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Chen Y, Gao B, Cai W, Lai J, Lai K, Wang Y. Oral mucosa: anti-inflammatory function, mechanisms, and applications. J Mater Chem B 2025; 13:4059-4072. [PMID: 40062381 DOI: 10.1039/d4tb02845g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Large soft tissue injuries require several weeks to heal and frequently leave fibrotic scars that can negatively impact tissue function. However, the applicability of traditional skin and mucous membrane transplantation for the treatment of lesions in the ocular surface and urethra is limited owing to the unique locations and functions of these tissues. Oral mucosa has been widely used in the repair of such injuries owing to its reduced propensity for inducing an inflammatory response, angiogenesis, and scarring. Enhancing chronic wound healing while avoiding scar formation requires a broader understanding of the cellular and molecular pathways that drive wound repair in the oral mucosa. This review integrates current knowledge on the mechanisms underlying the resistance of the oral mucosa to inflammation and its application as a graft material, highlighting its challenges and potential advancements. The aim of this review is to offer insights into future therapeutic strategies for wound healing and related conditions.
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Affiliation(s)
- Yani Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
| | - Bicong Gao
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
| | - Wenjin Cai
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
| | - Junhong Lai
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
| | - Kaichen Lai
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
| | - Ying Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, P. R. China.
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Bibak-Bejandi Z, Soleimani M, Arabpour Z, Karaca EE, Jalilian E, Asadigandomani H, Bibak-Bejandi R, D’jalilian AR. Advancing Bilateral Limbal Deficiency Surgery: A Comprehensive Review of Innovations with Mucosal Cells. Biomedicines 2025; 13:630. [PMID: 40149606 PMCID: PMC11940722 DOI: 10.3390/biomedicines13030630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/28/2025] [Accepted: 02/03/2025] [Indexed: 03/29/2025] Open
Abstract
Besides alternative surgical methods for bilateral limbal deficiency, such as KLAL (keratolimbal allograft), living-related conjunctival limbal allograft (LR-CLAL), and keratoprosthesis, regenerative medicine often necessitates the use of alternative sources of limbal cells in cases where access to fellow eye source cells is limited. Mucosal cells are most commonly used to restore limbal tissue in such scenarios. Current techniques involving mucosal cells include cultivated oral mucosal transplantation (COMT), oral mucosal graft transplantation (OMGT), and simple oral mucosal transplantation (SOMT). COMT requires suspension of cells and a culturing process that is time-consuming and cost-prohibitive. In contrast, OMGT requires solely a strip of mucosal graft for transplanting into the deficient eye. The most recently developed practice, SOMT, in which chopped biopsy tissue is transplanted into the deficient area, compensates for problems associated with both COMT and OMGT, making the process of addressing bilateral limbal deficiency easy, time-saving, and affordable. Although some undesirable outcomes, such as angiogenesis, can occur post-transplantation, and the ultimate goal of differentiation into limbal epithelial stem cells may not be achieved, mucosal cell sources can be a good alternative for stabilizing the ocular surface. Some studies emphasize that co-culturing limbal niches in mucosal cell cultures can enhance differentiation capability. This concept highlights the importance of the limbal environment in the differentiation process. In this review, we demonstrate the ongoing changes in surgical technique trends and how they have made mucosal cell transplantation easier and more effective for limbal regeneration.
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Affiliation(s)
- Zahra Bibak-Bejandi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
| | - Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
| | - Zohreh Arabpour
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
| | - Emine Esra Karaca
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
- Department of Ophthalmology, Ankara Bilkent City Hospital, University of Health Sciences, Ankara 06800, Turkey
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
| | | | | | - Ali R. D’jalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (Z.B.-B.); (M.S.); (Z.A.); (E.E.K.); (E.J.)
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Goto H, Ono T, Taketani Y, Kimakura M, Toyono T, Miyai T, Aihara M. Management of Intraocular Pressure Elevation After Commercially Available Cultivated Oral Mucosal Epithelial Cell Transplantation for Limbal Stem Cell Deficiency. Cureus 2025; 17:e81341. [PMID: 40296952 PMCID: PMC12034505 DOI: 10.7759/cureus.81341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
PURPOSE This study aimed to examine the changes in intraocular pressure (IOP) after commercially available cultivated oral mucosal epithelial cell transplantation (COMET) in Japanese patients with limbal stem cell deficiency (LSCD). METHODS This retrospective observational study included consecutive patients who underwent commercially available COMET (Ocural®, Japan Tissue Engineering Co., Ltd. (J-TEC), Tokyo, Japan, and Nidek Co., Ltd., Gamagori, Japan) for LSCD at the University of Tokyo Hospital from January to December 2023. Their medical charts were reviewed for background information, IOP measurements, medication use, and surgery for IOP elevation before and one day, one week, one month, three months, and six months after COMET and the final follow-up point. RESULTS Nine eyes from nine patients (mean age: 59.7±12.4 years) were included in the study. The primary diseases associated with LSCD were chemical burns (three eyes), Stevens-Johnson syndrome (two eyes), congenital aniridia (two eyes), and others (two eyes). IOP was significantly elevated from 9.7±4.1 mmHg before surgery to 23.0±12.3 mmHg one day after surgery (p=0.008) and to 20.2±7.0 mmHg one week after surgery (p=0.006). IOP was uncontrollable with eye drops in one eye (11.1%) two weeks after surgery, necessitating three sessions of micropulse transscleral cyclophotocoagulation. The mean number of antiglaucoma medications used did not change significantly during the observation period. CONCLUSION Commercially available COMET induces IOP elevation during the early postoperative period. Most cases of IOP elevation can be controlled with adequate management, but some instances of uncontrolled IOP necessitate careful consideration.
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Affiliation(s)
- Hiroki Goto
- Ophthalmology, University of Tokyo Hospital, Tokyo, JPN
| | - Takashi Ono
- Ophthalmology, University of Tokyo Hospital, Tokyo, JPN
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Elalfy M, Elsawah K, Maqsood S, Jordan N, Hassan M, Zaki A, Gatzioufas Z, Hamada S, Lake D. Allogenic Cultured Limbal Epithelial Transplantation and Cultivated Oral Mucosal Epithelial Transplantation in Limbal Stem Cells Deficiency: A Comparative Study. Ophthalmol Ther 2025; 14:413-432. [PMID: 39755899 PMCID: PMC11754549 DOI: 10.1007/s40123-024-01083-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 12/04/2024] [Indexed: 01/06/2025] Open
Abstract
INTRODUCTION This study compared the clinical outcomes of allogenic cultured limbal epithelial transplantation (ACLET) and cultivated oral mucosal epithelial transplantation (COMET) in the management of limbal stem cell deficiency (LSCD). METHODS Forty-one COMET procedures in 40 eyes and 69 ACLET procedures in 54 eyes were performed in the Corneoplastic Unit of Queen Victoria Hospital, East Grinstead. Data were examined for demographics, indications, ocular surface stability, absence of epithelial defect, ocular surface inflammation, visual outcomes, and intra- and postoperative complications. RESULTS Kaplan-Meier analysis showed that patients in the ACLET group with longer follow-up had a significantly higher graft survival rate (81.7%, n = 56) than the COMET group (60.7%, n = 25) and the difference was statistically significant (p = 0.01). In the COMET group, there was no statistically significant improvement in the visual acuity (VA) while in the ACLET group there was statistically significant improvement in the final VA. Elevated intraocular pressure (IOP) developed in 9 eyes (22.0%) in the COMET group and in 18 eyes (26.1%) in the ACLET group; infection developed in 4 eyes (9.8%) in the COMET group and in 10 eyes (14.5%) in the ACLET group; and perforation or melting happened in 4 eyes (9.8%) in the COMET group and in 1 eye (1.4%) in the ACLET group. Postoperative immunosuppression complications were noted in 9 eyes (13.0%) in the ACLET group. No graft rejection was observed in either group. CONCLUSION Both ACLET and COMET are effective therapeutic procedures for managing advanced and bilateral cases of LSCD. Although COMET has lower graft survival rate than ACLET, it does not mandate systemic immunosuppression therapy to protect against potential graft rejection.
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Affiliation(s)
- Mohamed Elalfy
- Corneoplastic Unit and Eye Bank, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK.
- Cornea Unit, Research Institute of Ophthalmology, Giza, Egypt.
- Department of Ophthalmology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK.
| | - Kareem Elsawah
- Cornea Unit, Research Institute of Ophthalmology, Giza, Egypt
| | - Sundas Maqsood
- Department of Ophthalmology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK
| | - Nigel Jordan
- Corneoplastic Unit and Eye Bank, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK
| | - Mansour Hassan
- Department of Ophthalmology, Beni Suef University, Beni Suef, Egypt
| | - Ahmed Zaki
- Cornea Unit, Research Institute of Ophthalmology, Giza, Egypt
| | - Zisis Gatzioufas
- Department of Ophthalmology, University of Basel, Basel, Switzerland
| | - Samer Hamada
- Corneoplastic Unit and Eye Bank, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK
| | - Damian Lake
- Corneoplastic Unit and Eye Bank, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK
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Edel MJ, Casellas HS, Osete JR, Nieto-Nicolau N, Arnalich-Montiel F, De Miguel MP, McLenachan S, Roshandel D, Casaroli-Marano RP, Alvarez-Palomo B. An Optimized Method to Produce Human-Induced Pluripotent Stem Cell-Derived Limbal Stem Cells Easily Adaptable for Clinical Use. Stem Cells Dev 2025; 34:49-60. [PMID: 39689863 DOI: 10.1089/scd.2024.0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2024] Open
Abstract
In adults, the limbal stem cells (LSC) reside in the limbal region of the eye, at the junction of the cornea and the sclera where they renew the outer epithelial layer of the cornea assuring transparency. LSC deficiencies (LSCD) due to disease or injury account for one of the major causes of blindness. Among current treatments for LSCD, cornea transparency can be restored by providing new LSC to the damaged eye and induced pluripotent stem cells (iPSC) holds great promise as a new advanced cell source. A synthetic mRNA-based protocol to produce human iPSC from bone marrow mesenchymal stem cells has been defined. The results demonstrate a standardizable method that can be easily adaptable for clinical-grade production standards, produce high-purity LSC-like cells in a relatively rapid timeframe of 12 days, and can be successfully seeded on amniotic membrane or a biodegradable fibrin gel for transplantation. In vivo data demonstrated it is feasible to transplant the iPSC-LSC fibrin patch. In conclusion, an efficient method has been developed to produce patient-specific LSC and seed them on a scaffold fibrin gel for future treatment of LSC-deficiency disease.
