Publications by authors named "Steven E Wilson"

138 Publications

TGFβ1 and TGFβ2 proteins in corneas with and without stromal fibrosis: Delayed regeneration of apical epithelial growth factor barrier and the epithelial basement membrane in corneas with stromal fibrosis.

Exp Eye Res 2021 Jan 22;202:108325. Epub 2020 Oct 22.

The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA. Electronic address:

The purpose of this study was to investigate the expression and localization of transforming growth factor (TGF) β1 and TGFβ2 in rabbit corneas that healed with and without stromal fibrosis, and to further study defective perlecan incorporation in the epithelial basement membrane (EBM) in corneas with scarring fibrosis. A total of 120 female rabbits had no surgery, -4.5D PRK, or -9D PRK. Immunohistochemistry (IHC) was performed at time points from unwounded to eight weeks after surgery, with four corneas at each time point in each group. Multiplex IHC was performed for TGFβ1 or TGFβ2, with Image-J quantitation, and keratocan, vimentin, alpha-smooth muscle actin (SMA), perlecan, laminin-alpha 5, nidogen-1 or CD11b. Corneas at the four-week peak for myofibroblast and fibrosis development were evaluated using Imaris 3D analysis. Delayed regeneration of both an apical epithelial growth factor barrier and EBM barrier function, including defective EBM perlecan incorporation, was greater in high injury -9D PRK corneas compared to -4.5D PRK corneas without fibrosis. Defective apical epithelial growth factor barrier and EBM allowed epithelial and tear TGFβ1 and tear TGFβ2 to enter the corneal stroma to drive myofibroblast generation in the anterior stroma from vimentin-positive corneal fibroblasts, and likely fibrocytes. Vimentin-positive cells and unidentified vimentin-negative, CD11b-negative cells also produce TGFβ1 and/or TGFβ2 in the stroma in some corneas. TGFβ1 and TGFβ2 were at higher levels in the anterior stroma in the weeks preceding myofibroblast development in the -9D group. All -9D corneas (beginning two to three weeks after surgery), and four -4.5D PRK corneas developed significant SMA + myofibroblasts and stromal fibrosis. Both the apical epithelial growth factor barrier and/or EBM barrier functions tended to regenerate weeks earlier in -4.5D PRK corneas without fibrosis, compared to -4.5D or -9D PRK corneas with fibrosis. SMA-positive myofibroblasts were markedly reduced in most corneas by eight weeks after surgery. The apical epithelial growth factor barrier and EBM barrier limit TGFβ1 and TGFβ2 entry into the corneal stroma to modulate corneal fibroblast and myofibroblast development associated with scarring stromal fibrosis. Delayed regeneration of these barriers in corneas with more severe injuries promotes myofibroblast development, prolongs myofibroblast viability and triggers stromal scarring fibrosis.
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http://dx.doi.org/10.1016/j.exer.2020.108325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856119PMC
January 2021

Fibroblastic and bone marrow-derived cellularity in the corneal stroma.

Exp Eye Res 2021 Jan 14;202:108303. Epub 2020 Oct 14.

Cole Eye Institute, I-32, Cleveland Clinic, 9500, Euclid Ave, Cleveland, OH, United States.

The unwounded, normal corneal stroma is a relatively simple, avascular tissue populated with quiescent keratocytes, along with corneal nerves and a few resident dendritic and monocyte/macrophage cells. In the past, the resting keratocytes were thought of as a homogenous cellular population, but recent work has shown local variations in vimentin and nestin expression, and responsiveness to transforming growth factor (TGF)-β1. Studies have also supported there being "stromal stem cells" in localized areas. After corneal wounding, depending on the site and severity of injury, profound changes in stromal cellularity occur. Anterior or posterior injuries to the epithelium or endothelium, respectively, trigger apoptosis of adjacent keratocytes. Many contiguous keratocytes transition to keratocan-negative corneal fibroblasts that are proliferative and produce limited amounts of disorganized extracellular matrix components. Simultaneously, large numbers of bone marrow-derived cells, including monocytes, neutrophils, fibrocytes and lymphocytes, invade the stroma from the limbal blood vessels. Ongoing adequate levels of TGFβ1, TGFβ2 and platelet-derived growth factor (PDGF) from epithelium, tears, endothelium and aqueous humor that penetrate defective or absent epithelial barrier function (EBF) and epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) drive corneal fibroblasts and fibrocytes to differentiate into alpha-smooth muscle actin (SMA)-positive myofibroblasts. If the EBF, EBM and/or DBM are repaired or replaced in a timely manner, typically measured in weeks, then corneal fibroblast and fibrocyte progeny, deprived of requisite levels of TGFβ1 and TGFβ2, undergo apoptosis or revert to their precursor cell-types. If the EBF, EBM and/or DBM are not repaired or replaced, stromal levels of TGFβ1 and TGFβ2 remain elevated, and mature myofibroblasts are generated from corneal fibroblasts and fibrocyte precursors that produce prodigious amounts of disordered extracellular matrix materials associated with scarring fibrosis. This fibrotic stromal matrix persists, at least until the EBF, EBM and/or DBM are regenerated or replaced, and keratocytes remove and reorganize the affected stromal matrix.
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http://dx.doi.org/10.1016/j.exer.2020.108303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855915PMC
January 2021

Quantitative proteomic comparison of myofibroblasts derived from bone marrow and cornea.

Sci Rep 2020 10 7;10(1):16717. Epub 2020 Oct 7.

Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA.

