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Keratoconus and Other Corneal Diseases: Pharmacologic Cross-Linking and Future Therapy

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Pharmacologic Therapy of Ocular Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 242))

Abstract

The ability to cross-link collagen fibers and use this technique to strengthen the cornea has become of great interest to ophthalmologists in the last decade. For progressive diseases such as keratoconus, collagen cross-linking confers the possibility of halting progression and stabilizing the cornea, a benefit that is not observed with any other current treatment. Collagen cross-linking uses riboflavin combined with ultraviolet A light to induce the formation of bonds between collagen fibrils that strengthen the cornea. This chapter will discuss the theory, technique, indications, and complications of corneal cross-linking. Much of what will be discussed is in areas of active research that will likely be further clarified as more experience is gained with this procedure.

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References

  • Alio J, Abbouda A, Valle DD, Del Castillo JB, Fernandez JG (2013) Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect 3(1):47

    Article  PubMed  PubMed Central  Google Scholar 

  • Arora R, Manudhane A, Saran RK, Goyal J, Goyal G, Gupta D (2013) Role of corneal collagen cross-linking in pseudophakic bullous keratopathy: a clinicopathological study. Ophthalmology 120(12):2413–2418

    Article  PubMed  Google Scholar 

  • Ashwin PT, McDonnell PJ (2010) Collagen cross-linkage: a comprehensive review and directions for future research. Br J Ophthalmol 94(8):965–970

    Article  CAS  PubMed  Google Scholar 

  • Asri D, Touboul D, Fournié P, Malet F, Garra C, Gallois A, Malecaze F, Colin J (2011) Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 37(12):2137–2143

    Article  PubMed  Google Scholar 

  • Avila M, Navia J (2010) Effect of genipin collagen crosslinking on porcine corneas. J Cataract Refract Surg 36(4):659–664

    Article  PubMed  Google Scholar 

  • Avila M, Gerena V, Navia J (2012) Corneal crosslinking with genipin, comparison with UV-riboflavin in ex-vivo model. Mol Vis 18:1068–1073

    CAS  PubMed  PubMed Central  Google Scholar 

  • Avni-Zauberman N, Rootman D (2014) Crosslinking and intracorneal ring segments-review of the literature. Eye Contact Lens 40(6):365–370

    Article  PubMed  Google Scholar 

  • Bagga B, Pahuja S, Murthy S, Sangwan V (2012) Endothelial failure after collagen cross-linking with riboflavin and UV-A: case report with literature review. Cornea 31(10):1197–1200

    Article  PubMed  Google Scholar 

  • Berra M, Galperín G, Boscaro G, Zarate J, Tau J, Chiaradia P, Berra A (2013) Treatment of Acanthamoeba keratitis by corneal cross-linking. Cornea 32(2):174–178

    Article  PubMed  Google Scholar 

  • Bettis D, Hsu M, Moshirfar M (2012) Corneal collagen cross-linking for nonectatic disorders: a systematic review. J Refract Surg 28(11):798–807

    Article  PubMed  Google Scholar 

  • Bikbova G, Bikbov M (2014) Transepithelial corneal collagen cross-linking by iontophoresis of riboflavin. Acta Ophthalmol 92(1):e30–e34

    Article  CAS  PubMed  Google Scholar 

  • Bottos K, Oliveira A, Bersanetti P, Nogueira R, Lima-Filho A, Cardillo J, Schor P, Chamon W (2013) Corneal absorption of a new riboflavin-nanostructured system for transepithelial collagen cross-linking. PLoS One 8(6), e66408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bunsen RW, Roscoe HE (1862) Photochemical researches.--Part V. On the measurement of the chemical action of direct and diffuse sunlight. Proc R Soc Lond 12:306–312

    Article  Google Scholar 

  • Caporossi A, Mazzotta C, Baiocchi S, Caporossi T (2010) Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol 149(4):585–593

    Article  CAS  PubMed  Google Scholar 

  • Chai D, Juhasz T, Brown D, Jester J (2013) Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia. J Biomed Opt 18(3)

    Google Scholar 

  • Chang H-Y, Chodosh J (2013) The genetics of keratoconus. Semin Ophthalmol 28(5-6):275–280

