Cornea

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Qureshi S, Dohlman TH. Penetrating Keratoplasty: Indications and Graft Survival by Geographic Region. Semin Ophthalmol 2023;38(1):31-43.Abstract
Corneal transplantation, or penetrating keratoplasty (PK), is the most common form of solid-organ transplantation performed worldwide. Here, we evaluated the indications for PK and rates of transplant survival around the world by geographic region. We conducted a literature search of PubMed, MEDLINE, and Google Scholar databases and identified 155 relevant studies from 41 countries published between 1987 and 2021. The most common indications for PK were keratoconus in Europe, Africa, the Middle East, Australia, New Zealand, and Central and South America, bullous keratopathy in North America, and corneal scarring in Asia. The overall global mean graft survival rates at 1-, 2-, 3-, 5-, and 10-years were 88.6%, 81.2%, 78.9%, 72.8%, and 61.2%, respectively. Through this systematic analysis of PK by region, we hope to bring a new perspective to the corneal transplantation literature and to potentially highlight global differences and unmet needs in patient care.
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Rahimi Darabad R, Suzuki T, Richards SM, Jensen RV, Jakobiec FA, Zakka FR, Liu S, Sullivan DA. Influence of aromatase absence on the gene expression and histology of the mouse meibomian gland. Invest Ophthalmol Vis Sci 2013;54(2):987-98.Abstract
PURPOSE: We hypothesize that aromatase, an enzyme that controls estrogen biosynthesis, plays a major role in the sex-related differences of the meibomian gland. To begin to test this hypothesis, we examined the influence of aromatase absence, which completely eliminates estrogen production, on glandular gene expression and histology in male and female mice. METHODS: Meibomian glands were obtained from adult, age-matched wild-type (WT) and aromatase knockout (ArKO) mice. Tissues were processed for histology or the isolation of total RNA, which was analyzed for differentially expressed mRNAs by using microarrays. RESULTS: Our results show that aromatase significantly influences the expression of more than a thousand genes in the meibomian gland. The nature of this effect is primarily sex-dependent. In addition, the influence of aromatase on sex-related differences in gene expression is predominantly genotype-specific. However, many of the sex-related variations in biological process, molecular function, and cellular component ontologies, as well as in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, are remarkably similar between WT and ArKO mice. The loss of aromatase activity has no obvious effect on the histology of meibomian glands in male or female mice. CONCLUSIONS: Our findings demonstrate that aromatase has a significant impact on gene expression in the meibomian gland. The nature of this influence is sex-dependent and genotype-specific; however, many of the sex-related variations in gene ontologies and KEGG pathways are similar between WT and ArKO mice. Consequently, it appears that aromatase, and by extension estrogen, do not play a major role in the sex-related differences of the mouse meibomian gland.
Rahimi Darabad R, Suzuki T, Richards SM, Jakobiec FA, Zakka FR, Barabino S, Sullivan DA. Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?. Exp Eye Res 2014;127:153-60.Abstract

Researchers have proposed that estrogen deficiency will lead to a Sjögren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice.

Rajaiya J, Zhou X, Barequet I, Gilmore MS, Chodosh J. Novel model of innate immunity in corneal infection. In Vitro Cell Dev Biol Anim 2015;Abstract

