Corneal Surface Disease Research Articles

Ten most progression of corneal and ocular surface disease research in China

Ten researches that may represent the most advanced cornea and ocular surface disease (OSD) related studies in China were voted by specialists from Chinese Cornea Group of Ophthalmology Society.These researches were concentrated in the following fields:Clinical and basic research in infectious keratitis ; clinical application of modern corneal surgeries and technology; tissue engineering corneal material development ; prevention and treatment of immune rejection after corneal transplantation,et al.These studies represented the level of our national cornea and ocular surface specialists in the international cornea and OSD field and have become the landmark study of our specialists. Key words: Cornea; Ocular surface disease; Surgical innovation ; Tissue engineering; Limbal stem cells; Immune rejection

Amniotic membrane transplantation in corneal and ocular surface diseases

The amniotic membrane has been shown to have anti-inflammatory,anti-fibrotic,anti-angiogenic properties and ability to provide a substrate for the growth of corneal and conjunctival epithelial cells,and it is an ideal material for ocular surface reconstruction.The treating patten of corneal and ocular surface diseases has changed due to the widespread using of amniotic membrane transplantation,but there are a lot of problems in the application of amniotic memebrane in clinic,such as how to grasp indications and reduce the failure rate,how to apply individual skill for different patients with corneal disease,and how to observe postoperative complicationsm and reasonably use medicine after operation.This paper give some personal experience and opinion in orde to achieve better effects in treatment of corneal and ocular surface diseases using amniotic membrane transplantation. Key words: Amniotic membrane transplantation; Corneal disease; Ocular surface disease

WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis.

The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.

Management strategies for persistent epithelial defects of the cornea

Management of patients with persistent epithelial defects of the cornea can be challenging to even the seasoned ophthalmologist. It is essential that one understands not only the pathophysiology of the failure of the epithelium to migrate and close a wound appropriately, but also the mechanism of action of the available treatment modalities at one’s disposal. This article serves as a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments that may change the way we manage corneal surface disease.

Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis

Neurotrophic keratitis (NK) represents a sight-threatening complication after trigeminal impairment. To our knowledge, the duration for which trigeminal injury may affect corneal structures and function has not been investigated previously. To describe the long-term clinical, morphological, and functional outcomes of NK after neurosurgical trigeminal damage. Observational case series performed at a corneal and ocular surface diseases referral center in 2010. Eight consecutive patients with monolateral NK from 1 to 19 years after neurosurgery and 20 age- and sex-matched healthy participants were included. Complete eye examination, tear film function tests, corneal staining, and Cochet-Bonnet esthesiometry were performed. The number and density of corneal nerves, number of hyperreflective keratocytes, and corneal epithelial, endothelial, and keratocyte cell densities were evaluated by in vivo slit scanning confocal microscopy. Clinical and morphological data were compared with the contralateral unaffected eyes and with the eyes of healthy control participants. All patients showed superficial punctate keratitis and dry eye in the NK eye and a healthy contralateral eye. Decreased corneal sensitivity was observed in all affected eyes (mean [SD], 2.0 [1.9] mm in the affected eyes vs 5.8 [0.3] mm in the contralateral unaffected eyes; P = .01) and was related to decreased subbasal nerve length (P = .04; R = 0.895). Corneal epithelial and endothelial cell densities were significantly decreased and the number of hyperreflective keratocytes was significantly increased in NK eyes compared with contralateral unaffected eyes and with the eyes of healthy participants. A longer duration of NK was associated with lower endothelial cell density (P = .046; R = -0.715). Corneal morphology and function were impaired even years after neurosurgical trigeminal damage, suggesting that assessment of tear film and corneal sensitivity as well as in vivo confocal microscopy examination should be performed in all patients with trigeminal impairment.