    Article  PubMed  Google Scholar 

  • Cheema A, Mozayan A, Channa P (2012) Corneal collagen crosslinking in refractive surgery. Curr Opin Ophthalmol 23(4):251–256

    Article  PubMed  Google Scholar 

  • Cherfan D, Verter E, Melki S, Gisel T, Doyle F, Scarcelli G, Yun S, Redmond R, Kochevar I (2013) Collagen cross-linking using rose bengal and green light to increase corneal stiffness. Invest Ophthalmol Vis Sci 54(5):3426–3433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cordeiro Barbosa M, Barbosa JB, Hirai F, Hofling-Lima AL (2010) Effect of cross-linking on corneal thickness in patients with corneal edema. Cornea 29(6):613–617

    Article  PubMed  Google Scholar 

  • Daxer A, Mahmoud H, Venkateswaran RS (2010) Corneal crosslinking and visual rehabilitation in keratoconus in one session without epithelial debridement: new technique. Cornea 29(10):1176–1179

    Article  PubMed  Google Scholar 

  • del Buey M, Cristóbal J, Casas P, Goñi P, Clavel A, Mínguez E, Lanchares E, García A, Calvo B (2012) Evaluation of in vitro efficacy of combined riboflavin and ultraviolet a for Acanthamoeba isolates. Am J Ophthalmol 153(3):399–404

    Article  PubMed  CAS  Google Scholar 

  • Demirci G, Ozdamar A (2013) A case of medication-resistant acanthamoeba keratitis treated by corneal crosslinking in Turkey. Case Rep Ophthalmol Med 2013:608253. doi:10.1155/2013/608253, Epub 2013 Dec 22

    PubMed  PubMed Central  Google Scholar 

  • Dhawan S, Rao K, Natrajan S (2011) Complications of corneal collagen cross-linking. J Ophthalmol 2011:1–5

    Article  Google Scholar 

  • Dudakova L, Liskova P, Trojek T, Palos M, Kalasova S, Jirsova K (2012) Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp Eye Res 104:74–81

    Article  CAS  PubMed  Google Scholar 

  • Dunn R (2012) Cross-linking in biomaterials. Plast Reconstr Surg 130:18S–26S

    Article  CAS  PubMed  Google Scholar 

  • Elbaz U, Shen C, Lichtinger A, Zauberman N, Goldich Y, Chan C, Slomovic A, Rootman D (2014) Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea 33(8):769–773

    Article  PubMed  Google Scholar 

  • Elsheikh A, Wang D, Brown M, Rama P, Campanelli M, Pye D (2007) Assessment of corneal biomechanical properties and their variation with age. Curr Eye Res 32(1):11–19

    Article  PubMed  Google Scholar 

  • Feder R, Gan T (2011) Noninflammatory ectatic disorders. In: Krachmer J, Mannis M, Holland E (eds) Cornea. Mosby, Philadelphia, pp 865–887

    Chapter  Google Scholar 

  • Filippello M, Stagni E, O’Brart D (2012) Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 38(2):283–291

    Article  PubMed  Google Scholar 

  • Freegard TJ (1997) The physical basis of transparency of the normal cornea. Eye (Lond) 11(Pt 4):465–471

    Article  Google Scholar 

  • Galperin G, Berra M, Tau J, Boscaro G, Zarate J, Berra A (2012) Treatment of fungal keratitis from Fusarium infection by corneal cross-linking. Cornea 31(2):176–180

    Article  PubMed  Google Scholar 

  • Garcia-Delpech S, Díaz-Llopis M, Udaondo P, Salom D (2010) Fusarium keratitis 3 weeks after healed corneal cross-linking. J Refract Surg 26(12):994–995

    Article  PubMed  Google Scholar 

  • Gatzioufas Z, Richoz O, Brugnoli E, Hafezi F (2013) Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. J Refract Surg 29(12):846–848

    Article  PubMed  Google Scholar 

  • Gautam, Jhanji V, Satpathy G, Khokhar S, Agarwal T (2013) Microsporidial keratitis after collagen cross-linking. Ocul Immunol Inflamm 21(6):495–497

