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Kittipibul T, Dalin CP, Masoudi A, Zheng J, Deng SX. Advances in the Diagnosis and Management of Limbal Stem Cell Deficiency. Cornea 2025; 44:405-411. [PMID: 39729420 PMCID: PMC11875906 DOI: 10.1097/ico.0000000000003775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 11/05/2024] [Indexed: 12/29/2024]
Abstract
ABSTRACT This concise review focuses on the latest advancements in the diagnosis and management of limbal stem cell deficiency (LSCD). Ensuring the standard of care for individuals affected by LSCD involves the crucial task for physicians to meticulously and accurately diagnose the condition and determine its specific stage. A standardized diagnostic approach forms the foundation for formulating and delivering customized therapeutic interventions to maximize treatment outcomes for each patient. In this review, we introduce a systematic diagnostic algorithm to guide the assessment of LSCD. In addition, the current management algorithm and emerging therapies for LSCD are summarized.
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Affiliation(s)
- Thanachaporn Kittipibul
- Department of Ophthalmology, Center of Excellence for Cornea and Stem Cell Transplantation, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Ophthalmology, Excellence Center for Cornea and Stem Cell Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Chea Piseth Dalin
- Ophthalmology Unit, Calmette Hospital, Phnom Penh, Kingdom of Cambodia
| | - Ali Masoudi
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Jie Zheng
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Sophie X Deng
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA
- Molecular Biology Institute, University of California, Los Angeles, CA
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Niruthisard D, Bonnet C, Fung SSM, Unhale R, Tseng CH, Muntham D, Deng SX. Co-existence of Neurotrophic Keratopathy in Eyes With Limbal Stem Cell Deficiency. Am J Ophthalmol 2024; 267:249-256. [PMID: 38945348 DOI: 10.1016/j.ajo.2024.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]
Abstract
PURPOSE To investigate whether neurotrophic keratopathy is present in limbal stem cell deficiency (LSCD), by measuring corneal sensation and characterizing corneal subbasal nerve plexus. DESIGN Prospective, cross-sectional, case-control comparative study. METHODS A total of 46 eyes with LSCD and 14 normal eyes were recruited from 2019 to 2022. Corneal sensation was measured using a Cochet-Bonnet esthesiometer, and subbasal nerve plexus was imaged using in vivo confocal microscopy (IVCM) at the central cornea and 4 limbal regions. Subbasal nerve density (SND, number of nerves/mm2), subbasal nerve length (SNL, total length of nerves/mm2) and subbasal nerve branch density (SNBD, number of branches/mm2) were quantified. LSCD was graded to stage 1, 2, and 3 using a previously established staging method consisting of clinical scores, basal cell density, central corneal epithelial thickness, and SNL. RESULTS The mean (±SD) cornea sensation in the central cornea and limbus were 29.2 ± 21.5 and 33.6 ± 15.1 mm in the LSCD group and 57.6 ± 5.8 and 54.3 ± 4.7 mm in the control group, respectively (all P < .001). In sectoral LSCD, the corneal sensation in the affected regions (29.1 ± 17.6 mm) decreased significantly compared to the unaffected regions (41.4 ± 18.2 mm, P < .001). Central corneal SND, SNL, and SNBD were reduced by 84.6%, 82.6%, and 89.2%, respectively, in LSCD compared to controls (all P < 0.05). The central corneal sensation negatively correlated with the severity of LSCD (rho = -0.64, P < .0001) and positively correlated with SND, SNL, and SNBD (rho = 0.63, 0.66, and 0.56, respectively; all P < .001). CONCLUSIONS Corneal sensation was reduced in eyes with LSCD. The degree of corneal sensation reduction positively correlated with the severity of LSCD. This finding demonstrated the coexistence of neurotropic keratopathy in LSCD.