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Affiliation(s)
- Michael J Edel
- Autonomous University of Barcelona, Faculty of Medicine, Unit of Anatomy and Embryology, Barcelona, Spain
- Discipline of Medical Sciences and Genetics, School of Biomedical Sciences, University of Western Australia, Perth 6009, Australia
| | | | - Jordi Requena Osete
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- NORMENT, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | | | | | - María P De Miguel
- Cell Engineering Laboratory, La Paz Hospital Research Institute (IdiPAZ), Madrid, Spain
| | - Samuel McLenachan
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia
- Lions Eye Institute (LEI), Perth, Western Australia, Australia
| | - Danial Roshandel
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia
- Lions Eye Institute (LEI), Perth, Western Australia, Australia
| | - Ricardo P Casaroli-Marano
- Department of Surgery, Faculty of Medicine and Health Science & Hospital Clinic de Barcelona (IDIBAPS), Universitat de Barcelona, Spain
| | - Belén Alvarez-Palomo
- Cell Therapy Service, Banc de Sang i Teixits (BST), Passeig Taulat 116, 08005, Barcelona, Spain
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Wu KY, Fujioka JK, Goodyear E, Tran SD. Polymers and Biomaterials for Posterior Lamella of the Eyelid and the Lacrimal System. Polymers (Basel) 2024; 16:352. [PMID: 38337241 PMCID: PMC10857064 DOI: 10.3390/polym16030352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
The application of biopolymers in the reconstruction of the posterior lamella of the eyelid and the lacrimal system marks a significant fusion of biomaterial science with clinical advancements. This review assimilates research spanning 2015 to 2023 to provide a detailed examination of the role of biopolymers in reconstructing the posterior lamella of the eyelid and the lacrimal system. It covers the anatomy and pathophysiology of eyelid structures, the challenges of reconstruction, and the nuances of surgical intervention. This article progresses to evaluate the current gold standards, alternative options, and the desirable properties of biopolymers used in these intricate procedures. It underscores the advancements in the field, from decellularized grafts and acellular matrices to innovative natural and synthetic polymers, and explores their applications in lacrimal gland tissue engineering, including the promise of 3D bioprinting technologies. This review highlights the importance of multidisciplinary collaboration between material scientists and clinicians in enhancing surgical outcomes and patient quality of life, emphasizing that such cooperation is pivotal for translating benchtop research into bedside applications. This collaborative effort is vital for restoring aesthetics and functionality for patients afflicted with disfiguring eyelid diseases, ultimately aiming to bridge the gap between innovative materials and their clinical translation.
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Affiliation(s)
- Kevin Y. Wu
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrook, QC J1G 2E8, Canada;
| | - Jamie K. Fujioka
- Faculty of Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Emilie Goodyear
- Department of Ophthalmology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada
- Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada
- Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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Thia ZZ, Ho YT, Shih KC, Tong L. New developments in the management of persistent corneal epithelial defects. Surv Ophthalmol 2023; 68:1093-1114. [PMID: 37301520 DOI: 10.1016/j.survophthal.2023.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 05/24/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
A persistent epithelial defect (PED) is a corneal epithelial defect that failed to heal after 2weeks. It is a condition that carries much morbidity, and our understanding of PED remains poor, with current treatment methods often having unsatisfactory outcomes. With PEDs becoming more prevalent, more efforts are required to establish reliable treatment modalities. Our reviews describe the causes of PEDs and the different approaches developed to manage them, as well as their associated limitations. Emphasis is placed on understanding various advances in the development of new treatment modalities. We have also described a case of a woman with a background of graft-versus-host disease on long-term topical corticosteroids who developed complicated PED involving both eyes. The current approach to managing PEDs generally involves exclusion of an active infection, followed by treatment modalities that aim to encourage corneal epithelial healing. Success rates, however, remain far from desirable, as treatment remains challenging due to multiple underlying etiologies. In summary, advances in the development of new therapies may be able to facilitate progress in the understanding and treatment of PED.
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Affiliation(s)
- Zhang Zhe Thia
- Singapore Eye Research Institute, Singapore, Singapore; National University Hospital, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yik To Ho
- Hong Kong University, Pok Fu Lam, Hong Kong
| | | | - Louis Tong
- Singapore Eye Research Institute, Singapore, Singapore; Singapore National Eye Center, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Yao TY, Wang JS, Geng W, Xie HT, Zhang MC. Conjunctival Limbal Autograft Combined with Amnion-Assisted Conjunctival Epithelial Redirection for Unilateral Total Limbal Stem Cell Deficiency after Severe Chemical Burn. J Clin Med 2023; 12:6235. [PMID: 37834878 PMCID: PMC10573734 DOI: 10.3390/jcm12196235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
(1) Background: To evaluate the efficacy of conjunctival limbal autograft (CLAU) combined with the amnion-assisted conjunctival epithelial redirection (ACER) procedure for patients with unilateral total limbal stem cell deficiency (LSCD) caused by severe chemical burn. (2) Methods: A retrospective interventional case series of unilateral total LSCD after chemical burn who underwent CLAU combined with ACER surgery between September 2021 and July 2023 was collected. Outcome measures included epithelialization of the cornea with donor limbus-derived epithelium, best corrected visual acuity (BCVA), and complications. (3) Results: Nine males and one female were included in this study. The mean age was 40.9 ± 9.63 (range, 26 to 55) years. The average duration between injury and CLAU combined with the ACER procedure was 7.67 ± 3.97 (range, 4 to 18) months. All patients achieved corneal epithelialization and improved BCVA. Postoperative complications occurred in four cases, including delayed corneal epithelial healing in one case, delayed amniotic membrane dissolution and detachment in two cases, and recurrence of symblepharon in one case. No complications were noted in the healthy donor eyes. (4) Conclusions: CLAU combined with ACER is a safe and effective treatment for unilateral total LSCD caused by severe chemical burn. This combined surgery restores visual function for patients with corneal blindness caused by chemical burn, reducing the burden on the families and society.
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Affiliation(s)
| | | | | | - Hua-Tao Xie
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (T.-Y.Y.); (J.-S.W.); (W.G.)
| | - Ming-Chang Zhang
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (T.-Y.Y.); (J.-S.W.); (W.G.)
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Toshida H, Kasahara T, Kiriyama M, Iwasaki Y, Sugita J, Ichikawa K, Ohta T, Miyahara K. Early Clinical Outcomes of the First Commercialized Human Autologous Ex Vivo Cultivated Oral Mucosal Epithelial Cell Transplantation for Limbal Stem Cell Deficiency: Two Case Reports and Literature Review. Int J Mol Sci 2023; 24:ijms24108926. [PMID: 37240280 DOI: 10.3390/ijms24108926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
The first product in the world for ex vivo cultivated oral mucosal epithelial cell transplantation (COMET) to treat limbal stem cell deficiency (LSCD), named Ocural®, was launched in June 2021 in Japan. COMET was performed on two patients, including the first case in the post-marketing phase of Ocural®. Pathological and immunohistochemical examinations were also carried out using specimens obtained before and after COMET and the spare cell sheet. In case 1, the ocular surface remained free from epithelial defects for approximately six months. In case 2, although defect of the cornea-like epithelia was observed after COMET for one month, it was resolved after the insertion of lacrimal punctal plugs. In case 1, adjuvant treatment was interrupted due to an accident during the second month after COMET, resulting in conjunctival ingrowth and corneal opacity. Eventually, a lamellar keratoplasty was required at six months after COMET. Immunohistochemistry revealed the presence of markers for stem cells (p63, p75), proliferation (Ki-67), and differentiation (Keratin-3, -4, and -13) in both the cornea-like tissue after COMET and a cultivated oral mucosal epithelial cell sheet. In conclusion, Ocural® can be accomplished without major complications, and the stem cells derived from oral mucosa might be successfully engrafted.
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Affiliation(s)
- Hiroshi Toshida
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Tomoto Kasahara
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Masamichi Kiriyama
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Yuma Iwasaki
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Jobu Sugita
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Kohei Ichikawa
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Toshihiko Ohta
- Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka 410-2211, Japan
| | - Katsumi Miyahara
- Laboratory of Morphology and Image Analysis, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan
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Yan Y, Ji Q, Fu R, Liu C, Yang J, Yin X, Li Q, Huang R. Biomaterials and tissue engineering strategies for posterior lamellar eyelid reconstruction: Replacement or regeneration? Bioeng Transl Med 2023. [DOI: 10.1002/btm2.10497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023] Open
Affiliation(s)
- Yuxin Yan
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Qiumei Ji
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Rao Fu
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Chuanqi Liu
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Jing Yang
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Xiya Yin
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
- Department of Plastic and Burn Surgery West China Hospital, Sichuan University Chengdu China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Ru‐Lin Huang
- Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
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Ying PX, Fu M, Huang C, Li ZH, Mao QY, Fu S, Jia XH, Cao YC, Hong LB, Cai LY, Guo X, Liu RB, Meng FK, Yi GG. Profile of biological characterizations and clinical application of corneal stem/progenitor cells. World J Stem Cells 2022; 14:777-797. [PMID: 36483848 PMCID: PMC9724387 DOI: 10.4252/wjsc.v14.i11.777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/08/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.