    Google Scholar 

  • Ghanem R, Santhiago M, Berti T, Thomaz S, Netto M (2010) Collagen crosslinking with riboflavin and ultraviolet-A in eyes with pseudophakic bullous keratopathy. J Cataract Refract Surg 36(2):273–276

    Article  PubMed  Google Scholar 

  • Goldich Y, Marcovich A, Barkana Y, Mandel Y, Hirsh A, Morad Y, Avni I, Zadok D (2012) Clinical and corneal biomechanical changes after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea 31(6):609–614

    Article  PubMed  Google Scholar 

  • Greenstein S, Fry K, Bhatt J, Hersh P (2010) Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 36(12):2105–2114

    Article  PubMed  Google Scholar 

  • Hafezi F (2011) Limitation of collagen cross-linking with hypoosmolar riboflavin solution: failure in an extremely thin cornea. Cornea 30(8):917–919

    Article  PubMed  Google Scholar 

  • Hafezi F, Mrochen M, Iseli HP, Seiler T (2009) Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 35(4):621–624

    Article  PubMed  Google Scholar 

  • Han B, Jaurequi J, Tang BW, Nimni M (2003) Proanthocyanidin: a natural crosslinking reagent for stabilizing collagen matrices. J Biomed Mater Res A 65(1):118–124

    Article  PubMed  CAS  Google Scholar 

  • Hassan Z, Nemeth G, Modis L, Szalai E, Berta A (2014) Collagen cross-linking in the treatment of pellucid marginal degeneration. Indian J Ophthalmol 62(3):367–370

    Article  PubMed  PubMed Central  Google Scholar 

  • Hersh P, Greenstein S, Fry K (2011) Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg 37(1):149–160

    Article  PubMed  Google Scholar 

  • Holmes D, Gilpin C, Baldock C, Ziese U, Koster A, Kadler K (2001) Corneal collagen fibril structure in three dimensions: structural insights into fibril assembly, mechanical properties, and tissue organization. Proc Natl Acad Sci 98(13):7307–7312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holopainen J, Krootila K (2011) Transient corneal thinning in eyes undergoing corneal cross-linking. Am J Ophthalmol 152(4):533–536

    Article  PubMed  Google Scholar 

  • Hovakimyan M, Guthoff R, Stachs O (2012) Collagen cross-linking: current status and future directions. J Ophthalmol 2012:1–12

    Article  Google Scholar 

  • Jacob S, Kumar DA, Agarwal A, Basu S, Sinha P, Agarwal A (2014) Contact lens-assisted collagen cross-linking (CACXL): a new technique for cross-linking thin corneas. J Refract Surg 30(6):366–372

    Article  PubMed  Google Scholar 

  • Kamaev P, Friedman M, Sherr E, Muller D (2012) Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 53(4):2360–2367

    Article  PubMed  Google Scholar 

  • Kanellopoulos AJ (2009) Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg 25(9)

    Google Scholar 

  • Kanellopoulos AJ (2012) Long-term safety and efficacy follow-up of prophylactic higher fluence collagen cross-linking in high myopic laser-assisted in situ keratomileusis. Clin Ophthalmol 6:1125–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanellopoulos AJ, Asimellis G (2014) Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the athens protocol). J Refract Surg 30(2):88–93

    Article  PubMed  Google Scholar 

  • Kanellopoulos J, Binder P (2007) Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea 26(7):891–895

    Article  PubMed  Google Scholar 

  • Kanellopoulos AJ, Binder P (2011) Management of corneal ectasia after LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the athens protocol. J Refract Surg 27(5):323–331

    Article  PubMed  Google Scholar 

  • Kanellopoulos AJ, Kahn J (2012) Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J Refract Surg 28(11 Suppl):S837–S840

    Article  PubMed  Google Scholar 

  • Kashiwabuchi R, Carvalho F, Khan Y, de Freitas D, Foronda A, Hirai F, Campos M, McDonnell P (2011) Assessing efficacy of combined riboflavin and UV-A light (365 nm) treatment of Acanthamoeba trophozoites. Invest Ophthalmol Vis Sci 52(13):9333–9338

