Publications by authors named "Reza Dana"

319 Publications

Growth factor-eluting hydrogels for management of corneal defects.

Mater Sci Eng C Mater Biol Appl 2021 Jan 10;120:111790. Epub 2020 Dec 10.

Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, United States. Electronic address:

With 1.5-2.0 million new cases annually worldwide, corneal injury represents a common cause of vision loss, often from irreversible scarring due to surface corneal defects. In this study, we assessed the use of hepatocyte growth factor (HGF) loaded into an in situ photopolymerizable transparent gelatin-based hydrogel for the management of corneal defects. In vitro release kinetics showed that, in regard to the total amount of HGF released over a month, 55 ± 11% was released during the first 24 h, followed by a slow release profile for up to one month. The effect of HGF was assessed using an ex vivo model of pig corneal defect. After three days of organ culture, epithelial defects were found to be completely healed for 89% of the corneas treated with HGF, compared to only 11% of the corneas that had fully re-epithelialized when treated with the hydrogel without HGF. The thickness of the epithelial layer was found to be significantly higher for the HGF-treated group compared to the group treated with hydrogel without HGF (p = 0.0012). Finally, histological and immunostaining assessments demonstrated a better stratification and adhesion of the epithelial layer in the presence of HGF. These results suggest that the HGF-loaded hydrogel system represents a promising solution for the treatment of persistent corneal defects at risk of scarring.
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http://dx.doi.org/10.1016/j.msec.2020.111790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867677PMC
January 2021

Corneal angiogenic privilege and its failure.

Exp Eye Res 2021 Jan 22;204:108457. Epub 2021 Jan 22.

Ophthalmology Operative Complex Unit, University Campus Bio-Medico, Rome, Italy.

The cornea actively maintains its own avascular status to preserve its ultimate optical function. This corneal avascular state is also defined as "corneal angiogenic privilege", which results from a critical and sensitive balance between anti-angiogenic and pro-angiogenic mechanisms. In our review, we aim to explore the complex equilibrium among multiple mediators which prevents neovascularization in the resting cornea, as well as to unveil the evolutive process which leads to corneal angiogenesis in response to different injuries.
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http://dx.doi.org/10.1016/j.exer.2021.108457DOI Listing
January 2021

Pigment Epithelium-Derived Factor Enhances the Suppressive Phenotype of Regulatory T Cells in a Murine Model of Dry Eye Disease.

Am J Pathol 2021 Jan 14. Epub 2021 Jan 14.

Laboratory of Corneal Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address:

Pigment epithelium-derived factor (PEDF) is a widely expressed 50-kDa glycoprotein belonging to the serine protease inhibitor family, with well-established anti-inflammatory functions. Recently, we demonstrated the immunoregulatory role played by PEDF in dry eye disease (DED) by suppressing the maturation of antigen-presenting cells at the ocular surface following exposure to the desiccating stress. In this study, we evaluated the effect of PEDF on the immunosuppressive characteristics of regulatory T cells (Tregs), which are functionally impaired in DED. In the presence of PEDF, the in vitro cultures prevented proinflammatory cytokine (associated with type 17 helper T cells)-induced loss of frequency and suppressive phenotype of Tregs derived from normal mice. Similarly, PEDF maintained the in vitro frequency and enhanced the suppressive phenotype of Tregs derived from DED mice. On systemically treating DED mice with PEDF, moderately higher frequencies and significantly enhanced suppressive function of Tregs were observed in the draining lymphoid tissues, leading to the efficacious amelioration of the disease. Our results demonstrate that PEDF promotes the suppressive capability of Tregs and attenuates their type 17 helper T-cell-mediated dysfunction in DED, thereby playing a role in the suppression of DED.
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http://dx.doi.org/10.1016/j.ajpath.2021.01.003DOI Listing
January 2021

Heterogeneity of eye drop use among symptomatic dry eye individuals in Japan: large-scale crowdsourced research using DryEyeRhythm application.

Jpn J Ophthalmol 2021 Jan 7. Epub 2021 Jan 7.

Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Purpose: To determine eye drop type and usage frequency and investigate risk factors for no eye drop use in individuals with symptomatic dry eye (DE) in Japan.

Study Design: Crowdsourced observational study.

Methods: This study was conducted using the DryEyeRhythm smartphone application between November 2016 and September 2019. Data collected included the type and frequency of eye drop use, demographics, medical history, lifestyle, and self-reported symptoms. Symptomatic DE was defined as an Ocular Surface Disease Index total score of ≥ 13. Risk factors for no eye drop use were identified using multivariate logistic regression analyses.

Results: Among 2619 individuals with symptomatic DE, 1876 did not use eye drops. The most common eye drop type was artificial tears (53.4%), followed by hyaluronic acid 0.1% (33.1%) and diquafosol sodium 3% (18.7%). Risk factors (odds ratio [95% confidence interval]) for no eye drop use were age (0.97 [0.97-0.98]), body mass index (1.04 [1.01-1.07]), brain disease (0.38 [0.15-0.98]), collagen disease (0.30 [0.13-0.68]), mental illness other than depression and schizophrenia (0.65 [0.45-0.93]), cataract surgery (0.12 [0.02-0.59]), ophthalmic surgery other than cataract and laser-assisted in situ keratomileusis (0.55 [0.34-0.88]), current (0.47 [0.38-0.57]) or past (0.58 [0.43-0.77]) contact lens use, >8 h screen exposure time (1.38 [1.05-1.81]), <6 h (1.24 [1.01-1.52]) and >9 h (1.34 [1.04-1.72]) sleep time, and water intake (0.97 [0.94-0.98]).