The cornea functions as the major refractive interface for vision and protects the internal eye from insult. Current understanding of innate immune responses to corneal infection derives from a synthesis of in vitro and in vivo analyses. However, monolayer cell cultures and mouse models do not accurately duplicate all aspects of innate immunity in human patients. Here, we describe a three-dimensional culture system that incorporates human cells and extracellular matrix to more completely simulate the human cornea for studies of infection. Human corneal stromal fibroblasts were mixed with type I collagen in 3-μm pore size transwell inserts, and overlayed with Matrigel to simulate a human corneal stroma and epithelial basement membrane. These were then infected with a cornea-tropic adenovirus, and exposed on their inferior side to leukocytes derived from human peripheral blood. Subsequent analyses were performed with histology, confocal microscopy, ELISA, and fluorescence-activated cell sorting (FACS). CXCL8, a neutrophil chemokine shown previously as the first cytokine induced in infection of human corneal cells, increased upon adenovirus infection of facsimiles in a dose-responsive fashion. Myeloperoxidase-positive cells infiltrated infected corneal facsimiles in a sub-Matrigel location, possibly due to CXCL8 colocalization with heparan sulfate, a Matrigel constituent. Cellular infiltration was significantly inhibited by treatment with chemical inhibitors of p38 MAPK and Src kinase, both constituents of a signaling cascade previously suggested to regulate inflammation after adenovirus infection. FACS analysis determined that both virus and corneal fibroblasts were necessary for the induction of leukocyte migration into the facsimiles. The corneal facsimile, literally a cornea in a test tube, permits mechanistic studies on human tissue in a highly tractable system.

Ramier A, Eltony AM, Chen YT, Clouser F, Birkenfeld JS, Watts A, Yun S-H. In vivo measurement of shear modulus of the human cornea using optical coherence elastography. Sci Rep 2020;10(1):17366.Abstract
Corneal stiffness plays a critical role in shaping the cornea with respect to intraocular pressure and physical interventions. However, it remains difficult to measure the mechanical properties noninvasively. Here, we report the first measurement of shear modulus in human corneas in vivo using optical coherence elastography (OCE) based on surface elastic waves. In a pilot study of 12 healthy subjects aged between 25 and 67, the Rayleigh-wave speed was 7.86 ± 0.75 m/s, corresponding to a shear modulus of 72 ± 14 kPa. Our data reveal two unexpected trends: no correlation was found between the wave speed and IOP between 13-18 mmHg, and shear modulus decreases with age (- 0.32 ± 0.17 m/s per decade). We propose that shear stiffness is governed by the interfibrillar matrix, whereas tensile strength is dominated by collagen fibrils. Rayleigh-wave OCE may prove useful for clinical diagnosis, refractive surgeries, and treatment monitoring.
Ramke M, Zhou X, Materne EC, Rajaiya J, Chodosh J. Resident corneal c-fms(+) macrophages and dendritic cells mediate early cellular infiltration in adenovirus keratitis. Exp Eye Res 2016;147:144-7.Abstract

The cornea contains a heterogeneous population of antigen-presenting cells with the capacity to contribute to immune responses. Adenovirus keratitis is a severe corneal infection with acute and chronic phases. The role of resident corneal antigen-presenting cells in adenovirus keratitis has not been studied. We utilized transgenic MaFIA mice in which c-fms expressing macrophages and dendritic cells can be induced to undergo apoptosis, in a mouse model of adenovirus keratitis. Clinical keratitis and recruitment of myeloperoxidase and CD45(+) cells were diminished in c-fms depleted, adenovirus infected mice, as compared to controls, consistent with a role for myeloid-lineage cells in adenovirus keratitis.