Myofibroblasts are fibroblastic cells that function in wound healing, tissue repair and fibrosis, and arise from bone marrow (BM)-derived fibrocytes and a variety of local progenitor cells. In the cornea, myofibroblasts are derived primarily from stromal keratocytes and from BM-derived fibrocytes after epithelial-stromal and endothelial-stromal injuries. Quantitative proteomic comparison of mature alpha-smooth muscle actin (α-SMA)+ myofibroblasts (verified by immunocytochemistry for vimentin, α-SMA, desmin, and vinculin) generated from rabbit corneal fibroblasts treated with transforming growth factor (TGF) beta-1 or generated directly from cultured BM treated with TGF beta-1 was pursued for insights into possible functional differences. Paired cornea-derived and BM-derived α-SMA+ myofibroblast primary cultures were generated from four New Zealand white rabbits and confirmed to be myofibroblasts by immunocytochemistry. Paired cornea- and BM-derived myofibroblast specimens from each rabbit were analyzed by LC MS/MS iTRAQ technology using an Orbitrap Fusion Lumos Tribrid mass spectrometer, the Mascot search engine, the weighted average quantification method and the UniProt rabbit and human databases. From 2329 proteins quantified with ≥ 2 unique peptides from ≥ 3 rabbits, a total of 673 differentially expressed (DE) proteins were identified. Bioinformatic analysis of DE proteins with Ingenuity Pathway Analysis implicate progenitor-dependent functional differences in myofibroblasts that could impact tissue development. Our results suggest BM-derived myofibroblasts may be more prone to the formation of excessive cellular and extracellular material that are characteristic of fibrosis.
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http://dx.doi.org/10.1038/s41598-020-73686-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541534PMC
October 2020

Corneal myofibroblasts and fibrosis.

Authors:
Steven E Wilson

Exp Eye Res 2020 12 30;201:108272. Epub 2020 Sep 30.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Myofibroblasts are alpha-smooth muscle actin (SMA)+ cells that have a critical role in the corneal stromal response to infections, injuries, and surgeries, and which produce corneal scarring fibrosis when they develop in excess. These contractile and opaque cells-produce large amounts of disordered extracellular matrix (ECM)-and develop from keratocyte-derived corneal fibroblasts or bone marrow-derived fibrocytes, and possibly other cell types, in response to TGFβ1, TGFβ2 and PDGF from the epithelium, tears, endothelium, and other stromal cells. Recent proteomic analyses have revealed that the myofibroblasts that develop from different progenitors aren't interchangeable, but have major differences in protein expression and functions. Absence or defective regeneration of the epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) results in development and persistence of myofibroblasts in the corneal stroma. The functions of myofibroblasts in the cornea include production of volume-additive ECM, tissue contraction, production of various growth factors, cytokines and chemokines that regulate stromal cells, including other myofibroblasts, production of collagenases and metalloproteinases involved in tissue remodeling, and the expression of toll-like receptors that likely have critical roles in the clearance of bacteria and viruses causing corneal infections.
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http://dx.doi.org/10.1016/j.exer.2020.108272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736212PMC
December 2020

Biological effects of mitomycin C on late corneal haze stromal fibrosis following PRK.

Exp Eye Res 2020 11 6;200:108218. Epub 2020 Sep 6.

The Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

This review details the current understanding of the mechanism of action and corneal effects of mitomycin C (MMC) for prophylactic prevention of stromal fibrosis after photorefractive keratectomy (PRK), and includes discussion of available information on dosage and exposure time recommended for MMC during PRK. MMC is an alkylating agent, with DNA-crosslinking activity, that inhibits DNA replication and cellular proliferation. It acts as a pro-drug and requires reduction in the tissue to be converted to an active agent capable of DNA alkylation. Although MMC augments the early keratocyte apoptosis wave in the anterior corneal stroma, its most important effect responsible for inhibition of fibrosis in surface ablation procedures such as PRK is via the inhibition of mitosis of myofibroblast precursor cells during the first few weeks after PRK. MMC use is especially useful when treating eyes with higher levels of myopia (≥approximately 6 D), which have shown higher risk of developing fibrosis (also clinically termed late haze). Studies have supported the use of MMC at a concentration of 0.02%, rather than lower doses (such as 0.01% or 0.002%), for optimal reduction of fibrosis after PRK. Exposure times for 0.02% MMC longer than 40 s may be beneficial for moderate to high myopia (≥6D), but shorter exposures times appear to be equally effective for lower levels of myopia. Although MMC treatment may also be beneficial in preventing fibrosis after PRK treatments for hyperopia and astigmatism, more studies are needed. Thus, despite the clinical use of MMC after PRK for nearly twenty years-with limited evidence of harmful effects in the cornea-many decades of experience will be needed to exclude late long-term effects that could be noted after MMC treatment.
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http://dx.doi.org/10.1016/j.exer.2020.108218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655619PMC
November 2020

3D in vitro corneal models: A review of current technologies.

Exp Eye Res 2020 11 3;200:108213. Epub 2020 Sep 3.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Three-dimensional (3D) in vitro models are excellent tools for studying complex biological systems because of their physiological similarity to in vivo studies, cost-effectiveness and decreased reliance on animals. The influence of tissue microenvironment on the cells, cell-cell interaction and the cell-matrix interactions can be elucidated in 3D models, which are difficult to mimic in 2D cultures. In order to develop a 3D model, the required cell types are derived from the tissues or stem cells. A 3D tissue/organ model typically includes all the relevant cell types and the microenvironment corresponding to that tissue/organ. For instance, a full corneal 3D model is expected to have epithelial, stromal, endothelial and nerve cells, along with the extracellular matrix and membrane components associated with the cells. Although it is challenging to develop a corneal 3D model, several attempts have been made and various technologies established which closely mimic the in vivo environment. In this review, three major technologies are highlighted: organotypic cultures, organoids and 3D bioprinting. Also, several combinations of organotypic cultures, such as the epithelium and stroma or endothelium and neural cultures are discussed, along with the disease relevance and potential applications of these models. In the future, new biomaterials will likely promote better cell-cell and cell-matrix interactions in organotypic corneal cultures.
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http://dx.doi.org/10.1016/j.exer.2020.108213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655665PMC
November 2020

The Efficacy of Topical HGF on Corneal Fibrosis and Epithelial Healing after Scar-Producing PRK Injury in Rabbits.

