Publications by authors named "Sophie X Deng"

92 Publications

Human limbal epithelial stem cell regulation, bioengineering and function.

Prog Retin Eye Res 2021 Mar 4:100956. Epub 2021 Mar 4.

Cornea Division, Stein Eye Institute, University of California, Los Angeles, CA, 90095, USA. Electronic address:

The corneal epithelium is continuously renewed by limbal stem/progenitor cells (LSCs), a cell population harbored in a highly regulated niche located at the limbus. Dysfunction and/or loss of LSCs and their niche cause limbal stem cell deficiency (LSCD), a disease that is marked by invasion of conjunctival epithelium into the cornea and results in failure of epithelial wound healing. Corneal opacity, pain, loss of vision, and blindness are the consequences of LSCD. Successful treatment of LSCD depends on accurate diagnosis and staging of the disease and requires restoration of functional LSCs and their niche. This review highlights the major advances in the identification of potential LSC biomarkers and components of the LSC niche, understanding of LSC regulation, methods and regulatory standards in bioengineering of LSCs, and diagnosis and staging of LSCD. Overall, this review presents key points for researchers and clinicians alike to consider in deepening the understanding of LSC biology and improving LSCD therapies.
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http://dx.doi.org/10.1016/j.preteyeres.2021.100956DOI Listing
March 2021

Limbal stem cell diseases.

Exp Eye Res 2021 Apr 8;205:108437. Epub 2021 Feb 8.

Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. Electronic address:

The function of limbal stem/progenitor cells (LSCs) is critical to maintain corneal epithelial homeostasis. Many external insults and intrinsic defects can be deleterious to LSCs and their niche microenvironment, resulting in limbal stem cell dysfunction or deficiency (LSCD). Ocular comorbidities, frequent in eyes with LSCD, can exacerbate the dysfunction of residual LSCs, and limit the survival of transplanted LSCs. Clinical presentation and disease evolution vary among different etiologies of LSCD. New ocular imaging modalities and molecular markers are now available to standardize the diagnosis criteria and stage the severity of the disease. Medical therapies may be sufficient to reverse the disease if residual LSCs are present. A stepwise approach should be followed to optimize the ocular surface, eliminate the causative factors and treat comorbid conditions, before considering surgical interventions. Furthermore, surgical options are selected depending on the severity and laterality of the disease. The standardized diagnostic criteria to stage the disease is necessary to objectively evaluate and compare the efficacy of the emerging customized therapies.
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http://dx.doi.org/10.1016/j.exer.2021.108437DOI Listing
April 2021

Therapeutic Potential of Extracellular Vesicles for the Treatment of Corneal Injuries and Scars.

Transl Vis Sci Technol 2020 11 2;9(12). Epub 2020 Nov 2.

David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Infection, trauma, and chemical exposure of the ocular surface can severely damage the cornea, resulting in visually significant stromal scars. Current medical treatments are ineffective in mitigating corneal scarring, and corneal transplantation is the only therapy able to restore vision in these eyes. However, because of a severe shortage of corneal tissues, risks of blinding complications associated with corneal transplants, and a higher rate of graft failure in these eyes, an effective and deliverable alternative therapy for the prevention and treatment of corneal scarring remains a significant unmet medical need globally. In recent years, the therapeutic potential of extracellular vesicles (EVs) secreted by cells to mediate cell-cell communication has been a topic of increasing interest. EVs derived from mesenchymal stem cells, in particular human corneal stromal stem cells, have antifibrotic, anti-inflammatory, and regenerative effects in injured corneas. The exact mechanism of action of these functional EVs are largely unknown. Therapeutic development of EVs is at an early stage and warrants further preclinical studies.
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http://dx.doi.org/10.1167/tvst.9.12.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645240PMC
November 2020

Sutured Custom Foldable Silicone Artificial Iris Implantation Combined With Intraocular Lens Implantation and Penetrating Keratoplasty: Safety and Efficacy Outcomes.

Cornea 2020 Oct 21. Epub 2020 Oct 21.

Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA.

Purpose: To assess safety and efficacy outcomes of sutured custom silicone artificial iris and intraocular lens implantation combined with penetrating keratoplasty (triple procedure).

Methods: Prospective consecutive surgical case series of patients who underwent the triple procedure between 2010 and 2019 at Stein Eye Institute, UCLA, followed up for 1 year minimum. Safety outcomes were changes from preoperative to last follow-up in corrected distance visual acuity (CDVA), endothelial cell count, intraocular pressure (IOP), and postoperative complications. Efficacy outcomes included changes in subjective glare (none to severe), cosmetic appearance (worse to very much improved), and visual function as assessed by the Visual Function Questionnaire-25 at 1-year follow-up.

Results: Among 82 eyes implanted with an artificial iris, 14 eyes (17.1%) underwent the triple procedure. The median follow-up was 18.1 months (range 12.0-54.9 months). The median CDVA improved from 2.0 log of minimum angle of resolution (logMAR) (range 0.9-2.3 logMAR) to 0.7 logMAR (range 0.2-2.6 logMAR) (P = 0.02). Average endothelial cell count decreased 57.6% (P < 0.01). Six eyes (42.9%) experienced IOP elevations, 13 eyes (92.3%) developed iritis, and 11 eyes (78.6%) underwent secondary surgery. Graft rejection or secondary graft failure occurred in 7 eyes each (50.0%). Cosmesis improved in 12 eyes (85.7%; P < 0.01). The Visual Function Questionnaire-25 score improved from 72 to 77 (P < 0.01). Glare symptoms did not change significantly.