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Affiliation(s)
- Duangratn Niruthisard
- From the Stein Eye Institute (D.N., C.B., S.S.M.F., R.U., S.X.D.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Department of Ophthalmology (D.N.), Banphaeo General Hospital, Samut Sakhon, Thailand
| | - Clémence Bonnet
- From the Stein Eye Institute (D.N., C.B., S.S.M.F., R.U., S.X.D.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Centre de Recherche des Cordeliers (C.B.), INSERM 1138, Paris Cité Université, AP-HP, F-75014, Paris, France
| | - Simon S M Fung
- From the Stein Eye Institute (D.N., C.B., S.S.M.F., R.U., S.X.D.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rutuja Unhale
- From the Stein Eye Institute (D.N., C.B., S.S.M.F., R.U., S.X.D.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Chi-Hong Tseng
- Division of General Internal Medicine and Health Services Research (C.-H.T.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Dittapol Muntham
- Section for Mathematics (D.M.), Faculty of Science and Technology, Rajamangala University of Technology Suvarnabhumi, Thailand
| | - Sophie X Deng
- From the Stein Eye Institute (D.N., C.B., S.S.M.F., R.U., S.X.D.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Molecular Biology Institute (S.X.D.), University of California, Los Angeles, California, USA.
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Yavuz Saricay L, Surico PL, Tandias R, Jurkunas UV, Dana R. Concurrent Limbal Stem Cell Deficiency and Mild Neurotrophic Keratopathy in Graft-Vs-Host Disease. Cornea 2024:00003226-990000000-00710. [PMID: 39565363 DOI: 10.1097/ico.0000000000003722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/05/2024] [Indexed: 11/21/2024]
Abstract
PURPOSE The purpose of this study was to delineate the concurrence of limbal stem cell deficiency (LSCD) and neurotrophic keratopathy in patients with ocular graft-vs-host disease (oGVHD). METHODS Medical records of patients with oGVHD were reviewed. Parameters collected included corneal sensitivity measured by using a noncontact esthesiometer, corneal fluorescein staining score (National Eye Institute grading scale), tear volume (Schirmer I test), and subbasal nerve density and limbal structure assessed by in vivo confocal microscopy. RESULTS Twenty-eight patients (mean age: 60.8 ± 10.4 years) with oGVHD were included; 50% (n = 14) had partial LSCD (P-LSCD), and 32% (n = 9) had complete LSCD (C-LSCD). Patients with C-LSCD showed significantly reduced total nerve density and branch nerve density compared with those with P-LSCD ( P < 0.02, P < 0.04) and no LSCD ( P < 0.01, P = 0.02). Dendritic cell density was significantly higher in the C-LSCD group compared with the no LSCD group ( P < 0.05). Corneal sensitivity was significantly reduced in patients with C-LSCD compared with those with P-LSCD ( P = 0.01) and no LSCD ( P < 0.02). Patients with C-LCSD had higher corneal fluorescein staining scores than patients with P-LSCD ( P < 0.01) and no LSCD ( P = 0.02). CONCLUSIONS This study highlights a significant concurrence of LSCD and neurotrophic keratopathy in patients with oGVHD, underscoring the link between inflammation, neurodegeneration, and loss of stem cell function.
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Affiliation(s)
- Leyla Yavuz Saricay
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA
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Fei K, Luo Z, Chen Y, Huang Y, Li S, Mazlin V, Boccara AC, Yuan J, Xiao P. Cellular structural and functional imaging of donor and pathological corneas with label-free dual-mode full-field optical coherence tomography. BIOMEDICAL OPTICS EXPRESS 2024; 15:3869-3888. [PMID: 38867788 PMCID: PMC11166435 DOI: 10.1364/boe.525116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 06/14/2024]
Abstract
In this study, a dual-mode full-field optical coherence tomography (FFOCT) was customized for label-free static and dynamic imaging of corneal tissues, including donor grafts and pathological specimens. Static images effectively depict relatively stable structures such as stroma, scar, and nerve fibers, while dynamic images highlight cells with active intracellular metabolism, specifically for corneal epithelial cells. The dual-mode images complementarily demonstrate the 3D microstructural features of the cornea and limbus. Dual-modal imaging reveals morphological and functional changes in corneal epithelial cells without labeling, indicating cellular apoptosis, swelling, deformation, dynamic signal alterations, and distinctive features of inflammatory cells in keratoconus and corneal leukoplakia. These findings propose dual-mode FFOCT as a promising technique for cellular-level cornea and limbus imaging.