Conclusion: Many participants with symptomatic DE did not use optimized eye drop treatment and identified risk factors for no eye drop use. The DryEyeRhythm application may help improve DE treatment.
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http://dx.doi.org/10.1007/s10384-020-00798-1DOI Listing
January 2021

Defining Dry Eye from a Clinical Perspective.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Cornea & Refractive Surgery, Massachusetts Eye & Ear, Boston, MA 02114, USA.

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.
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http://dx.doi.org/10.3390/ijms21239271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730816PMC
December 2020

Regulatory T Cells in Angiogenesis.

J Immunol 2020 Nov;205(10):2557-2565

Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114;

Regulatory T cells (Tregs) are crucial mediators of immune homeostasis. They regulate immune response by suppressing inflammation and promoting self-tolerance. In addition to their immunoregulatory role, a growing body of evidence highlights the dynamic role of Tregs in angiogenesis, the process of forming new blood vessels. Although angiogenesis is critically important for normal tissue regeneration, it is also a hallmark of pathological processes, including malignancy and chronic inflammation. Interestingly, the role of Tregs in angiogenesis has been shown to be highly tissue- and context-specific and as a result can yield either pro- or antiangiogenic effects. For these reasons, there is considerable interest in determining the molecular underpinnings of Treg-mediated modulation of angiogenesis in different disease states. The present review summarizes the role of Tregs in angiogenesis and mechanisms by which Tregs regulate angiogenesis and discusses how these mechanisms differ in homeostatic and pathological settings.
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http://dx.doi.org/10.4049/jimmunol.2000574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664842PMC
November 2020

Limbal Stem Cell Deficiency Associated With Herpes Keratitis.

Cornea 2020 Oct 2. Epub 2020 Oct 2.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Purpose: To describe the demographic features and clinical characteristics of patients with herpes keratitis (HK) and limbal stem cell deficiency (LSCD) and identify possible factors associated with development of LSCD after HK.

Methods: In this retrospective case-series study, records of patients with a clinical diagnosis of HK seen at Massachusetts Eye and Ear over a 5-year period were reviewed for evidence of LSCD. Patient demographics, medical history, treatment, and best-corrected visual acuities (BCVAs) were recorded.

Results: We identified 626 patients with HK. Fifty-seven had been diagnosed with LSCD (9.3%). Thirteen percent of patients with herpes zoster keratitis (N= 25) and 7% of patients with herpes simplex keratitis (N= 32) had LSCD (P = 0.01). Keratitis caused by herpes zoster virus [odds ratios (OR), 1.77; 95% confidence interval (CI), 0.97-3.19; P = 0.01], stromal involvement (OR, 2.28; 95% CI, 1.27-4.18; P = 0.02), and the use of topical antihypertensives (OR, 2.28; 95% CI, 1.27-4.18; P = 0.02) were found to be associated with a higher likelihood of developing LSCD. The final logarithm of the minimum angle of resolution (LogMAR) BCVA was significantly lower in patients with LSCD compared with those without LSCD with a mean BCVA of 1.34 ± 1.52 LogMar (∼20/200) as compared to 0.18 ± 0.54 LogMar (∼20/30 ± 20/60) in those patients without LSCD (P = 0.005).

Conclusions: Our data suggest that HK may be a risk factor for development of LSCD. Patients with HK should be monitored for the development of LSCD to reduce the risk of chronic ocular surface morbidity.
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http://dx.doi.org/10.1097/ICO.0000000000002557DOI Listing
October 2020

Prevalence and Risk Factors Associated With Corneal Perforation in Chronic Ocular Graft-Versus-Host-Disease.

Cornea 2020 Sep 16. Epub 2020 Sep 16.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Purpose: To determine the prevalence and risk factors associated with corneal perforation in patients with chronic ocular graft-versus-host disease (oGVHD).

Methods: We reviewed the case records of 405 patients diagnosed with chronic oGVHD over 8 years at a single academic center and assessed the prevalence of corneal perforation in the cohort. We reviewed patient demographics, indication for and type of hematopoietic stem cell transplantation (HSCT), time elapsed between HSCT and perforation, and clinical characteristics including oGVHD severity scores, ocular comorbidities, and topical medications at the time of perforation. Data were analyzed to determine the characteristics of patients with corneal perforation and establish the risk factors.

Results: Of the 405 patients with chronic oGVHD, 15 (3.7%) developed a corneal perforation. The mean age of patients at the time of perforation was 64 ± 11 years and 10 (67%) were men. The median time to corneal perforation was 3.3 years post-HSCT. Although perforation occurred unilaterally in all cases, 44% had epithelial defects and 38% had stromal abnormalities in the contralateral eye. Of the patients with corneal perforation, 9 (60%) had a National Institute of Health oGVHD severity score of 2 and 6 (40%) had a score of 3. Patients with chronic oGVHD on antiglaucoma drops had a significantly higher risk of corneal perforation (P < 0.001).

Conclusions: Corneal perforation is a rare but vision-threatening complication of chronic oGVHD. Our study emphasizes the need for frequent and long-term follow-up of patients with oGVHD regardless of the severity of disease. In particular, patients with chronic oGVHD on topical antiglaucoma medications should be monitored closely due to a higher risk for corneal perforation.
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http://dx.doi.org/10.1097/ICO.0000000000002526DOI Listing
September 2020

Association of α-Melanocyte-Stimulating Hormone With Corneal Endothelial Cell Survival During Oxidative Stress and Inflammation-Induced Cell Loss in Donor Tissue.

JAMA Ophthalmol 2020 Sep 17. Epub 2020 Sep 17.

Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston.

