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- DOI 10.18231/j.ijceo.v.11.i.3.4
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CrossMark
Non-healing corneal ulcers: Diagnostic approaches, and emerging therapeutic strategies
- Author Details:
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Subappratha Ashokan
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K. Ezhil Vendhan
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Aarthi K
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Sindhu Elavarasan *
K. Ezhil Vendhan
Aarthi K
Sindhu Elavarasan *
Non-healing corneal ulcers, also referred to as refractory or persistent epithelial defects, represent a significant challenge in ophthalmic practice due to their complex etiology and resistance to conventional therapies. These ulcers arise from a multitude of infectious and non-infectious factors, including microbial infections, autoimmune diseases, neurotrophic keratitis, and iatrogenic causes, leading to prolonged inflammation, stromal degradation, and impaired epithelial regeneration. This review provides a comprehensive overview of the anatomy and physiology of the cornea, elucidating the pathophysiological mechanisms underlying non-healing ulcers. It further explores the diagnostic modalities employed to identify these ulcers and differentiates them from other corneal pathologies. Current treatment strategies, encompassing medical management, surgical interventions, and barrier therapies, are critically analyzed. Special emphasis is placed on emerging therapeutic innovations such as stem cell therapy, tissue engineering, gene therapy, nanotechnology-based drug delivery systems, and artificial corneas, which offer promising avenues for effective management of refractory cases. The review also highlights the persistent challenges in treating these ulcers, including antibiotic resistance, delayed diagnosis, and management of chronic or recurrent cases. Finally, it outlines future directions and recommendations for improving patient outcomes through multidisciplinary care, biomarker development, and continued clinical research in this evolving field.
References
- Sharma N, Sachdev R, Jhanji V, Titiyal JS. Therapeutic keratoplasty for infectious keratitis. Curr Opin Ophthalmol 2020;21(4):293–300.
- Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: A global perspective. Bull World Health Organ. 2001;79(3):214–21.
- Sangwan VS, Burman S, Tejwani S, Mahesh SP, Murthy R. Amniotic membrane transplantation: A review of current indications in the management of ophthalmic disorders. Indian J Ophthalmol. 2012;55(4):251–60.
- Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog Retin Eye Res. 2015;49:17–45.
- Notara M, Alatza A, Gilfillan J, Harris AR, Levis HJ, Schrader S, et al. In sickness and in health: corneal epithelial stem cell biology, pathology and therapy. Exp Eye Res. 2010;90(2):188–95.
- Thomas PA, Geraldine P, Leck AK. Mycotic keratitis: Epidemiology, diagnosis, and management. Clin Microbiol Infect. 2013;19:210–3.
- DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg. 2011;37(3):588–98.
- Dua HS, Saini JS, Azuara-Blanco A, Gupta P. Limbal stem cell deficiency: concept, aetiology, clinical presentation, diagnosis and management. Indian J Ophthalmol. 2000;48(2):83–92.
- Maurice DM. The structure and transparency of the cornea. J Physiol 1957;136(2):263–86.
- Lu L, Reinach PS, Kao WW. Corneal epithelial wound healing. Exp Biol Med (Maywood). 2001;226(7):653–64
- Müller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76(5):521–42.
- Choi H, Kim SE, Kim T, Jang J, Hwang SY, Seo K. Clinical features and prognosis of corneal ulcers in dogs with chronic kidney disease. J Vet Clin. 2021;38(3):115–9.
- Ishimoto A, Araki-Sasaki K, Shima C, Tajika M, Toyokawa N, Takahashi K. Corneal ulcers with non-infectious appearance caused by nasolacrimal duct obstruction or canaliculitis. Am J Ophthalmol Case Rep. 2022;27:101651.
- Uhlig CE, Frings C, Rohloff N, Harmsen-Aasman C, Schmitz R, Kiesel L, et al. Long-term efficacy of glycerine-processed amniotic membrane transplantation in patients with corneal ulcer. Acta Ophthalmol. 2015;93(6):e481–7.
- Peyrecave-Capo X, Saulnier N, Maddens S, Gremillet B, Desjardins I. Equine umbilical cord serum composition and its healing effects in equine corneal ulceration. Front Vet Sci. 2022;9:843744.
- Mathew M, Arya AR, Cherian A. Factors associated with poor prognosis in corneal ulcer: a clinical and epidemiological study. Kerala J Ophthalmol. 2022;34(1):37–41.
- Sepulveda-Beltran PA, Carletti P, Banda V, Mulpuri L, Levine H, Amescua G, et al. Infectious and noninfectious corneal ulcers in ocular graft-versus-host disease: epidemiology, clinical characteristics, and outcomes. Am J Ophthalmol. 2024;257:236–46.