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Affiliation(s)
- Keyi Fei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Zhongzhou Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Yupei Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Yuancong Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Saiqun Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Viacheslav Mazlin
- Institut Langevin, ESPCI Paris, PSL Research University, CNRS, 1 rue Jussieu, Paris 75005, France
| | - Albert Claude Boccara
- Institut Langevin, ESPCI Paris, PSL Research University, CNRS, 1 rue Jussieu, Paris 75005, France
| | - Jin Yuan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Peng Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
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Tonti E, Manco GA, Spadea L, Zeppieri M. Focus on limbal stem cell deficiency and limbal cell transplantation. World J Transplant 2023; 13:321-330. [PMID: 38174150 PMCID: PMC10758683 DOI: 10.5500/wjt.v13.i6.321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/10/2023] [Accepted: 11/02/2023] [Indexed: 12/15/2023] Open
Abstract
Limbal stem cell deficiency (LSCD) causes severe vision impairment and can lead to blindness, representing one of the most challenging ocular surface disorders. Stem cell deficiency can be congenital or, more often, acquired. The categorization of ocular surface transplantation techniques is crucial to achieving treatment homogeneity and quality of care, according to the anatomic source of the tissue being transplanted, genetic source, autologous or allogenic transplantation (to reflect histocompatibility in the latter group), and cell culture and tissue engi neering techniques. The aim of this minireview is to provide a summary of the management of LSCD, from clinical characteristics and therapeutic outcomes to the development of novel therapeutic approaches. The manuscript also briefly summarizes recent findings in the current literature and outlines the future challenges to overcome in the management of the major types of ocular surface failure.
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Affiliation(s)
- Emanuele Tonti
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | | | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Density and distribution of dendritiform cells in the peripheral cornea of healthy subjects using in vivo confocal microscopy. Ocul Surf 2022; 26:157-165. [PMID: 35998820 DOI: 10.1016/j.jtos.2022.07.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 11/20/2022]
Abstract
PURPOSE To establish dendritiform cell (DC) density and morphological parameters in the central and peripheral cornea in a large healthy cohort, using in vivo confocal microscopy (IVCM). METHODS A prospective, cross-sectional, observational study was conducted in 85 healthy volunteers (n = 85 eyes). IVCM images of corneal center and four peripheral zones were analyzed for DC density and morphology to compare means and assess correlations (p < 0.05 being statistically significant). RESULTS Central cornea had lower DC density (40.83 ± 5.14 cells/mm2; mean ± SEM) as compared to peripheral cornea (75.42 ± 2.67 cells/mm2, p < 0.0001). Inferior and superior zones demonstrated higher DC density (105.01 ± 7.12 and 90.62 ± 4.62 cells/mm2) compared to the nasal and temporal zones (59.93 ± 3.42 and 51.77 ± 2.98 cells/mm2, p < 0.0001). Similarly, lower DC size, field and number of dendrites were observed in the central as compared to the average peripheral cornea (p < 0.0001), with highest values in the inferior zone (p < 0.001 for all, except p < 0.05 for number of dendrites in superior zone). DC parameters did not correlate with age or gender. Inter-observer reliability was 0.987 for DC density and 0.771-0.922 for morphology. CONCLUSION In healthy individuals, the peripheral cornea demonstrates higher DC density and larger morphology compared to the center, with highest values in the inferior zone. We provide the largest normative cohort for sub-stratified DC density and morphology, which can be used in future clinical trials to compare differential changes in diseased states. Furthermore, as DC parameters in the peripheral zones are dissimilar, random sampling of peripheral cornea may be inaccurate.