    Article  CAS  PubMed  Google Scholar 

  • Khan Y, Kashiwabuchi R, Martins S, Castro-Combs J, Kalyani S, Stanley P, Flikier D, Behrens A (2011) Riboflavin and ultraviolet light a therapy as an adjuvant treatment for medically refractive Acanthamoeba keratitis. Ophthalmology 118(2):324–331

    Article  PubMed  Google Scholar 

  • Kissner A, Spoerl E, Jung R, Spekl K, Pillunat L, Raiskup F (2010) Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking. Curr Eye Res 35(8):715–721

    Article  CAS  PubMed  Google Scholar 

  • Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat L (2006) Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 32(2):279–283

    Article  PubMed  Google Scholar 

  • Koller T, Mrochen M, Seiler T (2009) Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 35(8):1358–1362

    Article  PubMed  Google Scholar 

  • Kymionis G, Portaliou D, Bouzoukis D, Suh L, Pallikaris A, Markomanolakis M, Yoo S (2007) Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 33(11):1982–1984

    Article  PubMed  Google Scholar 

  • Kymionis G, Diakonis V, Coskunseven E, Jankov M, Yoo S, Pallikaris I (2009a) Customized pachymetric guided epithelial debridement for corneal collagen cross linking. BMC Ophthalmol 9:10

    Article  PubMed  PubMed Central  Google Scholar 

  • Kymionis G, Kontadakis G, Kounis G, Portaliou D, Karavitaki A, Magarakis M, Yoo S, Pallikaris I (2009b) Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg 25(9):S807–S811

    Article  PubMed  Google Scholar 

  • Kymionis G, Kounis G, Portaliou D, Grentzelos M, Karavitaki A, Coskunseven E, Jankov M, Pallikaris I (2009c) Intraoperative pachymetric measurements during corneal collagen cross-linking with riboflavin and ultraviolet A irradiation. Ophthalmology 116(12):2336–2339

    Article  PubMed  Google Scholar 

  • Kymionis G, Portaliou D, Diakonis V, Karavitaki A, Panagopoulou S, Jankov Ii M, Coskunseven E (2011) Management of post laser in situ keratomileusis ectasia with simultaneous topography guided photorefractive keratectomy and collagen cross-linking. Open Ophthalmol J 5:11–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Kymionis G, Portaliou D, Diakonis V, Kounis G, Panagopoulou S, Grentzelos M (2012) Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. Am J Ophthalmol 153(1):24–28

    Article  CAS  PubMed  Google Scholar 

  • Kymionis G, Tsoulnaras K, Grentzelos M, Liakopoulos D, Tsakalis N, Blazaki S, Paraskevopoulos T, Tsilimbaris M (2014a) Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol 158(4):671–675.e1

    Article  PubMed  Google Scholar 

  • Kymionis G, Tsoulnaras K, Grentzelos M, Plaka A, Mikropoulos D, Liakopoulos D, Tsakalis N, Pallikaris I (2014b) Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg 40(5):736–740

    Article  PubMed  Google Scholar 

  • Lam FC, Geourgoudis P, Nanavaty MA, Khan S, Lake D (2014) Sterile keratitis after combined riboflavin-UVA corneal collagen cross-linking for keratoconus. Eye (Lond) 28(11):1297–1303

    Article  CAS  Google Scholar 

  • Leccisotti A, Islam T (2010) Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg 26(12):942–948

    Article  PubMed  Google Scholar 

  • Li Z, Jhanji V, Tao X, Yu H, Chen W, Mu G (2013) Riboflavin/ultraviolet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol 97(5):669–671

    Article  PubMed  Google Scholar 

  • Li N, Peng X-J, Fan Z-J (2014) Progress of corneal collagen cross-linking combined with refractive surgery. Int J Ophthalmol 7(1):157–162

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lim L, Beuerman R, Lim L, Tan D (2011) Late-onset deep stromal scarring after riboflavin-UV-A corneal collagen cross-linking for mild keratoconus. Arch Ophthalmol 129(3):360–362

    Article  PubMed  Google Scholar 

  • MacGregor C, Tsatsos M, Hossain P (2014) Is accelerated corneal collagen cross-linking for keratoconus the way forward? No. Eye 28(7):786–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malhotra C, Shetty R, Kumar R, Veluri H, Nagaraj H, Shetty B (2012) In vivo imaging of riboflavin penetration during collagen cross-linking with hand-held spectral domain optical coherence tomography. J Refract Surg 28(11):776–780

