Qureshi S, Ferguson TJ, Lim M, You JY, Goshe JM, Hood CT. Acute Calcific Band Keratopathy as an Adverse Effect of Recombinant Human Nerve Growth Factor (Cenegermin): A Multicenter Case Series. Cornea 2022;41(1):52-59.Abstract
PURPOSE: Cenegermin, (OXERVATE) a recently Food and Drug Administration-approved topical formulation of recombinant human nerve growth factor, has been used for the treatment of neurotrophic keratopathy (NK). Corneal deposits have been previously reported as a potential adverse effect; however, the clinical characteristics, visual significance, and treatment options have not been fully described. The purpose of this article is to better characterize corneal deposits occurring during treatment with cenegermin for neurotrophic keratopathy. METHODS: This was a retrospective, multicenter consecutive case series. RESULTS: We identified 5 patients from 3 institutions who developed a white opacity in varying layers of the cornea, consistent with calcium deposition, during treatment with cenegermin. In all cases, the opacity occurred rapidly over the course of a few weeks after initiation of treatment. Histopathologic examination of the cornea from one corneal patient demonstrated extensive calcification of the stroma extending to 90% depth. Before treatment, all patients had stage 2 or 3 NK (Mackie classification). The deposits were visually significant in all patients and did not resolve after cessation of cenegermin. There were no differences in age, sex, etiology of the NK, corneal transplant status, or concurrent medications between the patients who developed a deposit and 15 other patients with stage 2 or 3 NK who did not. One patient was successfully treated with superficial keratectomy with ethylenediaminetetraacetic acid chelation, one patient underwent penetrating keratoplasty, and one patient received a Boston keratoprosthesis. CONCLUSIONS: We report the rapid onset of a corneal opacity after initiation of treatment with cenegermin in patients with stage 2 or 3 NK, consistent with acute calcific band keratopathy. This visually significant adverse finding has not previously been described. We could not identify any risk factors for development. We recommend close monitoring of patients receiving cenegermin therapy because the opacity may be irreversible and may require keratoplasty for visual rehabilitation.
Elbasiony E, Cho W, Mittal SK, Chauhan SK. Suppression of lipopolysaccharide-induced corneal opacity by hepatocyte growth factor. Sci Rep 2022;12(1):494.Abstract
Keratitis induced by bacterial toxins, including lipopolysaccharide (LPS), is a major cause of corneal opacity and vision loss. Our previous study demonstrates hepatocyte growth factor (HGF) promotes epithelial wound healing following mechanical corneal injury. Here, we investigated whether HGF has the capacity to suppress infectious inflammatory corneal opacity using a new model of LPS-induced keratitis. Keratitis, induced by two intrastromal injections of LPS on day 1 and 4 in C57BL/6 mice, resulted in significant corneal opacity for up to day 10. Following keratitis induction, corneas were topically treated with 0.1% HGF or PBS thrice daily for 5 days. HGF-treated mice showed a significantly smaller area of corneal opacity compared to PBS-treated mice, thus improving corneal transparency. Moreover, HGF treatment resulted in suppression of α-SMA expression, compared to PBS treatment. HGF-treated corneas showed normalized corneal structure and reduced expression of pro-inflammatory cytokine, demonstrating that HGF restores corneal architecture and immune quiescence in corneas with LPS-induced keratitis. These findings offer novel insight into the potential application of HGF-based therapies for the prevention and treatment of infection-induced corneal opacity.
Sun T, Shu H-Y, Wu J-L, Su T, Liu Y-J, Zhang L-J, Li Q-Y, Pan Y-C, Ge Q-M, Shao Y. Investigation of changes in the activity and function of dry eye-associated brain regions using the amplitude of low-frequency fluctuations method. Biosci Rep 2022;42(1)Abstract
OBJECTIVE: The local characteristics of spontaneous brain activity in patients with dry eye (DE) and its relationship with clinical characteristics were evaluated using the amplitude of low-frequency fluctuations (ALFF) method. METHODS: A total of 27 patients with DE (10 males and 17 females) and 28 healthy controls (HCs) (10 males and 18 females) were recruited, matched according to sex, age, weight and height, classified into the DE and HC groups, and examined using functional magnetic resonance imaging (fMRI) scans. Spontaneous brain activity changes were recorded using ALFF technology. Data were recorded and plotted on the receiver operating characteristic (ROC) curve, reflecting changes in activity in different brain areas. Finally, Pearson correlation analysis was used to calculate the potential relationship between spontaneous brain activity abnormalities in multiple brain regions and clinical features in patients with DE. GraphPad Prism 8 (GraphPad Software, Inc.) was used to analyze the linear correlation between the Hospital Anxiety and Depression Scale and ALFF value. RESULTS: Compared with HCs, the ALFF values of patients with DE were decreased in the right middle frontal gyrus (MFG)/right inferior orbitofrontal cortex (OFC), left triangle inferior frontal gyrus, left MFG, and right superior frontal gyrus. In contrast, the ALFF value of patients with DE was increased in the left calcarine. CONCLUSION: There are significant fluctuations in the ALFF value of specific brain regions in patients with DE versus HCs. This corroborates previous evidence showing that the symptoms of ocular surface damage in patients with DE are related to dysfunction in specific brain areas.