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Liang Q, Le Q, Wang L, Cordova D, Baclagon E, Garrido SG, Levin M, Jin Y, Tseng CH, Rao J, Deng SX. Cytokeratin 13 Is a New Biomarker for the Diagnosis of Limbal Stem Cell Deficiency. Cornea 2022; 41:867-873. [PMID: 34743102 PMCID: PMC9065215 DOI: 10.1097/ico.0000000000002903] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 09/07/2021] [Indexed: 11/27/2022]
Abstract
PURPOSE The purpose of this study was to evaluate the expression of cytokeratin (K) 13 on the corneal surface and to validate its application in the diagnosis of limbal stem cell deficiency (LSCD). METHODS This prospective comparative study included 26 corneal impression cytology (IC) specimens from patients diagnosed with LSCD. Twenty-three IC specimens from normal donors served as controls. K12 and K13 expression were detected on the IC specimens by immunohistochemistry study. The number of K12 + or K13 + cells in all areas of the IC was quantified using ImageJ software. RESULTS The epithelial cells harvested from IC specimens from control corneas were all K12 + . In eyes with LSCD, K13 + and K12 + /K13 + cells accounted for 93.8% and 2.6%, respectively, in the cornea. In eyes with sectoral LSCD, the median number of K13 + cells in the clinically affected area was higher than that in the unaffected area (810.0 vs. 115.0 cells/mm 2 ; P < 0.001). No significant correlation was found between the LSCD severity and the number of K12 + cells (r = -0.284, P = 0.16) or K13 + cells (r = -0.011, P = 0.95). The presence of at least 16 K13 + cells/mm 2 was suggestive of LSCD. CONCLUSIONS Identification of K13 + cells on IC specimens provides a simple and reliable method to detect conjunctival epithelial cells on the cornea. K13 is a marker for diagnosing LSCD and localizing the involved area in sectoral LSCD.
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Affiliation(s)
- Qingfeng Liang
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100005, China
| | - Qihua Le
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Department of Ophthalmology, Eye, Ear, Nose & Throat Hospital of Fudan University, Shanghai 200031, China
| | - Leying Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100005, China
| | - Daniel Cordova
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Elfren Baclagon
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Sheyla Gonzalez Garrido
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Mary Levin
- Department of Pathology and laboratory medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Yusheng Jin
- Department of Pathology and laboratory medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Chi-hong Tseng
- Department of Medicine, Statistic Core-General Internal Medicine and Health Service Research, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Jianyu Rao
- Department of Pathology and laboratory medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Sophie X. Deng
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, USA
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Kate A, Basu S. A Review of the Diagnosis and Treatment of Limbal Stem Cell Deficiency. Front Med (Lausanne) 2022; 9:836009. [PMID: 35692544 PMCID: PMC9175008 DOI: 10.3389/fmed.2022.836009] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/03/2022] [Indexed: 11/17/2022] Open
Abstract
Limbal stem cell deficiency (LSCD) can cause significant corneal vascularization and scarring and often results in serious visual morbidity. An early and accurate diagnosis can help prevent the same with a timely and appropriate intervention. This review aims to provide an understanding of the different diagnostic tools and presents an algorithmic approach to the management based on a comprehensive clinical examination. Although the diagnosis of LSCD usually relies on the clinical findings, they can be subjective and non-specific. In such cases, using an investigative modality offers an objective method of confirming the diagnosis. Several diagnostic tools have been described in literature, each having its own advantages and limitations. Impression cytology and in vivo confocal microscopy (IVCM) aid in the diagnosis of LSCD by detecting the presence of goblet cells. With immunohistochemistry, impression cytology can help in confirming the corneal or conjunctival source of epithelium. Both IVCM and anterior segment optical coherence tomography can help supplement the diagnosis of LSCD by characterizing the corneal and limbal epithelial changes. Once the diagnosis is established, one of various surgical techniques can be adopted for the treatment of LSCD. These surgeries aim to provide a new source of corneal epithelial stem cells and help in restoring the stability of the ocular surface. The choice of procedure depends on several factors including the involvement of the ocular adnexa, presence of systemic co-morbidities, status of the fellow eye and the comfort level of the surgeon. In LSCD with wet ocular surfaces, autologous and allogeneic limbal stem cell transplantation is preferred in unilateral and bilateral cases, respectively. Another approach in bilateral LSCD with wet ocular surfaces is the use of an autologous stem cell source of a different epithelial lineage, like oral or nasal mucosa. In eyes with bilateral LSCD with significant adnexal issues, a keratoprosthesis is the only viable option. This review provides an overview on the diagnosis and treatment of LSCD, which will help the clinician choose the best option amongst all the therapeutic modalities currently available and gives a clinical perspective on customizing the treatment for each individual case.