    Article  PubMed  Google Scholar 

  • Malik NS, Moss SJ, Ahmed N, Furth AJ, Wall RS, Meek KM (1992) Ageing of the human corneal stroma: structural and biochemical changes. Biochim Biophys Acta 1138(3):222–228

    Article  CAS  PubMed  Google Scholar 

  • Mangioris G, Papadopoulou D, Balidis M, Poulas J, Papadopoulos NT, Seiler T (2010) Corneal infiltrates after corneal collagen cross-linking. J Refract Surg 26(8):609–611

    Article  PubMed  Google Scholar 

  • Marcovich A, Brandis A, Daphna O, Feine I, Pinkas I, Goldschmidt R, Kalchenko V, Berkutzki T, Wagner D, Salomon Y, Scherz A (2012) Stiffening of rabbit corneas by the bacteriochlorophyll derivative WST11 using near infrared light. Invest Ophthalmol Vis Sci 53(10):6378–6388

    Article  CAS  PubMed  Google Scholar 

  • Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, Cano M, Dick J, Behrens A (2008) Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci 49(8):3402–3408

    Article  PubMed  Google Scholar 

  • Mastropasqua L, Nubile M, Lanzini M, Calienno R, Mastropasqua R, Agnifili L, Toto L (2013) Morphological modification of the cornea after standard and transepithelial corneal cross-linking as imaged by anterior segment optical coherence tomography and laser scanning in vivo confocal microscopy. Cornea 32(6):855–861

    Article  PubMed  Google Scholar 

  • Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A (2007) Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Exp Ophthalmol 35(6):580–582

    Article  PubMed  Google Scholar 

  • Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano M, Balestrazzi A, Caporossi A (2008) Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 146(4):527–533

    Article  CAS  PubMed  Google Scholar 

  • Mazzotta C, Caporossi T, Denaro R, Bovone C, Sparano C, Paradiso A, Baiocchi S, Caporossi A (2012) Morphological and functional correlations in riboflavin UV A corneal collagen cross-linking for keratoconus. Acta Ophthalmol 90(3):259–265

    Article  PubMed  Google Scholar 

  • Mazzotta C, Traversi C, Caragiuli S, Rechichi M (2014) Pulsed vs continuous light accelerated corneal collagen crosslinking: in vivo qualitative investigation by confocal microscopy and corneal OCT. Eye (Lond) 28(10):1179–1183

    Article  CAS  Google Scholar 

  • Meek K, Hayes S (2013) Corneal cross-linking--a review. Ophthalmic Physiol Opt 33(2):78–93

    Article  PubMed  Google Scholar 

  • Mencucci R, Marini M, Paladini I, Sarchielli E, Sgambati E, Menchini U, Vannelli G (2010) Effects of riboflavin/UVA corneal cross-linking on keratocytes and collagen fibres in human cornea. Clin Exp Ophthalmol 38(1):49–56

    Article  PubMed  Google Scholar 

  • Moshirfar M, Edmonds J, Behunin N, Christiansen S (2014) Current options in the management of pellucid marginal degeneration. J Refract Surg 30(7):474–485

    Article  PubMed  Google Scholar 

  • Munnerlyn CR, Koons SJ, Marshall J (1988) Photorefractive keratectomy: a technique for laser refractive surgery. J Cataract Refract Surg 14(1):46–52

    Article  CAS  PubMed  Google Scholar 

  • Nakayasu K, Tanaka M, Konomi H, Hayashi T (1986) Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas. Ophthalmic Res 18(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Saika S (2011) Corneal and sclera: anatomy and physiology. In: Krachmer J, Mannis M, Holland E (eds) Cornea, vol 1. Mosby, Philadelphia, pp 4–24

    Google Scholar 

  • O’Brart D, Chan E, Samaras K, Patel P, Shah S (2011) A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus. Br J Ophthalmol 95(11):1519–1524

    Article  PubMed  Google Scholar 

  • O’Brart D, Kwong T, Patel P, McDonald R, O’Brart N (2013) Long-term follow-up of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linking to halt the progression of keratoconus. Br J Ophthalmol 97(4):433–437