Transl Vis Sci Technol 2020 03 30;9(4):29. Epub 2020 Mar 30.

The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA.

Purpose: To determine the effect of topical hepatocyte growth factor (HGF) on myofibroblast development and corneal opacity after fibrosis-producing photorefractive keratectomy (PRK).

Methods: Twelve New Zealand rabbits had transepithelial PRK. Six rabbits received topical recombinant human HGF (rhHGF) (50 µL of 0.1 mg/mL) 3 times a day for 1 week beginning 6 hours prior surgery and until full closure of the epithelium, and 6 control rabbits received vehicle by the same schedule. Slit lamp photos were taken immediately and at 43 to 45 hours after surgery to determine the rate of epithelial healing. Slit lamp photographs and immunohistochemistry for α-smooth muscle actin were analyzed at 1 month in masked fashion.

Results: The rhHGF group tended to have slower re-epithelization when compared with the controls, but no statistically significant difference was noted ( = 0.62). There was no significant difference in the density of myofibroblasts in the central stroma ( = 0.49) or corneal opacity ( = 0.84) between the HGF and control groups at 1 month after PRK.

Conclusions: Topical rhHGF applied three times a day during the early postoperative period prior to epithelial closure did not significantly change the corneal epithelial healing rate, myofibroblast density, or opacity compared with vehicle after transepithelial -9.0 D PRK injury of the central cornea in rabbits.

Translational Relevance: HGF has been reported to decrease myofibroblast generation and fibrosis in many organs, but topical HGF applied to the cornea until epithelial healing had no effect on scarring fibrosis in rabbit corneas.
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http://dx.doi.org/10.1167/tvst.9.4.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396189PMC
March 2020

In Memoriam James L. Funderburgh, PhD (1945-2019).

Exp Eye Res 2020 Aug 12;197:108144. Epub 2020 Jul 12.

Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/j.exer.2020.108144DOI Listing
August 2020

In Memoriam, James D. Zieske, Ph.D. (1954-2020).

Authors:
Steven E Wilson

Exp Eye Res 2020 Aug 12;197:108142. Epub 2020 Jul 12.

Cole Eye Institute, The Cleveland Clinic, United States. Electronic address:

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http://dx.doi.org/10.1016/j.exer.2020.108142DOI Listing
August 2020

Biology of keratorefractive surgery- PRK, PTK, LASIK, SMILE, inlays and other refractive procedures.

Authors:
Steven E Wilson

Exp Eye Res 2020 09 10;198:108136. Epub 2020 Jul 10.

Cole Eye Institute, I-32, Cleveland Clinic, 9500, Euclid Ave, Cleveland, OH, United States. Electronic address:

The outcomes of refractive surgical procedures to improve uncorrected vision in patients-including photorefractive keratectomy (PRK), laser in-situ keratomileusis (LASIK), Small Incision Lenticule Extraction (SMILE) and corneal inlay procedures-is in large part determined by the corneal wound healing response after surgery. The wound healing response varies depending on the type of surgery, the level of intended correction of refractive error, the post-operative inflammatory response, generation of opacity producing myofibroblasts and likely poorly understood genetic factors. This article details what is known about these specific wound healing responses that include apoptosis of keratocytes and myofibroblasts, mitosis of corneal fibroblasts and myofibroblast precursors, the development of myofibroblasts from keratocyte-derived corneal fibroblasts and bone marrow-derived fibrocytes, deposition of disordered extracellular matrix by corneal fibroblasts and myofibroblasts, healing of the epithelial injury, and regeneration of the epithelial basement membrane. Problems with epithelial and stromal cellular viability and function that are altered by corneal inlays are also discussed. A better understanding of the wound healing response in refractive surgical procedures is likely to lead to better treatments to improve outcomes, limit complications of keratorefractive surgical procedures, and improve the safety and efficiency of refractive surgical procedures.
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http://dx.doi.org/10.1016/j.exer.2020.108136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508965PMC
September 2020

Welcome to the first corneal special issue.

Authors:
Steven E Wilson

Exp Eye Res 2020 08 7;197:108143. Epub 2020 Jul 7.

The Cole Eye Institute, The Cleveland Clinic, United States. Electronic address:

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http://dx.doi.org/10.1016/j.exer.2020.108143DOI Listing
August 2020

Corneal wound healing.

Authors:
Steven E Wilson

Exp Eye Res 2020 08 15;197:108089. Epub 2020 Jun 15.

Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, United States. Electronic address:

The corneal wound healing response is typically initiated by injuries to the epithelium and/or endothelium that may also involve the stroma. However, it can also be triggered by immune or infectious processes that enter the stroma via the limbal blood vessels. For mild injuries or infections, such as epithelial abrasions or mild controlled microbial infections, limited keratocyte apoptosis occurs and the epithelium or endothelium regenerates, the epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) is repaired, and keratocyte- or fibrocyte-derived myofibroblast precursors either undergo apoptosis or revert to the parent cell types. For more severe injuries with extensive damage to EBM and/or DBM, delayed regeneration of the basement membranes leads to ongoing penetration of the pro-fibrotic cytokines transforming growth factor (TGF) β1, TGFβ2 and platelet-derived growth factor (PDGF) that drive the development of mature alpha-smooth muscle actin (SMA)+ myofibroblasts that secrete large amounts of disordered extracellular matrix (ECM) components to produce scarring stromal fibrosis. Fibrosis is dynamic with ongoing mitosis and development of SMA + myofibroblasts and continued autocrine-or paracrine interleukin (IL)-1-mediated apoptosis of myofibroblasts and their precursors. Eventual repair of the EBM and/or DBM can lead to at least partial resolution of scarring fibrosis.
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http://dx.doi.org/10.1016/j.exer.2020.108089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483425PMC
August 2020

Descemet's membrane development, structure, function and regeneration.