Rao R, Borkar DS, Colby KA, Veldman PB. Descemet Membrane Endothelial Keratoplasty After Failed Descemet Stripping Without Endothelial Keratoplasty. Cornea 2017;36(7):763-766.Abstract
PURPOSE: To describe the clinical course, surgical experience, and postoperative outcomes of 3 patients with Fuchs endothelial dystrophy who underwent Descemet membrane endothelial keratoplasty (DMEK) after failed Descemet stripping without endothelial keratoplasty. METHODS: Three patients who underwent DMEK for management of persistent corneal edema after deliberate Descemet stripping in the setting of Fuchs endothelial dystrophy were identified. Patients were examined at day 1, week 1, and months 1, 3, and 6 after DMEK. Visual acuity, central corneal thickness (CCT), and evaluation of central corneal endothelial cell counts were recorded. RESULTS: Two women and one man, aged 56, 72, and 68 years, were included. The time interval between primary Descemet stripping and DMEK ranged from 3.5 to 8 months. Preoperative visual acuities were 20/200, 20/300, and 20/80. Immediately before DMEK, no patients had countable central endothelial cells, and CCTs were 825, 1034, and 878 μm. After DMEK, all patients had improvement in visual acuity to 20/70, 20/20, and 20/20 with CCTs of 529, 504, and 528. The postoperative period in the first case was notable for the immediate development of a pigmented pupillary membrane with posterior synechiae, as well as cystoid macular edema, of uncertain chronicity, noted 1 month postoperatively. The second case also developed posterior synechiae. Two cases completed 6-month endothelial cell counts totaling 2200 and 3114 cells per square millimeter (endothelial cell loss of 13% and 5.3%). CONCLUSIONS: DMEK is a reliable procedure to facilitate corneal rehabilitation and visual recovery in the event of poor corneal clearance after Descemet stripping without endothelial keratoplasty.
Rapoport Y, Singer JM, Ling JD, Gregory A, Kohanim S. A Comprehensive Review of Sex Disparities in Symptoms, Pathophysiology, and Epidemiology of Dry Eye Syndrome. Semin Ophthalmol 2016;Abstract

INTRODUCTION: The etiology, frequency, manifestation, and treatment of dry eye syndrome are commonly influenced by sex and gender. MATERIALS AND METHODS: This study aims to review the differences in epidemiology, pathophysiology, and associated diseases between the sexes. The terms men and male and women and female are used interchangeably throughout the review to refer to biological sex. RESULTS: There are numerous objective and subjective markers of dry eye syndrome but not one diagnostic criterion. There are numerous associated conditions with dry eye syndrome varying from autoimmune to allergic. Large epidemiologic studies reviewed suggest that there does indeed exist a difference between dry eye symptoms between men and women, with women having dry eye signs and reporting dry eye symptoms more often than men. The increased prevalence in women could be correlated to an increased association with certain systemic diseases, specifically autoimmune diseases, and to hormonal variations. Several studies found equivocal data about prevalence of dry eye symptoms between men and women. DISCUSSION: Interpreting studies that investigate epidemiology, pathogenesis, and treatment of dry-eye conditions is complicated by the lack of universally adapted diagnostic criteria and standardized, specific diagnostic tests, and inter-study variability in the definition of dry eye syndrome.