- Androudi S, Kaufman AR, Kouvalakis A, Mitsios A, Sapounas S, Al-Khatib D, et al. Non-healing corneal ulcer and uveitis following monkeypox disease: diagnostic and therapeutic challenges. Ocul Immunol Inflamm. 2024;32(3):253–8.
- Akosman S, Li R, Kwon B, West W, Asahi M, Wroblewski KJ. Sociodemographic and clinical predictors of prolonged length of corneal ulcer hospitalizations. JAMA Ophthalmol. 2024;142(3):235–41.
- Bremond-Gignac D, Daruich A, Robert MP, Chiambaretta F. Recent innovations with drugs in clinical trials for neurotrophic keratitis and refractory corneal ulcers. Expert Opin Investig Drugs. 2019;28(11):1013–20.
- Wang AL, Weinlander E, Metcalf BM, Barney NP, Gamm DM, Nehls SM, et al. Use of topical insulin to treat refractory neurotrophic corneal ulcers. Cornea. 2017;36(11):1426–8.
- Mohan M, Natarajan R, Kaur K, Gurnani B. Clinical approach to corneal ulcers. Tnoa J Ophthal Sci Res. 2023;61(4):386–95.
- Anastassiadis Z, Bayley KD, Read RA. Corneal diamond burr debridement for superficial non-healing corneal ulcers in cats. Vet Ophthalmol. 2022;25(6):476–82.
- Sebbag L. Non-healing corneal ulcer secondary to reopened conjunctival incision following cherry eye correction in a dog. Vet Rec Case Rep. 2025;e70047. Ashokan et al. / Indian Journal of Clinical and Experimental Ophthalmology 2025;11(3):380–391 391
- Schuerch K, Baeriswyl A, Frueh BE, Tappeiner C. Efficacy of amniotic membrane transplantation for the treatment of corneal ulcers. Cornea. 2020;39(4):479–83.
- Alio JL, Rodriguez AE, De Arriba P, Gisbert S, Abdelghany AA. Treatment with platelet-rich plasma of surgically related dormant corneal ulcers. Eur J Ophthalmol. 2018;28(5):515–20.
- Park J, Lee KM, Zhou H, Rabin M, Jwo K, Burton WB, et al. Community practice patterns for bacterial corneal ulcer evaluation and treatment. Eye Contact Lens. 2015;41(1):12–8.
- Casado-Santos A, González-Cubero E, González-Fernández ML, González-Rodríguez Y, García-Rodríguez MB, Villar-Suárez V. Equine corneal wound healing using mesenchymal stem cell secretome: case report. Animals (Basel). 2024;14(13):1842
- Lazreg S, Labetoulle M, Renault D, Baudouin C. Fast and sustained healing of resistant corneal ulcers using corneal scrubbing and matrix regenerating therapy. Eur J Ophthalmol. 2021;31(3):959–66.
- Jégou JP, Tromeur F. Superficial keratectomy for chronic corneal ulcers refractory to medical treatment in 36 cats. Vet Ophthalmol. 2015;18(4):335–40.
- Klimesova YM, Nemcokova M, Netukova M, Baxant AD, Hlavackova M, Kacerovska J, et al. Corneal stromal lenticule transplantation for the treatment of corneal ulcers. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2024;168(1):55–61.
- Chang YS, Tai MC, Ho CH, Chu CC, Wang JJ, Tseng SH, et al. Risk of corneal ulcer in patients with diabetes mellitus: a retrospective large-scale cohort study. Sci Rep. 2020;10(1):7388.
- Rechichi M, Ferrise M, Romano F, Gallelli L, Toschi V, Dominijanni A, et al. Autologous platelet-rich plasma in the treatment of refractory corneal ulcers: a case report. Am J Ophthalmol Case Rep 2020;20:100838.
- Brekke SR, Giri P, Byanju R, Pradhan S, Bhandari G, Bhandari S, et al. Risk factors for corneal abrasions in Nepal: a community- based study. Eye (Lond). 2024;38(5):945–50.
- Tsvetanova A, Powell RM, Tsvetanov KA, Smith KM, Gould DJ. Melting corneal ulcers (keratomalacia) in dogs: a 5-year clinical and microbiological study (2014–2018). Vet Ophthalmol. 2021;24(3):265–78.
- Martinez JA, Chiappini F, Barritault D. Case reports for topical treatment of corneal ulcers with a new matrix therapy agent or RGTA® in Dogs. Vet Sci. 2019;6(4):103.
- Arvola RPJ, Robciuc A, Holopainen JM. Matrix regeneration therapy: a case series of corneal neurotrophic ulcers. Cornea. 2016;35(4):451–5.