Exp Eye Res 2020 08 6;197:108090. Epub 2020 Jun 6.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Basement membranes are layers of extracellular matrix which anchor the epithelium or endothelium to connective tissues in most organs. Descemet's membrane- which is the basement membrane for the corneal endothelium- is a dense, thick, relatively transparent and cell-free matrix that separates the posterior corneal stroma from the underlying endothelium. It was historically named Descemet's membrane after Jean Descemet, a French physician, but it is also known as the posterior limiting elastic lamina, lamina elastica posterior, and membrane of Demours. Normal Descemet's membrane ultrastructure in humans has been shown to consist of an interfacial matrix that attaches to the overlying corneal stroma, an anterior banded layer and a posterior non-banded layer-upon which corneal endothelial cells attach. These layers have been shown to have unique composition and morphology, and to contribute to corneal homeostasis and clarity, participate in the control of corneal hydration and to modulate TGF-β-induced posterior corneal fibrosis. Pathophysiological alterations of Descemet's membrane are noted in ocular diseases such as Fuchs' dystrophy, bullous keratopathy, keratoconus, primary congenital glaucoma (Haab's striae), as well as in systemic conditions. Unrepaired extensive damage to Descemet's membrane results in severe corneal opacity and vision loss due to stromal fibrosis, which may require penetrating keratoplasty to restore corneal transparency. The purpose of this article is to highlight the current understanding of Descemet's membrane structure, function and potential for regeneration.
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http://dx.doi.org/10.1016/j.exer.2020.108090DOI Listing
August 2020

Bowman's layer in the cornea- structure and function and regeneration.

Authors:
Steven E Wilson

Exp Eye Res 2020 06 24;195:108033. Epub 2020 Apr 24.

Cole Eye Institute, I-32, Cleveland Clinic, 9500, Euclid Ave, Cleveland, OH, United States. Electronic address:

Bowman's layer lies immediately posterior to the epithelial basement membrane (EBM) and anterior to the stroma proper in humans, chickens, quail, zebra fish, deer, giraffe, antelope, California sea lions, guinea pig and several other species. It is not found in dog, wolf, cat, tiger, lions, rabbit, pigs, cows, goats, or horses. Developmental anomalies of Bowman's layer are rare, but acquired damage to Bowman's layer, or even complete destruction, is frequently seen in advanced bullous keratopathy or Fuchs' endothelial dystrophy. No detrimental effects of removal of Bowman's layer over the central 6-7 mm of central cornea have been noted in millions of patients who've had photorefractive keratectomy (PRK). Recent studies have suggested the randomly-oriented collagen fibrils that make up Bowman's layer do not have a significant barrier function in modulating the passage of moderate- to large-sized proteins. It is hypothesized that Bowman's layer develops in the corneas of those species that have one because of cytokine-mediated interactions occurring between corneal epithelial cells and underlying keratocytes, including negative chemotactic and apoptotic effects on the keratocytes by low levels of cytokines such as interleukin-1α that are gradually released as epithelial cells die and slough during their normal development. A "Bowman's like layer" can generate around stromal epithelial plugs after radial keratotomy, and possibly beneath the central corneal epithelial basement membrane many years after PRK.
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http://dx.doi.org/10.1016/j.exer.2020.108033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283008PMC
June 2020

Corneal epithelial basement membrane: Structure, function and regeneration.

Exp Eye Res 2020 05 13;194:108002. Epub 2020 Mar 13.

University of Sao Paulo, Sao Paulo, Brazil.

Basement membranes are highly specialized extracellular matrices. More than providing scaffolds, basement membranes are recognized as dynamic and versatile structures that modulate cellular responses to regulate tissue development, function, and repair. Increasing evidence suggests that, in addition to providing structural support to adjacent cells, basement membranes serve as reservoirs and modulators of growth factors that direct and fine-tune cellular functions. Since the corneal stroma is avascular and has a relatively low keratocyte density, it's likely that the corneal BM is different in composition from the BMs in other tissues. BMs are composed of a diverse assemblage of extracellular molecules, some of which are likely specific to the tissue where they function; but in general they are composed of four primary components-collagens, laminins, heparan sulfate proteoglycans, and nidogens-in addition to other components such as thrombospondin-1, matrilin-2, and matrilin-4 and fibronectin. Severe injuries to the cornea, including infection, surgery, and trauma, may trigger the development of myofibroblasts and fibrosis in the normally transparent connective tissue stroma. Ultrastructural studies have demonstrated that defective epithelial basement membrane (EBM) regeneration after injury to the cornea underlies the development of myofibroblasts from both bone marrow- and keratocyte-derived precursor cells. Defective EBM permits epithelium-derived and tear-derived transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), and possibly other modulators, to penetrate the stroma at sustained levels necessary to drive the development and persistence of vimentin + alpha-smooth muscle actin + desmin+ (V + A + D+) mature myofibroblasts. A recent discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts produce critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte/corneal fibroblast contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored if the EBM is fully regenerated, myofibroblasts are deprived of TGF-β and undergo apoptosis, and keratocytes reoccupy the anterior stroma and reabsorb the disordered extracellular matrix.
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http://dx.doi.org/10.1016/j.exer.2020.108002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217741PMC
May 2020

Fibrocytes, Wound Healing, and Corneal Fibrosis.

Invest Ophthalmol Vis Sci 2020 02;61(2):28

,.

Purpose: This review highlights the roles of fibrocytes-their origin, markers, regulation and functions-including contributions to corneal wound healing and fibrosis.

Methods: Literature review.