    Article  PubMed  Google Scholar 

  • Padmanabhan P, Dave A (2013) Collagen cross-linking in thin corneas. Indian J Ophthalmol 61(8):422–424

    Article  PubMed  PubMed Central  Google Scholar 

  • Paik D, Wen Q, Braunstein R, Airiani S, Trokel S (2009) Initial studies using aliphatic beta-nitro alcohols for therapeutic corneal cross-linking. Invest Ophthalmol Vis Sci 50(3):1098–1105

    Article  PubMed  Google Scholar 

  • Paik D, Solomon M, Wen Q, Turro N, Trokel S (2010) Aliphatic beta-nitroalcohols for therapeutic corneoscleral cross-linking: chemical mechanisms and higher order nitroalcohols. Invest Ophthalmol Vis Sci 51(2):836–843

    Article  PubMed  PubMed Central  Google Scholar 

  • Pérez-Santonja J, Artola A, Javaloy J, Alió J, Abad J (2009) Microbial keratitis after corneal collagen crosslinking. J Cataract Refract Surg 35(6):1138–1140

    Article  PubMed  Google Scholar 

  • Pollhammer M, Cursiefen C (2009) Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 35(3):588–589

    Article  PubMed  Google Scholar 

  • Price M, Tenkman L, Schrier A, Fairchild K, Trokel S, Price F (2012) Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg 28(10):706–713

    Article  PubMed  Google Scholar 

  • Rabinowitz YS (1995) Videokeratographic indices to aid in screening for keratoconus. J Refract Surg 11(5):371–379

    CAS  PubMed  Google Scholar 

  • Raiskup F, Spoerl E (2013) Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf 11(2):65–74

    Article  PubMed  Google Scholar 

  • Raiskup F, Hoyer A, Spoerl E (2009) Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 25(9)

    Google Scholar 

  • Raiskup F, Pinelli R, Spoerl E (2012) Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res 37(3):234–238

    Article  CAS  PubMed  Google Scholar 

  • Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat L (2008) Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 34(5):796–801

    Article  PubMed  Google Scholar 

  • Rama P, Di Matteo F, Matuska S, Paganoni G, Spinelli A (2009) Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. J Cataract Refract Surg 35(4):788–791

    Article  PubMed  Google Scholar 

  • Randleman B (2006) Post-laser in-situ keratomileusis ectasia: current understanding and future directions. Curr Opin Ophthalmol 17(4):406–412

    Article  PubMed  Google Scholar 

  • Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F (2013a) The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol 2(7):6

    Article  PubMed  PubMed Central  Google Scholar 

  • Richoz O, Mavrakanas N, Pajic B, Hafezi F (2013b) Corneal collagen cross-linking for ectasia after LASIK and photorefractive keratectomy: long-term results. Ophthalmology 120(7):1354–1359

    Article  PubMed  Google Scholar 

  • Richoz O, Tabibian D, Hammer A, Majo F, Nicolas M, Hafezi F (2014) The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus. Invest Ophthalmol Vis Sci 55(9):5783–5787

    Article  PubMed  Google Scholar 

  • Sady C, Khosrof S, Nagaraj R (1995) Advanced Maillard reaction and crosslinking of corneal collagen in diabetes. Biochem Biophys Res Commun 214(3):793–797

    Article  CAS  PubMed  Google Scholar 

  • Said D, Elalfy M, Gatzioufas Z, El-Zakzouk E, Hassan M, Saif M, Zaki A, Dua H, Hafezi F (2014) Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology 121(7):1377–1382

    Article  PubMed  Google Scholar 

  • Samaras K, O’Brart D, Doutch J, Hayes S, Marshall J, Meek K (2009) Effect of epithelial retention and removal on riboflavin absorption in porcine corneas. J Refract Surg 25(9):771–775

    Article  PubMed  Google Scholar 

  • Schumacher S, Oeftiger L, Mrochen M (2011) Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci 52(12):9048–9052

    Article  PubMed  Google Scholar 

  • Seiler T, Koufala K, Richter G (1998) Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg 14(3):312–317