Cost-Effectiveness of Osteo-Odonto Keratoprosthesis in Singapore

To determine the long-term cost-effectiveness of osteo-odonto keratoprosthesis (OOKP) relative to no treatment among patients with end-stage corneal and ocular surface diseases in Singapore. Cost-effectiveness analysis based on data from a retrospective cohort study. From a health system perspective, we calculated the incremental cost-effectiveness ratio of OOKP treatment relative to no treatment over a 30-year horizon, based on data from a cohort of 23 patients who underwent OOKP surgery between 2004 and 2009 at Singapore National Eye Centre. Preoperative and postoperative vision-related quality-of-life values were estimated from patients' visual outcomes and were used to calculate the gain in quality-adjusted life years (QALYs) resulting from OOKP treatment. Unsubsidized costs for surgery, consultations, examinations, medications, follow-up visits, and treatments for complications were retrieved from patients' bills to estimate the total costs associated with OOKP treatment. Sensitivity analyses were conducted to test the robustness of the model. Over a 30-year period, OOKP treatment, compared with no treatment, improved QALYs by 3.991 among patients with end-stage corneal and ocular surface diseases at an additional cost of S$67 840 (US$55 150), resulting in an incremental cost-effectiveness ratio of S$17 000/QALY (US$13 820/QALY). Based on commonly cited cost-effectiveness benchmarks, the OOKP is a cost-effective treatment for patients with end-stage corneal and ocular surface diseases.

Ocular protection in facial paralysis

Facial nerve paralysis has a profound impact on patients' quality of life, of which one of the most important sequelae is a risk of corneal surface disease. Herein, we discuss methods to protect the eye following insult to the facial nerve. Protection of the ocular surface in patients with facial nerve injury is of paramount importance to prevent corneal injury and potential blindness. Many interventions on the eye are temporary and therefore easily reversible. A systematic approach to managing the eye is required in these patients. This article provides a review of current methods used for ocular protection in patients with facial nerve paralysis.

Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases

The cornea is one of the few tissues which actively maintain an avascular state, i.e. the absence of blood and lymphatic vessels (corneal [lymph]angiogenic privilege). Nonetheless do several diseases interfere with this privilege and cause pathologic corneal hem- and lymphangiogenesis. The ingrowths of pathologic blood and lymphatic vessels into the cornea not only reduce transparency and thereby visual acuity up to blindness, but also significantly increases the rate of graft rejections after subsequent corneal transplantation. Therefore great interest exists in new strategies to target pathologic corneal (lymph)angiogenesis to promote graft survival. This review gives an overview on the vascular anatomy of the normal ocular surface, on the molecular mechanisms contributing to the corneal (lymph)angiogenic privilege and on the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea. In addition we summarize the current preclinical and clinical evidence for three novel treatment strategies against ocular surface diseases based on targeting pathologic (lymph)angiogenesis: (a) modulation of the immune responses after (corneal) transplantation by targeting pathologic (lymph)angiogenesis prior to and after transplantation, (b) novel concepts against metastasis and recurrence of ocular surface tumors such as malignant melanoma of the conjunctiva by anti(lymph)angiogenic therapy and (c) new ideas on how to target ocular surface inflammatory diseases such as dry eye by targeting conjunctival and corneal lymphatic vessels. Based on compelling preclinical evidence and early data from clinical trials the novel therapeutic concepts of promoting graft survival, inhibiting tumor metastasis and dampening ocular surface inflammation and dry eye disease by targeting (lymph)angiogenesis are on their way to translation into the clinic.

Management of Glaucoma Following Boston Keratoprosthesis

Boston keratoprosthesis (KPro) surgery has revolutionised the treatment of corneal and ocular surface disease. At present, glaucoma is the most important vision-threatening complication following KPro surgery. Diagnosis of glaucoma in KPro patients is difficult since the current method of determining intraocular pressure (IOP) by digital palpation is subjective and dependent upon the skill of the examiner. Optic nerve evaluation and visual field testing are important tools to follow glaucoma progression. Management of glaucoma following Boston KPro consists of medical therapy and surgical options. Glaucoma drainage devices are useful in this population but can have a variety of complications. Cyclophotocoagulation, either the non-invasive transscleral method or endocyclophotocoagulation, is also useful as an adjunctive measure in glaucoma management. Appropriate diagnosis and management of glaucoma is essential after KPro surgery to reduce the chance of vision loss.