- Ramaekers A, Aspeslagh S, De Brucker N, Van Mierlo C, Ten Tusscher M, Schauwvlieghe PP, et al. Bilateral corneal perforation in a patient under anti-PD1 therapy. Cornea. 2021;40(2):245–7.
- Alcalde I, Íñigo-Portugués A, Carreño N, Riestra AC, Merayo- Lloves JM. Effects of new biomimetic regenerating agents on corneal wound healing in an experimental model of post-surgical corneal ulcers [Article in English, Spanish]. Arch Soc Esp Oftalmol. 2015;90(10):467–74.
- Alvarado-Villacorta R, Davila-Alquisiras JH, Hernández-Quintela E, Ramos-Betancourt N. Solid platelet-rich plasma combined with silicone-hydrogel soft contact lens for non-healing corneal ulcers: a case series. Ocul Immunol Inflamm. 2022;30(5):1123–8.
- Cochener B, Zagnoli C, Hugny-Larroque C, Derrien S. Healing of resistant corneal neurotrophic ulcers using a matrix regenerating agent. J Fr Ophtalmol. 2019;42(2):159–65.
- Farghali HA, AbdElKader NA, AbuBakr HO, Ramadan ES, Khattab MS, Salem NY, et al. Corneal ulcer in dogs and cats: novel clinical application of regenerative therapy using subconjunctival injection of autologous platelet-rich plasma. Front Vet Sci. 2021;8:641265.
- Serrano-Giménez R, Contreras-Macías E, García-Bernal A, Fobelo- Lozano MJ. Insulin eye drops for treating corneal ulcer in a non- diabetic patient: regarding a case. Farm Hosp. 2020;44(6):297–9.
- Dang DH, Riaz KM, Karamichos D. Treatment of non-infectious corneal injury: review of diagnostic agents, therapeutic medications, and future targets. Drugs. 2022;82(2):145–67.
- Prucha VJS, Tichy A, Nell B. Equine non-healing corneal ulcers: a retrospective evaluation of 57 cases (2001-2017). Tierarztl Prax Ausg G Grosstiere Nutztiere. 2020;48(2):92–7.
- Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000;44(5):415–25.
- Rodríguez Fuentes DE, Flores Nucamendi K, Valdez-García JE, Raquel CDD, Isaac Alejandro VP, Cirian O, et al. Corneal tissue engineering: From research to industry, quality of life impact, and Latin American ophthalmologists’ perspectives. F1000Res 2024;13:608.
- Banou L, Sarrafpour S, Teng CC, Liu J. Ocular gene therapy: an overview of viral vectors, immune responses, and future directions. Yale J Biol Med. 2024;97(4):491–503.
- Sahoo S, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discov Today. 2008;13(3–4):144–51.
- Polisetti N, Islam MM, Griffith M. The artificial cornea. Methods Mol Biol. 2013:1014:45–52
- Tseng SCG. Amniotic Membrane Transplantation for Ocular Surface Reconstruction. Biosci Rep 2001;21(4):481–9.
- Soleimani M, Masoumi A, Momenaei B, Cheraqpour K, Koganti R, Chang AY, et al. Applications of mesenchymal stem cells in ocular surface diseases: sources and routes of delivery. Int J Mol Sci. 2023;24(7):6574.
- Mohan RR, Martin LM, Sinha NR. Novel insights into gene therapy in the cornea. Exp Eye Res. 2020;202:108361.
- Onugwu AL, Nwagwu CS, Onugwu OS, Echezona AC, Agbo CP, Ihim SA, et al. Nanotechnology based drug delivery systems for the treatment of anterior segment eye diseases. J Control Release. 2023;354:465–88.
- Dong L, Fan Z, Fang B, Zhao X, Yao H, Cai G, et al. Oriented cellulose hydrogel: Directed tissue regeneration for reducing corneal leukoplakia and managing fungal corneal ulcers. Bioact Mater. 2024;41:15–29.
- Xie HT, Zhao D, Liu Y, Zhang MC. Umbilical cord patch transplantation for corneal perforations and descemetoceles. J Ophthalmol. 2017;2017(1):2767053.
- Zemba M, Dumitrescu OM, Dimirache AE, Branisteanu DC, Balta F, Burcea M, et al. Diagnostic methods for the etiological assessment of infectious corneal pathology. Exp Ther Med. 2021;23(2):137.
- Milner MS, Beckman KA, Luchs JI, Allen QB, Awdeh RM, Berdahl J, et al. Dysfunctional tear syndrome: dry eye disease and associated tear film disorders – new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;28(Suppl 1):3–47.