Results: Peripheral blood fibroblast-like cells, called fibrocytes, are primarily generated as mature collagen-producing cells in the bone marrow. They are likely derived from the myeloid lineage, although the exact precursor remains unknown. Fibrocytes are identified by a combination of expressed markers, such as simultaneous expression of CD34 or CD45 or CD11b and collagen type I or collagen type III. Fibrocytes migrate into the wound from the blood where they participate in pathogen clearance, tissue regeneration, wound closure and angiogenesis. Transforming growth factor beta 1 (TGF-β1) and adiponectin induce expression of α-smooth muscle actin and extracellular matrix proteins through activation of Smad3 and adenosine monophosphate-activated protein kinase pathways, respectively. Fibrocytes are important contributors to the cornea wound healing response and there are several mechanisms through which fibrocytes contribute to fibrosis in the cornea and other organs, such as their differentiation into myofibroblasts, production of matrix metalloproteinase, secretion of tissue inhibitor of metalloproteinase, and release of TGF-β1. In some tissues, fibrocytes may also contribute to the basement membrane regeneration and to the resolution of fibrosis.

Conclusions: New methods that block fibrocyte generation, fibrocyte migration, and their differentiation into myofibroblasts, as well as their production of matrix metalloproteinases, tissue inhibitor of metalloproteinase, and TGF-β1, have therapeutic potential to reduce the accumulation of collagens, maintain tissue integrity and retard or prevent the development of fibrosis.
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http://dx.doi.org/10.1167/iovs.61.2.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326569PMC
February 2020

Pathophysiology and Treatment of Diffuse Lamellar Keratitis.

J Refract Surg 2020 Feb;36(2):124-130

Purpose: To review cytokine- and chemokine-mediated mechanisms of diffuse lamellar keratitis (DLK) after lamellar corneal surgical procedures.

Methods: Review of the basic science and clinical literature.

Results: DLK can occur early or late (months to decades) after all lamellar corneal surgeries, including laser in situ keratomileusis, small incision lenticule extraction, anterior lamellar keratoplasty, and Descemet's stripping automated endothelial keratoplasty. It is most commonly triggered by epithelial injury during or after lamellar surgery, which leads to the release of interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α from the epithelium and into the stroma. These chemokines directly attract inflammatory cells into the cornea from the limbal blood vessels and also bind to receptors on keratocytes and corneal fibroblasts where myriad chemokines are upregulated that also chemotactically attract monocytes, macrophages, granulocytes, lymphocytes, and other bone marrow-derived cells into the corneal stroma. Other factors that can trigger DLK include retained blood in the interface, endotoxins and other toxins, and excessive keratocyte necrosis caused by femtosecond lasers. Infiltrating cells show a preference to enter any lamellar interface in the cornea, regardless of the time since surgery, because of the ease of movement toward the chemotactic attractants relative to the surrounding stroma with intact collagen lamellae and stromal cells that serve as relative barriers impeding motility. The mainstay of treatment is topical corticosteroids, but severe cases may also be treated with flap lift irrigation and systemic corticosteroids.

Conclusions: DLK can occur early or late after any lamellar corneal surgical procedure and is most commonly triggered by epithelial-stromal-bone marrow-derived cellular interactions mediated by corneal cytokines and chemokines. [J Refract Surg. 2020;36(2):124-130.].
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http://dx.doi.org/10.3928/1081597X-20200114-01DOI Listing
February 2020

Coordinated Modulation of Corneal Scarring by the Epithelial Basement Membrane and Descemet's Basement Membrane.

Authors:
Steven E Wilson

J Refract Surg 2019 Aug;35(8):506-516

Purpose: To provide an overview of the importance of the coordinated role of the epithelial basement membrane (EBM) and Descemet's basement membrane (DBM) in modulating scarring (fibrosis) in the cornea after injuries, infections, surgeries, and diseases of the cornea.

Methods: Literature review.

Results: Despite their molecular and ultrastructural differences, the EBM and DBM act in a coordinated fashion to modulate the entry of transforming growth factor beta (TGF-β) and other growth factors from the epithelium/tear film and aqueous humor, respectively, into the corneal stroma where persistent levels of these modulators trigger the development and persistence of myofibroblasts that produced disordered, opaque extracellular matrix not usually present in the corneal stroma. The development of these myofibroblasts and the extracellular matrix they produce is often detrimental to visual function of the cornea after penetrating keratoplasty, LASIK buttonhole flaps, persistent epithelial defects, microbial keratitis, Descemet stripping automated endothelial keratoplasty, or Descemet membrane endothelial keratoplasty, while being beneficial in other situations such as the scarred edge of LASIK flaps and donor-recipient interface in penetrating keratoplasty. Efforts to modulate the repair or replacement of the EBM and DBM, and thereby the development or disappearance of myofibroblasts, should be a major emphasis of treatments provided by refractive and corneal surgeries, infections, trauma, or diseases of the cornea.

Conclusions: The EBM and DBM are critical modulators of the localization of profibrotic growth factors, such as TGF-β, that modulate the development and persistence of myofibroblasts that produce corneal scars (stromal fibrosis). Therapeutic efforts to regenerate or repair EBM and/or DBM, and interfere with the development of myofibroblasts or facilitate their disappearance are often the key to clinical outcomes. [J Refract Surg. 2019;35(8):506-516.].
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http://dx.doi.org/10.3928/1081597X-20190625-02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820003PMC
August 2019

Practical guidance for the use of cyclosporine ophthalmic solutions in the management of dry eye disease.

Clin Ophthalmol 2019 1;13:1115-1122. Epub 2019 Jul 1.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.

Dry eye disease (DED) is a multifactorial disease of ocular surface and tear film, and is a common disorder treated by eye care providers. It is well established that ocular surface inflammation has an important role in the pathophysiology of DED and that anti-inflammatory cyclosporine A (CsA) improves the treatment outcomes of most patients with DED. The purpose of this review is to provide guidance for practitioners in the use of topical CsA for the management of DED to improve patient satisfaction and the quality of life.
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http://dx.doi.org/10.2147/OPTH.S184412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612764PMC
July 2019

Descemet's Membrane Modulation of Posterior Corneal Fibrosis.

