Persistent corneal epithelial defects: an updated review of literature
Medical hypothesis, discovery & innovation in optometry,
Vol. 6 No. 3 (2025),
21 November 2025
,
Page 121-128
https://doi.org/10.51329/mehdioptometry231
Abstract
Background: Persistent corneal epithelial defects (PCEDs) represent a significant clinical challenge characterized by the failure of the corneal epithelium to heal within the normal period, leading to potential sight-threatening complications. These defects arise from a variety of underlying etiologies, including limbal stem cell deficiency, neurotrophic keratopathy, dry eye syndrome, and systemic diseases such as diabetes mellitus. Despite advances in ophthalmic care, PCEDs remain difficult to treat due to diverse pathophysiological mechanisms and variable response to conventional therapies. Recent developments in growth factor therapies, biological treatments, surgical techniques, and regenerative medicine have expanded therapeutic options but necessitate comprehensive review to guide clinical practice.
Methods: A comprehensive narrative review was conducted through a systematic search of major electronic databases including PubMed/MEDLINE, Embase, Scopus, and Google Scholar. The search incorporated keywords and Medical Subject Headings related to “persistent corneal epithelial defects”, “corneal epithelial healing”, “limbal stem cell deficiency”, “neurotrophic keratopathy”, “amniotic membrane transplantation”, and “emerging treatments”. Peer-reviewed original studies, clinical trials, reviews, and meta-analyses published between 2000 and 2025 were included. Articles were critically appraised and selected according to their relevance, methodological quality, and contribution to understanding PCED pathophysiology, diagnosis, and treatment advancements.
Results: The review delineates the anatomy and physiological roles of the corneal epithelium, highlighting mechanisms that lead to epithelial defect persistence, including impaired basement membrane integrity, stem cell deficiency, inflammation, and neurotrophic factors. Clinical presentation and diagnostic modalities such as fluorescein staining and advanced imaging techniques are discussed. Standard management with lubricants, therapeutic contact lenses, infection control, and autologous serum eye drops is described, alongside medical therapies targeting epithelial regeneration, including recombinant human nerve growth factor and platelet-rich plasma. Surgical interventions like amniotic membrane transplantation and novel regenerative approaches involving stem cell therapy and corneal neurotization show promising results in refractory cases. Emerging molecular therapies and bioengineered drug delivery systems represent the forefront of innovation in PCED treatment.
Conclusion: PCEDs pose complex therapeutic challenges necessitating a multifaceted treatment approach. Advances in molecular, cellular, and surgical therapies have substantially expanded management options and improved healing outcomes. However, continued research into personalized therapies, optimization of delivery methods, and long-term safety is essential. This review provides a comprehensive synthesis of current knowledge and emerging trends to inform clinicians and researchers in the effective management of PCEDs, ultimately aiming to preserve vision and enhance quality of life. Future research should focus on minimally invasive sustained-release therapies, biomarker-guided personalized interventions, and combination approaches targeting epithelium, inflammation, and nerves.
Keywords:
- corneal epithelium
- persistent corneal epithelial defects
- neurotrophic keratopathy
- limbal stem cell
- limbal stem cell deficiency
- corneal disease
- wound healings
- amniotic membrane
- stem cell transplantations
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2. Wirostko B, Rafii M, Sullivan DA, Morelli J, Ding J. Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone. Ocul Surf. 2015 Jul;13(3):204-212.e1. doi: 10.1016/j.jtos.2014.12.005. Epub 2015 Mar 28. PMID: 26045234; PMCID: PMC4498999.
3. Maqsood S, Elsawah K, Dhillon N, Soliman S, Laginaf M, Lodhia V, Lake D, Hamada S, Elalfy M. Management of Persistent Corneal Epithelial Defects with Human Amniotic Membrane-derived Dry Matrix. Clin Ophthalmol. 2021 May 28;15:2231-2238. doi: 10.2147/OPTH.S299141. PMID: 34093006; PMCID: PMC8169046.
4. Ahmad S. Concise review: limbal stem cell deficiency, dysfunction, and distress. Stem Cells Transl Med. 2012 Feb;1(2):110-5. doi: 10.5966/sctm.2011-0037. Epub 2012 Jan 26. PMID: 23197757; PMCID: PMC3659689.
5. Chen HF, Yeung L, Yang KJ, Sun CC. PERSISTENT CORNEAL EPITHELIAL DEFECT AFTER PARS PLANA VITRECTOMY. Retina. 2016 Jan;36(1):148-55. doi: 10.1097/IAE.0000000000000657. PMID: 26166798.