Sharifi S, Sharifi H, Akbari A, Lei F, Dohlman CH, Gonzalez-Andrades M, Guild C, Paschalis EI, Chodosh J. Critical media attributes in E-beam sterilization of corneal tissue. Acta Biomater 2022;138:218-227.Abstract
When ionizing irradiation interacts with a media, it can form reactive species that can react with the constituents of the system, leading to eradication of bioburden and sterilization of the tissue. Understanding the media's properties such as polarity is important to control and direct those reactive species to perform desired reactions. Using ethanol as a polarity modifier of water, we herein generated a series of media with varying relative polarities for electron beam (E-beam) irradiation of cornea at 25 kGy and studied how the irradiation media's polarity impacts properties of the cornea. After irradiation of corneal tissues, mechanical (tensile strength and modulus, elongation at break, and compression modulus), chemical, optical, structural, degradation, and biological properties of the corneal tissues were evaluated. Our study showed that irradiation in lower relative polarity media improved structural properties of the tissues yet reduced optical transmission; higher relative polarity reduced structural and optical properties of the cornea; and intermediate relative polarity (ethanol concentrations = 20-30% (v/v)) improved the structural properties, without compromising optical characteristics. Regardless of media polarity, irradiation did not negatively impact the biocompatibility of the corneal tissue. Our data shows that the absorbed ethanol can be flushed from the irradiated cornea to levels that are nontoxic to corneal and retinal cells. These findings suggest that the relative polarity of the irradiation media can be tuned to generate sterilized tissues, including corneal grafts, with engineered properties that are required for specific biomedical applications. STATEMENT OF SIGNIFICANCE: Extending the shelf-life of corneal tissue can improve general accessibility of cornea grafts for transplantation. Irradiation of donor corneas with E-beam is an emerging technology to sterilize the corneal tissues and enable their long-term storage at room temperature. Despite recent applications in clinical medicine, little is known about the effect of irradiation and preservation media's characteristics, such as polarity on the properties of irradiated corneas. Here, we have showed that the polarity of the media can be a valuable tool to change and control the properties of the irradiated tissue for transplantation.
Roldan AM, De Arrigunaga S, Ciolino JB. Effect of Autologous Serum Eye Drops on Corneal Haze after Corneal Cross-linking. Optom Vis Sci 2022;99(2):95-100.Abstract
SIGNIFICANCE: Corneal haze remains a frequent post-operative finding in patients undergoing corneal cross-linking. It has been shown that autologous serum tears promote epithelial healing and reduce post-operative pain; however, the role in the prevention of corneal haze has not been reported. PURPOSE: This study aimed to compare the effect of autologous serum tears versus preservative-free artificial tears on the prevention and resolution of post-cross-linking corneal haze. METHODS: A retrospective cohort study was conducted in a sample population from one surgeon at a tertiary eye center from 2016 to 2019. Seventy-six eyes of consecutive patients who underwent cross-linking were included. Records were reviewed for corneal Scheimpflug densitometry values and maximum keratometry, epithelial healing time, and the use of either autologous serum tears or preservative-free artificial tears. Corneal densitometry values, expressed in standardized grayscale units (GSU), were recorded for the anterior 150-μm corneal stroma and in the 0.0 to 2.0 mm and 2.0 to 6.0 mm zones. RESULTS: Forty-four eyes received autologous serum tears, whereas 32 eyes received preservative-free artificial tears. The baseline GSU of the anterior stromal 0 to 2 mm annulus and the 2 to 6 mm annulus did not significantly differ between groups (P = .50 and P = .40, respectively). There was a statistically significant increase in mean GSU for both anterior 0 to 2 mm and 2 to 6 mm zones between baseline and 1 month (P < .001) and 3 months (P < .001). When comparing the two groups, no statistically significant difference was found post-operatively between the mean GSU at 1 month for the anterior 0 to 2 mm (P = .38) nor the 2 to 6 mm zone (P = .12), or for the third month (P = .60 and P = .44, respectively). CONCLUSIONS: Using Scheimpflug densitometry, we did not find a significant difference in the post-cross-linking corneal haze at 1 and 3 post-operative months between patients who use autologous serum tears and those who use preservative-free artificial tears.
