Anti-VEGF Treatment in Corneal Diseases

Giuseppe	      Giannaccare; Marco	      Pellegrini; Cristina	      Bovone; Rossella	      Spena; Carlotta	      Senni; Vincenzo	      Scorcia; Massimo	      Busin
Abstract

Background: Corneal neovascularization (CN) is a clue feature of different ocular pathological conditions and can lead to corneal edema and opacification with subsequent vision loss. Vascular endothelial growth factor (VEGF), which plays a key role in new vessels formation, proliferation and migration, was found to be up-regulated in these conditions. Nowadays, it is possible to downregulate the angiogenic process by using anti-VEGF agents administered by different routes.
Objective: To evaluate the efficacy, safety and possible future directions of anti-VEGF agents used for the treatment of CNV owing to different aetiologies.
Methods: A computerized search of articles dealing with the topic of anti-VEGF therapy in CN was conducted in PubMed, Scopus and Medline electronic databases. The following key phrases were used: anti-VEGF agents, corneal neovascularization, bevacizumab, ranibizumab, vascular endothelial growth factor, angiogenesis.
Results: The use of anti-VEGF therapy in the treatment of CN reduced pathological vessel density without causing significant side effects. Various administration routes such as topical, subconjunctival and intrastromal ones are available, and the choice depends on patient and disease characteristics. Much more effectiveness is achieved in case of early administration before mature and wellestablished vessels take place. A combined approach between various drugs including anti-VEGF agents should be adopted in those cases at higher risk of neovascularization recurrence such as chronic long-standing diseases where ischemic and inflammatory stimuli are not definitively reversed.
Conclusion: The efficacy and safety of anti-VEGF agents support their adoption into the daily clinical practice for the management of CN.
Keywords: Anti-VEGF, neovessels, cornea, bevacizumab, avastin, ranibizumab, corneal neovascularization, vascular endothelial growth factor.
Graphical Abstract

[1] 
Zhang SX, Ma JX. Ocular neovascularization: Implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res  2007; 26(1): 1-37.
[http://dx.doi.org/10.1016/j.preteyeres.2006.09.002] [PMID:  17074526] 
[2] 
Ma DH, Chen JK, Zhang F, Lin KY, Yao JY, Yu JS. Regulation of corneal angiogenesis in limbal stem cell deficiency. Prog Retin Eye Res  2006; 25(6): 563-90.
[http://dx.doi.org/10.1016/j.preteyeres.2006.09.001] [PMID:  17079182] 
[3] 
Giannaccare G, Pellegrini M, Bernabei F, Scorcia V, Campos E. Ocular surface system alterations in ocular graft-versus-host disease: all the pieces of the complex puzzle. Graefes Arch Clin Exp Ophthalmol  2019; 257(7): 1341-51.
[http://dx.doi.org/10.1007/s00417-019-04301-6] [PMID:  30944986] 
[4] 
Busin M, Giannaccare G, Sapigni L, et al. Conjunctival and Limbal Transplantation From the Same Living-Related Bone Marrow Donor to Patients With Severe Ocular Graft-vs-Host Disease. JAMA Ophthalmol  2017; 135(10): 1123-5.
[http://dx.doi.org/10.1001/jamaophthalmol.2017.3204] [PMID:  28880979] 
[5] 
Agarwal S, Angayarkanni N, Iyer G, et al. Clinico-biochemical correlation of the effect of subconjunctival bevacizumab for corneal neovascularization. Cornea  2014; 33(10): 1016-21.
[http://dx.doi.org/10.1097/ICO.0000000000000198] [PMID:  25090164] 
[6] 
Roshandel D, Eslani M, Baradaran-Rafii A, et al. Current and emerging therapies for corneal neovascularization. Ocul Surf  2018; 16(4): 398-414.
[http://dx.doi.org/10.1016/j.jtos.2018.06.004] [PMID:  29908870] 
[7] 
Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol  1998; 43(3): 245-69.
[http://dx.doi.org/10.1016/S0039-6257(98)00035-6] [PMID:  9862312] 
[8] 
Lim M, Jacobs DS, Rosenthal P, Carrasquillo KG. The Boston Ocular Surface Prosthesis as a novel drug delivery system for bevacizumab. Semin Ophthalmol  2009; 24(3): 149-55.
[http://dx.doi.org/10.1080/08820530902802013] [PMID:  19437350] 
[9] 
Lee KJ, Lee JY, Lee SH, Choi TH. Accelerating repaired basement membrane after bevacizumab treatment on alkali-burned mouse cornea. BMB Rep  2013; 46(4): 195-200.
[http://dx.doi.org/10.5483/BMBRep.2013.46.4.193] [PMID:  23615260] 
[10] 
Kwon YS, Kim JC. Inhibition of corneal neovascularization by rapamycin. Exp Mol Med  2006; 38(2): 173-9.
[http://dx.doi.org/10.1038/emm.2006.21] [PMID:  16672771] 
[11] 
Lipman RM, Epstein RJ, Hendricks RL. Suppression of corneal neovascularization with cyclosporine. Arch Ophthalmol  1992; 110(3): 405-7.
[http://dx.doi.org/10.1001/archopht.1992.01080150103037] [PMID:  1543461] 
[12] 
Shakiba Y, Mansouri K, Arshadi D, Rezaei N. Corneal neovascularization: molecular events and therapeutic options. Recent Pat Inflamm Allergy Drug Discov  2009; 3(3): 221-31.
[http://dx.doi.org/10.2174/187221309789257450] [PMID:  19702562] 
[13] 
Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci  1998; 39(1): 18-22.
[PMID:  9430540] 
[14] 
Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol  1996; 114(8): 964-70.
[http://dx.doi.org/10.1001/archopht.1996.01100140172010] [PMID:  8694732] 
[15] 
Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am  2006; 19(3): 361-72.
[PMID:  16935211] 
[16] 
Singerman LJ, Masonson H, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol  2008; 92(12): 1606-11.
[http://dx.doi.org/10.1136/bjo.2007.132597] [PMID:  18614570] 
[17] 
Tshionyi M, Shay E, Lunde E, et al. Hemangiogenesis and lymphangiogenesis in corneal pathology. Cornea  2012; 31(1): 74-80.
[http://dx.doi.org/10.1097/ICO.0b013e31821dd986] [PMID:  22030600] 
[18] 
Keating AM, Jacobs DS. Anti-VEGF Treatment of Corneal Neovascularization. Ocul Surf  2011; 9(4): 227-37.