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Affiliation(s)
- Anahita Kate
- The Cornea Institute, KVC Campus, LV Prasad Eye Institute, Vijayawada, India
| | - Sayan Basu
- The Cornea Institute, KAR Campus, LV Prasad Eye Institute, Hyderabad, India
- Prof. Brien Holden Eye Research Centre (BHERC), LV Prasad Eye Institute, Hyderabad, Telangana, India
- *Correspondence: Sayan Basu
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Pushker N, Gorimanipalli B, Sharma N, Kashyap S, Bajaj MS. Mucous membrane grafting (fibrin glue vs. suture) for lid margin pathologies in Stevens-Johnson syndrome: randomized comparative study. Eye (Lond) 2021; 35:1985-1992. [PMID: 33024323 PMCID: PMC8225623 DOI: 10.1038/s41433-020-01203-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/23/2020] [Accepted: 09/21/2020] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE To compare fibrin glue (with three cardinal sutures) (FG) and polygalactin suture (PS) for mucous membrane grafting (MMG) in terms of graft apposition and recurrence of lid margin keratinization (LMK) and metaplastic lashes (ML) in patients with Stevens-Johnson syndrome (SJS). DESIGN Prospective randomized comparative interventional study. METHODS Twenty patients diagnosed with SJS and lid margin abnormalities including LMK with or without ML were randomized to undergo either fibrin glue (FG)-assisted MMG (n = 10) or continuous 8-0 polygalactin suture (PS)-assisted MMG (n = 10). They were evaluated preoperatively and during follow-up at 1 week and 1, 2, 3, and 6 months. The parameters assessed were best-corrected visual acuity (BCVA), tear break-up time (TBUT), Schirmer-1 test, corneal and conjunctival complications, graft apposition and width (GW), LMK, ML, impression cytology, and operative time. The primary outcome measures are incidence of graft displacement and recurrence of LMK and ML. RESULTS None of the eyelids in FG group (0/40) and 1 eyelid in PS group (1/40) had graft displacement. Recurrence of LMK occurred in 7.5% of eyelids (3/40) in both the study groups. Recurrence of ML occurred in 2.5% (1/40) in FG group and 5% (2/40) in PS group. The mean operative time for MMG in FG group was 39.5 ± 2.40 min and in PS group was 56 ± 1.63 min (p = 0.001). CONCLUSIONS As graft apposition with suture involves significantly longer intraoperative time, if cost is not a limiting factor then fibrin glue is a viable option for the MMG for lid margin pathologies.
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Affiliation(s)
- Neelam Pushker
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India.
| | | | - Namrata Sharma
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
| | - Seema Kashyap
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
| | - Mandeep S Bajaj
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
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Abstract
The cornea is a transparent outermost structure of the eye anterior segment comprising the highest density of innervated tissue. In the process of corneal innervation, trigeminal ganglion originated corneal nerves diligently traverse different corneal cell types in different corneal layers including the corneal stroma and epithelium. While crossing the stromal and epithelial cell layers during innervation, due to the existing physical contacts, close interactions occur between stromal keratocytes, epithelial cells, resident immune cells and corneal nerves. Furthermore, by producing various trophic and growth factors corneal cells assist in maintaining the growth and function of corneal nerves. Similarly, corneal nerve generated growth factors critically modify the corneal cell function in all the corneal layers. Due to their close association and contacts, on-going cross-communication between these cell types and corneal nerves play a vital role in the modulation of corneal nerve function, regeneration during wound healing. The present review highlights the influence of different corneal cell types and growth factors released from these cells on corneal nerve regeneration and function.