Argüeso P. Human ocular mucins: The endowed guardians of sight. Adv Drug Deliv Rev 2022;180:114074.Abstract
Mucins are an ancient group of glycoproteins that provide viscoelastic, lubricating and hydration properties to fluids bathing wet surfaced epithelia. They are involved in the protection of underlying tissues by forming a barrier with selective permeability properties. The expression, processing and spatial distribution of mucins are often determined by organ-specific requirements that in the eye involve protecting against environmental insult while allowing the passage of light. The human ocular surface epithelia have evolved to produce an extremely thin and watery tear film containing a distinct soluble mucin product secreted by goblet cells outside the visual axis. The adaptation to the ocular environment is notably evidenced by the significant contribution of transmembrane mucins to the tear film, where they can occupy up to one-quarter of its total thickness. This article reviews the tissue-specific properties of human ocular mucins, methods of isolation and detection, and current approaches to model mucin systems recapitulating the human ocular surface mucosa. This knowledge forms the fundamental basis to develop applications with a promising biological and clinical impact.
Lužnik Marzidovšek Z, Blanco T, Sun Z, Alemi H, Ortiz G, Nakagawa H, Chauhan SK, Taylor AW, Jurkunas UV, Yin J, Dana R. The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after Transplantation. Am J Pathol 2022;192(2):270-280.Abstract
Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.
Kenyon KR. Comment on "Cornea Classic Article: Kim JC and Tseng SCG: Transplantation of Preserved Amniotic Membrane for Surface Reconstruction in Severely Damaged Rabbit Corneas (Cornea 1995;14:473-484)". Cornea 2022;41(2):135-136.Abstract
ABSTRACT: Following identification of limbal stem cells, efforts have been devoted to restore and/or replace these essential progenitors of the corneal epithelium. Limbal stem cell deficiency, commonly a consequence of ocular chemical injury, results in clinically compromised vision consequent to corneal conjunctivalization. The insight of Kim and Tseng provided experimental proof of the concept that even in the presence of total limbal stem cell deficiency, amnion membrane overlay grafts can promote limbal recovery as a means of ocular surface reconstruction.
Singh RB, Das S, Chodosh J, Sharma N, Zegans ME, Kowalski RP, Jhanji V. Paradox of complex diversity: Challenges in the diagnosis and management of bacterial keratitis. Prog Retin Eye Res 2022;88:101028.Abstract
Bacterial keratitis continues to be one of the leading causes of corneal blindness in the developed as well as the developing world, despite swift progress since the dawn of the "anti-biotic era". Although, we have expeditiously developed our understanding about the different causative organisms and associated pathology leading to keratitis, extensive gaps in knowledge continue to dampen the efforts required for early and accurate diagnosis, and management in these patients, resulting in poor clinical outcomes. The ability of the causative bacteria to subdue the therapeutic challenge stems from their large genome encoding complex regulatory networks, variety of unique virulence factors, and rapid secretion of tissue damaging proteases and toxins. In this review article, we provide an overview of the established diagnostic techniques and therapeutics for keratitis caused by various bacteria. We extensively report the recent in-roads through novel tools for accurately diagnosing mono- and poly-bacterial corneal infections. Furthermore, we outline the recent progress by our groups and others in understanding the sub-cellular genomic changes that lead to antibiotic resistance in these organisms. Finally, we discuss in detail, the novel therapies and drug delivery systems in development for the efficacious management of bacterial keratitis.
Jumelle C, Yung A, Shirzaei Sani E, Taketani Y, Gantin F, Bourel L, Wang S, Yüksel E, Seneca S, Annabi N, Dana R. Development and characterization of a hydrogel-based adhesive patch for sealing open-globe injuries. Acta Biomater 2022;137:53-63.Abstract
Full-thickness wounds to the eye can lead to serious vision impairment. Current standards of care (from suturing to tissue transplantation) usually require highly skilled surgeons and use of an operating theater. In this study, we report the synthesis, optimization, and in vitro and ex vivo testing of photocrosslinkable hydrogel-based adhesive patches that can easily be applied to globe injuries or corneal incisions. According to the type and concentration of polymers used in the adhesive formulations, we were able to finely tune the physical properties of the bioadhesive including viscosity, elastic modulus, extensibility, ultimate tensile strength, adhesion, transparency, water content, degradation time, and swellability. Our in vitro studies showed no sign of cytotoxicity of the hydrogels. Moreover, the hydrogel patches showed higher adhesion on freshly explanted pig eyeballs compared to a marketed ocular sealant. Finally, ex vivo feasibility studies showed that the hydrogel patches could seal complex open-globe injuries such as large incision, cruciform injury, and injury associated with tissue loss. These results suggest that our photocrosslinkable hydrogel patch could represent a promising solution for the sealing of open-globe injuries or surgical incisions. STATEMENT OF SIGNIFICANCE: Current management of severe ocular injuries require advanced surgical skills and access to an operating theater. To address the need for emergent management of wounds that cannot be handled in the operating room, surgical adhesives have gained popularity, but none of the currently available adhesives have optimal bioavailability, adhesive or mechanical properties. This study describes the development, optimization and testing of a light-sensitive adhesive patch that can easily be applied to the eye. After solidification using visible light, the patch shows no toxicity and is more adherent to the tissue than a marketed sealant. Thus this technology could represent a promising solution to stabilize ocular injuries in emergency settings before definitive surgical repair.