[http://dx.doi.org/10.1016/S1542-0124(11)70035-0] [PMID:  22023817] 
[19] 
Cursiefen C, Chen L, Borges LP, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest  2004; 113(7): 1040-50.
[http://dx.doi.org/10.1172/JCI20465] [PMID:  15057311] 
[20] 
Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol  1994; 55(3): 410-22.
[http://dx.doi.org/10.1002/jlb.55.3.410] [PMID:  7509844] 
[21] 
Kvanta A, Sarman S, Fagerholm P, Seregard S, Steen B. Expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in inflammation-associated corneal neovascularization. Exp Eye Res  2000; 70(4): 419-28.
[http://dx.doi.org/10.1006/exer.1999.0790] [PMID:  10865990] 
[22] 
Nakao S, Hata Y, Miura M, et al. Dexamethasone inhibits interleukin-1beta-induced corneal neovascularization: role of nuclear factor-kappaB-activated stromal cells in inflammatory angiogenesis. Am J Pathol  2007; 171(3): 1058-65.
[http://dx.doi.org/10.2353/ajpath.2007.070172] [PMID:  17690185] 
[23] 
Biswas PS, Banerjee K, Kinchington PR, Rouse BT. Involvement of IL-6 in the paracrine production of VEGF in ocular HSV-1 infection. Exp Eye Res  2006; 82(1): 46-54.
[http://dx.doi.org/10.1016/j.exer.2005.05.001] [PMID:  16009363] 
[24] 
Strieter RM, Kunkel SL, Elner VM, et al. Interleukin-8. A corneal factor that induces neovascularization. Am J Pathol  1992; 141(6): 1279-84.
[PMID:  1281615] 
[25] 
Suryawanshi A, Mulik S, Sharma S, Reddy PB, Sehrawat S, Rouse BT. Ocular neovascularization caused by herpes simplex virus type 1 infection results from breakdown of binding between vascular endothelial growth factor A and its soluble receptor. J Immunol  2011; 186(6): 3653-65.
[http://dx.doi.org/10.4049/jimmunol.1003239] [PMID:  21325621] 
[26] 
Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci  2000; 41(9): 2514-22.
[PMID:  10937562] 
[27] 
Termote K, Schendel S, Moloney G, Holland SP, Lange AP. Focal limbal stem cell deficiency associated with soft contact lens wear. Can J Ophthalmol  2017; 52(6): 552-8.
[http://dx.doi.org/10.1016/j.jcjo.2017.03.017] [PMID:  29217022] 
[28] 
Vafeas C, Mieyal PA, Urbano F, et al. Hypoxia stimulates the synthesis of cytochrome P450-derived inflammatory eicosanoids in rabbit corneal epithelium. J Pharmacol Exp Ther  1998; 287(3): 903-10.
[PMID:  9864271] 
[29] 
Ferrari G, Hajrasouliha AR, Sadrai Z, Ueno H, Chauhan SK, Dana R. Nerves and neovessels inhibit each other in the cornea. Invest Ophthalmol Vis Sci  2013; 54(1): 813-20.
[http://dx.doi.org/10.1167/iovs.11-8379] [PMID:  23307967] 
[30] 
Hosseini H, Nejabat M, Mehryar M, Yazdchi T, Sedaghat A, Noori F. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Exp Ophthalmol  2007; 35(8): 745-8.
[http://dx.doi.org/10.1111/j.1442-9071.2007.01572.x] [PMID:  17997779] 
[31] 
Han KY, Chang JH, Lee H, Azar DT. Proangiogenic Interactions of Vascular Endothelial MMP14 With VEGF Receptor 1 in VEGFA-Mediated Corneal Angiogenesis. Invest Ophthalmol Vis Sci  2016; 57(7): 3313-22.
[http://dx.doi.org/10.1167/iovs.16-19420] [PMID:  27327585] 
[32] 
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J  1999; 13(1): 9-22.
[http://dx.doi.org/10.1096/fasebj.13.1.9] [PMID:  9872925] 
[33] 
Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem  2013; 153(1): 13-9.
[http://dx.doi.org/10.1093/jb/mvs136] [PMID:  23172303] 
[34] 
Klettner A, Roider J. Treating age-related macular degeneration - interaction of VEGF-antagonists with their target. Mini Rev Med Chem  2009; 9(9): 1127-35.
[http://dx.doi.org/10.2174/138955709788922665] [PMID:  19689408] 
[35] 
Aiello LP, Wong JS. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl  2000; 77: S113-9.
[http://dx.doi.org/10.1046/j.1523-1755.2000.07718.x] [PMID:  10997700] 
[36] 
Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol  1995; 146(5): 1029-39.
[PMID:  7538264] 
[37] 
Hoppenreijs VP, Pels E, Vrensen GF, Felten PC, Treffers WF. Platelet-derived growth factor: receptor expression in corneas and effects on corneal cells. Invest Ophthalmol Vis Sci  1993; 34(3): 637-49.
[PMID:  8449682] 
[38] 
Dell S, Peters S, Müther P, Kociok N, Joussen AM. The role of PDGF receptor inhibitors and PI3-kinase signaling in the pathogenesis of corneal neovascularization. Invest Ophthalmol Vis Sci  2006; 47(5): 1928-37.
[http://dx.doi.org/10.1167/iovs.05-1071] [PMID:  16639000] 
[39] 
Soubrane G, Jerdan J, Karpouzas I, et al. Binding of basic fibroblast growth factor to normal and neovascularized rabbit cornea. Invest Ophthalmol Vis Sci  1990; 31(2): 323-33.
[PMID:  1689281] 
[40] 
Mignatti P, Rifkin DB. Nonenzymatic interactions between proteinases and the cell surface: novel roles in normal and malignant cell physiology. Adv Cancer Res  2000; 78: 103-57.
[http://dx.doi.org/10.1016/S0065-230X(08)61024-6] [PMID:  10547669] 
[41] 
Papapetropoulos A, García-Cardeña G, Madri JA, Sessa WC. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest  1997; 100(12): 3131-9.
[http://dx.doi.org/10.1172/JCI119868] [PMID:  9399960] 
[42] 
Bryan BA, Dennstedt E, Mitchell DC, et al. RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis. FASEB J  2010; 24(9): 3186-95.