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Affiliation(s)
- Pei-Xi Ying
- Department of Ophthalmology, Zhujiang Hospital, The Second Clinical School, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Min Fu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Chang Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200030, China
- NHC Key Laboratory of Myopia, Fudan University, Shanghai 200030, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200030, China
| | - Zhi-Hong Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510550, Guangdong Province, China
| | - Qing-Yi Mao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Sheng Fu
- Hengyang Medical School, The University of South China, Hengyang 421001, Hunan Province, China
| | - Xu-Hui Jia
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yu-Chen Cao
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Bing Hong
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Yang Cai
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xi Guo
- Medical College of Rehabilitation, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ru-Bing Liu
- The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Fan-ke Meng
- Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Guo-Guo Yi
- Department of Ophthalmology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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Aziza Y, Itoi M, Ueta M, Inatomi T, Kinoshita S, Sotozono C. Limbal-Rigid Contact Lens Wear for the Treatment of Ocular Surface Disorders: A Review. Eye Contact Lens 2022; 48:313-317. [PMID: 35877181 PMCID: PMC9298148 DOI: 10.1097/icl.0000000000000924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
ABSTRACT Recently, the prescription of large-diameter rigid gas-permeable contact lenses (CLs), also known as "scleral lenses," "corneoscleral lenses," and "limbal-rigid CLs," is on the rise for the treatment of both moderate and severe ocular surface disorders (OSDs). Compared with scleral lenses, the diameter of limbal-rigid CLs is generally smaller, that is, a diameter ranging from 13.0 to 14.0 mm, and they are designed so that the peripheral edge bears on the limbus. The Suncon Kyoto-CS (Sun Contact Lens Co., Ltd.) is a novel limbal-rigid CL design with multistep curves on the peripheral edge for easy tear exchange during blinking that removes debris and prevents lens clouding or fogging, thus allowing patients to enjoy a longer daily duration of CL wear. In severe OSD cases, limbal-rigid CL wear after surgery is a noninvasive therapeutic approach that can neutralize corneal irregularities, decrease dry eye symptoms, prevent the progression or recurrence of symblepharon, and improve the patient's visual acuity and overall quality of life. Thus, surgeries such as amniotic membrane transplantation and cultivated oral mucosal epithelial transplantation, as well as limbal-rigid CL wear, which is noninvasive, are valuable and effective treatment strategies that can now be applied for the management of patients afflicted with severe OSDs.
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Affiliation(s)
- Yulia Aziza
- Department of Ophthalmology (Y.A., M.I., M.U., T.I., C.S.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Ophthalmology (T.I.), National Center for Geriatrics and Gerontology, Aichi, Japan; and Department of Frontier Medical Science and Technology for Ophthalmology (S.K.), Kyoto Prefectural University of Medicine, Kyoto, Japan
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Kitazawa K, Sotozono C, Kinoshita S. Current Advancements in Corneal Cell-Based Therapy. Asia Pac J Ophthalmol (Phila) 2022; 11:335-345. [PMID: 36041148 DOI: 10.1097/apo.0000000000000530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/10/2022] [Indexed: 12/13/2022] Open
Abstract
Corneal epithelial stem cells (CEpSCs) mostly reside at the limbal area and are responsible for tissue homeostasis throughout life. Once complete CEpSC deficiency occurs, regenerative medicine cell-based therapy using CEpSCs or their alternatives can provide successful clinical outcomes. Due to an improved understanding of CEpSCs and mucosal epithelial stem cells, major advancements have been made over the past few decades in in vivo and ex vivo cell-based ocular surface reconstruction therapies for the treatment of severe ocular surface diseases. New therapeutic concepts and clinical strategies are emerging for the treatment of corneal endothelial dysfunction. For example, unlike corneal epithelial cells, in vivo corneal endothelial cells (CECs) stop proliferating and are arrested in the G1 phase of the cell cycle due to cell-to-cell contact inhibition and exposure to a high concentration of transforming growth factor-beta in the aqueous humor. Thus, the production of CECs with good functionality in culture has consistently been difficult. To solve this problem, Rho-associated protein kinase inhibition has taken center stage, as it not only makes the production of human CECs in culture closely mimic the functional characteristics of in vivo healthy CECs possible but also helps sustain those biological properties. Thus, cultured human CEC injection therapy is now moving to the forefront for the treatment of corneal endothelial failure. Herein, we summarize key historical discoveries in corneal cell-based regenerative medicine and illustrate the concept of corneal cell therapy for the treatment of refractory corneal epithelial and endothelial diseases.
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Affiliation(s)
- Koji Kitazawa
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Aziza Y, Harada K, Ueta M, Fukuoka H, Kinoshita S, Sotozono C. Challenges in the management of bilateral eyelid closure in Stevens-Johnson Syndrome. Am J Ophthalmol Case Rep 2022; 26:101473. [PMID: 35308589 PMCID: PMC8924635 DOI: 10.1016/j.ajoc.2022.101473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 02/08/2022] [Accepted: 03/03/2022] [Indexed: 11/15/2022] Open
Abstract
Purpose Observations Conclusion and importance
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Affiliation(s)
- Yulia Aziza
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
| | - Kohei Harada
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
| | - Mayumi Ueta
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
| | - Hideki Fukuoka
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602-0841, Japan
- Corresponding author.
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Direct oral mucosal epithelial transplantation supplies stem cells and promotes corneal wound healing to treat refractory persistent corneal epithelial defects. Exp Eye Res 2022; 215:108934. [PMID: 35007520 DOI: 10.1016/j.exer.2022.108934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/23/2021] [Accepted: 01/05/2022] [Indexed: 11/20/2022]
Abstract
Persistent corneal epithelial defects (PED) can lead to irreversible blindness, seriously affecting the social function and life quality of these patients. When it comes to refractory PED, such as limbal stem cell deficiency (LSCD), that does not respond to standard managements, stem cell therapy is an ideal method. Oral mucosal epithelium (OME) abundant with stem cells within the base, is a promising autologous biomaterial, with much resemblance to corneal epithelial structures. In this experiment, uncultured autologous rat OME was directly applied to alkali burned corneas. Clinical evaluations and histological analyses showed that the transplantation accelerated the healing process, presenting faster re-epithelization and better formation of corneal epithelial barrier. To further investigate the therapeutic mechanism, oral epithelium was transplanted to de-epithelialized cornea in vitro for organ culture. It could be observed that the oral epithelial cells could migrate to the corneal surface and form smooth and stratified epithelium. Immunofluorescence staining results showed that the re-formed epithelium derived from OME, maintained stemness and transformed to corneal epithelial phenotype to some extent. Corneal stroma may provide the suitable microenvironment to promote the trans-differentiation of oral stem cells. Thus, both in vivo and in vitro experiments suggested that oral epithelium could play a positive role in treating refractory PED.
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Hwang S, Kuo SC. Corneal perforation in ocular cicatricial pemphigoid: A CARE-compliant case report. Medicine (Baltimore) 2021; 100:e28266. [PMID: 34941105 PMCID: PMC8702268 DOI: 10.1097/md.0000000000028266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 11/25/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Ocular cicatricial pemphigoid (OCP) is a potentially blinding, rare systemic autoimmune disease. The definite etiology of OCP remains under debate, early diagnosis is important to prevent rapid deterioration. The majority of the discussion has been focused on its medical therapeutic strategy, while little effort has been made to study the role of amniotic membrane transplantation (AMT). We describe the first case of OCP with minimal immunosuppressant and initial ocular surface reconstruction procedure using double layer AMT. PATIENT CONCERNS A 66-year-old female patient presented to our outpatient department with right eye pain for several days. DIAGNOSIS Slit lamp examination revealed the right eye cornea perforation with iris incarceration and total collapse of anterior chamber. Symblepharon formation and severe fornix shortening was also noted. While bulbi phthisis with ankyloblepharon and ocular surface keratinization was observed in the left eye. The final diagnosis was right eye stage III ocular cicatricial pemphigoid complicated with corneal perforation and iris prolapsed. INTERVENTIONS The patient underwent ocular surface reconstruction with the aid of amniotic membrane. The first layer of the amniotic membrane was attached with tissue adhesive and fibrin glue while the second layer amniotic membrane came with a conformer ring which supported the fornix space that was recreated. Postoperative care included topical medications for inflammation alleviation. Systemic immunosuppressive agents were not administered except for oral prednisolone. OUTCOMES No recurrence of symblepharon was noted during the one year follow-up. LESSONS We aim at highlighting the possible important role of AMT in advance OCP. Further investigation is still needed for providing evidence to incorporate the procedure into treatment protocol.
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Affiliation(s)
- Suan Hwang
- Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan
| | - Shu-Chun Kuo
- Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan
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Ma DHK, Hsueh YJ, Ma KSK, Tsai YJ, Huang SF, Chen HC, Sun CC, Kuo MT, Chao AS, Lai JY. Long-term survival of cultivated oral mucosal epithelial cells in human cornea: generating cell sheets using an animal product-free culture protocol. Stem Cell Res Ther 2021; 12:524. [PMID: 34620226 PMCID: PMC8496076 DOI: 10.1186/s13287-021-02564-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 08/20/2021] [Indexed: 02/08/2023] Open
Abstract
Previously, we reported a collagenase-based, animal product-free protocol for cultivated oral mucosal epithelial cell sheets for transplantation (COMET). Here, we reported the long-term outcomes of first 2 clinical cases. A 27-year-old man suffered from thermal burn, which resulted in symblepharon of lower fornix OD. COMET was performed, and the cornea remained clear with few peripheral NV and no more symblepharon 34 months postoperatively. Another 42-year-old man suffered from severe alkaline burn OD. He underwent COMET, followed by corneal transplantation half a year later. A biopsy taken two years after COMET showed stratified epithelium positive for keratin 4, 13, and 3 in the suprabasal layer. Staining for p63 and p75NTR was both positive in the basal layer. The graft remained clear up to post-OP 4 years. Our study confirmed the long-term survival of the transplanted OMECs, suggesting that collagenase-based spheroidal suspension culture is a promising technique for COMET.Trial registration ClinicalTrials.gov, ClinicalTrials.gov ID: NCT03943797 Registered 9 May 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03943797 .
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Affiliation(s)
- David Hui-Kang Ma
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan.
- Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.
- Department of Ophthalmology, Xiamen Chang Gung Hospital, Xiamen, Fujian, China.
| | - Yi-Jen Hsueh
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Kevin Sheng-Kai Ma
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Graduate Institute of Biomedical Electronics and Bioinformatics, College of Electrical Engineering and Computer Science, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yueh-Ju Tsai
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shiang-Fu Huang
- Department of Otolaryngology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan
| | - Hung-Chi Chen
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Chin Sun
- Department of Medicine, School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ming-Tse Kuo
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - An-Shine Chao
- Department of Obstetrics and Gynecology, New Taipei Municipal Tucheng Hospital, Tucheng, New Taipei City, Taiwan
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jui-Yang Lai
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan, Taiwan.