6. Vajpayee RB, Thomas S, Sharma N, Dada T, Tabin GC. Large-diameter lamellar keratoplasty in severe ocular alkali burns: A technique of stem cell transplantation. Ophthalmology. 2000 Sep;107(9):1765-8. doi: 10.1016/s0161-6420(00)00250-5. PMID: 10964842.
7. Thia ZZ, Ho YT, Shih KC, Tong L. New developments in the management of persistent corneal epithelial defects. Surv Ophthalmol. 2023 Nov-Dec;68(6):1093-1114. doi: 10.1016/j.survophthal.2023.06.001. Epub 2023 Jun 8. PMID: 37301520.
8. Morishige N, Uemura A, Morita Y, Nishida T. Promotion of Corneal Epithelial Wound Healing in Diabetic Rats by the Fibronectin-Derived Peptide PHSRN. Cornea. 2017 Dec;36(12):1544-1548. doi: 10.1097/ICO.0000000000001344. PMID: 28834817.
9. Feizi S, Masoudi A, Hosseini SB, Kanavi MR, Javadi MA. Microbiological Evaluation of Bandage Soft Contact Lenses Used in Management of Persistent Corneal Epithelial Defects. Cornea. 2019 Feb;38(2):146-150. doi: 10.1097/ICO.0000000000001810. PMID: 30422865.
10. Sridhar MS. Anatomy of cornea and ocular surface. Indian J Ophthalmol. 2018 Feb;66(2):190-194. doi: 10.4103/ijo.IJO_646_17. PMID: 29380756; PMCID: PMC5819093.
11. DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg. 2011 Mar;37(3):588-98. doi: 10.1016/j.jcrs.2010.12.037. PMID: 21333881.
12. Torricelli AA, Singh V, Santhiago MR, Wilson SE. The corneal epithelial basement membrane: structure, function, and disease. Invest Ophthalmol Vis Sci. 2013 Sep 27;54(9):6390-400. doi: 10.1167/iovs.13-12547. PMID: 24078382; PMCID: PMC3787659.
13. Wong HL, Poon SHL, Bu Y, Lo ACY, Jhanji V, Chan YK, Shih KC. A Systematic Review on Cornea Epithelial-Stromal Homeostasis. Ophthalmic Res. 2021;64(2):178-191. doi: 10.1159/000509030. Epub 2020 May 29. PMID: 32474566.
14. Vaidyanathan U, Hopping GC, Liu HY, Somani AN, Ronquillo YC, Hoopes PC, Moshirfar M. Persistent Corneal Epithelial Defects: A Review Article. Med Hypothesis Discov Innov Ophthalmol. 2019 Fall;8(3):163-176. PMID: 31598519; PMCID: PMC6778469.
15. Yan C, Jin L, Zhang Q, Liu X, Yu T, Zhao F, Mu Y, Xu J, Zhang L. Management of delayed corneal epithelial healing after refractive surgery: five case reports. Front Med (Lausanne). 2025 Mar 4;12:1517403. doi: 10.3389/fmed.2025.1517403. PMID: 40103788; PMCID: PMC11913852.
16. Fatima A, Iftekhar G, Sangwan VS, Vemuganti GK. Ocular surface changes in limbal stem cell deficiency caused by chemical injury: a histologic study of excised pannus from recipients of cultured corneal epithelium. Eye (Lond). 2008 Sep;22(9):1161-7. doi: 10.1038/sj.eye.6702895. Epub 2007 Jun 8. PMID: 17558385.
17. Sangwan VS. Limbal stem cells in health and disease. Biosci Rep. 2001 Aug;21(4):385-405. doi: 10.1023/a:1017935624867. PMID: 11900318.
18. Sacchetti M, Lambiase A. Neurotrophic factors and corneal nerve regeneration. Neural Regen Res. 2017 Aug;12(8):1220-1224. doi: 10.4103/1673-5374.213534. PMID: 28966630; PMCID: PMC5607810.
19. Sejpal K, Bakhtiari P, Deng SX. Presentation, diagnosis and management of limbal stem cell deficiency. Middle East Afr J Ophthalmol. 2013 Jan-Mar;20(1):5-10. doi: 10.4103/0974-9233.106381. PMID: 23580847; PMCID: PMC3617528.
20. Napoli PE, Braghiroli M, Iovino C, Demarinis G, Fossarello M. A study of refractory cases of persistent epithelial defects associated with dry eye syndrome and recurrent corneal erosions successfully treated with cyclosporine A 0.05% eye drops. Drug Des Devel Ther. 2019 Jun 19;13:2001-2008. doi: 10.2147/DDDT.S207453. PMID: 31354245; PMCID: PMC6590396.