[http://dx.doi.org/10.1096/fj.09-145102] [PMID:  20400538] 
[43] 
Wang Z, Cheng R, Lee K, et al. Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization. Arterioscler Thromb Vasc Biol  2015; 35(4): 855-64.
[http://dx.doi.org/10.1161/ATVBAHA.114.304627] [PMID:  25657312] 
[44] 
Kim SJ, Lee JW, Yeo ED, et al. The role of Nod1 signaling in corneal neovascularization. Cornea  2013; 32(5): 674-9.
[http://dx.doi.org/10.1097/ICO.0b013e3182781ea4] [PMID:  23328697] 
[45] 
Al-Torbak A, Al-Amri A, Wagoner MD. Deep corneal neovascularization after implantation with intrastromal corneal ring segments. Am J Ophthalmol  2005; 140(5): 926-7.
[http://dx.doi.org/10.1016/j.ajo.2005.05.020] [PMID:  16310478] 
[46] 
Cejkova J, Cejka C, Trosan P, Zajicova A, Sykova E, Holan V. Treatment of alkali-injured cornea by cyclosporine A-loaded electrospun nanofibers - An alternative mode of therapy. Exp Eye Res  2016; 147: 128-37.
[http://dx.doi.org/10.1016/j.exer.2016.04.016] [PMID:  27181227] 
[47] 
Park JH, Joo CK, Chung SK. Comparative study of tacrolimus and bevacizumab on corneal neovascularization in rabbits. Cornea  2015; 34(4): 449-55.
[http://dx.doi.org/10.1097/ICO.0000000000000336] [PMID:  25651492] 
[48] 
Baer JC, Foster CS. Corneal laser photocoagulation for treatment of neovascularization. Efficacy of 577 nm yellow dye laser. Ophthalmology  1992; 99(2): 173-9.
[http://dx.doi.org/10.1016/S0161-6420(92)31996-7] [PMID:  1553204] 
[49] 
Brooks BJ, Ambati BK, Marcus DM, Ratanasit A. Photodynamic therapy for corneal neovascularisation and lipid degeneration. Br J Ophthalmol  2004; 88(6): 840.
[http://dx.doi.org/10.1136/bjo.2003.035071] [PMID:  15148229] 
[50] 
Yoeruek E, Ziemssen F, Henke-Fahle S, et al. Tübingen Bevacizumab Study Group. Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol  2008; 86(3): 322-8.
[http://dx.doi.org/10.1111/j.1600-0420.2007.01049.x] [PMID:  17995975] 
[51] 
You IC, Kang IS, Lee SH, Yoon KC. Therapeutic effect of subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. Acta Ophthalmol  2009; 87(6): 653-8.
[http://dx.doi.org/10.1111/j.1755-3768.2008.01399.x] [PMID:  19021596] 
[52] 
Pożarowska D, Pożarowski P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent Eur J Immunol  2016; 41(3): 311-6.
[http://dx.doi.org/10.5114/ceji.2016.63132] [PMID:  27833450] 
[53] 
Andreoli CM, Miller JW. Anti-vascular endothelial growth factor therapy for ocular neovascular disease. Curr Opin Ophthalmol  2007; 18(6): 502-8.
[http://dx.doi.org/10.1097/ICU.0b013e3282f0ca54] [PMID:  18163003] 
[54] 
Kimoto K, Kubota T. Anti-VEGF agents for ocular angiogenesis and vascular permeability. J Ophthalmol 2012.2012852183
[http://dx.doi.org/10.1155/2012/852183] [PMID:  22132316] 
[55] 
Chang JH, Garg NK, Lunde E, Han KY, Jain S, Azar DT. Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol  2012; 57(5): 415-29.
[http://dx.doi.org/10.1016/j.survophthal.2012.01.007] [PMID:  22898649] 
[56] 
Park SC, Su D, Tello C. Anti-VEGF therapy for the treatment of glaucoma: a focus on ranibizumab and bevacizumab. Expert Opin Biol Ther  2012; 12(12): 1641-7.
[http://dx.doi.org/10.1517/14712598.2012.721772] [PMID:  22963411] 
[57] 
Popescu V, Pricopie S, Totir M, Iancu R, Yasyn S, Alexandrescu C. Clinical use of Bevacizumab in treating refractory glaucoma. J Med Life  2015; 8(1): 8-12.
[PMID:  25914729] 
[58] 
Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer  2011; 2(12): 1097-105.
[http://dx.doi.org/10.1177/1947601911423031] [PMID:  22866201] 
[59] 
Cardarelli WJ, Smith RA. Managed care implications of age-related ocular conditions. Am J Manag Care  2013; 19(5)(Suppl.): S85-91.
[PMID:  23725500] 
[60] 
Klein A, Loewenstein A. Therapeutic monoclonal antibodies and fragments: Bevacizumab. Dev Ophthalmol  2016; 55: 232-45.
[http://dx.doi.org/10.1159/000431199] [PMID:  26502311] 
[61] 
Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond)  2014; 28(5): 510-20.
[http://dx.doi.org/10.1038/eye.2014.13] [PMID:  24525867] 
[62] 
Ahn YJ, Hwang HB, Chung SK. Ranibizumab injection for corneal neovascularization refractory to bevacizumab treatment. Korean J Ophthalmol  2014; 28(2): 177-80.
[http://dx.doi.org/10.3341/kjo.2014.28.2.177] [PMID:  24688262] 
[63] 
Stevenson W, Cheng SF, Dastjerdi MH, Ferrari G, Dana R. Corneal neovascularization and the utility of topical VEGF inhibition: ranibizumab (Lucentis) vs bevacizumab (Avastin). Ocul Surf  2012; 10(2): 67-83.
[http://dx.doi.org/10.1016/j.jtos.2012.01.005] [PMID:  22482468] 
[64] 
Ferrari G, Giacomini C, Rama P. Corneal neovascularization: A translational perspective. J Clin Exp Ophthalmol  2015; 6: 387-95.
[65] 
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol  2008; 92(5): 667-8.
[http://dx.doi.org/10.1136/bjo.2007.134874] [PMID:  18356264] 
[66] 
Wang Q, Yang J, Tang K, et al. Pharmacological characteristics and efficacy of a novel anti-angiogenic antibody FD006 in corneal neovascularization. BMC Biotechnol  2014; 14(1): 17.