Importance: Corneal endothelial cell (CEnC) damage and loss are major issues in eye banking and transplantation. The underlying mechanisms for CEnC loss are incompletely understood, and cytoprotective strategies that enhance CEnC viability could have a major effect on donor tissue quality and graft survival.

Objective: To investigate the cytoprotective role of neuropeptide α-melanocyte-stimulating hormone (α-MSH) in preventing CEnC loss in eye bank cold-stored corneas under oxidative and inflammatory cytokine-induced stress.

Design, Setting, And Participants: This single-center comparative research study conducted ex vivo experiments using 16 pairs of research-grade human donor corneas (courtesy of Eversight Eye Bank). Data were collected from June 2018 to November 2019, and data were analyzed from December 2019 to January 2020.

Exposures: Two corneas from the same donor were randomized to either control or 0.1 mmol/L of α-MSH treatment and then subjected to oxidative stress (1.4 mmol/L of hydrogen peroxide-phosphate-buffered saline for 15 minutes at 37 °C; n = 8 pairs) or cytokine-induced stress (100 ng/mL of tumor necrosis factor-α and 100 ng/mL of interferon γ for 18 hours at 37 °C; n = 8 pairs). Corneas were then stored at 4 °C. Specular images were taken at baseline and repeated twice per week using a calibrated wide-field specular microscope. CEnC viability was assessed using a fluorescent live/dead viability assay.

Main Outcome And Measures: Endothelial morphometry analysis, central corneal thickness measurements, and percentage of dead cells at day 11.

Results: Of 16 donors who provided corneas, 9 (56%) were male, and the mean (SD) age was 57.9 (12.4) years. Corneas were paired, and baseline parameters were comparable between all groups. At all time points, CEnC loss was lower in the α-MSH groups compared with the control groups. This difference was statistically significant after cytokine-induced stress (20.2% vs 35.2%; sample estimate of median, -14.9; 95% CI, -23.6 to -6.3; P = .008). Compared with the control group, α-MSH treatment resulted in a smaller increase in central corneal thickness (cytokine-induced stress: 89.3 μm vs 169.8 μm; sample estimate of median, -84.9; 95% CI, -131.5 to -41.6; P = .008; oxidative stress: 43.6 μm vs 111.9 μm; sample estimate of median, -68.8; 95% CI, -100.0 to -34.5; P = .008) and a smaller proportion of cell death (cytokine-induced stress: 2.7% vs 10.4%; difference, -7.7; 95% CI, -13.1 to -2.4; P = .01; oxidative stress: 2.9% vs 12.4%; difference, 9.5; 95% CI, 5.1 to 13.9; P = .006).

Conclusions And Relevance: In this study, α-MSH treatment attenuated CEnC loss during cold storage after acute oxidative and cytokine-induced stress in human eye bank cold-stored corneas. These data suggest that supplementation of corneal storage solution with α-MSH may positively affect CEnC survival after transplant and protect the endothelium from proinflammatory cytokines and oxidative stress after full-thickness or endothelial keratoplasty, which is particularly valuable in patients at high risk of graft failure.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.3413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499243PMC
September 2020

Immune checkpoint inhibitors and corneal transplant rejection: a call for awareness.

Immunotherapy 2020 Sep 25;12(13):947-949. Epub 2020 Aug 25.

Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.

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http://dx.doi.org/10.2217/imt-2020-0100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482051PMC
September 2020

Ciprofloxacin-loaded bioadhesive hydrogels for ocular applications.

Biomater Sci 2020 Sep;8(18):5196-5209

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA and Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA and Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.

The management of corneal infections often requires complex therapeutic regimens involving the prolonged and high-frequency application of antibiotics that provide many challenges to patients and impact compliance with the therapeutic regimens. In the context of severe injuries that lead to tissue defects (e.g. corneal lacerations) topical drug regimens are inadequate and suturing is often indicated. There is thus an unmet need for interventions that can provide tissue closure while concurrently preventing or treating infection. In this study, we describe the development of an antibacterial bioadhesive hydrogel loaded with micelles containing ciprofloxacin (CPX) for the management of corneal injuries at risk of infection. The in vitro release profile showed that the hydrogel system can release CPX, a broad-spectrum antibacterial drug, for up to 24 h. Moreover, the developed CPX-loaded hydrogels exhibited excellent antibacterial properties against Staphylococcus aureus and Pseudomonas aeruginosa, two bacterial strains responsible for the most ocular infections. Physical characterization, as well as adhesion and cytocompatibility tests, were performed to assess the effect of CPX loading in the developed hydrogel. Results showed that CPX loading did not affect stiffness, adhesive properties, or cytocompatibility of hydrogels. The efficiency of the antibacterial hydrogel was assessed using an ex vivo model of infectious pig corneal injury. Corneal tissues treated with the antibacterial hydrogel showed a significant decrease in bacterial colony-forming units (CFU) and a higher corneal epithelial viability after 24 h as compared to non-treated corneas and corneas treated with hydrogel without CPX. These results suggest that the developed adhesive hydrogel system presents a promising suture-free solution to seal corneal wounds while preventing infection.
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http://dx.doi.org/10.1039/d0bm00935kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594650PMC
September 2020

Efficacy of cyanoacrylate tissue adhesive in the management of corneal thinning and perforation due to microbial keratitis.

Ocul Surf 2020 10 19;18(4):795-800. Epub 2020 Aug 19.

Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Purpose: Report the efficacy of cyanoacrylate tissue adhesive (CTA) application in the management of corneal thinning and perforations associated with microbial keratitis.