21. Kwon JE, Kang C, Moghtader A, Shahjahan S, Bibak Bejandi Z, Alzein A, Djalilian AR. Emerging Treatments for Persistent Corneal Epithelial Defects. Vision (Basel). 2025 Apr 1;9(2):26. doi: 10.3390/vision9020026. PMID: 40265394; PMCID: PMC12015846.
22. Hamrah P, Cruzat A, Dastjerdi MH, Zheng L, Shahatit BM, Bayhan HA, Dana R, Pavan-Langston D. Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology. 2010 Oct;117(10):1930-6. doi: 10.1016/j.ophtha.2010.07.010. Epub 2010 Sep 1. PMID: 20810171; PMCID: PMC2949523.
23. Vera-Duarte GR, Jimenez-Collado D, Kahuam-López N, Ramirez-Miranda A, Graue-Hernandez EO, Navas A, Rosenblatt MI. Neurotrophic keratopathy: General features and new therapies. Surv Ophthalmol. 2024 Sep-Oct;69(5):789-804. doi: 10.1016/j.survophthal.2024.04.004. Epub 2024 Apr 26. PMID: 38679146.
24. Srinivas SP, Rao SK. Ocular surface staining: Current concepts and techniques. Indian J Ophthalmol. 2023 Apr;71(4):1080-1089. doi: 10.4103/ijo.IJO_2137_22. PMID: 37026238; PMCID: PMC10276680.
25. Vilares Morgado R, Moura R, Moreira R, Falcão-Reis F, Pinheiro-Costa J. New Promising Therapeutic Approach for Refractory Corneal Epithelial Defects. Cureus. 2023 May 22;15(5):e39324. doi: 10.7759/cureus.39324. PMID: 37351246; PMCID: PMC10283014.
26. Katzman LR, Jeng BH. Management strategies for persistent epithelial defects of the cornea. Saudi J Ophthalmol. 2014 Jul;28(3):168-72. doi: 10.1016/j.sjopt.2014.06.011. Epub 2014 Jul 2. PMID: 25278792; PMCID: PMC4181455.
27. Vazirani J, Kate A, Agarwal S, Basu S, Bhalekar S, Chaudhary S, D'Souza S, Fogla R, Gour A, Goel S, Gokhale NS, Gupta N, Joshi P, Mehta P, Mittal V, Murthy SI, Pillai VS, Shanbhag SS, Singh S, Srinivasan B, Suman S, Sangwan VS. Preservative Related Ocular Surface Toxicity and the Need for Preservative Free Eye Drops in Ocular Surface Disorders - Recommendations of an Expert Group. Semin Ophthalmol. 2025 Sep 12:1-4. doi: 10.1080/08820538.2025.2555903. Epub ahead of print. PMID: 40937610.
28. Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R, Deng SX, Dong PN, Geerling G, Hida RY, Liu Y, Seo KY, Tauber J, Wakamatsu TH, Xu J, Wolffsohn JS, Craig JP. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017 Jul;15(3):575-628. doi: 10.1016/j.jtos.2017.05.006. Epub 2017 Jul 20. PMID: 28736343.
29. Tuli SS, Schultz GS, Downer DM. Science and strategy for preventing and managing corneal ulceration. Ocul Surf. 2007 Jan;5(1):23-39. doi: 10.1016/s1542-0124(12)70050-2. PMID: 17252163.
30. Golhait P, Peseyie R. Persistent Epithelial Defect. 2023 Jul 31. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 34424633.
31. Vote BJ, Elder MJ. Cyanoacrylate glue for corneal perforations: a description of a surgical technique and a review of the literature. Clin Exp Ophthalmol. 2000 Dec;28(6):437-42. doi: 10.1046/j.1442-9071.2000.00351.x. PMID: 11202468.
32. Chan SM, Tseng CL, Huang WH, Lin CT. Therapeutic Assessment of Diverse Doxycycline-Based Formulations in Promoting Deep Corneal Wound Healing: Evidence from a Rat Model. Vet Sci. 2025 Feb 8;12(2):143. doi: 10.3390/vetsci12020143. PMID: 40005905; PMCID: PMC11860526.
33. Hossain P. The corneal melting point. Eye (Lond). 2012 Aug;26(8):1029-30. doi: 10.1038/eye.2012.136. Epub 2012 Jul 6. PMID: 22766538; PMCID: PMC3420049.
34. Yu FS, Yin J, Xu K, Huang J. Growth factors and corneal epithelial wound healing. Brain Res Bull. 2010 Feb 15;81(2-3):229-35. doi: 10.1016/j.brainresbull.2009.08.024. Epub 2009 Sep 4. PMID: 19733636; PMCID: PMC3010187.
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