Invest Ophthalmol Vis Sci 2019 03;60(4):1010-1020

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States.

Purpose: The purpose of this study was to evaluate the effect of removal of Descemet's basement membrane and endothelium compared with removal of the endothelium alone on posterior corneal fibrosis.

Methods: Twelve New Zealand White rabbits were included in the study. Six eyes had removal of the Descemet's membrane-endothelial complex over the central 8 mm of the cornea. Six eyes had endothelial removal with an olive-tipped cannula over the central 8 mm of the cornea. All corneas developed stromal edema. Corneas in both groups were cryofixed in optimum cutting temperature (OCT) formula at 1 month after surgery. Immunohistochemistry (IHC) was performed for α-smooth muscle actin (SMA), keratocan, CD45, nidogen-1, vimentin, and Ki-67, and a TUNEL assay was performed to detect apoptosis.

Results: Six of six corneas that had Descemet's membrane-endothelial removal developed posterior stromal fibrosis populated with SMA+ myofibroblasts, whereas zero of six corneas that had endothelial removal alone developed fibrosis or SMA+ myofibroblasts (P < 0.01). Myofibroblasts in the fibrotic zone of corneas that had Descemet's membrane-endothelial removal were undergoing both mitosis and apoptosis at 1 month after surgery. A zone between keratocan+ keratocytes and SMA+ myofibroblasts contained keratocan-SMA-vimentin+ cells that were likely CD45- corneal fibroblasts and CD45+ fibrocytes.

Conclusions: Descemet's basement membrane has an important role in modulating posterior corneal fibrosis after injury that is analogous to the role of the epithelial basement membrane in modulating anterior corneal fibrosis after injury. Fibrotic areas had myofibroblasts undergoing mitosis and apoptosis, indicating that fibrosis is in dynamic flux.
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http://dx.doi.org/10.1167/iovs.18-26451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424532PMC
March 2019

Validation of the Percent Tissue Altered as a Risk Factor for Ectasia after LASIK.

Ophthalmology 2019 06 25;126(6):908-909. Epub 2019 Jan 25.

Department of Ophthalmology, University of Southern California, Los Angeles, California.

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http://dx.doi.org/10.1016/j.ophtha.2019.01.018DOI Listing
June 2019

The Impact of Photorefractive Keratectomy and Mitomycin C on Corneal Nerves and Their Regeneration.

J Refract Surg 2018 12;34(12):790-798

Purpose: To determine how photorefractive keratectomy (PRK) and mitomycin C (MMC) affect corneal nerves and their regeneration over time after surgery.

Methods: Twenty-eight New Zealand rabbits had corneal epithelial scraping with (n = 3) and without (n = 3) MMC 0.02% or -9.00 diopter PRK with (n = 6) and without (n = 16) MMC 0.02%. Corneas were removed after death and corneal nerve morphology was evaluated using acetylcholinesterase immunohistochemistry and beta-III tubulin staining after 1 day for all groups, after 1 month for PRK with and without MMC, and 2, 3, and 6 months after PRK without MMC. Image-Pro software (Media Cybernetics, Rockville, MD) was used to quantitate the area of nerve loss after the procedures and, consequently, regeneration of the nerves over time. Opposite eyes were used as controls.

Results: Epithelial scraping with MMC treatment did not show a statistically significant difference in nerve loss compared to epithelial scraping without MMC (P = .40). PRK with MMC was significantly different from PRK without MMC at 1 day after surgery (P = .0009) but not different at 1 month after surgery (P = .90). In the PRK without MMC group, nerves regenerated at 2 months (P < .0001) but did not return to the normal preoperative level of innervation until 3 months after surgery (P = .05). However, the morphology of the regenerating nerves was abnormal-with more tortuosity and aberrant innervation compared to the preoperative controls-even at 6 months after surgery.

Conclusions: PRK negatively impacts the corneal nerves, but they are partially regenerated by 3 months after surgery in rabbits. Nerve loss after PRK extended peripherally to the excimer laser ablated zone, indicating that there was retrograde degeneration of nerves after PRK. MMC had a small additive toxic effect on the corneal nerves when combined with PRK that was only significant prior to 1 month after surgery. [J Refract Surg. 2018;34(12):790-798.].
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http://dx.doi.org/10.3928/1081597X-20181112-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360090PMC
December 2018

IL-1 and TGF-β Modulation of Epithelial Basement Membrane Components Perlecan and Nidogen Production by Corneal Stromal Cells.

Invest Ophthalmol Vis Sci 2018 11;59(13):5589-5598

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States.

Purpose: To determine whether (1) the in vitro expression of epithelial basement membrane components nidogen-1, nidogen-2, and perlecan by keratocytes, corneal fibroblasts, and myofibroblasts is modulated by cytokines/growth factors, and (2) perlecan protein is produced by stromal cells after photorefractive keratectomy.

Methods: Marker-verified rabbit keratocytes, corneal fibroblasts, myofibroblasts were stimulated with TGF-β1, IL-1α, IL-1β, TGF-β3, platelet-derived growth factor (PDGF)-AA, or PDGF-AB. Real-time quantitative RT-PCR was used to detect expression of nidogen-1, nidogen-2, and perlecan mRNAs. Western blotting evaluated changes in protein expression. Immunohistochemistry was performed on rabbit corneas for perlecan, alpha-smooth muscle actin, keratocan, vimentin, and CD45 at time points from 1 day to 1 month after photorefractive keratectomy (PRK).