Methods: A retrospective review of consecutive patients who underwent CTA application for corneal thinning and perforation secondary to microbiologically proven infectious keratitis between 2001 and 2018 at a single center. We defined successful CTA application as an intact globe without tectonic surgical intervention.

Results: The cohort included 67 patients, and 37 presented with corneal perforation while 30 had corneal thinning. The perforation/thinning was central/paracentral in 43 eyes and peripheral in 23 eyes. The underlying infectious etiologies were monomicrobial in 42 cases (35 bacterial, 3 fungal, 2 viral, and 2 acanthamoeba cases) and polymicrobial in 25 cases (22 polybacterial cases and 3 cases with a combination of Gram positive bacteria and fungus). The median duration of glue retention was 29 days. The CTA success rate was 73%, 64%, and 44% at 10, 30, and 180 days, respectively. CTA application appears more successful in monomicrobial (vs. polymicrobial) and Gram positive bacterial (vs. Gram negative) keratitis but the differences are statistically non-significant. The location of perforation/thinning and the use of topical corticosteroid were not associated with CTA failure.

Conclusion: CTA was moderately effective in restoring globe integrity in severe corneal thinning and perforation secondary to microbial keratitis in the short term. However the majority of patients require tectonic surgical intervention within 6 months. CTA application success is not significantly associated with the location of thinning/perforation or the use of topical corticosteroid.
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http://dx.doi.org/10.1016/j.jtos.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686147PMC
October 2020

Clinical and Prodromal Ocular Symptoms in Coronavirus Disease: A Systematic Review and Meta-Analysis.

Invest Ophthalmol Vis Sci 2020 08;61(10):29

Department of Ophthalmology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Purpose: This systematic review aimed to determine currently reported clinical and prodromal ocular symptoms in patients with coronavirus disease 2019 (COVID-19).

Methods: An online article search was performed in PubMed and EMBASE. Altogether 15 studies (retrospective, prospective, or case studies) involving 1533 patients with COVID-19, reporting on ocular symptoms, and with outcome data available were identified. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Study-specific estimates (incidence rates of ocular symptoms in patients with COVID-19) of cases were combined using one-group meta-analysis in a random-effects model.

Results: Of all included studies, 11.2% (95% confidence interval, 5.5-16.9; 78/1526 cases) reported ocular symptoms. The most common ocular finding was conjunctivitis. Prodromal ocular symptoms occurred in 12.5% (13/104 cases) of patients with COVID-19. Positive real-time polymerase chain reaction results were obtained for 16.7% (10/60 cases) of conjunctival samples and 0% (0/17 cases) of tear samples. Twelve ocular conjunctival swab samples tested positive for SARS-CoV-2. Ten cases were from subjects showing ocular symptoms (16.7%, 10/60 cases), and the remaining two cases were from subjects without ocular manifestation (1.8%, 2/113 cases). Limitations included the short study period, small sample size, findings were limited to the Asian population, only seven articles included ophthalmologic examination details, and there is currently no consensus on COVID-19 management.

Conclusions: Ocular symptoms may occur in the presymptomatic phase as a prodromal symptom (12.5%, 13/104 cases), suggesting the possibility of viral transmission from the conjunctiva.
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http://dx.doi.org/10.1167/iovs.61.10.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441339PMC
August 2020

Efficacy and retention of silicone punctal plugs for treatment of dry eye in patients with and without ocular graft-versus-host-disease.

Ocul Surf 2020 10 30;18(4):731-735. Epub 2020 Jul 30.

Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Purpose: To examine the retention rates and efficacy of silicone punctal plugs for the treatment of dry eye disease (DED) in patients with ocular graft-versus-host-disease (oGVHD) in comparison to dry eye disease due to non-oGVHD etiologies.

Methods: We reviewed the case-records of 864 consecutive patients with DED who were symptomatic despite topical therapy and had silicone punctal plugs placed over an eight-year- period at a single academic center. We compared plug retention rates in oGVHD and non-oGVHD DED patients using Kaplan-Meier analyses. Furthermore, we analyzed changes in objective ocular surface parameters including tear breakup time (TBUT), Schirmer's test, and corneal fluorescein staining (CFS) score in plug-retaining patients at two-, six- and twelve-month follow-up.

Results: Median age of dry eye patients was 58 years, and 606 (70%) of patients were women. In the cohort, 264 (31%) patients were diagnosed with oGVHD. Plug retention was significantly lower in oGVHD-DED patients compared to non-oGVHD-DED patients (p < 0.0001). We observed significant improvement in CFS scores in plug retaining-oGVHD and non-oGVHD DED patients at all time points. Tear break-up time was significantly prolonged at six- and twelve-months follow-up in non-oGVHD patients, whereas significant change in TBUT in oGVHD patients was recorded only at twelve months post plug placement. Schirmer's score improved significantly in plug retaining-non-oGVHD DED patients at six- and twelve-months follow-up, however no significant change was observed in Schirmer's score in oGVHD DED patients.

Conclusions: An improvement in ocular surface disease parameters was observed in both plug-retaining oGVHD and non-oGVHD DED patients. However, a majority of oGVHD DED patients spontaneously lost their punctal plugs within 90 days of placement. Therefore, regular follow-up after plug placement is recommended to detect plug loss and ensure adequate disease control.
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http://dx.doi.org/10.1016/j.jtos.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686277PMC
October 2020

Animal models of high-risk corneal transplantation: A comprehensive review.

Exp Eye Res 2020 09 25;198:108152. Epub 2020 Jul 25.

Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. Electronic address:

Over the past century, corneal transplantation has become the most commonly performed allogeneic solid tissue transplantation. Although more than 80% of the corneal transplantations have favorable outcomes, immune-mediated rejection continues to be the major cause of failure in well over 50% of graft recipients that have inflamed and vascularized host beds. Over the past two decades, the progress in our understanding of the immunological pathways that mediate graft rejection has aided in the development of novel therapeutic strategies. In order to successfully test the efficacy of these interventions, it is essential to model the immunological processes occurring as a consequence of corneal transplantation. Herein, we have comprehensively reviewed the established animal models used for replicating the immunopathological processes causing graft rejection in high-risk corneal transplantation settings. We have also discussed the practical and technical differences, as well as biological and immunological variations in different animal models.
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http://dx.doi.org/10.1016/j.exer.2020.108152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508940PMC
September 2020

Prevalence of Persistent Corneal Epithelial Defects in Chronic Ocular Graft-Versus-Host Disease.

Am J Ophthalmol 2020 10 25;218:296-303. Epub 2020 Jul 25.

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

Purpose: To establish the prevalence, clinical characteristics, and risk factors for persistent corneal epithelial defects (PED) in patients with chronic ocular graft-versus-host disease (oGVHD) and to determine visual outcomes after healing.

Design: Retrospective cohort study.

Methods: A chart review was conducted of patients in whom chronic oGVHD was diagnosed between January 2011 and December 2018 and their demographic and clinical characteristics were collected. Data were analyzed to determine prevalence of PED, and multivariate logistic regression was performed to determine the risk factors associated with it.

Results: A total of 405 patients at a mean age of 60 ± 13 years in whom chronic oGVHD was diagnosed; 58% were men. The prevalence of PED was 8.1%. The median time for PED development after hematopoietic stem cell transplantation was approximately 24 months. Median time to PED resolution was 4.5 weeks after starting therapy. The mean best-corrected visual acuity declined by 2 lines post-PED resolution. The prevalence rates of corneal ulcer and perforation were 6.2% and 4.0%, respectively, over 8 years. Logistic regression analysis, used to determine factors associated with PED, showed diabetes (P = .006), limbal stem cell deficiency (LSCD) (P = .02), filamentary keratitis (P = .02), subconjunctival fibrosis (P = .02), and a higher National Institutes of Health (NIH) oGVHD score (P = .01) were significant risk factors for PED development.

Conclusions: The study found the prevalence rate of PED, corneal ulceration, and corneal perforation in chronic oGVHD to be 8.1%, 6.2%, and 4%, respectively. Analysis showed that oGVHD patients with diabetes, LSCD, filamentary keratitis, subconjunctival fibrosis, and a high NIH score were at higher risk of developing severe corneal disease.
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http://dx.doi.org/10.1016/j.ajo.2020.05.035DOI Listing
October 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

Stratification of Individual Symptoms of Contact Lens-Associated Dry Eye Using the iPhone App DryEyeRhythm: Crowdsourced Cross-Sectional Study.

J Med Internet Res 2020 06 26;22(6):e18996. Epub 2020 Jun 26.

Department of Ophthalmology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Background: Discontinuation of contact lens use is mainly caused by contact lens-associated dry eye. It is crucial to delineate contact lens-associated dry eye's multifaceted nature to tailor treatment to each patient's individual needs for future personalized medicine.

Objective: This paper aims to quantify and stratify individual subjective symptoms of contact lens-associated dry eye and clarify its risk factors for future personalized medicine using the smartphone app DryEyeRhythm (Juntendo University).

Methods: This cross-sectional study included iPhone (Apple Inc) users in Japan who downloaded DryEyeRhythm. DryEyeRhythm was used to collect medical big data related to contact lens-associated dry eye between November 2016 and January 2018. The main outcome measure was the incidence of contact lens-associated dry eye. Univariate and multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were determined by logistic regression analyses. The t-distributed Stochastic Neighbor Embedding algorithm was used to depict the stratification of subjective symptoms of contact lens-associated dry eye.

Results: The records of 4454 individuals (median age 27.9 years, SD 12.6), including 2972 female participants (66.73%), who completed all surveys were included in this study. Among the included participants, 1844 (41.40%) were using contact lenses, and among those who used contact lenses, 1447 (78.47%) had contact lens-associated dry eye. Multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were as follows: younger age, 0.98 (95% CI 0.96-0.99); female sex, 1.53 (95% CI 1.05-2.24); hay fever, 1.38 (95% CI 1.10-1.74); mental illness other than depression or schizophrenia, 2.51 (95% CI 1.13-5.57); past diagnosis of dry eye, 2.21 (95% CI 1.63-2.99); extended screen exposure time >8 hours, 1.61 (95% CI 1.13-2.28); and smoking, 2.07 (95% CI 1.49-2.88). The t-distributed Stochastic Neighbor Embedding analysis visualized and stratified 14 groups based on the subjective symptoms of contact lens-associated dry eye.

Conclusions: This study identified and stratified individuals with contact lens-associated dry eye and its risk factors. Data on subjective symptoms of contact lens-associated dry eye could be used for prospective prevention of contact lens-associated dry eye progression.
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http://dx.doi.org/10.2196/18996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381048PMC
June 2020

Restoration of Regulatory T-Cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor.

Am J Pathol 2020 09 29;190(9):1859-1866. Epub 2020 May 29.

Schepens Eye Research Institute of Massachusetts Eye and Ear, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. Electronic address:

Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions and a critical mediator in pain transmission. Recently, the role of SP was described in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface after exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. This study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor) antagonist. Furthermore, in vivo treatment with the neurokinin-1 receptor antagonist in DED mice effectively restored Treg function, suppressed pathogenic T helper 17 response, and significantly ameliorated the disease. Our results show that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppresses DED severity.
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http://dx.doi.org/10.1016/j.ajpath.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456741PMC
September 2020

The role of Th17 immunity in chronic ocular surface disorders.

