Risk of Induction of Corneal Neovascularization with Topical Erythropoietin: An Animal Safety Study


Purpose: To evaluate the pro-angiogenic effect of topical erythropoietin on cornea in chemical burn-injured rabbit eyes.

Methods: The corneal alkali-burn injury was induced in 10 eyes of 10 rabbits using filter paper saturated with 1.0 mol sodium hydroxide. The eyes were categorized into the treatment group (n = 5) that received topical erythropoietin (3000 IU/mL) every 8 hr for one month versus the control group (n = 5) that received normal saline every 8 hr for one month. All eyes were treated with topical ciprofloxacin every 8 hr until corneal re-epithelialization was complete. Corneal epithelial defects, stromal opacity, and neovascularization were evaluated after the injury. At the conclusion of the study, the rabbits were euthanized and their corneas were submitted to histopathological examination.

Results: Baseline characteristics including the rabbits’ weight and the severity of corneal injury were comparable in two groups. Time to complete corneal re-epithelialization was 37 days in the treatment group and 45 days in the control group (P = 0.83). There was no significant difference between the groups in the rate of epithelial healing or corneal opacification. Clinical and microscopic corneal neovascularization was observed in one eye (20%) in the treatment group and two eyes (40%) in the control group (P = 0.49).

 Conclusion: Recombinant human erythropoietin administered topically did not induce vessel formation in rabbit corneas after chemical burn.


Chemical Burns; Corneal Neovascularization; Rabbit Cornea; Topical Erythropoietin

1. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012;23:1631–1634.

2. Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med 2012;18:486–496.

3. Grasso G, Sfacteria A, Cerami A, Brines M. Erythropoietin as a tissue-protective cytokine in brain injury: What do we know and where do we go? Neuroscientist 2004;10:93– 98.

4. Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 2003;102:1340–1346.

5. Lund A, Lundby C, Olsen NV. High-dose erythropoietin for tissue protection. Eur J Clin Invest 2014;44:1230–1238.

6. Pagonopoulou O, Efthimiadou A, Lambropoulou M, Papadopoulos N, Nikolettos NK. Erythropoietin and growth factors exhibit differential angiogenic potential in mouse heart. In Vivo 2008;22:587–591.

7. Feizi S, Alemzadeh-Ansari M, Karimian F, Esfandiari H. Use of erythropoietin in ophthalmology: A review. Surv Ophthalmol 2021;67:427–439.

8. Feizi S, Kanavi MR, Safari S, Ebrahimi H, Javadi MA. Effects of topical erythropoietin on healing experimentallyinduced avascular scleral damage in a rabbit model. Exp Eye Res 2020;190:107898.

9. Feizi S, Javadi MA. Topical erythropoietin as a novel treatment for necrotizing scleritis after pterygium surgery: A pilot study. Cornea 2021;40:1011–1017.

10. Feizi S, Alemzadeh-Ansari M, Baradaran-Rafii A, Esfandiari H, Kheirkhah A. Topical erythropoietin for treatment of scleral necrosis. Ocul Immunol Inflamm 2021;30:1701– 1706.

11. Livny E, Livnat T, Yakimov M, Masoud M, Weinberger D, Bahar I. Effect of erythropoietin on healing of corneal epithelial defects in rabbits. Ophthalmic Res 2013;50:129– 133.

12. Luo L, Kaminoh Y, Chen HY, Zhang M-N, Zhang K, Ambati BK. Expression of erythropoietin and its receptor in normal and neovascularized murine corneas induced by alkali burns. Int J Ophthalmol 2009;2:30–33.

13. Sinclair AM, Coxon A, McCaffery I, Kaufman S, Paweletz K, Liu L, et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood 2010;115:4264–4272.

14. Holland EJ, Chan CC, Wetzig RP, Palestine AG, Nussenblatt RB. Clinical and immunohistologic studies of corneal rejection in the rat penetrating keratoplasty model. Cornea 1991;10:374–380.

15. Bachmann B, Taylor RS, Cursiefen C. Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: An evidence-based meta-analysis. Ophthalmology 2010;117:1300–1305.e7.

16. Cursiefen C, Colin J, Dana R, Diaz-Llopis M, Faraj LA, Garcia-Delpech S, et al. Consensus statement on indications for anti-angiogenic therapy in the management of corneal diseases associated with neovascularisation: Outcome of an expert roundtable. Br J Ophthalmol 2012;96:3–9.

17. Gal-Or O, Livny E, Sella R, Nisgav Y, Weinberger D, Livnat T, et al. Efficacy of subconjunctival aflibercept versus bevacizumab for prevention of corneal neovascularization in a rat model. Cornea 2016;35:991–996.

18. Feizi S, Azari AA, Safapour S. Therapeutic approaches for corneal neovascularization. Eye Vis 2017;4:28.

19. Arcasoy MO. The non-haematopoietic biological effects of erythropoietin. Br J Haematol 2008;141:14–31.

20. Chen J, Connor KM, Aderman CM, Smith LE. Erythropoietin deficiency decreases vascular stability in mice. J Clin Invest 2008;118:526–533.

21. Kang Y, Li S, Liu C, Liu M, Shi S, Xu M, et al. A rabbit model for assessing symblepharon after alkali burn of the superior conjunctival sac. Sci Rep 2019;9:13857.

22. Zhang W, Nie L, Du L, Chen W, Wu Z, Jin Y. Topical treatment of corneal alkali burns with Gly-thymosin β4 solutions and in situ hydrogels via inhibiting corneal neovascularization and improving corneal epidermal recovery in experimental rabbits. Burns 2017;43:1742–1747.

23. Duan CY, Xie HT, Zhao XY, Zhang MC. Limbal niche cells: A novel feeder cell for autologous cultivated oral mucosal epithelial transplantation. Regen Med 2019;14:49–62.

24. Lim P, Fuchsluger TA, Jurkunas UV. Limbal stem cell deficiency and corneal neovascularization. Semin Ophthalmol 2009;24:139–148.

25. Maddula S, Davis DK, Maddula S, Burrow MK, Ambati BK. Horizons in therapy for corneal angiogenesis. Ophthalmology 2011;118:591–599.