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Affiliation(s)
- Bhavani S Kowtharapu
- Department of Ophthalmology, Rostock University Medical Centre, Rostock, Germany
| | - Oliver Stachs
- Department of Ophthalmology, Rostock University Medical Centre, Rostock, Germany
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Patil S, D'Souza C, Patil P, Patil V, Prabhu M, Bargale A, Kaveeshwar V, Kumar S, Shetty P. Culture and characterization of human dental pulp‑derived stem cells as limbal stem cells for corneal damage repair. Mol Med Rep 2019; 20:4688-4694. [DOI: 10.3892/mmr.2019.10691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 03/06/2019] [Indexed: 12/13/2022] Open
Affiliation(s)
- Shankargouda Patil
- Department of Ophthalmology, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Clinton D'Souza
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Prakash Patil
- SDM Biomedical Research Center, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Vidya Patil
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Mridula Prabhu
- Department of Ophthalmology, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Anil Bargale
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Vishwas Kaveeshwar
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Sarath Kumar
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
| | - Praveenkumar Shetty
- Department of Biochemistry, SDM College of Medical Sciences and Hospital Campus, Manjushree Nagar, Dharwad, Karnataka‑580009, India
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Calonge M, Pérez I, Galindo S, Nieto-Miguel T, López-Paniagua M, Fernández I, Alberca M, García-Sancho J, Sánchez A, Herreras JM. A proof-of-concept clinical trial using mesenchymal stem cells for the treatment of corneal epithelial stem cell deficiency. Transl Res 2019; 206:18-40. [PMID: 30578758 DOI: 10.1016/j.trsl.2018.11.003] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 10/18/2018] [Accepted: 11/18/2018] [Indexed: 01/02/2023]
Abstract
Ocular stem cell transplantation derived from either autologous or allogeneic donor corneoscleral junction is a functional cell therapy to manage extensive and/or severe limbal stem cell deficiencies that lead to corneal epithelial failure. Mesenchymal stem cells have been properly tested in animal models of this ophthalmic pathology, but never in human eyes despite their potential advantages. We conducted a 6- to 12-month proof-of-concept, randomized, and double-masked pilot trial to test whether allogeneic bone marrow-derived mesenchymal stem cell transplantation (MSCT], n = 17) was as safe and as equally efficient as allogeneic cultivated limbal epithelial transplantation (CLET), (n = 11) to improve corneal epithelial damage due to limbal stem cell deficiency. Primary endpoints demanded combination of symptoms, signs, and the objective improvement of the epithelial phenotype in central cornea by in vivo confocal microscopy. This proof-of-concept trial showed that MSCT was as safe and efficacious as CLET. Global success at 6-12 months was 72.7%-77.8% for CLET cases and 76.5%-85.7% for MSCT cases (not significant differences). Central corneal epithelial phenotype improved in 71.4% and 66.7% of MSCT and CLET cases, respectively at 12 months (P = 1.000). There were no adverse events related to cell products. This trial suggests first evidence that MSCT facilitated improvement of a diseased corneal epithelium due to lack of its stem cells as efficiently as CLET. Consequently, not only CLET but also MSCT deserves more preclinical investigational resources before the favorable results of this proof-of-concept trial could be transformed into the larger numbers of the multicenter trials that would provide stronger evidence. (ClinicalTrials.gov number, NCT01562002.).
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Affiliation(s)
- Margarita Calonge
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
| | - Inmaculada Pérez
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain.
| | - Sara Galindo
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
| | - Teresa Nieto-Miguel
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
| | - Marina López-Paniagua
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
| | - Itziar Fernández
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
| | - Mercedes Alberca
- IBGM (Institute of Molecular Biology and Genetics), University of Valladolid and National Research Council (CSIC), and University Scientific Park, Valladolid, Spain.
| | - Javier García-Sancho
- IBGM (Institute of Molecular Biology and Genetics), University of Valladolid and National Research Council (CSIC), and University Scientific Park, Valladolid, Spain.
| | - Ana Sánchez
- IBGM (Institute of Molecular Biology and Genetics), University of Valladolid and National Research Council (CSIC), and University Scientific Park, Valladolid, Spain.
| | - José M Herreras
- IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain; CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials, and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain.
