOI Listing
August 2020

Objective Imaging Diagnostics for Dry Eye Disease.

J Ophthalmol 2020 22;2020:3509064. Epub 2020 Jul 22.

Singapore National Eye Centre, Singapore.

Traditional diagnostic tests for dry eye disease (DED), such as fluorescein tear film break-up time and the Schirmer test, are often associated with poor reproducibility and reliability, which make the diagnosis, follow-up, and management of the disease challenging. Advances in ocular imaging technology enables objective and reproducible measurement of changes in the ocular surface, tear film, and optical quality associated with DED. In this review, the authors will discuss the application of various imaging techniques, such as, noninvasive tear break-up time, anterior segment optical coherence tomography, in vivo confocal microscopy, meibography, interferometry, aberrometry, thermometry, and tear film imager in DED. Many studies have shown these devices to correlate with clinical symptoms and signs of DED, suggesting the potential of these imaging modalities as alternative tests for diagnosis and monitoring of the condition.
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http://dx.doi.org/10.1155/2020/3509064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396031PMC
July 2020

Reply.

Ophthalmology 2020 11 29;127(11):e100. Epub 2020 Jul 29.

Singapore National Eye Centre, Singapore; Singapore Eye Research Institute, The Academia, Singapore; Department of Ophthalmology and Visual Science, Duke-NUS Graduate Medical School, Singapore.

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http://dx.doi.org/10.1016/j.ophtha.2020.06.033DOI Listing
November 2020

Automated Clinical Assessment of Corneal Guttae in Fuchs Endothelial Corneal Dystrophy.

Am J Ophthalmol 2021 01 28;221:260-272. Epub 2020 Jul 28.

Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore; Singapore National Eye Centre, Singapore; Ophthalmology Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore; Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Purpose: To describe the validation and implementation of an automated system for the detection and quantification of guttae in Fuchs endothelial corneal dystrophy (FECD).

Design: Observational reliability study.

Methods: Patients with FECD underwent retroillumination corneal photography, followed by determination of the distributions and sizes of corneal guttae by an automated image analysis algorithm. Performance of the automated system was assessed via (1) validation against manual guttae segmentation, (2) reproducibility studies to ensure consistency, and (3) evaluation for agreement with the Krachmer scale. It was then deployed to perform large-scale guttae assessment with anatomic subregion analysis in a batch of 40 eyes.

Results: Compared to manual segmentation, the automated system was reasonably accurate in identifying the correct number of guttae (mean count of 78 guttae per 1 × 1 mm test frame, overestimation: +10 per frame), but had a tendency to significantly overestimate guttae size (mean guttae size 1073 μm, overestimation: +255 μm). Automated measurements of guttae counts and sizes were reproducible within a 1% discrepancy range across repeat intra-eye assessments. Automated guttae counts, interguttae distances, and density of interguttae gaps lesser than 40 μm (ie, D40 density) were highly correlated with the Krachmer scale (P < .001 for all). Large-scale guttae assessment demonstrated the automated system's potential to selectively identify a region of the corneal endothelium most affected by densely packed guttae.

Conclusions: Automated guttae assessment facilitates the precise identification and quantification of guttae characteristics in FECD patients. This can be used clinically as a personalized descemetorrhexis zone for Descemet stripping only and/or Descemet membrane transplantation.
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http://dx.doi.org/10.1016/j.ajo.2020.07.029DOI Listing
January 2021

Evolution of therapies for the corneal endothelium: past, present and future approaches.

Br J Ophthalmol 2020 Jul 24. Epub 2020 Jul 24.

Corneal and External Diseases Department, Singapore National Eye Centre, Singapore, Singapore

Corneal endothelial diseases are leading indications for corneal transplantations. With significant advancement in medical science and surgical techniques, corneal transplant surgeries are now increasingly effective at restoring vision in patients with corneal diseases. In the last 15 years, the introduction of endothelial keratoplasty (EK) procedures, where diseased corneal endothelium (CE) are selectively replaced, has significantly transformed the field of corneal transplantation. Compared to traditional penetrating keratoplasty, EK procedures, namely Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), offer faster visual recovery, lower immunological rejection rates, and improved graft survival. Although these modern techniques can achieve high success, there are fundamental impediments to conventional transplantations. A lack of suitable donor corneas worldwide restricts the number of transplants that can be performed. Other barriers include the need for specialized expertise, high cost, and risks of graft rejection or failure. Research is underway to develop alternative treatments for corneal endothelial diseases, which are less dependent on the availability of allogeneic tissues - regenerative medicine and cell-based therapies. In this review, an overview of past and present transplantation procedures used to treat corneal endothelial diseases are described. Potential novel therapies that may be translated into clinical practice will also be presented.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316149DOI Listing
July 2020