Fjaervoll H, Fjaervoll K, Magno M, Moschowits E, Vehof J, Dartt DA, Utheim TP. The association between visual display terminal use and dry eye: a review. Acta Ophthalmol 2022;100(4):357-375.Abstract
BACKGROUND: Dry eye disease (DED) is a multifactorial disease of the tear film and ocular surface. It causes ocular symptoms, reduced quality of life and a considerable economic burden on society. Prolonged use of visual display terminals (VDTs) has been suggested as an important risk factor for DED. PURPOSE: This review aims to study the association between DED and VDT use with an emphasis on the prevalence of DED among VDT users and harmful daily duration of VDT use. METHODS: A PubMed search was conducted and yielded 57 relevant articles based on a set of inclusion and exclusion criteria. The studies were subclassified according to study design. RESULTS: The far majority of the studies showed an association between VDT use and DED or DED-related signs and symptoms. The prevalence of definite or probable DED in VDT and office workers ranged from 26% to 70%, with as few as 1-2 hr of VDT exposure per day being associated with DED. CONCLUSION: VDT use is strongly associated with DED. VDT-associated DED is prevalent, but the exact prevalence needs to be further elucidated using standardized DED diagnosis criteria. Furthermore, a safe lower limit of daily VDT use has yet to be established. More research is needed on the effect of digitalization and digital transformation, which are particularly high during the time of the COVID-19 pandemic.
Català P, Thuret G, Skottman H, Mehta JS, Parekh M, Ní Dhubhghaill S, Collin RWJ, Nuijts RMMA, Ferrari S, LaPointe VLS, Dickman MM. Approaches for corneal endothelium regenerative medicine. Prog Retin Eye Res 2022;87:100987.Abstract
The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.
Böhm M, Leon P, Wylęgała A, Ong Tone S, Condron T, Jurkunas U. Cost-effectiveness analysis of preloaded versus non-preloaded Descemet membrane endothelial keratoplasty for the treatment of Fuchs endothelial corneal dystrophy in an academic centre. Br J Ophthalmol 2022;106(7):914-922.Abstract
AIMS: To determine the cost-effectiveness of preloaded Descemet membrane endothelial keratoplasty (pDMEK) versus non-preloaded DMEK (n-pDMEK) for the treatment of Fuchs endothelial corneal dystrophy (FECD). METHODS: From a societal and healthcare perspective, this retrospective cost-effectiveness analysis analysed a cohort of 58 patients with FECD receiving pDMEK (n=38) or n-pDMEK (n=30) from 2016 to 2018 in the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA. Exclusion criteria were previous ocular surgeries (other than uncomplicated cataract surgery), including other keratoplasty procedures, ocular pathological conditions as glaucoma, amblyopia, laser treatments, or any retinal or corneal disease. The main outcome parameters were the incremental cost-utility ratio (ICUR) and net monetary benefit (NMB). RESULTS: pDMEK was less costly compared with n-pDMEK (healthcare: $13 886 vs $15 329; societal: $20 805 vs $22 262), with a slighter greater utility (QALY 0.6682 vs QALY 0.6640) over a time horizon of 15 years. pDMEK offered a slightly higher clinical effectiveness (+0.0042 QALY/patient) at a lower cost (healthcare: -$1444 per patient; societal: -$1457 per patient) in improving visual acuity in this cohort of patients with FECD. pDMEK achieved a favourable ICUR and NMB compared with n-pDMEK. Based on sensitivity analyses performed, the economic model was robust. CONCLUSIONS: From the societal and healthcare perspective, pDMEK was less costly and generated comparable utility values relative to n-pDMEK. Therefore, pDMEK appears to be cost-effective and cost saving with respect to n-pDMEK. Further long-term follow-up data are needed to confirm these findings.