Results: IL-1α or -1β significantly upregulated perlecan mRNA expression in keratocytes. TGF-β1 or -β3 markedly downregulated nidogen-1 or -2 mRNA expression in keratocytes. None of these cytokines had significant effects on nidogen-1, -2, or perlecan mRNA expression in corneal fibroblasts or myofibroblasts. IL-1α significantly upregulated, while TGF-β1 significantly downregulated, perlecan protein expression in keratocytes. Perlecan protein expression was upregulated in anterior stromal cells at 1 and 2 days after -4.5 or -9 diopters (D) PRK, but the subepithelial localization of perlecan became disrupted at 7 days and later time points in -9-D PRK corneas when myofibroblasts populated the anterior stroma.

Conclusions: IL-1 and TGF-β1 have opposing effects on perlecan and nidogen expression by keratocytes in vitro. Proximate participation of keratocytes is likely needed to regenerate normal epithelial basement membrane after corneal injury.
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http://dx.doi.org/10.1167/iovs.18-25202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262649PMC
November 2018

Basement membranes in the cornea and other organs that commonly develop fibrosis.

Cell Tissue Res 2018 Dec 3;374(3):439-453. Epub 2018 Oct 3.

Cole Eye Institute, Cleveland Clinic, Cleveland Clinic, 9500 Euclid Ave, I-32, Cleveland, OH, USA.

Basement membranes are thin connective tissue structures composed of organ-specific assemblages of collagens, laminins, proteoglycan-like perlecan, nidogens, and other components. Traditionally, basement membranes are thought of as structures which primarily function to anchor epithelial, endothelial, or parenchymal cells to underlying connective tissues. While this role is important, other functions such as the modulation of growth factors and cytokines that regulate cell proliferation, migration, differentiation, and fibrosis are equally important. An example of this is the critical role of both the epithelial basement membrane and Descemet's basement membrane in the cornea in modulating myofibroblast development and fibrosis, as well as myofibroblast apoptosis and the resolution of fibrosis. This article compares the ultrastructure and functions of key basement membranes in several organs to illustrate the variability and importance of these structures in organs that commonly develop fibrosis.
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http://dx.doi.org/10.1007/s00441-018-2934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258348PMC
December 2018

The Corneal Basement Membranes and Stromal Fibrosis.

Invest Ophthalmol Vis Sci 2018 08;59(10):4044-4053

The Cole Eye Institute, The Cleveland Clinic, Cleveland, Ohio, United States.

Purpose: The purpose of this review was to provide detailed insights into the pathophysiology of myofibroblast-mediated fibrosis (scarring or late haze) after corneal injury, surgery, or infection.

Method: Literature review.

Results: The epithelium and epithelial basement membrane (EBM) and/or endothelium and Descemet's basement membrane (BM) are commonly disrupted after corneal injuries, surgeries, and infections. Regeneration of these critical regulatory structures relies on the coordinated production of BM components, including laminins, nidogens, perlecan, and collagen type IV by epithelial, endothelial, and keratocyte cells. Whether a cornea, or an area in the cornea, heals with transparency or fibrosis may be determined by whether there is injury to one or both corneal basement membranes (EBM and/or Descemet's BM) and delayed or defective regeneration or replacement of the BM. These opaque myofibroblasts, and the disordered extracellular matrix these cells produce, persist in the stroma until the EBM and/or Descemet's BM is regenerated or replaced.

Conclusions: Corneal stromal fibrosis (also termed "stromal scarring" or "late haze") occurs as a consequence of BM injury and defective regeneration in both the anterior (EBM) and posterior (Descemet's BM) cornea. The resolution of fibrosis and return of stromal transparency depends on reestablished BM structure and function. It is hypothesized that defective regeneration of the EBM or Descemet's BM allows key profibrotic growth factors, including transforming growth factor beta-1 (TGF-β1) and TGF-β2, to penetrate the stroma at sustained levels necessary to drive the development and maintenance of mature opacity-producing myofibroblasts from myofibroblast precursors cells, and studies suggest that perlecan and collagen type IV are the critical components in EBM and Descemet's BM that bind TGF-β1, TGF-β2, platelet-derived growth factor, and possibly other growth factors, and regulate their bioavailability and function during homeostasis and corneal wound healing.
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http://dx.doi.org/10.1167/iovs.18-24428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088801PMC
August 2018

Posterior stromal cell apoptosis triggered by mechanical endothelial injury and basement membrane component nidogen-1 production in the cornea.

Exp Eye Res 2018 07 27;172:30-35. Epub 2018 Mar 27.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

This study was performed to determine whether cells in the posterior stroma undergo apoptosis in response to endothelial cell injury and to determine whether basement membrane component nidogen-1 was present in the cornea. New Zealand White rabbits had an olive tip cannula inserted into the anterior chamber to mechanically injure corneal endothelial cells over an 8 mm diameter area of central cornea with minimal injury to Descemet's membrane. At 1 h (6 rabbits) and 4 h (6 rabbits) after injury, three corneas at each time point were cryopreserved in OCT for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry (IHC) for vimentin and nidogen-1, and three corneas at each time point were fixed for transmission electron microscopy (TEM). Uninjured corneas were controls. Stromal cells over approximately the posterior 25% of the stroma overlying to the site of corneal endothelial injury underwent apoptosis detected by the TUNEL assay. Many of these apoptotic cells were vimentin+, suggesting they were likely keratocytes or corneal fibroblasts. Stromal cells peripheral to the site of endothelial injury and more anterior stromal cells overlying the site of endothelial injury did not undergo apoptosis. Stromal cell death was confirmed to be apoptosis by TEM. No apoptosis of stromal cells was detected in control, uninjured corneas. Nidogen-1 was detected in the stroma of unwounded corneas, with higher nidogen-1 in the posterior stroma than the anterior stroma. After endothelial scrape injury, concentrations of nidogen-1 appeared to be in the extracellular matrix of the posterior stroma and, possibly, within apoptotic bodies of stromal cells. Thus, posterior stromal cells, likely including keratocytes, undergo apoptosis in response to corneal endothelial injury, analogous to anterior keratocytes undergoing apoptosis in response to epithelial injury.
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http://dx.doi.org/10.1016/j.exer.2018.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994196PMC
July 2018

Fibrocyte migration, differentiation and apoptosis during the corneal wound healing response to injury.