- Department of Materials Engineering, Ming Chi University of Technology, New Taipei City, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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Ocular mucous membrane pemphigoid: novel treatment strategies. Curr Opin Allergy Clin Immunol 2021; 21:486-492. [PMID: 34269741 DOI: 10.1097/aci.0000000000000767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW To describe current treatments of ocular mucous membrane pemphigoid (OMMP), including conventional systemic immunosuppression (CIST) and novel biologic agents. RECENT FINDINGS CIST remains the main stay therapy for the management of OMMP. The choice of agents is tailored to disease severity - mild disease is treated with dapsone, whereas moderately severe cases are often treated with mycophenolate mofetil or sulfa-based drugs and severe cases are treated with cyclophosphamide. In recalcitrant disease newer biologics such as Rituximab, intravenous immunoglobins and tumour necrosis alpha antagonists have proven to be effective in disease control. Control of inflammation with topical therapy and halting conjunctival fibrosis remain as areas of unmet clinical needs. SUMMARY OMMP is largely treated with CIST. The recent introduction of new biologic agents could shape the way the disease is treated in the near future.
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Oral Mucosal Epithelial Transplantation and Limbal-Rigid Contact Lens: A Therapeutic Modality for the Treatment of Severe Ocular Surface Disorders. Cornea 2021; 39 Suppl 1:S19-S27. [PMID: 33181721 DOI: 10.1097/ico.0000000000002566] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.
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Sotozono C, Ueta M, Kinoshita S. Japan: Diagnosis and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis With Severe Ocular Complications. Front Med (Lausanne) 2021; 8:657327. [PMID: 34395463 PMCID: PMC8355416 DOI: 10.3389/fmed.2021.657327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 06/17/2021] [Indexed: 11/30/2022] Open
Abstract
In 2005, the “Japanese Research Committee on Severe Cutaneous Adverse Reaction” (J-SCAR) presented the official “Diagnostic Criteria” for SJS/TEN, and the specific ocular findings are included in these very important criteria. In SJS/TEN cases involving ocular disorder, conjunctivitis often occurs prior to the onset of the high fever. In a Japanese survey, ocular involvement was observed in 77% of the cases, and the incidence of ocular sequelae increased depending on the score of the acute ocular severity findings. Pseudo-membrane formation and epithelial defects are considered to be high-risk signs of ocular sequelae. At the chronic stage, limbal stem cell deficiency, visual disturbance, and severe dryness of the ocular surface are the primary disease characteristics. In 2002, we started performing Cultivated Oral Mucosal Epithelial Transplantation (COMET) for the treatment of severe ocular disorders, including SJS/TEN. As an additional treatment method, we developed a new type of rigid contact lens (CL) that is 13 to 14.0-mm in diameter, known as the “Limbal Rigid Contact Lens (Limbal CL).” Our Limbal Rigid CL greatly enhances the postoperative outcome of COMET. The detection rate of ocular surface bacteria is high in SJS/TEN cases. Thus, appropriate use of topical antibiotics reduces the risk of ocular surface inflammation. Moreover, rebamipide is an ophthalmic solution for dry eye that was developed in Japan, and it also has the effect of suppressing ocular surface inflammation. From disease onset until the chronic stage, the control of inflammation and stem cell loss is key to successfully treating eyes afflicted with SJS/TEN.
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Affiliation(s)
- Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mayumi Ueta
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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21
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Metcalfe D, Iqbal O, Chodosh J, Bouchard CS, Saeed HN. Acute and Chronic Management of Ocular Disease in Stevens Johnson Syndrome/Toxic Epidermal Necrolysis in the USA. Front Med (Lausanne) 2021; 8:662897. [PMID: 34322500 PMCID: PMC8311126 DOI: 10.3389/fmed.2021.662897] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/31/2021] [Indexed: 11/25/2022] Open
Abstract
Stevens Johnson syndrome and toxic epidermal necrolysis are on a spectrum of a severe, immune-mediated, mucocutaneous disease. Ocular involvement occurs in the vast majority of cases and severe involvement can lead to corneal blindness. Treatment in the acute phase is imperative in mitigating the severity of chronic disease. Advances in acute treatment such as amniotic membrane transplantation have shown to significantly reduce the severity of chronic disease. However, AMT is not a panacea and severe chronic ocular disease can and does still occur even with aggressive acute treatment. Management of chronic disease is equally critical as timely intervention can prevent worsening of disease and preserve vision. This mini-review describes the acute and chronic findings in SJS/TEN and discusses medical and surgical management strategies.
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Affiliation(s)
- Derek Metcalfe
- Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, United States
| | - Omer Iqbal
- Loyola University Medical Center, Maywood, IL, United States
| | - James Chodosh
- Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, United States
| | | | - Hajirah N Saeed
- Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, United States
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22
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Komai S, Inatomi T, Nakamura T, Ueta M, Horiguchi G, Teramukai S, Kimura Y, Kagimura T, Fukushima M, Kinoshita S, Sotozono C. Long-term outcome of cultivated oral mucosal epithelial transplantation for fornix reconstruction in chronic cicatrising diseases. Br J Ophthalmol 2021; 106:1355-1362. [PMID: 34006509 PMCID: PMC9510423 DOI: 10.1136/bjophthalmol-2020-318547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/07/2021] [Accepted: 04/17/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND/AIMS To investigate the long-term outcomes of cultivated oral mucosal epithelial transplantation (COMET) for fornix reconstruction in eyes with chronic cicatrising disease. METHODS This retrospective cohort study involved 16 eyes of 15 patients who underwent COMET for symblepharon release and fornix reconstruction between June 2002 and December 2008. The mean postoperative follow-up period was 102.1±46.0 months (range: 32-183 months). The treated cicatrising disorders included ocular cicatricial pemphigoid (OCP, five eyes), thermal/chemical injury (three eyes) and other chronic diseases (seven eyes; including recurrent pterygium (two eyes), Stevens-Johnson syndrome (one eye) and graft-versus-host disease (one eye)). Ocular-surface appearance was evaluated before surgery, at 1, 4, 12 and 24 weeks postoperative, and then annually based on the previously reported scoring system. Main outcome measures included overall and disease-specific fornix-reconstruction success probabilities analysed by the Kaplan-Meier survival curve. Symblepharon/fornix-shortening recurrence at 24 weeks postoperative, and its relationship to long-term surgical success was also examined. RESULTS At 5 years postoperative, the mean±SD overall fornix-reconstruction success probability was 79.6%±10.7%, and success probability for thermal/chemical injury and OCP was 100% and 53.3%±24.8%, respectively (p=0.53, log-rank test). The 3-year success probability was significantly higher in the no-disease-recurrence group at 24 weeks postoperative (13 eyes) than in the disease-recurrence group (three eyes) (100% and 33.3%±27.2%, respectively) (p=0.0073, log-rank test). CONCLUSION COMET was found to be safe and effective for symblepharon release and long-term fornix reconstruction in eyes with chronic cicatrisation. Although the 5-year success probability differed depend on the underlying disease, ocular-surface appearance at 24 weeks postoperative is a factor for predicting long-term outcome.
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Affiliation(s)
- Seitaro Komai
- Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tsutomu Inatomi
- Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.,Ophthalmology, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Takahiro Nakamura
- Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Mayumi Ueta
- Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Go Horiguchi
- Clinical and Translational Research Center, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoshi Teramukai
- Biostatistics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuko Kimura
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Tatsuo Kagimura
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | | | - Shigeru Kinoshita
- Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Chie Sotozono
- Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Gao M, Chen Y, Zhai F, Liu Z, Liu Q, Wang Z. The effect of cultured autologous oral mucosal epithelial cells on ocular surface reconstruction. Arch Med Sci 2021; 20:813-821. [PMID: 39050175 PMCID: PMC11264149 DOI: 10.5114/aoms/115576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/20/2019] [Indexed: 07/27/2024] Open
Abstract
Introduction Oral epithelial cells were recently shown to be able to differentiate into corneal epithelium, and the efficacy of cultured autologous oral mucosal epithelial cells (CAOMEC) has been suggested by the presence of epithelium replacement. Therefore, the aim of this study was to evaluate the treatment outcome in limbal stem cell deficiency (LSCD) by adding CAOMEC to regular amniotic membrane (AM) treatment. Material and methods Eyes with LSCD were randomized to two groups to undergo either autologous oral mucosal epithelial cell sheet (CAOMECS) combined with AM transplantation (A group) or AM transplantation alone (B group). Clinical outcome measures were corneal epithelium healing, best corrected visual acuity, symblepharon, corneal transparency, corneal neovascularization and ocular surface inflammation. Results The normal corneal epithelialization rate in group A (73.33%) was higher than that in group B (35.48%), and the average healing time was shorter (3.45 ±2.12 weeks vs. 4.64 ±1.63 weeks). The symblepharon in the above two groups was improved in the first 3 months after surgery, but after 6 months, part of the B group had recurrence. In improving corneal transparency, group A has obvious advantages. Corneal neovascularization (CNV) was improved to some extent in the first 3 months after surgery, but group A (1.47 ±0.64) was better than group B (1.94 ±0.85) after 6 months. Both groups can improve the inflammatory state to some extent. Conclusions The transplantation of CAOMECS offers a viable and safe alternative in the reconstruction of a stable ocular surface. The effect is better than that of traditional AM transplantation, mainly in promoting corneal epithelialization, improving ocular surface structure, and reducing fiber and vascular infiltration.