[http://dx.doi.org/10.1186/1472-6750-14-17] [PMID:  24575750] 
[67] 
Singh N, Tiem M, Watkins R, et al. Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity. Blood  2013; 121(20): 4242-9.
[http://dx.doi.org/10.1182/blood-2012-08-453043] [PMID:  23476047] 
[68] 
Iriyama A, Usui T, Yanagi Y, et al. Gene transfer using micellar nanovectors inhibits corneal neovascularization in vivo. Cornea  2011; 30(12): 1423-7.
[http://dx.doi.org/10.1097/ICO.0b013e318206c893] [PMID:  21975440] 
[69] 
Cho YK, Zhang X, Uehara H, Young JR, Archer B, Ambati B. Vascular Endothelial Growth Factor Receptor 1 morpholino increases graft survival in a murine penetrating keratoplasty model. Invest Ophthalmol Vis Sci  2012; 53(13): 8458-71.
[http://dx.doi.org/10.1167/iovs.12-10408] [PMID:  23150613] 
[70] 
Jani PD, Singh N, Jenkins C, et al. Nanoparticles sustain expression of Flt intraceptors in the cornea and inhibit injury-induced corneal angiogenesis. Invest Ophthalmol Vis Sci  2007; 48(5): 2030-6.
[http://dx.doi.org/10.1167/iovs.06-0853] [PMID:  17460257] 
[71] 
Al-Latayfeh M, Silva PS, Sun JK, Aiello LP. Antiangiogenic therapy for ischemic retinopathies. Cold Spring Harb Perspect Med  2012; 2(6)a006411
[http://dx.doi.org/10.1101/cshperspect.a006411] [PMID:  22675660] 
[72] 
Ahmad S, Osei-Bempong C, Dana R, Jurkunas U. The culture and transplantation of human limbal stem cells. J Cell Physiol  2010; 225(1): 15-9.
[http://dx.doi.org/10.1002/jcp.22251] [PMID:  20506173] 
[73] 
Osei-Bempong C, Figueiredo FC, Lako M. The limbal epithelium of the eye--a review of limbal stem cell biology, disease and treatment. BioEssays  2013; 35(3): 211-9.
[http://dx.doi.org/10.1002/bies.201200086] [PMID:  23129317] 
[74] 
Hosseini H, Nowroozzadeh MH, Salouti R, Nejabat M. Anti-VEGF therapy with bevacizumab for anterior segment eye disease. Cornea  2012; 31(3): 322-34.
[http://dx.doi.org/10.1097/ICO.0b013e31822480f9] [PMID:  22157572] 
[75] 
Singh P, Tyagi M, Kumar Y, Gupta KK, Sharma PD. Ocular chemical injuries and their management. Oman J Ophthalmol  2013; 6(2): 83-6.
[http://dx.doi.org/10.4103/0974-620X.116624] [PMID:  24082664] 
[76] 
Manzano RP, Peyman GA, Khan P, et al. Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol  2007; 91(6): 804-7.
[http://dx.doi.org/10.1136/bjo.2006.107912] [PMID:  17179168] 
[77] 
Barros LF, Belfort R Jr. The effects of the subconjunctival injection of bevacizumab (Avastin) on angiogenesis in the rat cornea. An Acad Bras Cienc  2007; 79(3): 389-94.
[http://dx.doi.org/10.1590/S0001-37652007000300004] [PMID:  17768531] 
[78] 
Oh JY, Kim MK, Shin MS, Lee HJ, Lee JH, Wee WR. The anti-inflammatory effect of subconjunctival bevacizumab on chemically burned rat corneas. Curr Eye Res  2009; 34(2): 85-91.
[http://dx.doi.org/10.1080/02713680802607740] [PMID:  19219678] 
[79] 
Doganay S, Firat PG, Cankaya C, Kirimlioglu H. Evaluation of the effects of resveratrol and bevacizumab on experimental corneal alkali burn. Burns  2013; 39(2): 326-30.
[http://dx.doi.org/10.1016/j.burns.2012.07.018] [PMID:  22922008] 
[80] 
DeStafeno JJ, Kim T. Topical bevacizumab therapy for corneal neovascularization. Arch Ophthalmol  2007; 125(6): 834-6.
[http://dx.doi.org/10.1001/archopht.125.6.834] [PMID:  17562998] 
[81] 
Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization. Cornea  2008; 27(2): 142-7.
[http://dx.doi.org/10.1097/ICO.0b013e318159019f] [PMID:  18216566] 
[82] 
Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology  2006; 113(3): 363-372.e5.
[http://dx.doi.org/10.1016/j.ophtha.2005.11.019] [PMID:  16458968] 
[83] 
Nguyen QD, Shah S, Tatlipinar S, Do DV, Anden EV, Campochiaro PA. Bevacizumab suppresses choroidal neovascularisation caused by pathological myopia. Br J Ophthalmol  2005; 89(10): 1368-70.
[http://dx.doi.org/10.1136/bjo.2005.066431] [PMID:  16170134] 
[84] 
Rosenfeld PJ, Schwartz SD, Blumenkranz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology  2005; 112(6): 1048-53.
[http://dx.doi.org/10.1016/j.ophtha.2005.01.043] [PMID:  15885778] 
[85] 
Bock F, König Y, Kruse F, Baier M, Cursiefen C. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol  2008; 246(2): 281-4.
[http://dx.doi.org/10.1007/s00417-007-0684-4] [PMID:  17934753] 
[86] 
Kuhlmann A, Amann K, Schlötzer-Schrehardt U, Kruse FE, Cursiefen C. Endothelin-1 and ETA/ETB receptor protein and mRNA: expression in normal and vascularized human corneas. Cornea  2005; 24(7): 837-44.
[http://dx.doi.org/10.1097/01.ico.0000157400.81408.2b] [PMID:  16160501] 
[87] 
Remeijer L, Osterhaus A, Verjans G. Human herpes simplex virus keratitis: the pathogenesis revisited. Ocul Immunol Inflamm  2004; 12(4): 255-85.
[http://dx.doi.org/10.1080/092739490500363] [PMID:  15621867] 
[88] 
Hayashi T, Ishioka M, Ito N, et al. Bilateral herpes simplex keratitis in a patient with chronic graft-versus-host disease. Clin Ophthalmol  2008; 2(2): 457-9.