Exp Eye Res 2018 05 24;170:177-187. Epub 2018 Feb 24.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States. Electronic address:

The aim of this study was to determine whether bone marrow-derived fibrocytes migrate into the cornea after stromal scar-producing injury and differentiate into alpha-smooth muscle actin (αSMA) + myofibroblasts. Chimeric mice expressing green fluorescent protein (GFP) bone marrow cells had fibrosis (haze)-generating irregular phototherapeutic keratectomy (PTK). Multiplex immunohistochemistry (IHC) for GFP and fibrocyte markers (CD34, CD45, and vimentin) was used to detect fibrocyte infiltration into the corneal stroma and the development of GFP+ αSMA+ myofibroblasts. IHC for activated caspase-3, GFP and CD45 was used to detect fibrocyte and other hematopoietic cells undergoing apoptosis. Moderate haze developed in PTK-treated mouse corneas at 14 days after surgery and worsened, and persisted, at 21 days after surgery. GFP+ CD34+ CD45+ fibrocytes, likely in addition to other CD34+ and/or CD45+ hematopoietic and stem/progenitor cells, infiltrated the cornea and were present in the stroma in high numbers by one day after PTK. The fibrocytes and other bone marrow-derived cells progressively decreased at four days and seven days after surgery. At four days after PTK, 5% of the GFP+ cells expressed activated caspase-3. At 14 days after PTK, more than 50% of GFP+ CD45+ cells were also αSMA+ myofibroblasts. At 21 days after PTK, few GFP+ αSMA+ cells persisted in the stroma and more than 95% of those remaining expressed activated caspase-3, indicating they were undergoing apoptosis. GFP+ CD45+ SMA+ cells that developed from 4 to 21 days after irregular PTK were likely developed from fibrocytes. After irregular PTK in the strain of C57BL/6-C57/BL/6-Tg(UBC-GFP)30Scha/J chimeric mice, however, more than 95% of fibrocytes and other hematopoietic cells underwent apoptosis prior to the development of mature αSMA+ myofibroblasts. Most GFP+ CD45+ αSMA+ myofibroblasts that did develop subsequently underwent apoptosis-likely due to epithelial basement membrane regeneration and deprivation of epithelium-derived TGFβ requisite for myofibroblast survival.
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http://dx.doi.org/10.1016/j.exer.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924631PMC
May 2018

Pathophysiology of Corneal Scarring in Persistent Epithelial Defects After PRK and Other Corneal Injuries.

J Refract Surg 2018 Jan;34(1):59-64

Purpose: To analyze corneal persistent epithelial defects that occurred at 3 to 4 weeks after -4.50 diopter (D) photorefractive keratectomy (PRK) in rabbits and apply this pathophysiology to the treatment of persistent epithelial defects that occur after any corneal manipulations or diseases.

Methods: Two of 168 corneas that had -4.50 D PRK to study epithelial basement membrane regeneration developed spontaneous persistent epithelial defects that did not heal at 3 weeks after PRK. These were studied with slit-lamp photographs, immunohistochemistry for the myofibroblast marker alpha-smooth muscle actin (α-SMA), and transmission electron microscopy.

Results: Myofibroblasts developed at the stromal surface within the persistent epithelial defect and for a short distance peripheral to the leading edge of the epithelium. No normal epithelial basement membrane was detectable within the persistent epithelial defect or for up to 0.3 mm behind the leading edge of the epithelium, although epithelial basement membrane had normally regenerated in other areas of the zone ablated by an excimer laser where the epithelium healed promptly.

Conclusions: A persistent epithelial defect in the cornea results in the development of myofibroblasts and disordered extracellular matrix produced by these cells that together cause opacity within, and a short distance beyond, the persistent epithelial defect. Clinicians should treat persistent epithelial defects within 10 days of non-closure of the epithelium to facilitate epithelial healing to prevent long-term stromal scarring (fibrosis). [J Refract Surg. 2018;34(1):59-64.].
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http://dx.doi.org/10.3928/1081597X-20171128-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788463PMC
January 2018

Femtosecond Lasers and Corneal Surgical Procedures.

Asia Pac J Ophthalmol (Phila) 2017 Sep-Oct;6(5):456-464. Epub 2017 Jul 31.

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Our purpose is to present a broad review about the principles, early history, evolution, applications, and complications of femtosecond lasers used in refractive and nonrefractive corneal surgical procedures. Femtosecond laser technology added not only safety, precision, and reproducibility to established corneal surgical procedures such as laser in situ keratomileusis (LASIK) and astigmatic keratotomy, but it also introduced new promising concepts such as the intrastromal lenticule procedures with refractive lenticule extraction (ReLEx). Over time, the refinements in laser optics and the overall design of femtosecond laser platforms led to it becoming an essential tool for corneal surgeons. In conclusion, femtosecond laser is a heavily utilized tool in refractive and nonrefractive corneal surgical procedures, and further technological advances are likely to expand its applications.
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http://dx.doi.org/10.22608/APO.2017163DOI Listing
December 2017

TFOS DEWS II iatrogenic report.

Ocul Surf 2017 07 20;15(3):511-538. Epub 2017 Jul 20.

Aston University, Birmingham, UK.

Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. Preservatives, such as benzalkonium chloride, may further aggravate DED. A variety of systemic drugs can also induce DED secondary to multiple mechanisms. Moreover, the use of contact lens induces or is associated with DED. However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs. Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. Novel research into detection of early dry eye prior to surgeries, efforts to establish appropriate therapeutics and a greater attempt to regulate and oversee medications, preservatives and procedures should be considered.
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http://dx.doi.org/10.1016/j.jtos.2017.05.004DOI Listing
July 2017