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Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 2019; 38:364-375. [PMID: 30614902 PMCID: PMC6363877 DOI: 10.1097/ico.0000000000001820] [Citation(s) in RCA: 215] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Despite extensive knowledge gained over the last 3 decades regarding limbal stem cell deficiency (LSCD), the disease is not clearly defined, and there is lack of agreement on the diagnostic criteria, staging, and classification system among treating physicians and research scientists working on this field. There is therefore an unmet need to obtain global consensus on the definition, classification, diagnosis, and staging of LSCD. METHODS A Limbal Stem Cell Working Group was first established by The Cornea Society in 2012. The Working Group was divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to obtain agreement on a strategic plan and methodology from all participants after a comprehensive literature search, and final agreement was reached on the definition, classification, diagnosis, and staging of LSCD. A writing group was formed to draft the current manuscript, which has been extensively revised to reflect the consensus of the Working Group. RESULTS A consensus was reached on the definition, classification, diagnosis, and staging of LSCD. The clinical presentation and diagnostic criteria of LSCD were clarified, and a staging system of LSCD based on clinical presentation was established. CONCLUSIONS This global consensus provides a comprehensive framework for the definition, classification, diagnosis, and staging of LSCD. The newly established criteria will aid in the correct diagnosis and formulation of an appropriate treatment for different stages of LSCD, which will facilitate a better understanding of the condition and help with clinical management, research, and clinical trials in this area.
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Affiliation(s)
- Sophie X. Deng
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles
| | - Vincent Borderie
- Quinze-Vingts National Eye Hospital, Faculté de Médecine Sorbonne Université, Paris, France
| | - Clara C. Chan
- University of Toronto Department of Ophthalmology & Vision Sciences Toronto, Ontario
| | - Reza Dana
- Massachusetts Eye and Ear Infirmary, Harvard Medical School
| | - Francisco C. Figueiredo
- Department of Ophthalmology, Royal Victoria Infirmary and Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - José A. P. Gomes
- Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina/Universidade Federal de São Paulo (EPM/UNIFESP), Brazil
| | - Graziella Pellegrini
- Centre for Regenerative Medicine, University of Modena and Reggio Emilia; Holostem Terapie Avanzate, Modena, Italy
| | - Shigeto Shimmura
- Department of Ophthalmology, Keio University School of Medicine, Japan
| | - Friedrich E. Kruse
- Department of Ophthalmology, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
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Le Q, Xu J, Deng SX. The diagnosis of limbal stem cell deficiency. Ocul Surf 2018; 16:58-69. [PMID: 29113917 PMCID: PMC5844504 DOI: 10.1016/j.jtos.2017.11.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 08/24/2017] [Accepted: 11/03/2017] [Indexed: 12/15/2022]
Abstract
Limbal stem cells (LSCs) maintain the normal homeostasis and wound healing of corneal epithelium. Limbal stem cell deficiency (LSCD) is a pathologic condition that results from the dysfunction and/or an insufficient quantity of LSCs. The diagnosis of LSCD has been made mainly based on medical history and clinical signs, which often are not specific to LSCD. Methods to stage the severity of LSCD have been lacking. With the application of newly developed ocular imaging modalities and molecular methods as diagnostic tools, standardized quantitative criteria for the staging of LSCD can be established. Because of these recent advancements, effective patient-specific therapy for different stages of LSCD may be feasible.
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Affiliation(s)
- Qihua Le
- Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, USA; Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Jianjiang Xu
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Sophie X Deng
- Stein Eye Institute, Cornea Division, David Geffen School of Medicine, University of California, Los Angeles, USA.
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Abstract
PURPOSE To quantify the changes in the subbasal nerve plexus in patients with limbal stem cell deficiency (LSCD) using in vivo laser scanning confocal microscopy. METHODS In this retrospective cross-sectional comparative study, confocal images of 51 eyes of 37 patients with LSCD collected between 2010 and 2015 by the Heidelberg Retina Tomograph III Rostock Corneal Module Confocal Microscope were analyzed. Two independent observers evaluated the scans of the central cornea. Seventeen normal eyes of 13 subjects served as controls. Total subbasal nerve density (SND), density of long nerves (ie, nerves 200 μm or longer), and the degree of tortuosity were quantified. RESULTS The mean (±SD) total SND and long nerve density were 48.0 ± 34.2 and 9.7 ± 10.9 nerves/mm, respectively, in all eyes with LSCD and 97.3 ± 29.9 and 35.3 ± 25.3 nerves/mm, respectively, in eyes of the control group (P < 0.001 for both comparisons). Compared with SND in control subjects, SND was reduced by 34.9% in the early stage, 54.0% in the intermediate stage, and 73.5% in the late stage of LSCD. The degrees of nerve tortuosity were significantly greater in patients with LSCD than in control subjects and differed among the early, intermediate, and late stages of LSCD. Reductions in total SND and long nerve density were positively correlated with the severity of LSCD. CONCLUSIONS Reductions in total SND and long nerve density were accompanied by increases in nerve tortuosity in eyes with LSCD. These parameters could be used as quantifiable measures of LSCD severity.
