6/2/2019 Updates on Corneal Disclosures • Dr. Fuller – provides statistical Cross‐Linking & support for a non‐funded, independent clinical evaluation Myopia Control of a CXL device • Educational consultant to • Alcon, • Allergan, Daniel G. Fuller, OD, FAAO Dipl, FSLS • B+L, Chief, Cornea Contact Lens Service • Cooper Vision and Supervisor, Cornea Contact Lens Refractive Surgery Residency • JJV The Eye Center, Southern College of Optometry Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 1 2 Part 1: Objectives What is CXL? • To clarify the underlying principles • Collagen fibrils branch and • To critically review the scientific literature extend limbus to limbus • To provide an update on these technologies • Cross‐linking occurs • To guide selection of the appropriate between fibrils in the same candidates lamellar layer • To assist in identifying and managing potential • Provides biomechanical adverse events or loss of efficacy stability • To guide the integration of these technologies into practice Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 3 4 6/2/2019 Man‐made Natural • Polymer chemistry uses – • Advanced glycation end • Enzymatic CXL –lysyl this is responsible for some products (AGE’s)– age & DM oxidase; a deficiency can of the differences in (prevent or decrease lead to Ehlers‐Danlos; modulus in SiHy lenses severity of KCN) maybe a gene defect in KCN • Reduction in • Photo‐oxidative CXL –UV & • Non‐enzymatic CXL – biodegradation – collagen‐ ionizing radiation glutaraldehyde; based bioprosthesis formaldehyde; diphenylphosphoryl; nitroalcohole; genipin https://www.medtronic.com/us‐en/healthcare‐professionals/products/cardiovascular/heart‐valves‐ surgical/hancock‐ii‐hancock‐ii‐ultra‐bioprostheses.html Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 5 6 Initial Candidates Potential Candidates • Primary corneal ectasias • Off‐label • Combined procedures – with • Keratoconus LASIK, INTACS, and cataract • Pellucid marginal procedures degeneration • PiXL – treat low amounts of • Must demonstrate myopia without LASIK progression • Microbial keratitis – sterilize the wound • Age cut‐off is arguable • Sclera – to strengthen grafts • Secondary corneal ectasias or melts • LASIK/PRK • Corneal dystrophies – Fuch’s Fuller, 2019 (COPE# 61275‐AS) and other Fuller, 2019 (COPE# 61275‐AS) 7 8 6/2/2019 Physical Properties Absorption of UVA/Emittance CXL Process UV Spectrum • Riboflavin has two peak absorption maxima • Photochemical process • Ultraviolet spectrum • 375nm • Non‐thermal • UVA – 320‐400 nm • 445nm • Comparison to photocoagulation • UVB – 280‐320 nm • Photocoagulation – 630 • W/cm2 • UVC – 180‐280 nm Emits fluorescence at • Photochemical – 3 mW/cm2 534nm • M◦aximum temp. increase of2‐ 3C Lombardo, M et al. Interaction of ultraviolet light with the cornea: Clinical implications for corneal crosslinking. J Cataract Ref Surg. 2015; 41(2):446‐459. Mencucci R1, Mazzotta C, Rossi F, Ponchietti C, Pini R, Baiocchi S, Caporossi A, Menchini U. Riboflavin and ultraviolet A collagen crosslinking: in vivo thermographic analysis of the corneal surface. J Cataract Refract Surg. 2007 Jun;33(6):1005‐8. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 9 10 Absorption of UVA Tissue Changes • RF 0.1% sol. • Increase in modulus and firmness by a factor of 1.7x • Selected for an average KCN pach of 400 microns • Increase in shrinkage temp. from 63◦C • Biomechanical effect is independent of concentration over to 70◦C a large area • Decrease in swelling percentage • Higher conc. actually reduce CXL effect • Increase in collagen fibril thickness by • Produces a large absorption coefficient of 90% in the 4.5% stroma protecting the endothelium, lens and retina. • Increased resistance to collagenase • Creation of molecular aggregates with • 65% absorbed in the first 200 microns higher molecular weights • Decrease in permeability Wollensak G1, Spoerl E, Seiler T. Stress‐strain measurements of human and porcine corneas after riboflavin‐ultraviolet‐A‐induced cross‐linking. J Cataract RefractSurg. Fuller, 2019 (COPE# 61275‐AS) 2003 Sep;29(9):1780‐5. Fuller, 2019 (COPE# 61275‐AS) 11 12 6/2/2019 Histological changes in human cornea after cross‐linkingwith Cellular Changes riboflavin and ultraviolet A Epithelium • Epithelial cells • Epi‐off – cells grow back in 3‐4 days 250 microns • Normal thickness at 3 to 6 months • Intact epithelium protects limbal stem cells • Keratocytes • Increases apoptosis in first 250‐300 microns • New cells migrate from periphery • Alterations occur up to 36 mos. Endo. Acta Ophthalmologica Volume 88, Issue 2, pages e17‐e18, 23 APR 2009 DOI: Wollensak G1, Spoerl E, Reber F, Seiler T Keratocyte cytotoxicity of riboflavin/UVA‐treatment in vitro. Eye (Lond). 