Efficacy of 3 Different Artificial Tears for the Treatment of Dry Eye in Frequent Computer Users and/or Contact Lens Users

To compare the efficacy of 3 different artificial tears (AT) acting primarily in one of the 3 tear film layers (Tears Again®, lipidic; Opticol®, aqueous; Optive®, mucin) in recovering the tear film changes in patients with dry eye symptoms due to external causes. A total of 27 patients, with dry eye symptoms associated with extra hours of computer or contact lenses use, were randomized to 4 treatment groups: A received Tears Again®; B received Optive®; C received Opticol®; D received no treatment (control). Patients were observed in 3 visits: day 0, day 7, and day 30. Tear break-up time (TBUT) and Schirmer tests and the Ocular Surface Disease Index were performed. Data analysis was performed. There were no significant differences between the groups. From day 0 to day 30, there was a decrease in the number of eyes with abnormal TBUT (not significant) and Schirmer (significant in A, B, D; p<0.031). There was an increase in the average TBUT for all groups (significant in A, C; p<0.001) and a decrease in the average Schirmer value in groups B, C, and D (not significant) and an increase in group A (p = 0.002). There was a decrease in the average Ocular Surface Disease Index value in all groups (p<0.045). All AT were efficient at recovering the tear film, but those acting primarily on the internal and intermediate layer led to a mild decline on lachrymal production. An association of different kinds of AT acting on each layer can be the best treatment for corneal surface diseases affecting eye lubrication.

Comparison of Candidate Materials for a Synthetic Osteo-Odonto Keratoprosthesis Device

Osteo-odonto keratoprosthesis is one of the most successful forms of keratoprosthesis surgery for end-stage corneal and ocular surface disease. There is a lack of detailed comparison studies on the biocompatibilities of different materials used in keratoprosthesis. The aim of this investigation was to compare synthetic bioinert materials used for keratoprosthesis surgery with hydroxyapatite (HA) as a reference. Test materials were sintered titanium oxide (TiO(2)), aluminum oxide (Al(2)O(3)), and yttria-stabilized zirconia (YSZ) with density >95%. Bacterial adhesion on the substrates was evaluated using scanning electron microscopy and the spread plate method. Surface properties of the implant discs were scanned using optical microscopy. Human keratocyte attachment and proliferation rates were assessed by cell counting and MTT assay at different time points. Morphologic analysis and immunoblotting were used to evaluate focal adhesion formation, whereas cell adhesion force was measured with a multimode atomic force microscope. The authors found that bacterial adhesion on the TiO(2), Al(2)O(3), and YSZ surfaces were lower than that on HA substrates. TiO(2) significantly promoted keratocyte proliferation and viability compared with HA, Al(2)O(3,) and YSZ. Immunofluorescent imaging analyses, immunoblotting, and atomic force microscope measurement revealed that TiO(2) surfaces enhanced cell spreading and cell adhesion compared with HA and Al(2)O(3). TiO(2) is the most suitable replacement candidate for use as skirt material because it enhanced cell functions and reduced bacterial adhesion. This would, in turn, enhance tissue integration and reduce device failure rates during keratoprosthesis surgery.

Clinical analysis of 98 cases of Corneal transplantation in treating corneal and ocular surface diseases

Objective To analyze the eharaeteristics of the penetrating keratoplasty and lamellar keratoplasty in treating corneal and ocular surface diseases. Methods The retrospective study ineluded 101 eyes in 98 patients who underwent penetrating kerato- plasty, lamellar keratoplasty, or lamellar keratoplasty combined with amnion transplantation. The postoperative visual acuity, postoperative rejection, glaucoma and reeurrence of disease were observed. They were followed-up for 6-24 months, avergely 12. 8 months. Results The postoperative visual acuity of 62 cases from 79 patients （82 eyes） （78.9%） who underwent penetrating keratoplasty was improved compared with the preoperative vision acuity. There were 11 eases （12 eyes） of rejection, 3 cases （3 eyes） of reeurrence, and 10 cases （ 10 eyes） of glaucoma. The postoperative visual acuity of patients who underwent lamellar keratoplasty was not different obviously. No secondary glaucoma or recurrence of disease was found. Rejection occurred in one case. Conclusion The corneal transplantation is the effectual method for treating corneal and ocular surface diseases and its treatment effect is affirmative. Positive precaution and treatment of postoperative complications could promote graft survival after corneal transplantation. Key words： cornea transplantation; corneal and ocular surface diseases, clinical analysis

Glial cell-derived neurotrophic factor gene delivery enhances survival of human corneal epithelium in culture and the overexpression of GDNF in bioengineered constructs