Conclusions: The triple procedure was effective at improving CDVA, cosmesis, and quality of life; however, it was associated with frequent postoperative complications, of which iritis, IOP elevation, and secondary graft failure were the most common.
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http://dx.doi.org/10.1097/ICO.0000000000002564DOI Listing
October 2020

Expansion of Human Limbal Epithelial Stem/Progenitor Cells Using Different Human Sera: A Multivariate Statistical Analysis.

Int J Mol Sci 2020 Aug 25;21(17). Epub 2020 Aug 25.

Department of Cell Biology and Histology, School of Medicine and Nursing, Biocruces Bizkaia Health Research Institute, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain.

Transplantation of human cultured limbal epithelial stem/progenitor cells (LESCs) has demonstrated to restore the integrity and functionality of the corneal surface in about 76% of patients with limbal stem cell deficiency. However, there are different protocols for the expansion of LESCs, and many of them use xenogeneic products, being a risk for the patients' health. We compared the culture of limbal explants on the denuded amniotic membrane in the culture medium-supplemental hormone epithelial medium (SHEM)-supplemented with FBS or two differently produced human sera. Cell morphology, cell size, cell growth rate, and the expression level of differentiation and putative stem cell markers were examined. Several bioactive molecules were quantified in the human sera. In a novel approach, we performed a multivariate statistical analysis of data to investigate the culture factors, such as differently expressed molecules of human sera that specifically influence the cell phenotype. Our results showed that limbal cells cultured with human sera grew faster and contained similar amounts of small-sized cells, higher expression of the protein p63α, and lower of cytokeratin K12 than FBS cultures, thus, maintaining the stem/progenitor phenotype of LESCs. Furthermore, the multivariate analysis provided much data to better understand the obtaining of different cell phenotypes as a consequence of the use of different culture methodologies or different culture components.
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http://dx.doi.org/10.3390/ijms21176132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503296PMC
August 2020

Role of Jagged1-mediated Notch Signaling Activation in the Differentiation and Stratification of the Human Limbal Epithelium.

Cells 2020 08 22;9(9). Epub 2020 Aug 22.

Cornea Division, Stein Eye Institute, University of California, Los Angeles, CA 90095, USA.

The Notch signaling pathway plays a key role in proliferation and differentiation. We investigated the effect of Jagged 1 (Jag1)-mediated Notch signaling activation in the human limbal stem/progenitor cell (LSC) population and the stratification of the limbal epithelium in vitro. After Notch signaling activation, there was a reduction in the amount of the stem/progenitor cell population, epithelial stratification, and expression of proliferation markers. There was also an increase of the corneal epithelial differentiation. In the presence of Jag1, asymmetric divisions were decreased, and the expression pattern of the polarity protein Par3, normally present at the apical-lateral membrane of basal cells, was dispersed in the cells. We propose a mechanism in which Notch activation by Jag1 decreases p63 expression at the basal layer, which in turn reduces stratification by decreasing the number of asymmetric divisions and increases differentiation.
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http://dx.doi.org/10.3390/cells9091945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564045PMC
August 2020

Global Consensus on the Management of Limbal Stem Cell Deficiency.

Cornea 2020 Oct;39(10):1291-1302

Singapore Eye Research Institute, Singapore, Singapore.

Purpose: In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD.

Methods: An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study.

Results: A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established.

Conclusions: This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.
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http://dx.doi.org/10.1097/ICO.0000000000002358DOI Listing
October 2020

Long-Term Outcomes of Descemet Membrane Endothelial Keratoplasty in Eyes with Prior Glaucoma Surgery.

Am J Ophthalmol 2020 10 30;218:288-295. Epub 2020 Jun 30.

Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. Electronic address:

Purpose: The purpose of this study was to evaluate the long-term outcomes of Descemet membrane endothelial keratoplasty (DMEK) in eyes that had previously undergone trabeculectomy and/or drainage device implantation.

Design: Retrospective, noncomparative case series.

Methods: Medical records of 251 consecutive DMEK procedures performed by 1 surgeon (S.X.D.) from 2013 to 2017 were reviewed. Patients with ≥2 years of follow-up were divided into 3 groups: eyes with prior glaucoma surgery (ST), eyes with medically treated glaucoma (MT), and eyes without glaucoma (NG). Main outcomes measured were visual acuity, endothelial cell count (ECC), rates of secondary graft failure (SGF), and postoperative complications.

Results: Ninety procedures (87 eyes) met inclusion criteria. The mean follow-up period of all eyes was 38.4 ± 11.2 months (range, 24.2-64.4 months). At last follow-up, the proportion of eyes reaching a vision of ≥20/40 was higher than that before the DMEK procedure in each group (all P < .05). The rate of ECC loss was the highest in the ST group compared to that in the MT and NG groups (63.8% vs 47.6% vs 44.0%, respectively; P < .05) as well as the rate of SGF (41.6% vs 0% vs 2.4%, respectively; P < .05). The rate of SGF of repeat DMEK was higher than that of primary DMEK (P < .05). The rates of postoperative complications were similar among all groups (all P > .05).