Rashad R, Shanbhag SS, Kwan J, Chodosh J, Saeed S, Saeed HN. Chronic ocular complications in lamotrigine vs. trimethoprim-sulfamethoxazole induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Ocul Surf 2021;21:16-18.Abstract
PURPOSE: The purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS). METHODS: This retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system. RESULTS: Forty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes. CONCLUSIONS: Compared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.
Reshef ER, Wolkow N, Jakobiec FA, Yoon MK. Histopathologic Findings of Linear Scleroderma Displaying Focal Trichiasis Secondary to Tarsal Thinning. Ophthalmic Plast Reconstr Surg 2018;34(4):e124-e127.Abstract
Linear scleroderma en coup de sabre with ophthalmic findings has been previously described in the literature on numerous occasions. A 57-year-old woman presented with focal trichiasis secondary to tarsal thinning, adjacent to a linear brow and forehead deformity consistent with linear scleroderma en coup de sabre. Cases of linear scleroderma en coup de sabre involving the eyelids have been reported, most often with madarosis, ptosis, or skin atrophy; however, to the authors' knowledge, this is the first reported case of linear scleroderma associated with trichiasis and involvement of the deeper eyelid tissues, particularly the tarsus.
Riau AK, Venkatraman SS, Dohlman CH, Mehta JS. Surface Modifications of the PMMA Optic of a Keratoprosthesis to Improve Biointegration. Cornea 2017;36 Suppl 1:S15-S25.Abstract
Biointegration of a keratoprosthesis (KPro) is critical for the mitigation of various long-term postoperative complications. Biointegration of a KPro occurs between the haptic skirt (corneal graft) and the central optic [poly(methyl methacrylate) (PMMA)]. Various studies have highlighted common problems associated with poor bonding and biointegration between these 2 incompatible biomaterials. Resolution of these issues could be achieved by surface modification of the inert material (PMMA). A calcium phosphate (CaP) coating deposited on dopamine-activated PMMA sheets by simulated body fluid incubation (d-CaP coating) was shown to improve adhesion to collagen type I (main component of corneal stroma) compared with untreated PMMA and PMMA with other surface modifications. However, the d-CaP coating could easily undergo delamination, thereby reducing its potential for modification of KPro optical cylinders. In addition, the coating did not resemble the Ca and P composition of hydroxyapatite (HAp). A novel dip-coating method that involves the creation of cavities to trap and immobilize HAp nanoparticles on the PMMA surface was introduced to address the problems associated with the d-CaP coating. The newly obtained coating offered high hydrophilicity, resistance to delamination, and preservation of the Ca and P composition of HAp. These advantages resulted in improved adhesion strength by more than 1 order of magnitude compared with untreated PMMA. With respect to biointegration, human corneal stromal fibroblasts were able to adhere strongly and proliferate on HAp-coated PMMA. Furthermore, the new coating technique could be extended to immobilization of HAp nanoparticles on 3-mm-diameter PMMA cylinders, bringing it closer to clinical application.
Riau AK, Lwin NC, Gelfand L, Hu H, Liedberg B, Chodosh J, Venkatraman SS, Mehta JS. Surface modification of corneal prosthesis with nano-hydroxyapatite to enhance in vivo biointegration. Acta Biomater 2020;107:299-312.Abstract