    CAS  PubMed  Google Scholar 

  • Sharma N, Maharana P, Singh G, Titiyal J (2010) Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. J Cataract Refract Surg 36(3):517–520

    Article  PubMed  Google Scholar 

  • Sharma A, Nottage JM, Mirchia K, Sharma R, Mohan K, Nirankari VS (2012) Persistent corneal edema after collagen cross-linking for keratoconus. Am J Ophthalmol 154(6)

    Google Scholar 

  • Sharma N, Roy S, Maharana P, Sehra S, Sinha R, Tandon R, Titiyal J, Vajpayee R (2014) Outcomes of corneal collagen crosslinking in pseudophakic bullous keratopathy. Cornea 33(3):243–246

    Article  PubMed  Google Scholar 

  • Sherif AM (2014) Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clin Ophthalmol 8:1435–1440

    Article  PubMed  PubMed Central  Google Scholar 

  • Shetty R, Kaweri L, Nuijts R, Nagaraja H, Arora V, Kumar R (2014a) Profile of microbial keratitis after corneal collagen cross-linking. Biomed Res Int 2014:340509. doi:10.1155/2014/340509, Epub 2014 Sept 11

    Google Scholar 

  • Shetty R, Nagaraja H, Jayadev C, Shivanna Y, Kugar T (2014b) Collagen crosslinking in the management of advanced non-resolving microbial keratitis. Br J Ophthalmol 98(8):1033–1035

    Google Scholar 

  • Shoulders M, Raines R (2009) Collagen structure and stability. Annu Rev Biochem 78(1):929–958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorkin N, Varssano D (2014) Corneal collagen crosslinking: a systematic review. Ophthalmologica 232(1):10–27

    Article  CAS  PubMed  Google Scholar 

  • Spadea L (2010) Corneal collagen cross-linking with riboflavin and UVA irradiation in pellucid marginal degeneration. J Refract Surg 26(5):375–377

    Article  PubMed  Google Scholar 

  • Spoerl E, Seiler T (1999) Techniques for stiffening the cornea. J Refract Surg 15(6):711–713

    CAS  PubMed  Google Scholar 

  • Spoerl E, Huhle M, Seiler T (1998) Induction of cross-links in corneal tissue. Exp Eye Res 66(1):97–103

    Article  CAS  PubMed  Google Scholar 

  • Spoerl E, Wollensak G, Dittert D-D, Seiler T (2004a) Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica 218(2):136–140

    Article  CAS  PubMed  Google Scholar 

  • Spoerl E, Wollensak G, Seiler T (2004b) Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 29(1):35–40

    Article  CAS  PubMed  Google Scholar 

  • Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S, Utheim TP (2012) Safety and efficacy of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper stromal riboflavin saturation. J Ophthalmol 2012

    Google Scholar 

  • Sugar J, Macsai M (2012) What causes keratoconus? Cornea 31(6):716–719

    Article  PubMed  Google Scholar 

  • Sutton G, Lawless M, Hodge C (2014) Laser in situ keratomileusis in 2012: a review. Clin Exp Optom 97(1):18–29

    Article  PubMed  Google Scholar 

  • Tao X, Yu H, Zhang Y, Li Z, Jhanji V, Ni S, Wang Y, Mu G (2013) Role of corneal epithelium in riboflavin/ultraviolet-A mediated corneal cross-linking treatment in rabbit eyes. Biomed Res Int 2013:624563. doi:10.1155/2013/624563, Epub 2013 Jun 27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tomita M, Mita M, Huseynova T (2014) Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg 40(6):1013–1020

    Article  PubMed  Google Scholar 

  • Touboul D, Efron N, Smadja D, Praud D, Malet F, Colin J (2012) Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. J Refract Surg 28(11):769–776

    Article  PubMed  Google Scholar 

  • Tsatsos M, MacGregor C, Kopsachilis N, Anderson D (2014) Is accelerated corneal collagen cross-linking for keratoconus the way forward? Yes. Eye 28(7):784–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vajpayee R, Shafi S, Maharana P, Sharma N, Jhanji V (2015) Evaluation of corneal collagen cross-linking as an additional therapy in mycotic keratitis. Clin Exp Ophthalmol 43:103–107