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Affiliation(s)
- Minghong Gao
- The General Hospital of Northern Theater Command, Shenyang, China
| | - Yingxin Chen
- The General Hospital of Northern Theater Command, Shenyang, China
| | - Fengying Zhai
- The General Hospital of Northern Theater Command, Shenyang, China
| | - Zhiling Liu
- The General Hospital of Northern Theater Command, Shenyang, China
| | - Qiming Liu
- The General Hospital of Northern Theater Command, Shenyang, China
| | - Ziyue Wang
- The General Hospital of Northern Theater Command, Shenyang, China
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Oie Y, Komoto S, Kawasaki R. Systematic review of clinical research on regenerative medicine for the cornea. Jpn J Ophthalmol 2021; 65:169-183. [PMID: 33591470 DOI: 10.1007/s10384-021-00821-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/09/2020] [Indexed: 11/29/2022]
Abstract
PURPOSE To conduct a systematic review of clinical research on the use of regenerative medicine for the cornea in human patients. METHODS A systematic literature search of MEDLINE and the Cochrane Library was performed in May 2020. RESULTS Forty-two articles were identified. Thirty-eight of those articles focused on the treatment for limbal stem cell deficiency (LSCD), of which 17 articles involved autologous cultured limbal epithelial cell sheet transplantation (CLET), 13 involved allogeneic CLET, and 14 involved autologous cultured oral mucosal epithelial cell sheet transplantation (COMET). For autologous CLET, the median ocular surface reconstruction rate, visual recovery rate, incidence of immunologic rejection, infectious keratitis, and ocular hypertension/glaucoma were 74.1%, 54.5%, 0%, 4.6%, and 6.3%, respectively. For allogeneic CLET, they were 71.4%, 71.4%, 7.1%, 12.0%, and 7.1%, respectively. For autologous COMET, they were 66.7%, 66.7%, 0%, 5.3%, and 8.1%, respectively. Systemic immunosuppressants and steroid medications were predominantly used following allogeneic CLET, whereas they were not routinely used after autologous CLET. Three studies focused on the treatment of keratoconus using autologous adipose-derived adult stem cells and reported no marked adverse events. One study reported on the treatment of bullous keratopathy using allogeneic cultured corneal endothelial cells. All patients achieved an endothelial cell density of >500 cells, and the corrected distance visual acuity improved in 82% of the treated eyes. CONCLUSIONS The results show that regenerative medicine for the cornea demonstrated a satisfactory efficacy and safety. Through translational research, we are expecting to establish a new treatment for waiting patients.
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Affiliation(s)
- Yoshinori Oie
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Room E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Shimpei Komoto
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Room E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryo Kawasaki
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Room E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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25
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Venugopal R, Nagpal R, Mohanty S, Sen S, Kashyap S, Agarwal T, Maharana PK, Vajpayee RB, Sharma N. Outcomes of Cultivated Oral Mucosal Epithelial Transplantation in Eyes With Chronic Stevens-Johnson Syndrome Sequelae. Am J Ophthalmol 2021; 222:82-91. [PMID: 32818447 DOI: 10.1016/j.ajo.2020.08.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 08/10/2020] [Accepted: 08/10/2020] [Indexed: 11/19/2022]
Abstract
PURPOSE To study the outcomes of cultivated oral mucosal epithelial transplantation (COMET) in eyes with chronic Stevens-Johnson syndrome (SJS) sequelae. DESIGN Prospective interventional case series. METHODS Forty-five eyes of 41 patients with chronic SJS sequelae were recruited and evaluated from 2013 to 2017 in an institutional setting. All patients underwent COMET, with an aim of fornix reconstruction and visual rehabilitation. Change in corrected distance visual acuity (CDVA), severity scores of various ocular surface parameters, and the occurrence of complications were documented during a follow up period of 2 years. Attainment and maintenance of a stable ocular surface, as assessed by change in the ocular surface severity scores was the primary outcome measure, while change in CDVA was the secondary outcome measure. RESULTS The mean preoperative CDVA was 2.7± 0.5 logMAR, which improved to 1.5± 0.7 logMAR and 1.49± 0.98 postoperatively, at 1- and 2-year follow-up visit. Overall, 82.2% eyes (37/45) had improvement in visual acuity, 13.3% (6/45) experienced no change, whereas 2 eyes (4.4%) had worsening of visual acuity. The total ocular surface severity scores improved from a mean preoperative value of 29.1± 9.7 to 18.7± 7.2 postoperatively, at 2-year follow-up. Two eyes developed persistent epithelial defects, with progression to corneal melting requiring keratoplasty. CONCLUSIONS COMET allows successful and sustained restoration of ocular surface anatomy with functional improvement, in eyes with chronic sequelae of SJS.
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Affiliation(s)
- Renu Venugopal
- Cornea, Cataract & Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Ritu Nagpal
- Cornea, Cataract & Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Sen
- Department of Ocular Pathology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Kashyap
- Department of Ocular Pathology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Tushar Agarwal
- Cornea, Cataract & Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Prafulla K Maharana
- Cornea, Cataract & Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Rasik B Vajpayee
- Vision Eye Institute, Royal Victorian Eye and Ear Hospital, North West Academic Centre, University of Melbourne, Melbourne, Australia
| | - Namrata Sharma
- Cornea, Cataract & Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
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Attico E, Galaverni G, Pellegrini G. Clinical Studies of COMET for Total LSCD: a Review of the Methods and Molecular Markers for Follow-Up Characterizations. CURRENT OPHTHALMOLOGY REPORTS 2021. [DOI: 10.1007/s40135-020-00263-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Little A, Dietze-Fiedler M, Fernstrum C, Mancera N, Wilcox R, Do V. Magnesium ocular injury – A case report. BURNS OPEN 2021. [DOI: 10.1016/j.burnso.2020.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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28
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Nosrati H, Alizadeh Z, Nosrati A, Ashrafi-Dehkordi K, Banitalebi-Dehkordi M, Sanami S, Khodaei M. Stem cell-based therapeutic strategies for corneal epithelium regeneration. Tissue Cell 2020; 68:101470. [PMID: 33248403 DOI: 10.1016/j.tice.2020.101470] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022]
Abstract
Any significant loss of vision or blindness caused by corneal damages is referred to as corneal blindness. Corneal blindness is the fourth most common cause of blindness worldwide, representing more than 5% of the total blind population. Currently, corneal transplantation is used to treat many corneal diseases. In some cases, implantation of artificial cornea (keratoprosthesis) is suggested after a patient has had a donor corneal transplant failure. The shortage of donors and the side effects of keratoprosthesis are limiting these approaches. Recently, researchers have been actively pursuing new approaches for corneal regeneration because of these limitations. Nowadays, tissue engineering of different corneal layers (epithelium, stroma, endothelium, or full thickness tissue) is a promising approach that has attracted a great deal of interest from researchers and focuses on regenerative strategies using different cell sources and biomaterials. Various sources of corneal and non-corneal stem cells have shown significant advantages for corneal epithelium regeneration applications. Pluripotent stem cells (embryonic stem cells and iPS cells), epithelial stem cells (derived from oral mucus, amniotic membrane, epidermis and hair follicle), mesenchymal stem cells (bone marrow, adipose-derived, amniotic membrane, placenta, umbilical cord), and neural crest origin stem cells (dental pulp stem cells) are the most promising sources in this regard. These cells could also be used in combination with natural or synthetic scaffolds to improve the efficacy of the therapeutic approach. As the ocular surface is exposed to external damage, the number of studies on regeneration of the corneal epithelium is rising. In this paper, we reviewed the stem cell-based strategies for corneal epithelium regeneration.
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Affiliation(s)
- Hamed Nosrati
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Zohreh Alizadeh
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Anatomical Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Nosrati
- School of Mechanical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Korosh Ashrafi-Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mehdi Banitalebi-Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Samira Sanami
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Khodaei
- Department of Materials Science and Engineering, Golpayegan University of Technology, Golpayegan, Iran
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Hancox Z, Heidari Keshel S, Yousaf S, Saeinasab M, Shahbazi MA, Sefat F. The progress in corneal translational medicine. Biomater Sci 2020; 8:6469-6504. [PMID: 33174878 DOI: 10.1039/d0bm01209b] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cornea tissue is in high demand by tissue donation centres globally, and thus tissue engineering cornea, which is the main topic of corneal translational medicine, can serve as a limitless alternative to a donated human cornea tissue. Tissue engineering aims to produce solutions to the challenges associated with conventional cornea tissue, including transplantation and use of human amniotic membrane (HAM), which have issues with storage and immune rejection in patients. Accordingly, by carefully selecting biomaterials and fabrication methods to produce these therapeutic tissues, the demand for cornea tissue can be met, with an improved healing outcome for recipients with less associated harmful risks. In this review paper, we aim to present the recent advancements in the research and clinical applications of cornea tissue, applications including biomaterial selection, fabrication methods, scaffold structure, cellular response to these scaffolds, and future advancements of these techniques.
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Affiliation(s)
- Zoe Hancox
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, UK.
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30
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Nosrati H, Abpeikar Z, Mahmoudian ZG, Zafari M, Majidi J, Alizadeh A, Moradi L, Asadpour S. Corneal epithelium tissue engineering: recent advances in regeneration and replacement of corneal surface. Regen Med 2020; 15:2029-2044. [PMID: 33169642 DOI: 10.2217/rme-2019-0055] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Currently, many corneal diseases are treated by corneal transplantation, artificial corneal implantation or, in severe cases, keratoprosthesis. Owing to the shortage of cornea donors and the risks involved with artificial corneal implants, such as infection transmission, researchers continually seek new approaches for corneal regeneration. Corneal tissue engineering is a promising approach that has attracted much attention from researchers and is focused on regenerative strategies using various biomaterials in combination with different cell types. These constructs should have the ability to mimic the native tissue microenvironment and present suitable optical, mechanical and biological properties. In this article, we review studies that have focused on the current clinical techniques for corneal replacement. We also describe tissue-engineering and cell-based approaches for corneal regeneration.