Ocul Surf 2021 Jan 26;19:157-168. Epub 2020 May 26.

Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Th17 cells have been implicated in the pathogenesis of numerous inflammatory and autoimmune conditions. At the ocular surface, Th17 cells have been identified as key effector cells in chronic ocular surface disease. Evidence from murine studies indicates that following differentiation and expansion, Th17 cells migrate from the lymphoid tissues to the eye, where they release inflammatory cytokines including, but not limited to, their hallmark cytokine IL-17A. As the acute phase subsides, a population of long-lived memory Th17 cells persist, which predispose hosts both to chronic inflammation and severe exacerbations of disease; of great interest is the small subset of Th17/1 cells that secrete both IL-17A and IFN-γ in acute-on-chronic disease exacerbation. Over the past decade, substantial progress has been made in deciphering how Th17 cells interact with the immune and neuroimmune pathways that mediate chronic ocular surface disease. Here, we review (i) the evidence for Th17 immunity in chronic ocular surface disease, (ii) regulatory mechanisms that constrain the Th17 immune response, and (iii) novel therapeutic strategies targeting Th17 cells.
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http://dx.doi.org/10.1016/j.jtos.2020.05.009DOI Listing
January 2021

Long-term Outcomes of Punctal Cauterization in the Management of Ocular Surface Diseases.

Cornea 2021 Feb;40(2):168-171

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Purpose: To evaluate the long-term outcomes of surgical occlusion of lacrimal puncta using thermal cautery in the management of ocular surface diseases.

Methods: We reviewed medical records of 80 consecutive patients from a single academic center who underwent punctal cauterization. Patient demographics, ocular history, symptoms, and signs of ocular surface diseases pre- and post-cauterization were recorded.

Results: A total of 80 patients (171 puncta) were included, with an average age of 59 years and a follow-up duration of 27 months. The most common ocular morbidity was ocular graft-versus-host disease (n = 36), followed by primary keratoconjunctivitis sicca (n = 15). Indications for punctal cauterization included plug loss (n = 51), difficulty in plug fitting (n = 11), plug-related complications (n = 6), recanalization of previous cauterization (n = 7), and severe ocular surface disease requiring permanent punctal closure (n = 4). After punctal cauterization, the percentage of eyes with severe (21%) and moderate (25%) dry eye decreased significantly (8% and 19% at 3 months and 6% and 17% at 12 months, P = 0.0006). Fifty-four percent of patients reported improvement in their symptoms. The rate of recanalization was 21% during the follow-up period. The use of topical corticosteroids was associated with higher recanalization rate. Associated complications were limited to temporary pain and swelling.

Conclusions: Punctal cauterization is an effective modality in treating severe ocular surface diseases in patients who repeatedly lose punctal plugs, and it can be easily performed in a clinic setting without major complications. However, cauterization may need to be repeated in up to a quarter of cases because of recanalization.
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http://dx.doi.org/10.1097/ICO.0000000000002384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704919PMC
February 2021

Pigment Epithelium-derived Factor secreted by corneal epithelial cells regulates dendritic cell maturation in dry eye disease.

Ocul Surf 2020 07 6;18(3):460-469. Epub 2020 May 6.

Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address:

Purpose: In this study, we quantify Pigment Epithelium-derived Factor (PEDF) secreted by corneal epithelial cells and evaluate its immunomodulatory functions in a murine model of dry eye disease (DED).

Methods: We induced DED in female C57BL/6 mice using a controlled environment chamber for 14 days. We quantified mRNA expression of Serpinf1 gene and PEDF protein synthesis by corneal epithelial cells (CEpCs) using RT-PCR and ELISA. CEpCs from normal or DED mice were cultured with IFNγ-stimulated-dendritic cells (DCs) for 24 h, and expression of MHC-II and CD86 by DCs was determined using flow cytometry. Next, we either added recombinant PEDF (rPEDF) or anti-PEDF antibody to co-culture, and DC expression of the above maturation markers was quantified. Lastly, we treated DED mice with either topical rPEDF, anti-PEDF Ab or murine serum albumin (MSA), and DC maturation, expression of pro-inflammatory cytokines, and DED severity were investigated.

Results: Serpinf1 mRNA expression and PEDF protein production levels by CEpCs were upregulated in DED. CEpCs from DED mice exhibited an enhanced suppressive effect on the expression of MHC-II and CD86 by DCs, compared to normal mice. This effect was abolished by blocking endogenous PEDF with anti-PEDF Ab or enhanced by supplementing with rPEDF. Treatment with anti-PEDF antibody blocked the effect of endogenous-PEDF and increased DC maturation, expression of pro-inflammatory cytokines in conjunctivae, and exacerbated disease severity in DED mice. Conversely, topical rPEDF enhanced the suppressive effect of endogenous PEDF on DC maturation, decreased expression of pro-inflammatory cytokines in conjunctivae, and reduced disease severity.

Conclusions: The results from our study elucidate the role of PEDF in impeding DC maturation, and suppression of ocular surface inflammation, explicating a promising therapeutic potential of PEDF in limiting the corneal epitheliopathy as a consequence of DED.
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http://dx.doi.org/10.1016/j.jtos.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322788PMC
July 2020

The functions of IL-23 and IL-2 on driving autoimmune effector T-helper 17 cells into the memory pool in dry eye disease.

Mucosal Immunol 2021 01 23;14(1):177-186. Epub 2020 Apr 23.

Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 02114, USA.