[http://dx.doi.org/10.2147/OPTH.S1858] [PMID:  19668737] 
[89] 
Zheng M, Schwarz MA, Lee S, Kumaraguru U, Rouse BT. Control of stromal keratitis by inhibition of neovascularization. Am J Pathol  2001; 159(3): 1021-9.
[http://dx.doi.org/10.1016/S0002-9440(10)61777-4] [PMID:  11549594] 
[90] 
Benayoun Y, Adenis JP, Casse G, Forte R, Robert PY. Effects of subconjunctival bevacizumab on corneal neovascularization: results of a prospective study. Cornea  2012; 31(8): 937-44.
[http://dx.doi.org/10.1097/ICO.0b013e31823f8d71] [PMID:  22357391] 
[91] 
Petsoglou C, Balaggan KS, Dart JKG, et al. Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial. Br J Ophthalmol  2013; 97(1): 28-32.
[http://dx.doi.org/10.1136/bjophthalmol-2012-302137] [PMID:  23087419] 
[92] 
Carrasco MA. Subconjunctival bevacizumab for corneal neovascularization in herpetic stromal keratitis. Cornea  2008; 27(6): 743-5.
[http://dx.doi.org/10.1097/01.ico.0000611440.32234.8f] [PMID:  18580272] 
[93] 
You IC, Im SK, Lee SH, Yoon KC. Photodynamic therapy with verteporfin combined with subconjunctival injection of bevacizumab for corneal neovascularization. Cornea  2011; 30(1): 30-3.
[http://dx.doi.org/10.1097/ICO.0b013e3181dc81a0] [PMID:  20861729] 
[94] 
Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C. Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol  2009; 247(10): 1375-82.
[http://dx.doi.org/10.1007/s00417-009-1099-1] [PMID:  19415316] 
[95] 
Yeung SN, Lichtinger A, Kim P, Amiran MD, Slomovic AR. Combined use of subconjunctival and intracorneal bevacizumab injection for corneal neovascularization. Cornea  2011; 30(10): 1110-4.
[http://dx.doi.org/10.1097/ICO.0b013e31821379aa] [PMID:  21673570] 
[96] 
Pleyer U, Steuhl KP, Weidle EG, Lisch W, Thiel HJ. Corneal graft rejection: incidence, manifestation, and interaction of clinical subtypes. Transplant Proc  1992; 24(5): 2034-7.
[PMID:  1412962] 
[97] 
Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol  2003; 121(8): 1087-92.
[http://dx.doi.org/10.1001/archopht.121.8.1087] [PMID:  12912684] 
[98] 
Wagoner MD, Ba-Abbad R, Sutphin JE, Zimmerman MB. Corneal transplant survival after onset of severe endothelial rejection. Ophthalmology  2007; 114(9): 1630-6.
[http://dx.doi.org/10.1016/j.ophtha.2006.12.012] [PMID:  17367863] 
[99] 
Bock F, Onderka J, Dietrich T, et al. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci  2007; 48(6): 2545-52.
[http://dx.doi.org/10.1167/iovs.06-0570] [PMID:  17525183] 
[100] 
Cursiefen C, Schlötzer-Schrehardt U, Küchle M, et al. Lymphatic vessels in vascularized human corneas: immunohistochemical investigation using LYVE-1 and podoplanin. Invest Ophthalmol Vis Sci  2002; 43(7): 2127-35.
[PMID:  12091407] 
[101] 
Lipp M, Bucher F, Parthasarathy A, et al. Blockade of the VEGF isoforms in inflammatory corneal hemangiogenesis and lymphangiogenesis. Graefes Arch Clin Exp Ophthalmol  2014; 252(6): 943-9.
[http://dx.doi.org/10.1007/s00417-014-2626-2] [PMID:  24728466] 
[102] 
Yan H, Yuan J, Peng R, et al. The Blockade of Vascular Endothelial Growth Factor C Effectively Inhibits Corneal Lymphangiogenesis and Promotes Allograft Survival. J Ocul Pharmacol Ther  2015; 31(9): 546-54.
[http://dx.doi.org/10.1089/jop.2015.0007] [PMID:  26172526] 
[103] 
Park PJ, Chang M, Garg N, Zhu J, Chang JH, Shukla D. Corneal lymphangiogenesis in herpetic stromal keratitis. Surv Ophthalmol  2015; 60(1): 60-71.
[http://dx.doi.org/10.1016/j.survophthal.2014.06.001] [PMID:  25444520] 
[104] 
Harooni H, Reddy V, Root T, Ambati B. Bevacizumab for graft rejection. Ophthalmology  2007; 114(10): 1950.
[http://dx.doi.org/10.1016/j.ophtha.2007.05.016] [PMID:  17908597] 
[105] 
Erdurmus M, Totan Y. Subconjunctival bevacizumab for corneal neovascularization. Graefes Arch Clin Exp Ophthalmol  2007; 245(10): 1577-9.
[http://dx.doi.org/10.1007/s00417-007-0587-4] [PMID:  17458556] 
[106] 
Awadein A. Subconjunctival bevacizumab for vascularized rejected corneal grafts. J Cataract Refract Surg  2007; 33(11): 1991-3.
[http://dx.doi.org/10.1016/j.jcrs.2007.07.012] [PMID:  17964413] 
[107] 
Rocha G, Deschênes J, Rowsey JJ. The immunology of corneal graft rejection. Crit Rev Immunol  1998; 18(4): 305-25.
[http://dx.doi.org/10.1615/CritRevImmunol.v18.i4.20] [PMID:  9704192] 
[108] 
Fasciani R, Mosca L, Giannico MI, Ambrogio SA, Balestrazzi E. Subconjunctival and/or intrastromal bevacizumab injections as preconditioning therapy to promote corneal graft survival. Int Ophthalmol  2015; 35(2): 221-7.
[http://dx.doi.org/10.1007/s10792-014-9938-4] [PMID:  24715230] 
[109] 
Niederer RL, Sherwin T, McGhee CNJ. In vivo confocal microscopy of subepithelial infiltrates in human corneal transplant rejection. Cornea  2007; 26(4): 501-4.
[http://dx.doi.org/10.1097/ICO.0b013e3180318107] [PMID:  17457206] 
[110] 
Jarrín E, Ruiz-Casas D, Mendivil A. Efficacy of bevacizumab against interface neovascularization after deep anterior lamellar keratoplasty. Cornea  2012; 31(2): 188-90.