This paper evaluates the effects of adenoviral vector-mediated glial cell-derived neurotrophic factor (GDNF) gene delivery on survival of primary human corneal epithelial cells (PHCEC) established from limbal explants in vitro and the overexpression of GDNF gene in bioengineered human corneal constructs on substrate of corneal stromal discs followed by autograft ex vivo. In vitro, the overexpression of GDNF in the supernatant of PHCEC peaked at day 4, but lasted for at least 4 weeks after the transduction mediated by adenoviral vector. At day 10, the cell viability was 2-fold greater ( P < 0.001), the number of terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL)-positive cells was more than 50% lower ( P < 0.01) in the GDNF transduction group than the non-transduction group. 5 weeks after the transduction, the living cell population was greater in the GDNF transduction group than the non-transduction group ( P < 0.01). In the ex vivo autograft of the bioengineered human corneal constructs, outgrowth of enhanced green fluorescent protein (eGFP) positive cells on the recipient corneoscleral tissue was observed. Overexpression of GDNF in the supernatant peaked at day 2, but was observed for at least 4 weeks after transplantation. At day 5, immunofluorescent staining showed expression of GDNF by all layers of epithelial cells on the graft. Our findings revealed that GDNF is a survival growth factor for cultured human corneal epithelium. The use of bioengineered human corneal constructs containing GDNF-transduced epithelial cells represents a novel method for delivering of this gene to promote survival of transplanted corneal epithelium to treat various corneal surface diseases.

Visual and refractive results of combined PTK/PRK in patients with corneal surface disease and refractive errors

To investigate the changes in symptoms, refraction, and visual acuity (VA) in patients with corneal surface disease and refractive errors who had phototherapeutic keratectomy (PTK) combined with photorefractive keratectomy (PRK). University-based referral practice. Patients with myopia or astigmatism and map-dot-fingerprint dystrophy or recurrent erosions were treated. The corneal epithelium was removed with a 64 blade, and laser was performed using a Visx Star S3 laser. Nineteen eyes of 14 patients were treated. Preoperatively, mean myopia was -3.76 diopters (D) (range -7.50 to -0.75 D), mean astigmatism was +0.96 D (range 0.00 to +2.25 D), and mean UCVA was 20/400. At 3 months, mean myopia was -0.53 D (range -1.75 to +0.75 D) (P<.001), mean astigmatism was +0.58 D (range 0.00 to +1.25 D) (P = .05), and mean uncorrected VA was 20/23 (P<.001). At 6 months, mean myopia was -0.31 D (range -1.00 to +0.75 D) (P<.001), mean astigmatism was +0.56 D (range 0.00 to +1.25 D) (P = .05), and mean uncorrected VA was 20/23 (P<.001). The change in astigmatism was confirmed by vector analysis. Only 1 patient lost 1 line of acuity, and all patients were asymptomatic. Patients with myopia and astigmatism and symptomatic epithelial basement membrane disorders who had PTK/PRK had resolution of their symptoms and nearly achieved emmetropia. Therefore, this procedure is safe and effective for patients with corneal surface disease and myopia.

Brightness VS Challenge: adult stem cells application in corneal and ocular surface disease

视觉是保障人类生存质量最重要的指标之一.全球有数以亿计的视障患者处于黑暗中,近年来的干细胞研究为这些患者带来了曙光.然而,干细胞领域还有许多尚待揭示的奥秘,干细胞分化的内在分子调控机制尚不明了,这又向科学工作者提出了挑战。

Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor).

Corneal disease is the most common cause of bilateral blindness in the world. Visual loss in this condition is often due to changes in morphology and function of the corneal epithelial surface. Corneal disease-1 (corn1) and corn1(2J) are spontaneous mouse mutants that develop irregular thickening of the corneal epithelium, similar to that observed in human corneal surface disease. These autosomal-recessive mutations cause an increase in the rate of proliferation of the corneal epithelial cells. Here, we report that the phenotypes in both mutants are caused by mutations within the destrin gene (also known as actin-depolymerizing factor). By positional cloning, we identified a deletion encompassing the entire coding sequence of the destrin gene in corn1 mice, and a point mutation (Pro106Ser) in the coding sequence of destrin in corn1(2J) mice. In situ analysis showed that destrin is highly expressed in the corneal epithelium. Consistent with the cellular roles for destrin, an essential regulator of actin filament turnover that acts by severing and enhancing depolymerization of actin filament, we observed that the corn1 mutations increased the content of filamentous actin in corneal epithelial cells. Our results suggest an in vivo connection between remodeling of the actin cytoskeleton and the control of cell proliferation, and a new pathway through which an aberrant actin cytoskeleton can cause epithelial hyperproliferation.