Conclusions: In eyes with prior glaucoma surgery, DMEK achieved good long-term visual outcomes but experienced a higher rate of SGF than eyes without such comorbidity.
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http://dx.doi.org/10.1016/j.ajo.2020.06.022DOI Listing
October 2020

Mulitmodal Corneal Imaging of Genetically Confirmed Keratitis-Ichthyosis-Deafness Syndrome.

Cornea 2020 Nov;39(11):1446-1449

Stein Eye Institute, University of California, Los Angeles, CA.

Background: Keratitis-ichthyosis-deafness (KID) syndrome is characterized by a congenital triad of keratitis, ichthyosis, and deafness, and is most commonly associated with mutations in the gap junction protein beta 2 gene (GJB2) on chromosome 13q11-q12.

Methods: Multimodal anterior segment imaging and genetic testing were used to supplement clinical examination findings in the diagnosis and management of a 12-year-old boy with suspected KID syndrome.

Results: The patient presented with hearing loss, ichthyosis of the face and extremities, and corneal scarring and keratinization. The corneal limbal stem cell population was found to be normal on in vivo confocal microscopy, whereas the basal epithelium of the cornea demonstrated scarring and areas of cellular loss. Screening of GJB2 revealed a presumed pathogenic heterozygous missense mutation, c.148G>A, confirming the diagnosis of KID syndrome.

Conclusions: Multimodal imaging including in vivo confocal microscopy suggests that dysfunctional corneal basal epithelium maturation might contribute to the pathophysiology of keratopathy in KID syndrome.
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http://dx.doi.org/10.1097/ICO.0000000000002415DOI Listing
November 2020

Corneal Endothelial Decompensation.

Klin Monbl Augenheilkd 2020 Jun 9;237(6):745-753. Epub 2020 Jun 9.

Stein Eye Institute, UCLA, Los Angeles, California, United States.

Endothelial decompensation can occur from a variety of insults to the endothelium that result in loss of stromal clarity. Direct insults to the endothelium commonly occur in inherited, inflammatory, traumatic, immunological, and infectious etiologies. These injuries may cause transient injury without decompensation, but repetitive injury or severe isolated injury can lead to permanent non-compensatory endothelial cell loss. Elevated intraocular pressure can induce stromal hydration, either primarily or secondarily. With partial and full thickness corneal transplants, chronic endothelial dysfunction can be treated surgically when medical therapy proves inadequate. Practitioners should be aware of the underlying causes for corneal endothelial injury.
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http://dx.doi.org/10.1055/a-1128-4445DOI Listing
June 2020

A Small-Molecule Wnt Mimic Improves Human Limbal Stem Cell Ex Vivo Expansion.

iScience 2020 May 18;23(5):101075. Epub 2020 Apr 18.

Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address:

Ex vivo cultured limbal stem/progenitor cells is an effective alternative to other surgical treatments for limbal stem cell deficiency, but a standard xenobiotic-free method for culturing the LSCs in vitro needs to be optimized. Because Wnt ligands are required for LSC expansion and preservation in vitro, to create a small-molecule Wnt mimic, we created a consolidated compound by linking a Wnt inhibitor that binds to the Wnt co-receptor Frizzled to a peptide derived from the N-terminal Dickkopf-1 that binds to Lrp (low-density lipoprotein receptor-related protein) 5/6, another Wnt co-receptor. This Wnt mimic not only enhances cellular Wnt signaling activation, but also improves the progenitor cell phenotype of in vitro cultured limbal epithelial cells. As the maintenance of stem cell characteristics in the process of culture expansion is essential for the success of ocular surface reconstruction, the small molecules generated in this study may be helpful in the development of pharmaceutical reagents for treating corneal wounds.
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http://dx.doi.org/10.1016/j.isci.2020.101075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200314PMC
May 2020

Outcomes of Limbal Stem Cell Transplant: A Meta-analysis.

JAMA Ophthalmol 2020 06;138(6):660-670

David Geffen School of Medicine, Stein Eye Institute, Cornea Division, University of California, Los Angeles.

Importance: Limbal stem cell transplant (LSCT) can be categorized as direct autologous limbal transplant (AULT), direct allogenic limbal transplant (ALLT), cultivated autologous limbal stem cells transplant (cAULT), and cultivated allogenic limbal stem cells transplant (cALLT). To our knowledge, there is no study directly comparing the outcomes and complications of these procedures.

Objective: To evaluate the outcomes of different LSCT procedures.

Data Source: We searched PubMed, EMBASE, Web of Science, and Cochrane without language filter for peer-reviewed articles about LSCT. The latest search was performed on June 30, 2019.

Study Selection: Clinical studies with the outcome of at least 20 eyes after LSCT were included. Animal studies and studies of other surgical interventions were excluded.

Data Extraction And Synthesis: Two reviewers independently abstracted the data from each study. Heterogeneity was evaluated with the I2 statistic, and a meta-analysis was performed using the random-effects model.

Main Outcomes And Measures: Outcome measures included the improvement of ocular surface, visual acuity (VA), and adverse events of recipient eyes and donor eyes.