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Affiliation(s)
- Hamed Nosrati
- Department of Tissue Engineering & Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Abpeikar
- Department of Tissue Engineering & Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Gholami Mahmoudian
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahdi Zafari
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - Jafar Majidi
- Cellular & Molecular Research Center, Basic Health Science Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Akram Alizadeh
- Department of Tissue Engineering & Applied Cell Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Lida Moradi
- The Ronald O Perelman Department of Dermatology, New York University, School of Medicine, New York, NY 10016, USA.,Department of Cell Biology, New York University, School of Medicine, New York, NY, 10016 USA
| | - Shiva Asadpour
- Department of Tissue Engineering & Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Cellular & Molecular Research Center, Basic Health Science Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Predictive biomarkers for the progression of ocular complications in chronic Stevens-Johnson syndrome and toxic Eeidermal necrolysis. Sci Rep 2020; 10:18922. [PMID: 33144639 PMCID: PMC7609677 DOI: 10.1038/s41598-020-76064-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/22/2020] [Indexed: 11/12/2022] Open
Abstract
This study aimed to clarify predictive biomarkers of mild and severe ocular complications of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) by examining the cytokines in tears. In 121 chronic-phase SJS/TEN eyes, cytokines in tear samples collected using Schirmer test strips were measured, and ocular sequelae severity was evaluated using an Ocular Surface Grading Score (OSGS) involving 7 components (conjunctivalization, neovascularization, opacification, keratinization, symblepharon, and upper/lower conjunctival-sac shortening), with findings categorized into grades 0–3 (maximum total OSGS: 21). Changes in cytokines between the mild and severe groups (mild: total OSGS of 10 or less, severe: total OSGS of 11 or more), and changes between SJS/TEN cases with and without each of the 7 components, were compared. In the severe group, there was significant upregulation of interleukin (IL)-8 (P < 0.01) and Granzyme B (GrzB) (P < 0.05). IL-8 was significantly upregulated in eyes with conjunctivalization, neovascularization, or opacification, GrzB was upregulated in eyes with keratinization, interferon-γ-inducible protein 10 (IP-10) was downregulated in eyes with conjunctivalization or neovascularization, and IL-1α was upregulated in eyes with opacification (all: P < 0.05). IL-8 and IP-10 was involved in conjunctivalization and neovascularization, while GrzB was involved in keratinization. IL-8 and GrzB in tears may reflect SJS/TEN-related ocular sequelae severity.
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32
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Shimazaki J, Satake Y, Higa K, Yamaguchi T, Noma H, Tsubota K. Long-term outcomes of cultivated cell sheet transplantation for treating total limbal stem cell deficiency. Ocul Surf 2020; 18:663-671. [DOI: 10.1016/j.jtos.2020.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/03/2020] [Accepted: 06/08/2020] [Indexed: 01/23/2023]
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Tidu A, Schanne-Klein MC, Borderie VM. Development, structure, and bioengineering of the human corneal stroma: A review of collagen-based implants. Exp Eye Res 2020; 200:108256. [PMID: 32971095 DOI: 10.1016/j.exer.2020.108256] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 01/15/2023]
Abstract
Bio-engineering technologies are currently used to produce biomimetic artificial corneas that should present structural, chemical, optical, and biomechanical properties close to the native tissue. These properties are mainly supported by the corneal stroma which accounts for 90% of corneal thickness and is mainly made of collagen type I. The stromal collagen fibrils are arranged in lamellae that have a plywood-like organization. The fibril diameter is between 25 and 35 nm and the interfibrillar space about 57 nm. The number of lamellae in the central stroma is estimated to be 300. In the anterior part, their size is 10-40 μm. They appear to be larger in the posterior part of the stroma with a size of 60-120 μm. Their thicknesses also vary from 0.2 to 2.5 μm. During development, the acellular corneal stroma, which features a complex pattern of organization, serves as a scaffold for mesenchymal cells that invade and further produce the cellular stroma. Several pathways including Bmp4, Wnt/β-catenin, Notch, retinoic acid, and TGF-β, in addition to EFTFs including the mastering gene Pax-6, are involved in corneal development. Besides, retinoic acid and TGF- β seem to have a crucial role in the neural crest cell migration in the stroma. Several technologies can be used to produce artificial stroma. Taking advantage of the liquid-crystal properties of acid-soluble collagen, it is possible to produce transparent stroma-like matrices with native-like collagen I fibrils and plywood-like organization, where epithelial cells can adhere and proliferate. Other approaches include the use of recombinant collagen, cross-linkers, vitrification, plastically compressed collagen or magnetically aligned collagen, providing interesting optical and mechanical properties. These technologies can be classified according to collagen type and origin, presence of telopeptides and native-like fibrils, structure, and transparency. Collagen matrices feature transparency >80% for the appropriate 500-μm thickness. Non-collagenous matrices made of biopolymers including gelatin, silk, or fish scale have been developed which feature interesting properties but are less biomimetic. These bioengineered matrices still need to be colonized by stromal cells to fully reproduce the native stroma.
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Affiliation(s)
- Aurélien Tidu
- Institut de la Vision, Sorbonne Université, INSERM, CNRS, Centre Hospitalier, National d'Ophtalmologie des 15-20, 75571, Paris, France; Groupe de Recherche Clinique 32, Sorbonne Université, Paris, France
| | - Marie-Claire Schanne-Klein
- Laboratory for Optics and Biosciences, LOB, Ecole Polytechnique, CNRS, Inserm, Université Paris-Saclay, 91128, Palaiseau, France
| | - Vincent M Borderie
- Institut de la Vision, Sorbonne Université, INSERM, CNRS, Centre Hospitalier, National d'Ophtalmologie des 15-20, 75571, Paris, France; Groupe de Recherche Clinique 32, Sorbonne Université, Paris, France.
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Allogenic Simple Limbal Epithelial Transplantation Versus Amniotic Membrane Grafting in the Early Management of Severe-Grade Ocular Chemical Injuries-A Retrospective Comparative Study. Am J Ophthalmol 2020; 217:297-304. [PMID: 32437668 DOI: 10.1016/j.ajo.2020.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 05/01/2020] [Accepted: 05/01/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE To compare outcomes of management in the early stage of severe chemical injury (grade 4 and worse; Dua classification) with amniotic membrane grafting (AMG) alone vs allogenic simple limbal epithelial transplantation (alloSLET). DESIGN Retrospective comparative interventional case series. METHODS Retrospective comparative interventional series. Records of patients with severe ocular chemical injury who underwent AMG alone (between 2009 and 2013) vs alloSLET (between 2013 and 2017) were analyzed for grade of injury, time of and interventions for epithelial healing, ocular surface status post healing (grade of symblepharon, and limbal stem cell deficiency [LSCD]), and type of and need for interventions in the chronic stage. RESULTS Among patients presenting in early stage of severe chemical injury, 38 eyes (median age 11 years) managed with AMG alone were compared with 39 eyes (median age 8 years) managed with alloSLET. The mean time of presentation post injury was 33.85 ± 27.5 and 40.6 ± 23.5 days in the AMG and alloSLET group, respectively. The rate of epithelial healing was faster in the alloSLET group and the difference was noted to be statistically significant (odds ratio [OR] 0.966, P = .001). Similarly, the lower occurrence of LSCD (OR 0.137, P = .004) and need for keratoplasty (OR 0.093, P = .003) favored alloSLET over AMG. Final best-corrected visual acuity of >20/200 was achieved in 39.4% and 53.8% in the AMG and alloSLET groups, respectively. CONCLUSION AlloSLET helps in faster epithelialization of the surface, thus reducing the need for subsequent surgeries in the chronic stage and aiding faster visual rehabilitation. The outcomes of alloSLET appear superior to amniotic membrane grafting alone and should be considered in eyes with grade 4 and above (Dua classification) chemical injuries in the early stage.
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Cabral JV, Jackson CJ, Utheim TP, Jirsova K. Ex vivo cultivated oral mucosal epithelial cell transplantation for limbal stem cell deficiency: a review. Stem Cell Res Ther 2020; 11:301. [PMID: 32693830 PMCID: PMC7374839 DOI: 10.1186/s13287-020-01783-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/26/2020] [Accepted: 06/18/2020] [Indexed: 01/19/2023] Open
Abstract
Destruction or dysfunction of limbal epithelial stem cells (LESCs) leads to unilateral or bilateral limbal stem cell deficiency (LSCD). Fifteen years have passed since the first transplantation of ex vivo cultivated oral mucosal epithelial cells (COMET) in humans in 2004, which represents the first use of a cultured non-limbal autologous cell type to treat bilateral LSCD. This review summarizes clinical outcomes from COMET studies published from 2004 to 2019 and reviews results with emphasis on the culture methods by which grafted cell sheets were prepared.
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Affiliation(s)
- Joao Victor Cabral
- Laboratory of the Biology and Pathology of the Eye, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Catherine Joan Jackson
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.,Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway.,Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway
| | - Tor Paaske Utheim
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.,Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway.,Department of Ophthalmology, Sørlandet Hospital Trust Arendal, Arendal, Norway
| | - Katerina Jirsova
- Laboratory of the Biology and Pathology of the Eye, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
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36
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Charlton OA, Harris V, Phan K, Mewton E, Jackson C, Cooper A. Toxic Epidermal Necrolysis and Steven-Johnson Syndrome: A Comprehensive Review. Adv Wound Care (New Rochelle) 2020; 9:426-439. [PMID: 32520664 PMCID: PMC7307670 DOI: 10.1089/wound.2019.0977] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/21/2019] [Indexed: 12/13/2022] Open
Abstract
Significance: Toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome (SJS) are potentially fatal acute mucocutaneous vesiculobullous disorders. Evidence to date suggests that outcomes for patients with both TEN and SJS are largely dependent on stopping the causative agent, followed by supportive care and appropriate wound management in a specialized burns unit. These are life-threatening conditions characterized by widespread full-thickness cutaneous and mucosal necrosis. This article outlines the approach to holistic management of such patients, in a specialized unit, highlighting various practical aspects of wound care to prevent complications such as infection, mucosal and adhesions, and ocular scaring. Recent Advances: There is improved understanding of pain and morbidity with regard to the type and frequency of dressing changes. More modern dressings, such as nanocrystalline, are currently favored as they may be kept in situ for longer periods. The most recent evidence on systemic agents, such as corticosteroids and cyclosporine, and novel treatments, are also discussed. Critical Issues: Following cessation of the culprit trigger, management in a specialized burns unit is the most important management step. It is now understood that a multidisciplinary team is essential in the care of these patients. Following admission of such patients, dermatology, ear, nose, and throat surgery, ophthalmology, urology, colorectal surgery, and gynecology should all be consulted to prevent disease sequelae. Future Directions: Looking forward, research is aimed at achieving prospective data on the efficacy of systemic immunomodulating agents and dressing types. Tertiary centers with burns units should develop policies for such patients to ensure that the relevant teams are consulted promptly to avoid mucocutaneous complications.