Long-lived memory T-helper 17 (Th17) cells actively mediate the chronic inflammation in autoimmune disorders, including dry eye disease (DED). The mechanisms responsible for the maintenance and reactivation of these cells in autoimmunity have been subject of investigation. However, the process through which memory Th17 are generated from their effector precursors remains to be elucidated. Herein, using our murine model of DED, we detect a linear transition from effector-to-memory Th17 cells during the abatement phase of acute inflammation, which is accompanied by persistently high levels of IL-23 and diminished levels of IL-2. In addition, in vitro culture of effector Th17 cells derived from the DED animals with IL-23, but not IL-2, leads to significant generation of memory Th17 cells, along with upregulated expression levels of IL-7R and IL-15R by these cells. Furthermore, supplementation of IL-2 abolishes and blockade of IL-2 enhances IL-23-induced generation of memory Th17 cells in vitro. Finally, in vivo blockade of IL-23 signaling during the contraction phase of primary response inhibits the generation of memory Th17 cells from their effector precursors. Together, our data demonstrate a new dichotomy between IL-23 and IL-2 in driving effector Th17 cells into the memory pool in autoimmune-mediated ocular surface inflammation.
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http://dx.doi.org/10.1038/s41385-020-0289-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581618PMC
January 2021

Aged Mice Exhibit Severe Exacerbations of Dry Eye Disease with an Amplified Memory Th17 Cell Response.

Am J Pathol 2020 07 11;190(7):1474-1482. Epub 2020 Apr 11.

Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts. Electronic address:

The prevalence as well as the severity of dry eye disease increase with age. Memory T helper 17 (Th17) cells (CD4IL-17ACD44) drive the chronic and relapsing course of dry eye disease. Here, we investigated the contribution of memory Th17 cells to age-related dry eye disease, and evaluated memory Th17 cell depletion with anti-IL-15 antibody as a strategy to abrogate the severe exacerbations of dry eye disease observed in aged mice. After initial exposure to desiccating stress, aged mice maintained higher frequencies of memory Th17 cells in the draining lymph nodes relative to young mice. Upon secondary exposure to desiccating stress, aged mice developed more severe corneal epitheliopathy than young mice, which is associated with increased local frequencies of Th17 cells (CD4IL-17A). Treatment with anti-IL-15 antibody decreased the enlarged memory Th17 pool in aged mice to frequencies comparable with young mice. Furthermore, anti-IL-15-treated mice showed significantly reduced conjunctival infiltration of Th17 cells and lower corneal fluorescein staining scores compared with saline-treated control mice. Our data suggest that age-related increases in the memory Th17 compartment predispose aged mice toward the development of severe corneal epithelial disease after exposure to a dry environment. Selectively targeting memory Th17 cells may be a viable therapeutic approach in the treatment of age-related dry eye disease.
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http://dx.doi.org/10.1016/j.ajpath.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369573PMC
July 2020

Patient-Reported Burden of Dry Eye Disease in the United States: Results of an Online Cross-Sectional Survey.

Am J Ophthalmol 2020 08 8;216:7-17. Epub 2020 Apr 8.

Takeda, Lexington, Massachusetts, USA; College of Allied Health Sciences, Augusta University, Augusta, Georgia, USA.

Purpose: To evaluate functional vision, general health status, and work productivity in individuals with and without dry eye disease (DED).

Design: Cross-sectional study.

Methods: Setting: General US population (2018).

Study Population: Adults ≥18 years with (n = 1003) or without (n = 1006) self-reported DED.

Main Outcome Measures: All respondents completed the National Eye Institute Visual Function Questionnaire (VFQ) and the EuroQol 5-dimensions 5-levels (EQ-5D-5L). All respondents with DED completed the eye dryness score (EDS) visual analogue scale, Ocular Comfort Index (OCI), and Work Productivity and Activity Impairment (WPAI) questionnaire. Half of respondents with DED completed the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire; the other half completed the Dry Eye Questionnaire 5 (DEQ-5) and Standardized Patient Evaluation of Eye Dryness (SPEED), McMonnies, and Symptom Assessment in Dry Eye (SANDE) questionnaires. All analyses were descriptive.

Results: Respondents with DED reported more comorbidities, greater exposure to adverse environmental conditions, and lower (worse) mean (standard deviation) scores on the modified Rasch-scored 28-item VFQ (VFQ-28R) total score (68.8 [11.9] vs 81.2 [12.7]) and EQ-5D-5L (0.82 [0.13] vs 0.88 [0.14]) than respondents without DED. Respondents with DED and EDS ≥60 (highest discomfort) fared worse on OCI, VFQ-28R, and WPAI than respondents with DED and EDS <40 (lowest discomfort). Similar findings were observed with IDEEL, DEQ-5, SPEED, McMonnies, and SANDE scores.

Conclusions: There is a substantial burden of DED on functional vision, general health status, and productivity; and further, these parameters appear to worsen with increasing EDS.
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http://dx.doi.org/10.1016/j.ajo.2020.03.044DOI Listing
August 2020

Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling.

FASEB J 2020 05 12;34(5):6229-6243. Epub 2020 Mar 12.

Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.