Role of immunity and inflammation in corneal and ocular surface disease associated with dry eye.

Dry eye syndromes (DES) represent a common but highly heterogeneous group of ocular surface disorders (OSD) that affect millions of individuals, in particular women, in the United States alone. While efforts to better classify disease categories and determine relevant diagnostic tests for each disea sesubtype continue, common features of DES are shared by the tear-deficient and non-tear-deficient (evaporative) forms of DES serving as common denominators of disease. These common denominators include ocular surface epitheliopathy, tear hyperosmolarity, an unstable preocular tear film and symptoms of dry eye associated with varying degrees of inflammation.’ As such, an increasing number of investigators contend ocular irritation or discomfort, virtually invariable components of severe tear-deficient dry eye, are clinical correlates of ocular surface inflammation which at the cellular and molecular levels are requisite factors for the pathogenesis of DES. In this brief overview, we will first examine the factors involved in the generation of immune responsiveness to antigens in the ocular surface and anterior segment. We will then critically evaluate whether the data generated to date provide a causal link between the generation of adaptive immunity and OSD in DES, or if the well-described inflammatory response in the ocular surface could be primarily a consequence of the myriad pathological

Corneal Surface Disease Topology

The specific morphology and distribution of corneal surface lesions may point toward a specific diagnosis and pathogenesis in individual cases (see Fig 1). Staining lesions may be fine (e.g., staphylococcal) or punctate (e.g., keratitis sicca). The size and appearance of staining and nonstaining lesions of the epithelium and subepithelial cornea may be characteristic for a particular disease process (e.g., HSV, EKC). Finally, the location of lesions is important. Inferior staining (staphylococcal disease, lagophthalmos) will be incited by a different cause as compared to superior (molluscum, trachoma, vernal keratoconjunctivitis) and peripheral (contact lens-induced, collagen vascular disease) staining patterns. Central lesions are more likely to indicate tear deficiency, superficial corneal dystrophies, viral infections, or metabolic conditions. Knowledge of these patterns of disease can allow accurate diagnosis and more expedient and successful treatment of corneal surface disease.

Corneal Epithelial Permeability of Dry Eyes Before and After Treatment with Artificial Tears

The question of whether artificial tears can lead to objective improvement of ocular surface disease in dry eyes is still unanswered. The aim of the current study is to assess the influence of artificial tears on corneal epithelial permeability of dry eyes. Furthermore, the effect of benzalkonium chloride, used as a preservative of artificial tears, on corneal epithelial permeability is investigated. The corneal epithelial permeability of 40 dry eye patients (80 eyes) was measured by computerized objective fluorophotometry before and 6 weeks after treatment with artificial tears containing either polyvinyl pyrrolidone 2% without preservative (20 patients) or polyvinyl pyrrolidone 2% preserved with benzalkonium chloride 0.005% (20 patients). Before treatment, the epithelial permeability of the dry eye patients was found to be 2.7 times that of a control group. After treatment, the epithelial permeability of patients treated with unpreserved polyvinyl pyrrolidone 2% had decreased significantly (-37%; P less than 0.001), whereas patients who had been treated with polyvinyl pyrrolidone 2% preserved with benzalkonium chloride 0.005% showed an increase in epithelial permeability (+21%; P = 0.05%). These data suggest that, in dry eyes, treatment with unpreserved artificial tears may lead to an objective improvement in corneal surface disease. However, this effect may be counteracted by preservation of tear substitutes with benzalkonium chloride.

Microsporidial Keratoconjunctivitis in Acquired Immunodeficiency Syndrome

We describe three patients with acquired immunodeficiency syndrome who presented with a bilateral coarse superficial epithelial keratitis due to infection with the protozoal parasite Microspora, Encephalitozoon cuniculi. Despite the extent of the corneal surface disease, conjunctival inflammation was minimal. Visual acuity ranged from 20/20 to 20/200. In one patient, the keratitis was complicated by the development of a surface defect with secondary Pseudomonas species infection. All patients had a history of exposure to household pets. Standard cultures were negative. Diagnosis was established in two of the three cases based on characteristic appearance of the protozoan in conjunctival scrapings. Electron microscopy of a conjunctival biopsy specimen in one patient confirmed the species. No recognized effective treatment is available for this infection.