Results: Forty studies (2202 eyes) with a mean (SD) follow-up of 31.3 (20.9) months met the inclusion criteria. The mean (SD) age of study participants was 38.4 (13.1) years, and men accounted for 74%. The number of eyes that underwent AULT, ALLT, cAULT, and cALLT were 505, 742, 771, and 184, respectively. Improvement of the ocular surface was achieved in 74.5% of all eyes, 85.7% of eyes after AULT (95% CI, 79.5%-90.3%), 84.7% after cAULT (95% CI, 77.2%-90.0%), 57.8% after ALLT (95% CI, 49.0%-66.1%), and 63.2% after cALLT (95% CI, 49.3%-75.2%). Autologous limbal transplantation resulted in a greater VA improvement rate (76%) than did the other 3 procedures (cAULT: 56.4%; ALLT: 52.3%; cALLT: 43.3%; all P < .001). The most common adverse events in all recipient eyes were recurrent/persistent epithelial erosion (10.5%; 95% CI, 7.2%-23.3%) and elevated intraocular pressure (intraocular pressure, 1.7%; 95% CI, 0.5%-7.8%). Patients who underwent ALLT had the highest rate of recurrent epithelial erosion (27.8%; 95% CI, 17.1%-41.9%) and intraocular pressure elevation (6.3%; 95% CI, 1.8%-19.4%).

Conclusions And Relevance: These findings suggest LSCT can improve or stabilize the corneal surface with a low rate of severe ocular complications and that autologous LSCT may have a higher success rate and fewer complications than allogenic LSCT.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180742PMC
June 2020

Corneal Epithelial Thickness Measured Using Anterior Segment Optical Coherence Tomography as a Diagnostic Parameter for Limbal Stem Cell Deficiency.

Am J Ophthalmol 2020 08 10;216:132-139. Epub 2020 Apr 10.

Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. Electronic address:

Objective: Using anterior segment optical coherence tomography (AS-OCT), we investigated the epithelial thickness (ET) of the central cornea and limbal regions in patients with limbal stem cell deficiency (LSCD) as a diagnostic and staging parameter.

Design: Prospective, cross-sectional study.

Methods: The central corneal epithelium thickness (CET) and maximum limbal epithelium thickness (mLET) were measured in the superior, inferior, nasal, and temporal limbus on AS-OCT images of the normal and eyes with LSCD. CET was obtained by 1-point (OCT-CET1) and 3-point measurement (OCT-CET3). The values of OCT-CET1 and OCT-CET3 were compared to the CET obtained with in vivo confocal microscopy (IVCM-CET).

Results: Sixty-eight eyes of 50 patients with LSCD and 52 eyes of 34 normal subjects were included. The mean (±standard deviation) OCT-CET3 was 55.0 ± 3.0 μm (range, 50.6-62.0 μm) in the control group and 41.6 ± 10.8 μm (range, 0-56.3 μm) in the LSCD group (P < .001). OCT-CET3 had a better correlation with IVCM-CET (r = 0.91) than did OCT-CET1 (r = 0.87, P = .001). The degree of reduction in OCT-CET3 increased in more advanced clinical stages of LSCD (all P < .001). The OCT-CET3 cutoff value that suggests LSCD was 46.6 μm. Compared with the control group, the LSCD group had decreases in mLET in all 4 limbal regions (all P < .001). The sensitivity and specificity of OCT-CET3 is the highest among all mLET in detecting LSCD.

Conclusions: Both CET and mLET were thinner in patients with LSCD than in normal subjects. OCT-CET3 appears to be a reliable parameter to confirm LSCD when there is clinical suspicion.
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http://dx.doi.org/10.1016/j.ajo.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434708PMC
August 2020

Limbal Stem Cell Deficiency After Glaucoma Surgery.

Cornea 2020 May;39(5):566-572

Cornea Division, Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA.

Purpose: To characterize the clinical presentation of limbal stem cell deficiency (LSCD) associated with glaucoma surgeries.

Methods: This is a retrospective cross-sectional study of patients with LSCD and glaucoma who presented to the Stein Eye Institute at the University of California, Los Angeles, between 2009 and 2018. Patients who underwent trabeculectomy and/or aqueous shunt surgery were included. The severity of LSCD was staged using global consensus guidelines and a clinical scoring system, and basal epithelial cell density was measured by in vivo confocal microscopy. Anatomic locations of glaucoma and non-glaucoma surgeries, locations of LSCD, and severity of LSCD were compared.

Results: Fifty-one eyes of 41 patients with LSCD associated with glaucoma surgery were included in this study. LSCD in these patients uniquely featured sectoral replacement of corneal epithelium by conjunctival epithelium, without corneal neovascularization or pannus. The sites of glaucoma surgery strongly correlated with the locations of LSCD (P = 0.002). There was a trend toward increased severity of LSCD in eyes with 2 or more glaucoma surgeries as compared to eyes with 1 glaucoma surgery, although the difference did not reach statistical significance (P = 0.3). Use of topical glaucoma medications correlated with LSCD severity, while the impact of antimetabolites did not reach statistical significance. The location of glaucoma drainage surgery is correlated with the location of LSCD.

Conclusions: LSCD associated with glaucoma surgery has clinical features distinct from LSCD resulting from other etiologies. Further study is required to delineate the full impact of glaucoma surgery on limbal stem cell function and survival.
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http://dx.doi.org/10.1097/ICO.0000000000002249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018231PMC
May 2020

Evaluation of Cryopreservation Media for the Preservation of Human Corneal Stromal Stem Cells.

Tissue Eng Part C Methods 2020 01 5;26(1):37-43. Epub 2019 Dec 5.

Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California.