The majority of clinical corneal prostheses (KPros) adopt a core-skirt configuration. This configuration is favored owing to the optic core (generally a cylindrical, acrylic-based material, such as PMMA), that not only provides a clear window for the patients' vision, but also confers resistance to biodegradability. The surrounding skirt (typically a biological material, such as corneal tissue) allows for host tissue integration. However, due to poor biointegration between the dissimilar core and skirt materials, it results in a weak adhesion at the interface, giving rise to clinical complications, such as bacterial infections in the tissue-PMMA interface and device extrusion. Here, we physically immobilized nano-hydroxyapatite (nHAp) on a PMMA cylinder via a dip-coating technique, to create a bioactive surface that improved biointegration in vivo. We established that the nHAp coating was safe and stable in the rabbit cornea over five weeks. More importantly, we found that apoptotic, wound healing and inflammatory responses to nHAp-coated PMMA were substantially milder than to non-coated PMMA. More mature collagen, similar to the non-operated cornea, was maintained in the corneal stroma adjacent to the nHAp-coated implant edge. However, around the non-coated cylinder, an abundant new and loose connective tissue formed, similar to bone tissue response to bioinert scaffolds. As a result of superior biointegration, tissue adhesion with nHAp-coated PMMA cylinders was also significantly enhanced compared to non-coated cylinders. This study set a precedent for the future application of the nHAp coating on clinical KPros. STATEMENT OF SIGNIFICANCE: Currently, all clinical corneal prostheses utilize as-manufactured, non-surface modified PMMA optic cylinder. The bioinert cylinder, however, has poor biointegration and adhesion with the surrounding biological tissue, which can give rise to postoperative complications, such as microbial invasion in the tissue-PMMA loose interface and PMMA optic cylinder extrusion. In the current study, we showed that surface modification of the PMMA cylinder with bioactive nano-hydroxyapatite (nHAp) significantly enhanced its biointegration with corneal stromal tissue in vivo. The superior biointegration of the nHAp-coated PMMA was signified by a more attenuated corneal wound healing, inflammatory and fibrotic response, and better tissue apposition, as well as a significantly improved corneal stromal tissue adhesion when compared to the non-coated PMMA.
Rico-Sánchez L, Garzón I, González-Andrades M, Ruíz-García A, Punzano M, Lizana-Moreno A, Muñoz-Ávila JI, Sánchez-Quevedo MDC, Martínez-Atienza J, Lopez-Navas L, Sanchez-Pernaute R, Oruezabal RI, Medialdea S, Gonzalez-Gallardo MDC, Carmona G, Sanbonmatsu-Gámez S, Perez M, Jimenez P, Cuende N, Campos A, Alaminos M. Successful development and clinical translation of a novel anterior lamellar artificial cornea. J Tissue Eng Regen Med 2019;13(12):2142-2154.Abstract
Blindness due to corneal diseases is a common pathology affecting up to 23 million individuals worldwide. The tissue-engineered anterior human cornea, which is currently being tested in a Phase I/II clinical trial to treat severe corneal trophic ulcers with preliminary good feasibility and safety results. This bioartificial cornea is based on a nanostructured fibrin-agarose biomaterial containing human allogeneic stromal keratocytes and cornea epithelial cells, mimicking the human native anterior cornea in terms of optical, mechanical, and biological behavior. This product is manufactured as a clinical-grade tissue engineering product, fulfilling European requirements and regulations. The clinical translation process included several phases: an initial in vitro and in vivo preclinical research plan, including preclinical advice from the Spanish Medicines Agency followed by additional preclinical development, the adaptation of the biofabrication protocols to a good manufacturing practice manufacturing process, including all quality controls required, and the design of an advanced therapy clinical trial. The experimental development and successful translation of advanced therapy medicinal products for clinical application has to overcome many obstacles, especially when undertaken by academia or SMEs. We expect that our experience and research strategy may help future researchers to efficiently transfer their preclinical results into the clinical settings.
Robert M-C, Črnej A, Shen LQ, Papaliodis GN, Dana R, Foster SC, Chodosh J, Dohlman CH. Infliximab after Boston Keratoprosthesis in Stevens-Johnson Syndrome: An Update. Ocul Immunol Inflamm 2016;:1-5.Abstract