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Affiliation(s)
- Olivia A. Charlton
- Department of Dermatology, Royal North Shore Hospital, Sydney, Australia
- Northern Clinical School, University of Sydney, Sydney, Australia
| | - Victoria Harris
- Department of Dermatology, Prince of Wales Hospital, Sydney, Australia
| | - Kevin Phan
- Department of Dermatology, Liverpool Hospital, Sydney, Australia
| | - Erin Mewton
- Department of Dermatology, Royal North Shore Hospital, Sydney, Australia
| | - Chris Jackson
- Northern Clinical School, University of Sydney, Sydney, Australia
- Kolling Institute of Medical Research, Sydney, Australia
| | - Alan Cooper
- Department of Dermatology, Royal North Shore Hospital, Sydney, Australia
- Northern Clinical School, University of Sydney, Sydney, Australia
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O'Callaghan AR, Dziasko MA, Sheth-Shah R, Lewis MP, Daniels JT. Oral Mucosa Tissue Equivalents for the Treatment of Limbal Stem Cell Deficiency. ACTA ACUST UNITED AC 2020; 4:e1900265. [PMID: 32515079 DOI: 10.1002/adbi.201900265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 05/07/2020] [Indexed: 12/13/2022]
Abstract
Cultured limbal and oral epithelial cells have been successfully used to treat patients with limbal stem cell deficiency (LSCD). The most common culture method for these cell therapies utilizes amniotic membrane as a cell support and/or murine 3T3s as feeder fibroblasts. The aim of this study is to refine the production of autologous oral mucosal cell therapy for the treatment of LSCD. Real architecture for 3D tissue (RAFT) is used as an alternative cell culture support. In addition, oral mucosal cells (epithelial and fibroblast) are used as autologous alternatives to donor human limbal epithelial cells (HLE) and murine 3T3s. The following tissue equivalents are produced and characterized: first, for patients with bilateral LSCD, an oral mucosa tissue equivalent consisting of human oral mucosal epithelial cells on RAFT supported by human oral mucosal fibroblasts (HOMF). Second, for patients with unilateral LSCD, HLE on RAFT supported by HOMF. For both tissue equivalent types, features of the cornea are observed including a multi-layered epithelium with small cells with a stem cell like phenotype in the basal layer and squamous cells in the top layers, and p63α and PAX6 expression. These tissue equivalents may therefore be useful in the treatment of LSCD.
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Affiliation(s)
- Anna R O'Callaghan
- Cells for Sight, UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
| | - Marc A Dziasko
- Cells for Sight, UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
| | - Radhika Sheth-Shah
- Cells for Sight, UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
| | - Mark P Lewis
- National Centre for Sport and Exercise Medicine (NCSEM), School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, LE11 3TU, UK
| | - Julie T Daniels
- Cells for Sight, UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
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Itoi M, Ueta M, Ogino K, Sumi E, Imai K, Teramukai S, Kinoshita S, Sotozono C. Clinical trial to evaluate the therapeutic benefits of limbal-supported contact lens wear for ocular sequelae due to Stevens-Johnson syndrome/toxic epidermal necrolysis. Cont Lens Anterior Eye 2020; 43:535-542. [PMID: 32513522 DOI: 10.1016/j.clae.2020.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 05/06/2020] [Accepted: 05/10/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE To analyze the therapeutic benefits of limbal-supported contact lens (CL) wear in patients with ocular sequelae due to Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). METHODS This interventional study enrolled 10 chronic SJS/TEN eyes with a spectacle best-corrected visual acuity (BCVA) of between 0.01 and 0.7 that were fitted with a limbal-supported CL. At baseline and at after 3-months CL use, CL-wear BCVA and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores were measured, and then compared. Incidence rates and severities of adverse events were also analyzed. RESULTS At after 3-months CL use, BCVA with the fitted CL significantly improved compared to that with spectacle correction at baseline (LogMAR: 0.76-0.15) (P = 0.0039), all NEI VFQ-25 scores improved, however, only in ocular pain and mental health showed statistically significant improvement (P = 0.0078 and 0.0039). No serious adverse events were observed during the follow-up. CONCLUSION Wearing of the limbal-supported CL improved vision compared to spectacles and reduced ocular pain in patients with ocular sequelae due to SJS/TEN.
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Affiliation(s)
- Motohiro Itoi
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramach-dori, Kamigyo-ku, Kyoto 602-0841, Japan.
| | - Mayumi Ueta
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramach-dori, Kamigyo-ku, Kyoto 602-0841, Japan.
| | - Ken Ogino
- Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
| | - Eriko Sumi
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
| | - Kojiro Imai
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Satoshi Teramukai
- Department of Biostatistics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Shigeru Kinoshita
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramach-dori, Kamigyo-ku, Kyoto 602-0841, Japan.
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Ueta M. Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications. Expert Rev Clin Immunol 2020; 16:285-291. [PMID: 32045311 DOI: 10.1080/1744666x.2020.1729128] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Stevens-Johnson syndrome (SJS) and its severe phenotype, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. Approximately 50% of SJS/TEN patients diagnosed by dermatologists and in burn units suffer from severe ocular complications (SOC) in the acute stage.Areas covered: Earlier studies on patients with SJS/TEN with SOC identified cold medicines including multi-ingredient cold medications and non-steroidal anti-inflammatory drugs as the main eliciting drugs. HLA analyzes showed that genetic predisposition might play a role in the response to these drugs. Our analysis of the association between HLA genotypes and cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC revealed that certain HLA genotypes play a role in the development of SJS/TEN with SOC. Genetic predisposition and other factors contributing to the elicitation of CM-SJS/TEN with SOC and the management of patients in the acute and chronic stage of the disease are discussed.Expert opinion: The main sequelae of SJS/TEN are ocular sequelae with visual disturbance. SJS/TEN with SOC needs ophthalmic treatment in addition to systemic treatment from the onset time to reduce the ophthalmic sequelae. In addition, HLA examination and public awareness of SJS/TEN with SOC due to cold medicine use might contribute to preventing visual disturbance due to SJS/TEN.Abbreviations: SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; SOC: severe ocular complications.
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Affiliation(s)
- Mayumi Ueta
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) for Visual Rehabilitation in Limbal Stem Cell Deficiency. Eye Contact Lens 2020; 46:359-363. [DOI: 10.1097/icl.0000000000000685] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Long-term Progression of Ocular Surface Disease in Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis. Cornea 2020; 39:745-753. [DOI: 10.1097/ico.0000000000002263] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Borrelli M, Geerling G, Spaniol K, Witt J. Eye Socket Regeneration and Reconstruction. Curr Eye Res 2020; 45:253-264. [DOI: 10.1080/02713683.2020.1712423] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- M. Borrelli
- Department of Ophthalmology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - G. Geerling
- Department of Ophthalmology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - K. Spaniol
- Department of Ophthalmology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - J. Witt
- Department of Ophthalmology, University Hospital Duesseldorf, Duesseldorf, Germany
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Clinical Trials of Limbal Stem Cell Deficiency Treated with Oral Mucosal Epithelial Cells. Int J Mol Sci 2020; 21:ijms21020411. [PMID: 31936462 PMCID: PMC7014181 DOI: 10.3390/ijms21020411] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/04/2020] [Accepted: 01/07/2020] [Indexed: 12/11/2022] Open
Abstract
The corneal surface is an essential organ necessary for vision, and its clarity must be maintained. The corneal epithelium is renewed by limbal stem cells, located in the limbus and in palisades of Vogt. Palisades of Vogt maintain the clearness of the corneal epithelium by blocking the growth of conjunctival epithelium and the invasion of blood vessels over the cornea. The limbal region can be damaged by chemical burns, physical damage (e.g., by contact lenses), congenital disease, chronic inflammation, or limbal surgeries. The degree of limbus damage is associated with the degree of limbal stem cells deficiency (partial or total). For a long time, the only treatment to restore vision was grafting part of the healthy cornea from the other eye of the patient or by transplanting a cornea from cadavers. The regenerative medicine and stem cell therapies have been applied to restore normal vision using different methodologies. The source of stem cells varies from embryonic stem cells, mesenchymal stem cells, to induced pluripotent stem cells. This review focuses on the use of oral mucosa epithelial stem cells and their use in engineering cell sheets to treat limbal stem cell deficient patients.
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Simple oral mucosal epithelial transplantation in a rabbit model. Sci Rep 2019; 9:18088. [PMID: 31792300 PMCID: PMC6889162 DOI: 10.1038/s41598-019-54571-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 11/12/2019] [Indexed: 01/22/2023] Open
Abstract
This study investigated a rabbit model of autologous simple oral mucosal epithelium transplantation (SOMET) for limbal stem cell deficiency (LSCD). LSCD was created in the SOMET group and the Control group. In the SOMET group, oral mucosa harvested from the buccal region was treated with dispase, cut into small pieces, and placed on the exposed corneal stroma without using graft sutures, amniotic membrane, and/or glue. A soft contact lens was positioned and tarsorrhaphy was performed in both groups. Postoperative corneal neovascularization and fluorescein staining scores were evaluated by slit lamp microscopy in both groups. At 2 weeks postoperatively, eyes were excised and subjected to immunohistochemical staining for CK3, CK13, CK15, and p63. In the SOMET group, transplantation of oral mucosa led to complete recovery of LSCD, as indicated by low neovascularization scores, low fluorescein staining scores, and detection of stratified K3/K13-positive cells on the stroma at 2 weeks after surgery. In contrast, corneal epithelial defects persisted in the Control group at 2 weeks. SOMET achieved re-epithelialization of the corneal surface in this rabbit LSCD model. It is a simple technique that does not require culture and could be a promising option for ocular surface reconstruction in bilateral LSCD.