Human corneal stromal stem cells (CSSCs) have gained increasing attention in the treatment of corneal stromal scars. In view of this, the preparation and storage of CSSCs are critical to maintaining the regenerative potential of CSSCs. The goal of the study was to investigate the human serum (HS) concentration in the cryomedia that could best preserve CSSCs. Three different cryopreservation media, varying in HS concentration were evaluated in their ability to preserve the viability and phenotype of CSSCs: 2% HS (FS1), 4% HS (FS2), and 90% HS (FS3). After thawing, CSSCs morphology, recovery rate, cell proliferation, relative gene expression of CSSC markers (, , , , and ), and their anti-inflammatory response (level of ) were compared with those of unfrozen CSSCs (control). Cryopreserved CSSCs had similar cell morphology as the control. Cell viability was significantly higher using FS2 (92.7 ± 1.3%) compared with FS1 (88 ± 0.8%,  = 0.018). Doubling times of CSSCs were maintained in all cryopreserved conditions, as in the control ( > 0.05), which were 0.9 ± 0.1 days and 1.8 ± 0.0 days at passages 3 and 4, then increased to 18.2 ± 1.9 days at passage 6 ( > 0.05). The expression level of stem cell/progenitor cell markers investigated was not affected by the cryopreservation with any of the three media. In addition, cryopreserved CSSCs have a similar expression level of after stimulation with proinflammatory cytokines as the control ( > 0.05). Our results indicated that all three cryopreservation media maintained CSSCs phenotype after undergoing one freezing/thawing cycle. Impact Statement Corneal stromal stem cells (CSSCs) offer an alternative for the treatment of corneal stromal scars. Cryopreservation of CSSCs is necessary as it enables feasibility of using CSSCs as a cell therapy candidate. The current study shows that media used to cryopreserve CSSCs could be optimized to maintain cell viability, phenotype, and potency of CSSCs after thawing.
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http://dx.doi.org/10.1089/ten.TEC.2019.0195DOI Listing
January 2020

Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial.

Ophthalmology 2020 01 26;127(1):14-26. Epub 2019 Aug 26.

Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Electronic address:

Purpose: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy.

Design: Multicenter, randomized, double-masked, vehicle-controlled trial.

Participants: Patients with neurotrophic persistent epithelial defect with or without stromal thinning.

Methods: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat.

Main Outcome Measures: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8.

Results: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient.

Conclusions: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.
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http://dx.doi.org/10.1016/j.ophtha.2019.08.020DOI Listing
January 2020

Reply.

Cornea 2019 12;38(12):e56-e57

Department of Ophthalmology, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany.

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http://dx.doi.org/10.1097/ICO.0000000000002145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870173PMC
December 2019

Notch Inhibition Prevents Differentiation of Human Limbal Stem/Progenitor Cells in vitro.

Sci Rep 2019 07 17;9(1):10373. Epub 2019 Jul 17.

Cornea Division, Stein Eye Institute, University of California, Los Angeles, CA, 90095, USA.

Notch signaling has been shown to regulate the homeostasis and wound healing of the corneal epithelium. We investigated the effect of Notch inhibition in the human limbal stem/progenitor cells (LSCs) in vitro by using small molecules. Treatment of the LSCs with DAPT and SAHM1 reduced the proliferation rate and maintained the undifferentiated state of the LSCs in a concentration dependent manner. Stratification and differentiation of the corneal epithelium were not reduced after Notch inhibition, indicating that the function of the corneal basal cells is retained. Our findings suggest that Notch signaling plays a role in the proliferation and maintenance of LSCs.
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http://dx.doi.org/10.1038/s41598-019-46793-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637172PMC
July 2019

Differentiation Capacity of Human Mesenchymal Stem Cells into Keratocyte Lineage.

Invest Ophthalmol Vis Sci 2019 07;60(8):3013-3023

Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States.

Purpose: Mesenchymal stem cells (MSCs) have been extensively studied for their capacity to enhance wound healing and represent a promising research field for generating cell therapies for corneal scars. In the present study, we investigated MSCs from different tissues and their potential to differentiate toward corneal keratocytes.

Methods: Adipose-derived stem cells, bone marrow MSCs, umbilical cord stem cells, and corneal stromal stem cells (CSSCs) were characterized by their expression of surface markers CD105, CD90, and CD73, and their multilineage differentiation capacity into adipocytes, osteoblasts, and chondrocytes. MSCs were also evaluated for their potential to differentiate toward keratocytes, and for upregulation of the anti-inflammatory protein TNFα-stimulated gene-6 (TNFAIP6) after simulation by IFN-γ and TNF-α.

Results: Keratocyte lineage induction was achieved in all MSCs as indicated by the upregulated expression of keratocyte markers, including keratocan, lumican, and carbohydrate sulfotransferase. TNFAIP6 response to inflammatory stimulation was observed only in CSSCs; increasing by 3-fold compared with the control (P < 0.05).

Conclusions: Based on our findings, CSSCs appeared to have the greatest differentiation potential toward the keratocyte lineage and the greatest anti-inflammatory properties in vitro.
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http://dx.doi.org/10.1167/iovs.19-27008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636549PMC
July 2019

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA.

Stem Cells Transl Med 2019 11 10;8(11):1192-1201. Epub 2019 Jul 10.

Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Mesenchymal stem cells from corneal stromal stem cells (CSSC) prevent fibrotic scarring and stimulate regeneration of transparent stromal tissue after corneal wounding in mice. These effects rely on the ability of CSSC to block neutrophil infiltration into the damaged cornea. The current study investigated the hypothesis that tissue regeneration by CSSC is mediated by secreted extracellular vesicles (EVs). CSSC produced EVs 130-150 nm in diameter with surface proteins that include CD63, CD81, and CD9. EVs from CSSC reduced visual scarring in murine corneal wounds as effectively as did live cells, but EVs from human embryonic kidney (HEK)293T cells had no regenerative properties. CSSC EV treatment of wounds decreased expression of fibrotic genes Col3a1 and Acta2, blocked neutrophil infiltration, and restored normal tissue morphology. CSSC EVs labeled with carboxyfluorescein succinimidyl ester dye, rapidly fused with corneal epithelial and stromal cells in culture, transferring microRNA (miRNA) to the target cells. Knockdown of mRNA for Alix, a component of the endosomal sorting complex required for transport, using siRNA, resulted in an 85% reduction of miRNA in the secreted EVs. The EVs with reduced miRNA were ineffective at blocking corneal scarring. Furthermore, CSSC with reduced Alix expression also lost their regenerative function, suggesting EVs as an obligate component in the delivery of miRNA. The results of these studies support an essential role for extracellular vesicles in the process by which CSSC cells block scarring and initiate regeneration of transparent corneal tissue after wounding. EVs appear to serve as a delivery vehicle for miRNA, which affects the regenerative action. Stem Cells Translational Medicine 2019;8:1192-1201.
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http://dx.doi.org/10.1002/sctm.18-0297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811691PMC
November 2019

Diagnostic criteria for limbal stem cell deficiency before surgical intervention-A systematic literature review and analysis.

Surv Ophthalmol 2020 Jan - Feb;65(1):32-40. Epub 2019 Jul 2.

Stein Eye Institute, Cornea Division, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, California. Electronic address:

An accurate diagnosis of limbal stem cell deficiency (LSCD) is the premise of an appropriate treatment; however, there is no consensus about the diagnostic criteria for LSCD. We performed a systematic literature search of the peer-reviewed articles on PubMed, Medline, and Ovid to investigate how LSCD was diagnosed before surgical intervention. The methods used to diagnose LSCD included clinical presentation, impression cytology, and in vivo confocal microscopy. Among 131 eligible studies (4054 eyes), 26 studies (459 eyes, 11.3%) did not mention the diagnostic criteria. In the remaining 105 studies, the diagnosis of LSCD was made on the basis of clinical examination alone in 2398 eyes (62.9%), and additional diagnostic tests were used in 1047 (25.8%) eyes. Impression cytology was used in 981 eyes (24.2%), in vivo confocal microscopy was used in 29 eyes (0.7%), and both impression cytology and in vivo confocal microscopy were used in 37 eyes (0.9%). Our findings suggest that only a small portion of patients underwent a diagnostic test to confirm the diagnosis of LSCD. Treating physicians should be aware of the limitations of clinical examination in diagnosing LSCD and perform a diagnostic test whenever possible before surgical intervention.
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http://dx.doi.org/10.1016/j.survophthal.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911822PMC
March 2021

Comparison of Endothelial Keratoplasty Techniques in Patients With Prior Glaucoma Surgery: A Case-Matched Study.

Am J Ophthalmol 2019 10 30;206:94-101. Epub 2019 Mar 30.

Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. Electronic address:

Purpose: To compare the outcomes of Descemet membrane endothelial keratoplasty (DMEK) with those of Descemet's stripping endothelial keratoplasty (DSEK) in eyes with prior glaucoma surgery.

Design: Case-matched retrospective comparative case series.

Methods: Setting/study population: 46 DMEK procedures were matched with 46 DSEK procedures at a single institution.

Observation Procedures: cases were matched based on preoperative visual acuity, lens status, and surgical indication.

Main Outcome Measurements: the outcome measurements included visual acuity improvement, primary and secondary graft failure, endothelial rejection, intraocular pressure (IOP) elevation, and the need for additional glaucoma intervention.

Results: Best-corrected visual acuity (BCVA) improved by -0.89 logMAR in the DMEK group and -0.62 logMAR in the DSEK group (P = 0.005) at 1 year follow-up. Visual acuity was significantly better in the DMEK group at postoperative months 1, 3, and 12 and at last follow-up. The percentage of patients achieving 20/40 or better best-corrected visual acuity was higher in the DMEK group at all time points, notably 47% in the DMEK group versus 15% in the DSEK group at 1 year (P = 0.002). Secondary graft failure was lower in the DMEK group (DMEK 0% vs. DSEK 17%; P = 0.006). Primary graft failure rates and rebubling rates were similar. There were no differences in the rates of postoperative IOP elevation or in the need for additional glaucoma intervention.

Conclusions: In complex eyes with prior glaucoma surgery, DMEK offers faster visual recovery, better final visual acuity, and a lower rate of secondary graft failure compared to DSEK during the first postoperative year and beyond.
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http://dx.doi.org/10.1016/j.ajo.2019.03.020DOI Listing
October 2019

Wnt Signaling Is Required for the Maintenance of Human Limbal Stem/Progenitor Cells In Vitro.

Invest Ophthalmol Vis Sci 2019 01;60(1):107-112

Stein Eye Institute, University of California, Los Angeles, California, United States.

Purpose: A chemical approach to examine the role of Wnt signaling in maintaining the stemness and/or proliferation of limbal stem/progenitor cells (LSCs).