PURPOSE: To report our experience using intravenous infliximab for the treatment of tissue melt after Boston keratoprosthesis (B-KPro) types I and II in patients with autoimmune disease. METHODS: Case series. RESULTS: We identified four patients who were treated with intravenous infliximab in the context of tissue melt after B-KPro. Stevens-Johnson syndrome-associated corneal blindness was the primary surgical indication for B-KPro implantation in all patients. Two patients received a B-KPro type I and two patients received a B-KPro type II. The patients received intravenous infliximab for skin retraction around B-KPro type II, melting of the carrier graft or leak. Treatment resulted in a dramatic decrease in inflammation and, in some cases, arrest of the melting process. Cost and patient adherence were limiting factors to pursuing infliximab therapy. In addition, one patient developed infusion reactions. CONCLUSIONS: Intravenous infliximab may be considered as globe- and sight-saving therapy for tissue melt after B-KPro.

Robert M-C, Arafat SN, Spurr-Michaud S, Chodosh J, Dohlman CH, Gipson IK. Tear Matrix Metalloproteinases and Myeloperoxidase Levels in Patients With Boston Keratoprosthesis Type I. Cornea 2016;35(7):1008-14.Abstract

PURPOSE: To investigate the tear levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 in eyes after Boston keratoprosthesis type I (B-KPro) implantation and to correlate these markers with the established B-KPro prognostic categories. METHODS: Tear washes were collected from 40 patients (7 with autoimmune disease, 2 with chemical burn, and 31 with other noncicatrizing diagnoses). Tear levels of MMPs, MPO, and tissue inhibitor of metalloproteinase-1 were quantified using multianalyte bead-based enzyme-linked immunosorbent assays. The total MMP activity was determined using a fluorimetric assay. The analytes were compared to the underlying diagnosis and other clinical factors. RESULTS: The MMP-8, MMP-9, and MPO levels were markedly elevated in the eyes with B-KPro (80 ± 31, 291 ± 77, and 244 ± 33 pg/μg, respectively). Chemical burn was associated with significantly higher tear MMP-8 (474 ± 376 pg/μg) and MMP-9 levels (1300 ± 635 pg/μg) compared with noncicatrizing diseases (MMP-8: 41 ± 15 pg/μg, P = 0.02 and MMP-9: 196 ± 57 pg/μg, P = 0.02) and higher MMP-9 levels compared with autoimmune diseases (MMP-8: 96 ± 65 pg/μg, P = 0.21 and MMP-9: 306 ± 196 pg/μg, P = 0.04). Similar analyte levels were observed in the B-KPro eye and the contralateral non-B-KPro eye of patients with bilateral diseases. MMP-8, MMP-9, and total MMP activities correlated strongly with each other. CONCLUSIONS: In the eyes with B-KPro, tear MMP-8 and MMP-9 levels seem to be related to the underlying ocular surface pathology and not significantly influenced by the presence of the prosthesis.

Robert M-C, Khreim N, Todani A, Melki SA. Anterior chamber gas bubble emergence pattern during femtosecond LASIK-flap creation. Br J Ophthalmol 2015;99(9):1201-5.Abstract

AIM: To characterise the emergence pattern of cavitation bubbles into the anterior chamber (AC) following femtosecond laser-assisted in situ keratomileusis (LASIK)-flap creation METHODS: Retrospective review of patients undergoing femtosecond LASIK surgery at Boston Laser, a private refractive surgery practice in Boston, Massachusetts, between December 2008 and February 2014. Patient charts were reviewed to identify all cases with gas bubble migration into the AC. Surgical videos were examined and the location of bubble entry was recorded separately for right and left eyes. RESULTS: Five thousand one hundred and fifty-eight patients underwent femtosecond LASIK surgery. Air bubble migration into the AC, presumably via the Schlemm's canal and trabecular meshwork, occurred in 1% of cases. Patients with AC bubbles had an average age of 33±8 years with a measured LASIK flap thickness of 96±21 μm. The occurrence of gas bubbles impaired iris registration in 64% of cases. Gas bubbles appeared preferentially in the nasal or inferior quadrants for right (92% of cases) and left (100% of cases) eyes. This bubble emergence pattern is significantly different from that expected with a random distribution (p<0.0001) and did not seem associated with decentration of the femtosecond laser docking system. CONCLUSIONS: The migration of gas bubbles into the AC is a rare occurrence during femtosecond laser flap creation. The preferential emergence of gas bubbles into the nasal and inferior quadrants of the AC may indicate a distinctive anatomy of the nasal Schlemm's canal.

Robert M-C, Arafat SN, Ciolino JB. Collagen cross-linking of the Boston keratoprosthesis donor carrier to prevent corneal melting in high-risk patients. Eye Contact Lens 2014;40(6):376-81.Abstract

OBJECTIVE: To examine the clinical relevance and pathophysiology of Boston keratoprosthesis (B-KPro)-related corneal keratolysis (cornea melt) and to describe a novel method of preventing corneal melt using ex vivo crosslinked cornea tissue carrier. METHODS: A review of B-KPro literature was performed to highlight cases of corneal melt. Studies examining the effect of corneal collagen cross-linking (CXL) on the biomechanical properties of corneal tissue are summarized. The use of crosslinked corneal tissue as a carrier to the B-KPro is illustrated with a case. RESULTS: Corneal melting after B-KPro is a relatively rare event, occurring in 3% of eyes during the first 3 years of postoperative follow-up. The risk of post-KPro corneal melting is heightened in eyes with chronic ocular surface inflammation such as eyes with Stevens-Johnson syndrome and mucous membrane pemphigoid. This chronic inflammation results in high tear levels of matrix metalloproteinases, the enzymes responsible for collagenolysis and corneal melt. Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. We have previously optimized the technique for ex vivo corneal CXL and are currently studying its impact on the prevention of corneal melting after B-KPro surgery in high-risk eyes. Crosslinked carrier tissue was used in a 52-year-old man with familial aniridia and severe post-KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year. CONCLUSION: Collagen crosslinking was previously shown to halt the enzymatic degradation of corneal buttons ex vivo. This study demonstrates the safety and potential benefit of using crosslinked corneal grafts as carriers for the B-KPro, especially in eyes at higher risk of postoperative melt.