[http://dx.doi.org/10.1097/ICO.0b013e31820ca19e] [PMID:  22146545] 
[111] 
Hashemian MN, Zare MA, Rahimi F, Mohammadpour M. Deep intrastromal bevacizumab injection for management of corneal stromal vascularization after deep anterior lamellar keratoplasty, a novel technique. Cornea  2011; 30(2): 215-8.
[http://dx.doi.org/10.1097/ICO.0b013e3181e291a6] [PMID:  20885312] 
[112] 
Saxena S, Kishore P, Pandey S, Khattri M, Kumar D. Topical bevacizumab for corneal neovascularization after penetrating keratoplasty. Eur J Ophthalmol  2009; 19(5): 870-2.
[http://dx.doi.org/10.1177/112067210901900530] [PMID:  19787612] 
[113] 
Catt CJ, Hamilton GM, Fish J, Mireskandari K, Ali A. Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children. Am J Ophthalmol  2016; 166: 68-75.
[http://dx.doi.org/10.1016/j.ajo.2016.03.020] [PMID:  27018234] 
[114] 
Cursiefen C, Masli S, Ng TF, et al. Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis. Invest Ophthalmol Vis Sci  2004; 45(4): 1117-24.
[http://dx.doi.org/10.1167/iovs.03-0940] [PMID:  15037577] 
[115] 
Phillips K, Arffa R, Cintron C, et al. Effects of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Arch Ophthalmol  1983; 101(4): 640-3.
[http://dx.doi.org/10.1001/archopht.1983.01040010640024] [PMID:  6188447] 
[116] 
Ambati BK, Joussen AM, Ambati J, et al. Angiostatin inhibits and regresses corneal neovascularization. Arch Ophthalmol  2002; 120(8): 1063-8.
[http://dx.doi.org/10.1001/archopht.120.8.1063] [PMID:  12149060] 
[117] 
Corrent G, Roussel TJ, Tseng SCG, Watson BD. Promotion of graft survival by photothrombotic occlusion of corneal neovascularization. Arch Ophthalmol  1989; 107(10): 1501-6.
[http://dx.doi.org/10.1001/archopht.1989.01070020575043] [PMID:  2478111] 
[118] 
Pillai CT, Dua HS, Hossain P. Fine needle diathermy occlusion of corneal vessels. Invest Ophthalmol Vis Sci  2000; 41(8): 2148-53.
[PMID:  10892856] 
[119] 
Qian CX, Bahar I, Levinger E, Rootman D. Combined use of superficial keratectomy and subconjunctival bevacizumab injection for corneal neovascularization. Cornea  2008; 27(9): 1090-2.
[http://dx.doi.org/10.1097/ICO.0b013e31817c41e3] [PMID:  18812781] 
[120] 
Uy HS, Chan PS, Ang RE. Topical bevacizumab and ocular surface neovascularization in patients with stevens-johnson syndrome. Cornea  2008; 27(1): 70-3.
[http://dx.doi.org/10.1097/ICO.0b013e318158f6ad] [PMID:  18245970] 
[121] 
Kesarwani S, Sahu SK, Basu S. Bilateral response after unilateral subconjunctival bevacizumab injection in a child with Stevens-Johnson syndrome. J AAPOS  2012; 16(3): 309-11.
[http://dx.doi.org/10.1016/j.jaapos.2011.12.153] [PMID:  22459106] 
[122] 
Yoon HJ, Kim MK, Seo KY, Ueta M, Yoon KC. Effectiveness of photodynamic therapy with verteporfin combined with intrastromal bevacizumab for corneal neovascularization in Stevens-Johnson syndrome. Int Ophthalmol  2019; 39(1): 55-62.
[http://dx.doi.org/10.1007/s10792-017-0786-x] [PMID:  29256167] 
[123] 
Kim MJ, Han ES, Kim J, Kim TW. Aqueous humor concentration of bevacizumab after subconjunctival injection in rabbit. J Ocul Pharmacol Ther  2010; 26(1): 49-53.
[http://dx.doi.org/10.1089/jop.2009.0022] [PMID:  20148650] 
[124] 
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology  2007; 114(5): 855-9.
[http://dx.doi.org/10.1016/j.ophtha.2007.01.017] [PMID:  17467524] 
[125] 
Abu El-Asrar AM, Al-Mansouri S, Tabbara KF, Missotten L, Geboes K. Immunopathogenesis of conjunctival remodelling in vernal keratoconjunctivitis. Eye (Lond)  2006; 20(1): 71-9.
[http://dx.doi.org/10.1038/sj.eye.6701811] [PMID:  15746957] 
[126] 
Nguyen CL, Chen TS, Tran K, Smith JEH, Lewis N. Simultaneous Subconjunctival Triamcinolone and Bevacizumab Injections for Management of Blepharokeratoconjunctivitis in Children. Case Rep Ophthalmol Med 2018.20182602487
[http://dx.doi.org/10.1155/2018/2602487] [PMID:  29967706] 
[127] 
Elbaz U, Mireskandari K, Shen C, Ali A. Corneal Fine Needle Diathermy With Adjuvant Bevacizumab to Treat Corneal Neovascularization in Children. Cornea  2015; 34(7): 773-7.
[http://dx.doi.org/10.1097/ICO.0000000000000419] [PMID:  25811720] 
[128] 
Taurone S, Spoletini M, Ralli M, et al. Ocular mucous membrane pemphigoid: a review. Immunol Res  2019; 67(2-3): 280-9.
[http://dx.doi.org/10.1007/s12026-019-09087-7] [PMID:  31327149] 
[129] 
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf  2017; 15(3): 276-83.
[http://dx.doi.org/10.1016/j.jtos.2017.05.008] [PMID:  28736335] 
[130] 
Calonge M, Enríquez-de-Salamanca A, Diebold Y, et al. Dry eye disease as an inflammatory disorder. Ocul Immunol Inflamm  2010; 18(4): 244-53.
[http://dx.doi.org/10.3109/09273941003721926] [PMID:  20482396] 
[131] 
Li DQ, Chen Z, Song XJ, Luo L, Pflugfelder SC. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci  2004; 45(12): 4302-11.
[http://dx.doi.org/10.1167/iovs.04-0299] [PMID:  15557436] 
[132] 
Yoo SA, Kwok SK, Kim WU. Proinflammatory role of vascular endothelial growth factor in the pathogenesis of rheumatoid arthritis: prospects for therapeutic intervention. Mediators Inflamm 2008.2008129873
[http://dx.doi.org/10.1155/2008/129873] [PMID:  19223981] 
[133] 
Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med  2003; 9(6): 669-76.