    Article  PubMed  Google Scholar 

  • van Dijk K, Parker J, Tong CM, Ham L, Lie JT, Groeneveld-van Beek EA, Melles GR (2014) Midstromal isolated Bowman layer graft for reduction of advanced keratoconus: a technique to postpone penetrating or deep anterior lamellar keratoplasty. JAMA Ophthalmol 132(4):495–501

    Article  PubMed  Google Scholar 

  • Vazirani J, Basu S (2013) Keratoconus: current perspectives. Clin Ophthalmol 7:2019–2030

    PubMed  PubMed Central  Google Scholar 

  • Vazirani J, Vaddavalli P (2013) Cross-linking for microbial keratitis. Indian J Ophthalmol 61(8):441–444

    Article  PubMed  PubMed Central  Google Scholar 

  • Vinciguerra R, Romano M, Camesasca F, Azzolini C, Trazza S, Morenghi E, Vinciguerra P (2013) Corneal cross-linking as a treatment for keratoconus. Ophthalmology 120(5):908–916

    Article  PubMed  Google Scholar 

  • Wittig-Silva C, Chan E, Islam F, Wu T, Whiting M, Snibson G (2014) A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology 121(4):812–821

    Article  PubMed  Google Scholar 

  • Wollensak G (2010) Histological changes in human cornea after cross-linking with riboflavin and ultraviolet A. Acta Ophthalmol 88(2):e17–e18

    Article  PubMed  Google Scholar 

  • Wollensak G, Iomdina E (2009a) Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg 35(3):540–546

    Article  PubMed  Google Scholar 

  • Wollensak G, Iomdina E (2009b) Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol 87(1):48–51

    Article  PubMed  Google Scholar 

  • Wollensak G, Spoerl E, Seiler T (2003a) Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 135(5):620–627

    Article  CAS  PubMed  Google Scholar 

  • Wollensak G, Spoerl E, Seiler T (2003b) Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg 29(9):1780–1785

    Article  PubMed  Google Scholar 

  • Wollensak G, Spoerl E, Wilsch M, Seiler T (2003c) Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg 29(9):1786–1790

    Article  PubMed  Google Scholar 

  • Wollensak G, Spoerl E, Wilsch M, Seiler T (2004a) Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 23(1):43–49

    Article  PubMed  Google Scholar 

  • Wollensak G, Wilsch M, Spoerl E, Seiler T (2004b) Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/UVA. Cornea 23(5):503–507

    Article  PubMed  Google Scholar 

  • Xia Y, Chai X, Zhou C, Ren Q (2011) Corneal nerve morphology and sensitivity changes after ultraviolet A/riboflavin treatment. Exp Eye Res 93(4):541–547

    Article  CAS  PubMed  Google Scholar 

  • Yildirim A, Cakir H, Kara N, Uslu H, Gurler B, Ozgurhan EB, Colak HN (2014) Corneal collagen crosslinking for ectasia after laser in situ keratomileusis: long-term results. J Cataract Refract Surg 40(10):1591–1596

    Article  PubMed  Google Scholar 

  • Yuksel N, Bilgihan K, Hondur A (2011) Herpetic keratitis after corneal collagen cross-linking with riboflavin and ultraviolet-A for progressive keratoconus. Int Ophthalmol 31(6):513–515

    Article  PubMed  Google Scholar 

  • Zamora K, Males J (2009) Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report. Cornea 28(4):474–476

    Article  PubMed  Google Scholar 

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  1. University of Illinois at Chicago, Chicago, IL, 60612, USA

    Kimberly M. Hsu & Joel Sugar

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  1. Akrivista and Whitecap Biosciences, Mission Viejo, California, USA

    Scott M. Whitcup

  2. Illinois Eye and Ear Infirmary, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA

    Dimitri T. Azar

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Hsu, K.M., Sugar, J. (2016). Keratoconus and Other Corneal Diseases: Pharmacologic Cross-Linking and Future Therapy. In: Whitcup, S., Azar, D. (eds) Pharmacologic Therapy of Ocular Disease. Handbook of Experimental Pharmacology, vol 242. Springer, Cham. https://doi.org/10.1007/164_2016_23

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