2004 10.1111/j.1755‐3768.2008.01474.x Jul;18(7):718‐22. http://onlinelibrary.wiley.com/doi/10.1111/j.1755‐3768.2008.01474.x/full#f1 Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 13 14 From: Collagen Cross-Linking Using Rose Bengal and Green Light to Increase Corneal Stiffness Invest. Ophthalmol. Vis. Sci.. 2013;54(5):3426-3433. doi:10.1167/iovs.12-11509 Cellular Changes •Endothelial cells • Statistically non‐significant reduction • Density and morphology unchanged at 1 year • Threshold for damage is 0.35 mW/cm2 ; exposure levels are 0.18 mW/cm2 • Assuming a 400 micron thick or greater cornea Figure Legend: Keratocytes in cornea after photo-cross-linking. (A, B) RB was applied to cornea and exposed to 100 or 200 J/cm2 green light (A) or kept in dark (B). (C, D) Riboflavin/dextran was applied to cornea and exposed to 8.7 J/cm2 UVA (C) or kept in dark (D). Corneas were cultured for 24 hours then fixed, paraffin-embedded, and H&E-stained. (E) Cells in stroma of corneas treated with RB, then with 100 or 200 J/cm2 green light or kept in dark. Only cells in most anterior stroma (200 μm) on section were counted. (F) Cells in Wollensak G1, Spörl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. corneas treated with riboflavin, then with 8.7 J/cm2 UVA or kept in dark. Cells to a depth of 500 μm on the sections were counted. n Ophthalmic Res. 2003 Nov‐Dec;35(6):324‐8. = 3 to 4 cornea for each treatmentcondition. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) The Association for Research in Vision and Ophthalmology Copyright © 2015. All rights reserved. Date of download: 6/10/2015 15 16 6/2/2019 Cellular Changes Cellular Changes •Nerves • Deeper structures • Subepithelial • Lens – protected by the absorption of UVA by RF and nerve plexus cornea disappears • Retina – also protected by absorption and lack of • Regenerates after irradiation being focused in its plane 7 days and is normal by 6 mos. Xia Y1, Chai X, Zhou C, Ren Q. Corneal nerve morphology and sensitivity changes after ultravioletA/riboflavin treatment. Exp Eye Res. 2011 Oct;93(4):541‐7. Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 17 18 Riboflavin Overseas Riboflavin Used in the US Trials Riboflavin Formula Use Epithelum Cross‐linking for MedioCROSS 0.25% Riboflavin, 1.2% keratoconus and corneal On • Riboflavin (vitamin B2) 0.1% sol. – m.w. 376 TE HPMC, 0.01% BAC ectasia gm/mol (Photrexa 0.12% / Photrexa Viscous Cross‐linking for 0.1% Riboflavin, 1.1% MedioCROSS M keratoconus and corneal Off 0.12% with Dextran 20% from Avedro) HPMC ectasia • Non‐toxic 0.22% Riboflavin, Saline, Stromal VibeX Xtra LASIK • Absorbs UVA light Isotonic Bed • Used to create free radicals which cross‐link the 0.1% Riboflavin, Saline, VibeX Rapid Accelerated CXL Off carbonyl groups within and between collagen fibrils HPMC in the same lamellae not between lamellae 0.25% Riboflavin, HPMC, ParaCel Accelerated CXL On • There may be some inter‐fibrillar bonds between BAC proteoglycans Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 19 20 6/2/2019 Procedures: Dresden v. Athens Comparison of outcomes Bunsen‐Roscoe Law (Intensity x Time= Exposure) • Dresden protocol • Athens protocol • Outcomes of treatment efficacy • Demarcation line depth is the 2 • Accelerated CXL – shallower measure of treatment efficacy. • Intensity is 3 mW/cm • Maximum intensity up to • Conventional CXL – deeper • Treatment time 30 mins. 43 mW/cm2; Treatment • Regression > with A‐CXL at 2 to 5 min. intervals time 2 min. • Problem epi‐off 3 mW/cm2 epi‐off 10 mW/cm2 • Typical protocols (Kymionis et al.) • Less available oxygen in • Applied over an 8 mm accelerated CXL with epi‐on. • 9mW/cm2 for 14min diameter area to protect • Solution 2 limbus, sclera and goblet • 18mW/cm for 7min • 30mW Pulsed therapy at 1s epi‐on Ionto. 10 mW/cm2 epi‐on 3 mW/cm2 cells • May pulse doses intervals of 3‐ 8min; allows O 2 more time to penetrate Spadea L, et al. Corneal stromal demarcation line after 4 protocols of corneal crosslinking in keratoconus determined with anterior segment optical coherence tomography. J Cataract Kymionis GD, et al. Accelerated versus conventional corneal Ref Surg. 2018; 44(5)596‐602. Fuller, 2019 (COPE# 61275‐AS) crosslinking for refractive instability: an update. Curr Opin Fuller, 2019 (COPE# 61275‐AS) Ophthalmol. 2017;28:343‐347 21 22 Epithelium‐on (Transepithelial) Delivery of Epithelium‐off Delivery of Riboflavin Riboflavin • RF 0.1% every 1 to 5 • Improving penetration • Increase contact time (viscous mins. for 30 mins. sol. or ring application) • Eliminates the barrier to • Change permeability (pilocarpine with either BAK and EDTA; diffusion presented by tetracaine; hypo‐osmotic the epithelium riboflavin sol.) • Dextran inhibits conductance • Diffusion achieves a when added, whereas 0.01% BAC maximum in the anterior and 0.44% NaCl increase stroma at 20 to 30 mins., permeability. • Using a Daya disrupter you can protecting the pock‐mark the epithelium endothelium/lens/retina improving permeability Fuller, 2019 (COPE# 61275‐AS) Fuller, 2019 (COPE# 61275‐AS) 23 24 6/2/2019 Direct Application of Riboflavin Iontophoresis Delivery of Riboflavin http://www.eyegatepharma.com/technology/iontophoresis‐delivery‐system/ • Create a pocket as in Intacs • Riboflavin in negatively charged • Current is delivered for 5 mins.