Methods: LSCs were isolated from human donor eyes and cultured as single cells for 12 to 14 days with the following small molecules: IIIC3, an antagonist of the Wnt signaling inhibitor Dickkopf (DKK), and IC15, a Wnt signaling inhibitor. Proliferation of LSCs in the presence of IIIC3 and IC15 was determined by the number of cells and colonies established. Maintenance of stemness was determined by p63α, cytokeratin (K)12, and K14 expression.

Results: Activation of Wnt, through IIIC3-mediated DKK inhibition, resulted in similar colony forming efficiency (CFE) as in the untreated LSCs, but significantly increased the number of cultivated cells 7.21% with 5 μM. Inhibition of Wnt with IC15 significantly reduced the CFE (P ≤ 0.01) and the number of cultivated cells by 16% to 29%. Percentage of cells expressing high levels of p63α (p63αbright) and quantity of small cells (≤12 μm), which contain the LSCs, increased 4.71% and 11.26% (both P < 0.05), respectively, with 5 μM IIIC3. All concentrations of IIIC3 and IC15 retained the K14 undifferentiated marker (97%), while differentiation, as detected by expression of K12, was found in up to 2% of cells in 1 μM IIIC3, 1 μM IC15, or 5 μM IIIC3.

Conclusions: Wnt signaling is required in LSC proliferation and maintenance of an undifferentiated state. The current study is a proof of concept that the Wnt pathway could be modulated in LSCs to enhance or decrease the efficiency of human LSC expansion.
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http://dx.doi.org/10.1167/iovs.18-25740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333110PMC
January 2019

The application of human amniotic membrane in the surgical management of limbal stem cell deficiency.

Ocul Surf 2019 04 8;17(2):221-229. Epub 2019 Jan 8.

Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, USA. Electronic address:

The application of human amniotic membrane (AM) has a wide spectrum of indications in the treatment of ocular surface disorders. Transplantation of AM has been incorporated routinely as a component of ocular surface reconstruction in a variety of ocular pathologies. The application of human AM can be combined with nearly all types of limbal transplantation in treating limbal stem cell deficiency (LSCD). AM provides support and possible protection to the transplanted limbal tissues and limbal stem cells owing to its mechanical and biological properties, and these properties are thought to enhance the success rate of LSC transplantation. This paper reviews the current literature on the applications of AM in the surgical management of LSCD and summarizes the outcome of different surgical approaches. The current literature contains mostly low-level evidences in supporting the role of AM. The efficacy of AM in LSC transplantation needs to be confirmed by randomized controlled clinical trials.
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http://dx.doi.org/10.1016/j.jtos.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529245PMC
April 2019

Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency.

Cornea 2019 Mar;38(3):364-375

Department of Ophthalmology, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Purpose: Despite extensive knowledge gained over the last 3 decades regarding limbal stem cell deficiency (LSCD), the disease is not clearly defined, and there is lack of agreement on the diagnostic criteria, staging, and classification system among treating physicians and research scientists working on this field. There is therefore an unmet need to obtain global consensus on the definition, classification, diagnosis, and staging of LSCD.

Methods: A Limbal Stem Cell Working Group was first established by The Cornea Society in 2012. The Working Group was divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to obtain agreement on a strategic plan and methodology from all participants after a comprehensive literature search, and final agreement was reached on the definition, classification, diagnosis, and staging of LSCD. A writing group was formed to draft the current manuscript, which has been extensively revised to reflect the consensus of the Working Group.

Results: A consensus was reached on the definition, classification, diagnosis, and staging of LSCD. The clinical presentation and diagnostic criteria of LSCD were clarified, and a staging system of LSCD based on clinical presentation was established.

Conclusions: This global consensus provides a comprehensive framework for the definition, classification, diagnosis, and staging of LSCD. The newly established criteria will aid in the correct diagnosis and formulation of an appropriate treatment for different stages of LSCD, which will facilitate a better understanding of the condition and help with clinical management, research, and clinical trials in this area.
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http://dx.doi.org/10.1097/ICO.0000000000001820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363877PMC
March 2019

Classification of Limbal Stem Cell Deficiency Using Clinical and Confocal Grading.

Cornea 2019 Jan;38(1):1-7

Cornea Division, Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles, CA.

Purpose: To grade the severity of limbal stem cell deficiency (LSCD) based on the extent of clinical presentation and central corneal basal epithelial cell density (BCD).

Methods: This is a retrospective observational comparative study of 48 eyes of 35 patients with LSCD and 9 eyes of 7 normal subjects (controls). Confocal images of the central cornea were acquired. A clinical scoring system was created based on the extent of limbal and corneal surface involvement. LSCD was graded as mild, moderate, and severe stages based on the clinical scores. The degree of BCD reduction was given a score of 0 to 3.

Results: Compared with BCD in controls, BCD decreased by 23.0%, 40.4%, and 69.5% in the mild, moderate, and severe stages of LSCD classified by the clinical scoring system, respectively. The degree of BCD reduction was positively correlated with larger limbal and corneal surface involvement and when the central visual axis was affected (all P ≤ 0.0005). Mean corrected distance visual acuity logarithm of the minimum angle of resolution was 0.0 ± 0.0 in control eyes, 0.2 ± 0.5 in mild LSCD, 0.6 ± 0.4 in moderate LSCD, and 1.6 ± 1.1 in severe LSCD (P < 0.0001). There was a significant correlation between a higher clinical score and corrected distance visual acuity logarithm of the minimum angle of resolution (rho = 0.82; P < 0.0001) and a greater decrease in BCD (rho = -0.78; P < 0.0001).