[http://dx.doi.org/10.1038/nm0603-669] [PMID:  12778165] 
[134] 
Jiang X, Lv H, Qiu W, Liu Z, Li X, Wang W. Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye. Drug Des Devel Ther  2015; 9: 3043-50.
[PMID:  26109847] 
[135] 
Jiang X, Wang Y, Lv H, Liu Y, Zhang M, Li X. Efficacy of intra-meibomian gland injection of the anti-VEGF agent bevacizumab for the treatment of meibomian gland dysfunction with lid-margin vascularity. Drug Des Devel Ther  2018; 12: 1269-79.
[http://dx.doi.org/10.2147/DDDT.S146556] [PMID:  29805249] 
[136] 
Mastyugin V, Mosaed S, Bonazzi A, Dunn MW, Schwartzman ML. Corneal epithelial VEGF and cytochrome P450 4B1 expression in a rabbit model of closed eye contact lens wear. Curr Eye Res  2001; 23(1): 1-10.
[http://dx.doi.org/10.1076/ceyr.23.1.1.5422] [PMID:  11821980] 
[137] 
Zaki AA, Farid SF. Subconjunctival bevacizumab for corneal neovascularization. Acta Ophthalmol  2010; 88(8): 868-71.
[http://dx.doi.org/10.1111/j.1755-3768.2009.01585.x] [PMID:  19519730] 
[138] 
Banifatemi M, Razeghinejad MR, Hosseini H, Gholampour A. Bevacizumab and ocular wound healing after primary pterygium excision. J Ocul Pharmacol Ther  2011; 27(1): 17-21.
[http://dx.doi.org/10.1089/jop.2010.0094] [PMID:  20977367] 
[139] 
Razeghinejad MR, Hosseini H, Ahmadi F, Rahat F, Eghbal H. Preliminary results of subconjunctival bevacizumab in primary pterygium excision. Ophthalmic Res  2010; 43(3): 134-8.
[http://dx.doi.org/10.1159/000252980] [PMID:  19887878] 
[140] 
Mauro J, Foster CS. Pterygia: pathogenesis and the role of subconjunctival bevacizumab in treatment. Semin Ophthalmol  2009; 24(3): 130-4.
[http://dx.doi.org/10.1080/08820530902801106] [PMID:  19437347] 
[141] 
Marcovich AL, Morad Y, Sandbank J, et al. Angiogenesis in pterygium: morphometric and immunohistochemical study. Curr Eye Res  2002; 25(1): 17-22.
[http://dx.doi.org/10.1076/ceyr.25.1.17.9959] [PMID:  12518239] 
[142] 
Jin J, Guan M, Sima J, et al. Decreased pigment epithelium-derived factor and increased vascular endothelial growth factor levels in pterygia. Cornea  2003; 22(5): 473-7.
[http://dx.doi.org/10.1097/00003226-200307000-00015] [PMID:  12827055] 
[143] 
Lee DH, Cho HJ, Kim JT, Choi JS, Joo CK. Expression of vascular endothelial growth factor and inducible nitric oxide synthase in pterygia. Cornea  2001; 20(7): 738-42.
[http://dx.doi.org/10.1097/00003226-200110000-00013] [PMID:  11588427] 
[144] 
Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium. Curr Eye Res  2008; 33(1): 23-8.
[http://dx.doi.org/10.1080/02713680701799101] [PMID:  18214740] 
[145] 
Nava-Castañeda A, Olvera-Morales O, Ramos-Castellon C, Garnica-Hayashi L, Garfias Y. Randomized, controlled trial of conjunctival autografting combined with subconjunctival bevacizumab for primary pterygium treatment: 1-year follow-up. Clin Exp Ophthalmol  2014; 42(3): 235-41.
[http://dx.doi.org/10.1111/ceo.12140] [PMID:  23777441] 
[146] 
Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, et al. Pan American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol  2008; 246(1): 81-7.
[http://dx.doi.org/10.1007/s00417-007-0660-z] [PMID:  17674014] 
[147] 
Hurmeric V, Vaddavalli P, Galor A, Perez VL, Roman JS, Yoo SH. Single and multiple injections of subconjunctival ranibizumab for early, recurrent pterygium. Clin Ophthalmol  2013; 7: 467-73.
[PMID:  23486999] 
[148] 
Kim SW, Ha BJ, Kim EK, Tchah H, Kim TI. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology  2008; 115(6): e33-8.
[http://dx.doi.org/10.1016/j.ophtha.2008.02.013] [PMID:  18439681] 
[149] 
Ferrari G, Dastjerdi MH, Okanobo A, et al. Topical ranibizumab as a treatment of corneal neovascularization. Cornea  2013; 32(7): 992-7.
[http://dx.doi.org/10.1097/ICO.0b013e3182775f8d] [PMID:  23407316] 
[150] 
Dastjerdi MH, Al-Arfaj KM, Nallasamy N, et al. Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol  2009; 127(4): 381-9.
[http://dx.doi.org/10.1001/archophthalmol.2009.18] [PMID:  19365012] 
[151] 
Chen WL, Lin CT, Lin NT, et al. Subconjunctival injection of bevacizumab (avastin) on corneal neovascularization in different rabbit models of corneal angiogenesis. Invest Ophthalmol Vis Sci  2009; 50(4): 1659-65.
[http://dx.doi.org/10.1167/iovs.08-1997] [PMID:  18997093] 
[152] 
Gerten G. Bevacizumab (avastin) and argon laser to treat neovascularization in corneal transplant surgery. Cornea  2008; 27(10): 1195-9.
[http://dx.doi.org/10.1097/ICO.0b013e318180e50f] [PMID:  19034142] 
[153] 
Doctor PP, Bhat PV, Foster CS. Subconjunctival bevacizumab for corneal neovascularization. Cornea  2008; 27(9): 992-5.
[http://dx.doi.org/10.1097/ICO.0b013e31817786ad] [PMID:  18812760] 
[154] 
Dastjerdi MH, Saban DR, Okanobo A, et al. Effects of topical and subconjunctival bevacizumab in high-risk corneal transplant survival. Invest Ophthalmol Vis Sci  2010; 51(5): 2411-7.