Blood vessels and nerves travel together to supply most tissues in the body. However, there is a knowledge gap in the mechanisms underlying the direct regulation of angiogenesis by nerves. In the current study, we examined the regulation of angiogenesis by sensory nerves in response to inflammation using the cornea, a normally avascular and densely innervated ocular tissue, as a model. We used desiccating stress as an inflammatory stimulus in vivo and found that sub-basal and epithelial nerve densities in the cornea were reduced in dry eye disease (DED). We established a co-culture system of trigeminal ganglion sensory neurons and vascular endothelial cells (VEC) and found that neurons isolated from mice with DED directly promoted VEC proliferation and tube formation compared with normal controls. In addition, these neurons expressed and secreted higher levels of substance P (SP), a proinflammatory neuropeptide. SP potently promoted VEC activation in vitro and blockade of SP signaling with spantide I, an antagonist of SP receptor Neurokinin-1, significantly reduced corneal neovascularization in vivo. Spantide I and siRNA knockdown of SP abolished the promotion of VEC activation by DED neurons in vitro. Taken together, our data suggested that sensory neurons directly promote angiogenesis via SP signaling in response to inflammation in the cornea.
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http://dx.doi.org/10.1096/fj.201903236RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200295PMC
May 2020

Association between dry eye and depressive symptoms: Large-scale crowdsourced research using the DryEyeRhythm iPhone application.

Ocul Surf 2020 04 27;18(2):312-319. Epub 2020 Feb 27.

Juntendo University Faculty of Medicine, Department of Ophthalmology, Tokyo, Japan.

Purpose: Dry eye (DE) disease and depression are increasing in modern times. We investigated the association between DE and depressive symptoms using the iPhone application, DryEyeRhythm.

Methods: This large-scale crowdsourced observational study was conducted within iPhone users in Japan who downloaded DryEyeRhythm. Participants with a Zung Self-rating Depression Scale (SDS) score ≥ 40 were defined as having depressive symptoms, and those with an Ocular Surface Disease Index (OSDI) score ≥ 13 were defined as having DE symptoms (mild, 13-22; moderate, 23-32; and severe, 33-100). We compared SDS scores between participants with normal eye and mild, moderate, and severe OSDI-based DE symptoms. Logistic regression analyses were used to determine the association between DE severity and depressive symptoms after adjustment for demographic characteristics, medical history, and lifestyle habits.

Results: This study included 4454 participants (mean age, 27.9 ± 12.6 years; female, 66.7%). Participants with SDS scores ≥40 accounted for 58.2%, 70.9%, 79.4%, and 85.0% of normal controls and participants with mild, moderate, and severe DE symptoms, respectively (P trend < 0.001). The adjusted odds ratios (95% confidence interval) for depressive symptoms (SDS score of ≥40) were 1.62 (1.35-1.95) for mild, 2.39 (1.92-2.97) for moderate, and 3.29 (2.70-4.00) for severe DE symptoms.

Conclusion: This large-scale crowdsourced clinical study using DryEyeRhythm suggests that depressive symptoms are more common in individuals with more severe DE symptoms. DryEyeRhythm could play a role in earlier prevention or future prospective interventions for depressive symptoms in individuals with DE symptoms.
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http://dx.doi.org/10.1016/j.jtos.2020.02.007DOI Listing
April 2020

Advances and limitations of drug delivery systems formulated as eye drops.

J Control Release 2020 05 3;321:1-22. Epub 2020 Feb 3.

Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address:

Topical instillation of eye drops remains the most common and easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surfaces. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance in in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. This review article focuses on the recent advances for the development of ocular drug delivery systems. In addtion, the potential challenges for commercialization of new DDS are presented.
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http://dx.doi.org/10.1016/j.jconrel.2020.01.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170772PMC
May 2020

A standardized methodology for longitudinal assessment of corneal endothelial morphometry in eye banked corneas.

J Biol Methods 2019 20;6(4):e120. Epub 2019 Nov 20.

Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.

Eye banked research-grade human donor corneas serve as principal source for studying the mechanisms that underlie corneal endothelial cell damage/death and survival. Wide-field specular microscopy can be used for corneal endothelial visualization and allows for indirect assessment of endothelial cell function by analyzing endothelial cell density and morphometric parameters. However, a standardized approach is needed to observe corneal endothelial changes over time. This protocol describes reliable methods for consecutive analyses of human donor corneal endothelial cell density and morphometric parameters change using a wide-field dual imaging specular microscope. This protocol involves tissue warming, acquisition and analysis of specular endothelial images, assessment of corneal layers with the new Enhance mode, optical pachymetry measurement, and qualitative image quality grading scales. This quantitative and qualitative evaluation of donor corneas allows for a systematic analysis of endothelial dynamic responses to induced stress and can be used as a valuable tool to better elucidate specular findings and mechanisms mediating corneal endothelial cell loss in corneal disease and after transplantation.
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http://dx.doi.org/10.14440/jbm.2019.304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888603PMC
November 2019

Regulatory T cell modulation of cytokine and cellular networks in corneal graft rejection.

Curr Ophthalmol Rep 2018 Dec 6;6(4):266-274. Epub 2018 Oct 6.

Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA.

Purpose Of Review: Corneal allografts placed in vascularized or inflamed host beds are at increased risk of graft rejection due to the preponderance of activated immune cells in the host bed. Regulatory T cells (Tregs) are master regulators of the adaptive immune response and play a key role in the induction of immune tolerance. The aim of this review is to discuss mechanisms through which Tregs mediate tolerance in corneal transplantation and the novel therapeutic approaches that target Tregs to promote transplant survival.

Recent Findings: The inflammatory environment of high-risk allografts not only promotes activation of effector T cells and their infiltration to graft site, but also impairs Treg immunomodulatory function. Recent studies have shown that expansion of Tregs and enhancing their modulatory function significantly improve graft survival.

Summary: As our understanding of the cellular and molecular pathways in corneal transplantation has deepened, novel therapeutic strategies have been developed to improve allograft survival. In this review, we discuss therapeutic approaches that focus on Tregs to promote corneal allograft survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894425PMC
December 2018