Conclusions: A clinical scoring system was developed to assess the extent of clinical presentation of LSCD. A classification system to grade the severity of LSCD can be established by combining the BCD score with the clinical score.
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http://dx.doi.org/10.1097/ICO.0000000000001799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279551PMC
January 2019

In Vivo Evaluation of the Limbus Using Anterior Segment Optical Coherence Tomography.

Transl Vis Sci Technol 2018 Jul 7;7(4):12. Epub 2018 Aug 7.

Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Purposes: To investigate the limbal structure using anterior segment optical coherence tomography (AS-OCT) and compare the difference between a Chinese Han population and a Caucasian population.

Methods: Sixty healthy Chinese Han subjects (109 eyes, Chinese group) and 32 healthy Caucasian subjects (51 eyes, Caucasian group) were included in this comparative cross-sectional study. The central cornea and the superior, inferior, nasal, and temporal limbal regions of each subject underwent Fourier-domain AS-OCT. The following parameters were measured: corneal epithelial thickness (CET), maximum limbal epithelial thickness (LET), the mean LET, the width of limbus, distance between scleral spur and the location where limbal epithelium was the thickest (S-T), and limbal epithelial area between scleral spur and the end of Bowman's layer (LEA).

Results: CET was similar in both groups ( = 0.577). The width of limbus was more than 32.8% greater in all limbal quadrants in the Caucasian group (range, 1.25-2.20 mm) than in the Chinese group (range, 0.81-1.40 mm). S-T and LEA were also significantly higher in all limbal quadrants in the Caucasian group (all < 0.001). The maximum LET and mean LET were 7.8% and 6.9% thicker at the nasal limbus and 8.1% and 8.7% thicker in the temporal limbus in Caucasian subjects than in Chinese subjects.

Conclusions: The limbal structures can be visualized using AS-OCT and differ significantly between the Caucasian and Chinese eyes.

Translational Relevance: Research of the limbus and surgeons performing procedures involving the limbal area should take into consideration of the anatomic differences especially when limbus is used as an anatomic reference.
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http://dx.doi.org/10.1167/tvst.7.4.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082326PMC
July 2018

A Case of Corneal Neovascularization Misdiagnosed as Total Limbal Stem Cell Deficiency.

Cornea 2018 Aug;37(8):1067-1070

Cornea Division, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA.

Purpose: To report a case of corneal neovascularization misdiagnosed as total limbal stem cell deficiency (LSCD).

Methods: This is a case report of a 61-year-old woman who has a history of bilateral idiopathic scleritis, keratitis, and uveitis for more than 20 years. She was diagnosed with total LSCD in her left eye based on clinical presentation alone and was confirmed as a candidate for limbal transplantation at several major tertiary eye care centers in the United States. After referral to the Stein Eye Institute, in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) were performed to clarify the diagnosis.

Results: Slit-lamp examination of the left eye revealed 360-degree severe thinning at the limbus and peripheral corneal pannus and neovascularization that spared the central cornea, a smooth epithelium without fluorescein staining at the central cornea, an uneven surface, and pooling of fluorescein at the peripheral cornea accompanied by minimal fluorescein staining of the sectoral peripheral epithelium. IVCM showed that epithelial cells in the central cornea exhibited a corneal phenotype and that the morphology of the epithelium in all limbal regions except the nasal limbus was normal. Epithelial cellular density and thickness were within the normal range. AS-OCT showed severe thinning in the limbus and a normal epithelial layer in the cornea and limbus. Based on the findings of IVCM and AS-OCT, we concluded that the patient had minimal LSCD, and limbal stem cell transplantation was not recommended.

Conclusions: Clinical presentation alone is insufficient to correctly diagnose LSCD in complex cases. Additional diagnostic tests, such as IVCM, are necessary to confirm the diagnosis before any surgical intervention.
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http://dx.doi.org/10.1097/ICO.0000000000001631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037563PMC
August 2018

Optical System Design for Noncontact, Normal Incidence, THz Imaging of Human Cornea.

IEEE Trans Terahertz Sci Technol 2018 Jan 22;8(1):1-12. Epub 2017 Nov 22.

UCLA Dept. of Electrical Engineering, Los Angeles, CA 90095.

Reflection mode Terahertz (THz) imaging of corneal tissue water content (CTWC) is a proposed method for early, accurate detection and study of corneal diseases. Despite promising results from and cornea studies, interpretation of the reflectivity data is confounded by the contact between corneal tissue and dielectric windows used to flatten the imaging field. Herein, we present an optical design for non-contact THz imaging of cornea. A beam scanning methodology performs angular, normal incidence sweeps of a focused beam over the corneal surface while keeping the source, detector, and patient stationary. A quasioptical analysis method is developed to analyze the theoretical resolution and imaging field intensity profile. These results are compared to the electric field distribution computed with a physical optics analysis code. Imaging experiments validate the optical theories behind the design and suggest that quasioptical methods are sufficient for designing of THz corneal imaging systems. Successful imaging operations support the feasibility of non-contact imaging. We believe that this optical system design will enable the first, clinically relevant, exploration of CTWC using THz technology.
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http://dx.doi.org/10.1109/TTHZ.2017.2771754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808441PMC
January 2018