[http://dx.doi.org/10.1167/iovs.09-3745] [PMID:  19892863] 
[155] 
Ahmed A, Berati H, Nalan A, Aylin S. Effect of bevacizumab on corneal neovascularization in experimental rabbit model. Clin Exp Ophthalmol  2009; 37(7): 730-6.
[http://dx.doi.org/10.1111/j.1442-9071.2009.02112.x] [PMID:  19788671] 
[156] 
Ozdemir O, Altintas O, Altintas L, Ozkan B, Akdag C, Yüksel N. Comparison of the effects of subconjunctival and topical anti-VEGF therapy (bevacizumab) on experimental corneal neovascularization. Arq Bras Oftalmol  2014; 77(4): 209-13.
[PMID:  25410169] 
[157] 
Kim YC, Grossniklaus HE, Edelhauser HF, Prausnitz MR. Intrastromal delivery of bevacizumab using microneedles to treat corneal neovascularization. Invest Ophthalmol Vis Sci  2014; 55(11): 7376-86.
[http://dx.doi.org/10.1167/iovs.14-15257] [PMID:  25212779] 
[158] 
Vieira AC, Höfling-Lima AL, Gomes JÁ. Freitas Dd, Farah ME, Belfort R Jr. Intrastromal injection of bevacizumab in patients with corneal neovascularization. Arq Bras Oftalmol  2012; 75(4): 277-9.
[http://dx.doi.org/10.1590/S0004-27492012000400012] [PMID:  23258661] 
[159] 
Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina  2006; 26(3): 262-9.
[http://dx.doi.org/10.1097/00006982-200603000-00002] [PMID:  16508424] 
[160] 
Costa RA, Jorge R, Calucci D, Cardillo JA, Melo LA Jr, Scott IU. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study. Invest Ophthalmol Vis Sci  2006; 47(10): 4569-78.
[http://dx.doi.org/10.1167/iovs.06-0433] [PMID:  17003454] 
[161] 
Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol  2006; 90(11): 1344-9.
[http://dx.doi.org/10.1136/bjo.2006.099598] [PMID:  16854824] 
[162] 
Symes RJ, Poole TR. Corneal graft surgery combined with subconjunctival bevacizumab (avastin). Cornea  2010; 29(6): 691-3.
[http://dx.doi.org/10.1097/ICO.0b013e3181ba0ae2] [PMID:  20458243] 
[163] 
van Setten GB. Vascular endothelial growth factor (VEGF) in normal human corneal epithelium: detection and physiological importance. Acta Ophthalmol Scand  1997; 75(6): 649-52.
[http://dx.doi.org/10.1111/j.1600-0420.1997.tb00623.x] [PMID:  9527324] 
[164] 
Yu CQ, Zhang M, Matis KI, Kim C, Rosenblatt MI. Vascular endothelial growth factor mediates corneal nerve repair. Invest Ophthalmol Vis Sci  2008; 49(9): 3870-8.
[http://dx.doi.org/10.1167/iovs.07-1418] [PMID:  18487369] 
[165] 
Goldhardt R, Batawi HIM, Rosenblatt M, Lollett IV, Park JJ, Galor A. Effect of Anti-Vascular Endothelial Growth Factor Therapy on Corneal Nerves. Cornea  2019; 38(5): 559-64.
[http://dx.doi.org/10.1097/ICO.0000000000001871] [PMID:  30933961] 
[166] 
Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol  2007; 171(1): 53-67.
[http://dx.doi.org/10.2353/ajpath.2007.061237] [PMID:  17591953] 
[167] 
Kernt M, Welge-Lüssen U, Yu A, Neubauer AS, Kampik A. [Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells. Ophthalmologe  2007; 104(11): 965-71.
[http://dx.doi.org/10.1007/s00347-007-1569-y] [PMID:  17653724] 
[168] 
Lichtinger A, Yeung SN, Kim P, Amiran MD, Elbaz U, Slomovic AR. Corneal endothelial safety following subconjunctival and intrastromal injection of bevacizumab for corneal neovascularization. Int Ophthalmol  2014; 34(3): 597-601.
[http://dx.doi.org/10.1007/s10792-013-9807-6] [PMID:  23722674] 
[169] 
Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol  2011; 56(2): 95-113.
[http://dx.doi.org/10.1016/j.survophthal.2010.08.006] [PMID:  21335144] 
[170] 
van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA  2005; 293(12): 1509-13.
[http://dx.doi.org/10.1001/jama.293.12.1509] [PMID:  15784876] 
[171] 
Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol  2006; 168(6): 2036-53.
[http://dx.doi.org/10.2353/ajpath.2006.050588] [PMID:  16723717] 
[172] 
Pérez-Santonja JJ, Campos-Mollo E, Lledó-Riquelme M, Javaloy J, Alió JL. Inhibition of corneal neovascularization by topical bevacizumab (Anti-VEGF) and Sunitinib (Anti-VEGF and Anti-PDGF) in an animal model. Am J Ophthalmol  2010; 150(4): 519-528.e1.
[http://dx.doi.org/10.1016/j.ajo.2010.04.024] [PMID:  20591397] 
[173] 
Lopez ES, Ortiz GA, Potilinski C, Croxatto JO, Gallo JE. Corneal Neovascularization: A Combined Approach of Bevacizumab and Suramin Showed Increased Antiangiogenic Effect Through Downregulation of BFGF and P2X2. Curr Eye Res  2018; 43(4): 466-73.
[http://dx.doi.org/10.1080/02713683.2017.1416146] [PMID:  29265937] 
[174] 
Ma X, Ottino P, Bazan HE, Bazan NG. Platelet-activating factor (PAF) induces corneal neovascularization and upregulates VEGF expression in endothelial cells. Invest Ophthalmol Vis Sci  2004; 45(9): 2915-21.
[http://dx.doi.org/10.1167/iovs.04-0128] [PMID:  15326102] 
[175] 
Papathanassiou M, Theodoropoulou S, Analitis A, Tzonou A, Theodossiadis PG. Vascular endothelial growth factor inhibitors for treatment of corneal neovascularization: a meta-analysis. Cornea  2013; 32(4): 435-44.
[http://dx.doi.org/10.1097/ICO.0b013e3182542613] [PMID:  22668582] 
Cite As
Current Drug Targets

Anti-VEGF Treatment in Corneal Diseases

Abstract

Graphical Abstract