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Sakimoto T, Sakimoto A, Yamagami S. Autologous transplantation of conjunctiva by modifying simple limbal epithelial transplantation for limbal stem cell deficiency. Jpn J Ophthalmol 2019; 64:54-61. [PMID: 31760516 DOI: 10.1007/s10384-019-00701-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 10/31/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE As a treatment to replace regenerative medicine to treat limbal stem cell deficiency (LSCD), we performed 4 consecutive cases of autologous transplantation of conjunctival explants by modifying simple limbal epithelial transplantation (SLET). STUDY DESIGN Single-center case series. METHODS Four patients with LSCD were enrolled in this study. After resection of scar tissue with neovascularization from the ocular surface, human amniotic membrane (AM) was placed over the bare ocular surface. The bulbar conjunctiva of the operated eye was dissected at the temporal superior fornix, divided into small pieces, and transplanted onto AM with fibrin glue. Keratoplasty was performed simultaneously or few months after surgery. RESULTS Epithelialization was achieved in all patients. Best-corrected visual acuity was improved in all patients. CONCLUSION This is the first report of ocular surface reconstruction using autologous conjunctival epithelial transplants from the affected eye. Transplantation by modifying SLET effectively restored a clear corneal surface with minimal neovascularization in 4 patients with LSCD. Autologous conjunctival transplants combined with AM transplantation could be a practical option for treating bilateral LSCD in patients without symblepharon or severe keratinization.
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Affiliation(s)
- Tohru Sakimoto
- Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Akira Sakimoto
- Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Satoru Yamagami
- Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan.
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Bizrah M, Yusuf A, Ahmad S. An update on chemical eye burns. Eye (Lond) 2019; 33:1362-1377. [PMID: 31086244 PMCID: PMC7002428 DOI: 10.1038/s41433-019-0456-5] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 02/06/2019] [Accepted: 04/02/2019] [Indexed: 01/20/2023] Open
Abstract
Ocular chemical injuries vary in severity, with the more severe end of the spectrum having profound visual consequences and medicolegal implications. Grading of ocular injuries is critical for determining acute treatment and visual prognosis. Poor immediate management results in more challenging treatment of acute disease. Similarly, poorly controlled acute disease results in more treatment-resistant chronic ocular disease. Despite several decades of research and public health initiatives, simple and effective interventions such as wearing protective eyewear and immediate irrigation of eyes remain as key challenges. Education and prevention are therefore important public health messages. Hurdles in the acute management of disease include poor evidence-base for commonly used treatments (e.g. based on experimental animal studies), reduced treatment adherence rates and high clinic non-attendance rates. The evolution of treatment strategies, particularly limbal stem cell transplantation, has revolutionised the visual and cosmetic outcomes in chronic phases of disease. It is therefore increasingly important to consider tertiary referral for patients with limbal stem cell failure or vision-limiting corneal scarring.
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Affiliation(s)
- Mukhtar Bizrah
- Imperial College Healthcare NHS Trust, Western Eye Hospital, 153-173 Marylebone Road, London, NW1 5QH, UK.
| | - Ammar Yusuf
- UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Sajjad Ahmad
- Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK
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Le Q, Chauhan T, Deng SX. Diagnostic criteria for limbal stem cell deficiency before surgical intervention-A systematic literature review and analysis. Surv Ophthalmol 2019; 65:32-40. [PMID: 31276736 DOI: 10.1016/j.survophthal.2019.06.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 06/12/2019] [Accepted: 06/17/2019] [Indexed: 11/24/2022]
Abstract
An accurate diagnosis of limbal stem cell deficiency (LSCD) is the premise of an appropriate treatment; however, there is no consensus about the diagnostic criteria for LSCD. We performed a systematic literature search of the peer-reviewed articles on PubMed, Medline, and Ovid to investigate how LSCD was diagnosed before surgical intervention. The methods used to diagnose LSCD included clinical presentation, impression cytology, and in vivo confocal microscopy. Among 131 eligible studies (4054 eyes), 26 studies (459 eyes, 11.3%) did not mention the diagnostic criteria. In the remaining 105 studies, the diagnosis of LSCD was made on the basis of clinical examination alone in 2398 eyes (62.9%), and additional diagnostic tests were used in 1047 (25.8%) eyes. Impression cytology was used in 981 eyes (24.2%), in vivo confocal microscopy was used in 29 eyes (0.7%), and both impression cytology and in vivo confocal microscopy were used in 37 eyes (0.9%). Our findings suggest that only a small portion of patients underwent a diagnostic test to confirm the diagnosis of LSCD. Treating physicians should be aware of the limitations of clinical examination in diagnosing LSCD and perform a diagnostic test whenever possible before surgical intervention.
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Affiliation(s)
- Qihua Le
- Stein Eye Institute, Cornea Division, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, California; Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China
| | - Tulika Chauhan
- Stein Eye Institute, Cornea Division, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Sophie X Deng
- Stein Eye Institute, Cornea Division, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, California.
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Bains KK, Fukuoka H, Hammond GM, Sotozono C, Quantock AJ. Recovering vision in corneal epithelial stem cell deficient eyes. Cont Lens Anterior Eye 2019; 42:350-358. [PMID: 31047800 PMCID: PMC6611221 DOI: 10.1016/j.clae.2019.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 12/13/2022]
Abstract
Corneal limbal epithelial stem cells deficiencies cause severe ocular surface instability and visual impairment. These conditions, caused by injury or disease, are very difficult to treat. Laboratory-grown epithelial cell sheets expanded from healthy limbal tissue can be used to reconstruct the ocular surface. Other epithelia, such as the oral mucosa, can be used to generate the therapeutic cell sheets. A healthy corneal epithelium, which is essential for proper vision and protection from external pathogens, is continuously replenished throughout life by stem cells located at the limbus. In diseased or injured eyes, however, in which stem cells are deficient, severe ocular problems manifest themselves. These are notoriously difficult to manage and as a result the last 20 or so years has seen a number of therapeutic strategies emerge that aim to recover the ocular surface and restore vision in limbal stem cell deficient eyes. The dominant concept involves the generation of laboratory cultivated epithelial cell sheets expanded from small biopsies of the epithelial limbus (for patient or donors) or another non-corneal epithelial tissue such as the oral mucosa. Typically, cells are grown on sterilised human amniotic membrane as a substrate, which then forms part of the graft, or specially formulated plastic culture dishes from which cells sheets can be released by lowering the temperature, and thus the adherence of the plastic to the cells. Overall, clinical results are promising, as is discussed, with new cultivation methodologies and different cell lineages currently being investigated to augment the treatment options for visual disturbance caused by a corneal epithelial limbal stem cell deficiency.
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Affiliation(s)
- Kiranjit K Bains
- Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cardiff, Wales, United Kingdom.
| | - Hideki Fukuoka
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8065, Japan.
| | - Greg M Hammond
- Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cardiff, Wales, United Kingdom
| | - Chie Sotozono
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8065, Japan.
| | - Andrew J Quantock
- Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cardiff, Wales, United Kingdom; Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8065, Japan.
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Comparison of the efficacy of different cell sources for transplantation in total limbal stem cell deficiency. Graefes Arch Clin Exp Ophthalmol 2019; 257:1253-1263. [PMID: 31004182 DOI: 10.1007/s00417-019-04316-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/12/2019] [Accepted: 04/01/2019] [Indexed: 02/04/2023] Open
Abstract
PURPOSE The purpose of this study was to compare the efficacy of allogeneic cultured limbal epithelial transplantation (ACLET) and cultivated oral mucosal epithelial transplantation (COMET) in treating total limbal stem cell deficiency (LSCD). METHODS In this retrospective cohort study, 73 patients (76 eyes) with total LSCD, including 41 patients (42 eyes) treated with ACLET and 32 patients (34 eyes) receiving COMET, were evaluated. The age, gender and injury cause of all patients were recorded. RESULTS The mean follow-up was 23.3 ± 9.9 months in the ACLET group and 16.1 ± 5.8 months in the COMET group. A higher incidence of persistent epithelial defect was observed after COMET (P = 0.023). The overall ocular surface grading scores were all lower in the ACLET group than in the COMET group at 3, 6, and 12 months after surgery and the last follow-up. Kaplan-Meier survival curve analysis demonstrated a significantly higher success rate of ACLET (71.4%), compared with that of COMET (52.9%; P = 0.043). The risk of graft failure was higher in patients with entropion and trichiasis, incomplete eyelid closure and treated with COMET. The graft failure risk rate after COMET was 3.5 times higher than that of ACLET. CONCLUSIONS For total LSCD patients, ACLET should be prioritized, since limbal epithelial cells have better ability to maintain corneal epithelial integrity and ocular surface stability and benefit the ocular surface when compared with oral mucosal epithelial cells. Preoperative and postoperative eyelid abnormalities should be corrected as early as possible.
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Mieno H, Ueta M, Yamada K, Yamanaka Y, Nakayama T, Watanabe A, Kinoshita S, Sotozono C. Expression of prostaglandin E2 receptor 3 in the eyelid epidermis of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Ophthalmol 2019; 104:1022-1027. [DOI: 10.1136/bjophthalmol-2018-313587] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/27/2019] [Accepted: 04/03/2019] [Indexed: 11/03/2022]
Abstract
Background/aimsIn a previous genome-wide association study of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) patients we reported the association between SJS/TEN and the prostaglandin E receptor 3 (PTGER3) gene, and that its protein PGE2 receptor 3 (EP3) was markedly downregulated in the conjunctival epithelium of SJS/TEN patients. Here we examined EP3 expression of the eyelid epidermis in SJS/TEN patients with severe ocular complications and investigated the function of EP3.MethodsFor the immunohistochemical study, we obtained eyelid samples from five SJS/TEN patients and five patients without SJS/TEN (control subjects) who were undergoing surgery to treat trichiasis, and investigated the expression of EP3 protein in the epidermis of those samples. To investigate the EP3 function in the human epidermal keratinocytes, we performed ELISA and quantitative reverse transcription polymerase chain reaction, since it is reported that PGE2 suppresses cytokine production via EP3 in human conjunctival epithelium.ResultsThe results of the immunohistochemical study revealed that EP3 expression in the eyelid epidermis of the SJS/TEN patients was the same as that in the controls. PGE2 and a selective EP3 agonist suppressed cytokine production and expression induced by polyinosine-polycytidylic acid stimulation, such as chemokine ligand 5 and chemokine motif ligand 10.ConclusionOur findings revealed that in chronic-phase SJS/TEN, EP3 protein was expressed in the eyelid epidermis and was not downregulated, unlike in conjunctival epithelium, and that PGE2 could suppress cytokine production via EP3 in human epidermal keratinocytes. Thus, EP3 expression in the epidermis might contribute to a silencing of skin inflammation in chronic-phase SJS/TEN.
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