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Immunocytochemical Diagnosis of Limbal Stem Cell Deficiency: Comparative Analysis of Current Corneal and Conjunctival Biomarkers. Cornea 2016; 34:817-23. [PMID: 25970431 DOI: 10.1097/ico.0000000000000457] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To evaluate and compare corneal and conjunctival biomarkers for immunocytochemical diagnosis of limbal stem cell deficiency (LSCD). METHODS In accordance with the current literature, we selected K12 as the corneal biomarker and K7/K13/K19/MUC5AC as the conjunctival ones. The specificity and accuracy for each biomarker were assessed and compared on 10 healthy subjects and tissues of deceased donors. Twelve eyes of 9 patients clinically suspected of LSCD were enrolled. Epithelial cells (ECs) from the central cornea were collected using impression cytology (IC) and assessed for each biomarker. The presence of conjunctival cells in the central cornea was diagnostic proof of LSCD, whereas the detection of corneal residual cells would quantify the degree of LSCD. RESULTS K12 and K7/K13/MUC5AC are, respectively, highly specific of corneal and conjunctival differentiation, whereas K19 is not. Normal corneal ECs are not desquamative enough to be suitable for IC. Among 12 eyes with suspected LSCD, 84% (10 of 12) of IC samples were suitable for analysis. K3/K7/K19 immunostaining was positive in 100%, MUC5AC in 40%, and K12 was never observed. CONCLUSIONS Clinical examination can lead to misdiagnosis of LSCD. Immunocytochemical detection of K7/K13 on corneal ECs collected by IC is reproducible, noninvasive, and highly effective in this indication, but without any quantification of the degree of the disease. This time-consuming technique requires skilled technicians and laboratory facilities, reserving it for planned limbal reconstruction.
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In Vivo Confocal Microscopy 1 Year after Autologous Cultured Limbal Stem Cell Grafts. Ophthalmology 2015; 122:1660-8. [DOI: 10.1016/j.ophtha.2015.04.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/27/2015] [Accepted: 04/06/2015] [Indexed: 10/23/2022] Open
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de Araujo AL, Gomes JP. Corneal stem cells and tissue engineering: Current advances and future perspectives. World J Stem Cells 2015; 7:806-814. [PMID: 26131311 PMCID: PMC4478627 DOI: 10.4252/wjsc.v7.i5.806] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 01/05/2015] [Accepted: 04/20/2015] [Indexed: 02/06/2023] Open
Abstract
Major advances are currently being made in regenerative medicine for cornea. Stem cell-based therapies represent a novel strategy that may substitute conventional corneal transplantation, albeit there are many challenges ahead given the singularities of each cellular layer of the cornea. This review recapitulates the current data on corneal epithelial stem cells, corneal stromal stem cells and corneal endothelial cell progenitors. Corneal limbal autografts containing epithelial stem cells have been transplanted in humans for more than 20 years with great successful rates, and researchers now focus on ex vivo cultures and other cell lineages to transplant to the ocular surface. A small population of cells in the corneal endothelium was recently reported to have self-renewal capacity, although they do not proliferate in vivo. Two main obstacles have hindered endothelial cell transplantation to date: culture protocols and cell delivery methods to the posterior cornea in vivo. Human corneal stromal stem cells have been identified shortly after the recognition of precursors of endothelial cells. Stromal stem cells may have the potential to provide a direct cell-based therapeutic approach when injected to corneal scars. Furthermore, they exhibit the ability to deposit organized connective tissue in vitro and may be useful in corneal stroma engineering in the future. Recent advances and future perspectives in the field are discussed.
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