Rodriguez JD, Lane KJ, Ousler GW, Angjeli E, Smith LM, Abelson MB. Blink: Characteristics, Controls, and Relation to Dry Eyes. Curr Eye Res 2018;43(1):52-66.Abstract
Blink is a complex phenomenon that is profoundly affected by diverse endogenous and exogenous stimuli. It has been studied in the context of cognition, emotional, and psychological states, as an indicator of fatigue and sleepiness, particularly in the automobile and transportation industry, in visual tasking, and finally, as it relates to tear film stability and ocular surface health. The fact that it is highly variable and has input from so many sources makes it very difficult to study. In the present review, the behavior of blink in many of these systems is discussed, ultimately returning in each instance to a discussion of how these factors affect blink in the context of dry eyes. Blink is important to ocular surface health and to an individual's optimal functioning and quality of life. Disturbances in blink, as cause or effect, result in a breakdown of tear film stability, optical clarity, and visual function.
Rodriguez JD, Lane KJ, Ousler GW, Angjeli E, Smith LM, Bateman KM, Abelson MB. Diurnal Tracking of Blink and Relationship to Signs and Symptoms of Dry Eye. Cornea 2016;35(8):1104-11.Abstract

PURPOSE: To assess diurnal changes in the signs and symptoms of dry eyes and their relationship to diurnal interblink interval (IBI) in normal subjects and in subjects with dry eye. METHODS: Blink data were collected from 9:00 AM to 8:00 PM during 2 days of normal activity using an electrocardiogram monitoring device. All subjects recorded ocular discomfort (0-5 scale) and primary activity hourly each day in a diary. Inferior and central fluorescein staining was graded by slit lamp (0-4) at the start and end of each day. Blink activity was detected using an algorithm based on recognition of the waveform corresponding to the kinematic properties of the blink signal. RESULTS: Normal subjects (N = 12) reported negligible symptoms, and results did not show a diurnal change in group hourly IBI. Mean daily IBI for the group with dry eye (N = 15) (4.63 ± 1.63 s) was shorter than that for the normal group (5.28 ± 1.48 s) (P = 0.0483). Correlation of diurnal symptoms and mean hourly IBI was relatively weak (r = -0.248). A repeated-measures model found IBI to be significantly associated with the time of day (P = 0.0028). Inferior corneal staining showed a small but significant diurnal increase for both normal group and group with dry eyes. CONCLUSIONS: Diurnal blink tracking reveals significant trending with symptoms. Diurnal change in IBI may be an appropriate surrogate for symptoms in the study of dry eye.

Rodriguez Benavente MC, Argüeso P. Glycosylation pathways at the ocular surface. Biochem Soc Trans 2018;46(2):343-350.Abstract
Glycosylation is a major form of enzymatic modification of organic molecules responsible for multiple biological processes in an organism. The biosynthesis of glycans is controlled by a series of glycosyltransferases, glycosidases and glycan-modifying enzymes that collectively assemble and process monosaccharide moieties into a diverse array of structures. Many studies have provided insight into various pathways of glycosylation at the ocular surface, such as those related to the biosynthesis of mucin-type -glycans and -glycans on proteins, but many others still remain largely unknown. This review provides an overview of the different classes of glycans described at the ocular surface focusing on their biosynthetic pathways and biological relevance. A precise understanding of these pathways under physiological and pathological conditions could help identify biomarkers and novel targets for therapeutic intervention.

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