Granted Patent
B2
US 12,427,062 · App. 17/509,337 · Granted Sep 30, 2025
Systems and methods for cross-linking treatments of an eye
Inventors:
Marc D. Friedman (Needham, MA); Pavel Kamaev (Lexington, MA); Mikhail Smirnov (North Andover, MA)
Assignee:
Avedro, Inc.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
A system for corneal treatment includes a light source that activates cross-linking in at least one selected region of a cornea treated with a cross-linking agent. The light source delivers photoactivating light to the at least one selected region of the cornea according to a set of parameters. The system includes a controller that receives input relating to the cross-linking agent and the set of parameters. The controller includes computer-readable storage media storing: (A) program instructions for determining cross-linking resulting from reactions involving ROS including at least peroxides, superoxides, and hydroxyl radicals, and (B) program instructions for determining cross-linking from reactions not involving oxygen. The controller executes the program instructions to output a calculated amount of cross-linking in the at least one selected region of the cornea. In response to the calculated amount of cross-linking, the light source adjusts at least one value in the set of parameters.
Claims (25)
1. A system for corneal treatment, comprising:
a light source configured to activate cross-linking in at least one selected region of a cornea treated with a cross-linking agent, the light source being configured to deliver photoactivating light to the at least one selected region of the cornea; and
a controller configured to:
receive input relating to pre-clinical patient information;
determine a patient-specific treatment plan by analyzing the pre-clinical patient information, wherein the patient-specific treatment plan specifies a set of parameters for the light source to deliver the photoactivating light, and the set of parameters for the light source is based on a cross-linking model resulting from determined by: (A) reactions involving reactive oxygen species (ROS) including at least peroxides, superoxides, or hydroxyl radicals, and (B) reactions not involving oxygen; and
cause the light source to be adjusted to deliver the photoactivating light according to the set of parameters.
2. The system of claim 1 , further comprising an oxygen source and an oxygen delivery device configured to provide a concentration of oxygen from the oxygen source to the at least one selected region of the cornea,
wherein the controller is further configured to receive input relating to the concentration of oxygen and to determine the set of parameters for the light source based additionally on the concentration of oxygen.
3. The system of claim 1 , wherein the controller is further configured to receive input relating to the cross-linking agent and to determine the set of parameters for the light source based additionally on the cross-linking agent.
4. The system of claim 3 , wherein the input relating to the cross-linking agent indicates a concentration of the cross-linking agent and a soak time for treating the cornea with the cross-linking agent.
5. The system of claim 1 , wherein the set of parameters for the light source is based additionally on cross-linking resulting from reactions involving reactive oxygen species (ROS) including singlet oxygen.
6. A method for corneal treatment, comprising:
providing a light source configured to activate cross-linking in at least one selected region of a cornea treated with a cross-linking agent, the light source being configured to deliver photoactivating light to the at least one selected region of the cornea; and
receiving input relating to pre-clinical patient information;
determining a patient-specific treatment plan by combining the pre-clinical patient information with finite element biomechanical computer modeling, wherein the patient-specific treatment plan specifies a set of parameters for a light source to deliver photoactivating light, and the set of parameters for the light source is based on a cross-linking model determined by: (A) reactions involving reactive oxygen species (ROS) including at least peroxides, superoxides, or hydroxyl radicals, and (B) reactions not involving oxygen; and
causing the light source to be adjusted to deliver the photoactivating light according to the set of parameters.
7. The method of claim 6 , further comprising:
providing an oxygen source and an oxygen delivery device configured to provide a concentration of oxygen from the oxygen source to the at least one selected region of the cornea;
receiving input relating to the concentration of oxygen; and
determining the set of parameters for the light source based additionally on the concentration of oxygen.
8. The method of claim 6 , further comprising:
receiving input relating to the cross-linking agent; and
determining the set of parameters for the light source based additionally on the cross-linking agent.
9. The method of claim 8 , wherein the input relating to the cross-linking agent indicates a concentration of the cross-linking agent and a soak time for treating the cornea with the cross-linking agent.
10. The method of claim 6 , wherein the set of parameters for the light source is based additionally on cross-linking resulting from reactions involving reactive oxygen species (ROS) including singlet oxygen.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 14, 2022
From: FRIEDMAN, MARC D.; KAMAEV, PAVEL; SMIRNOV, MIKHAIL
To: AVEDRO, INC.
Reel/Frame 061096/0152 →
Continuity (5)
Continuation In Part
PCTUS2015057628
· Oct 27, 2015
Provisional Application
62069094
· Oct 27, 2014
References Cited (400)
US 3169459A
· Friedberg et al.
· 1965
[cited by applicant]
US 4034750A
· Seiderman
· 1977
[cited by applicant]
US 4161013A
· Grodzinsky et al.
· 1979
[cited by applicant]
US 4326529A
· Doss et al.
· 1982
[cited by applicant]
US 4381007A
· Doss
· 1983
[cited by applicant]
US 4665913A
· L'Esperance, Jr.
· 1987
[cited by applicant]
US 4712543A
· Baron
· 1987
[cited by applicant]
US 4764007A
· Task
· 1988
[cited by applicant]
US 4805616A
· Pao
· 1989
[cited by applicant]
US 4881543A
· Trembly et al.
· 1989
[cited by applicant]
US 4891043A
· Zeimer et al.
· 1990
[cited by applicant]
US 4969912A
· Kelman et al.
· 1990
[cited by applicant]
US 4994058A
· Raven et al.
· 1991
[cited by applicant]
US 5016615A
· Driller et al.
· 1991
[cited by applicant]
US 5019074A
· Muller
· 1991
[cited by applicant]
US 5098426A
· Sklar et al.
· 1992
[cited by applicant]
US 5103005A
· Gyure et al.
· 1992
[cited by applicant]
US 5171254A
· Sher
· 1992
[cited by applicant]
US 5171318A
· Gibson et al.
· 1992
[cited by applicant]
US 5281211A
· Parel et al.
· 1994
[cited by applicant]
US 5332802A
· Kelman et al.
· 1994
[cited by applicant]
US 5450144A
· Ben Nun
· 1995
[cited by applicant]
US 5461212A
· Seiler et al.
· 1995
[cited by applicant]
US 5490849A
· Smith
· 1996
[cited by applicant]
US 5512966A
· Snook
· 1996
[cited by applicant]
US 5562656A
· Sumiya
· 1996
[cited by applicant]
US 5608472A
· Szirth et al.
· 1997
[cited by applicant]
US 5618284A
· Sand
· 1997
[cited by applicant]
US 5624437A
· Freeman et al.
· 1997
[cited by applicant]
US 5634921A
· Hood et al.
· 1997
[cited by applicant]
US 5766171A
· Silvestrini
· 1998
[cited by applicant]
US 5779696A
· Berry et al.
· 1998
[cited by applicant]
US 5786893A
· Fink et al.
· 1998
[cited by applicant]
US 5814040A
· Nelson et al.
· 1998
[cited by applicant]
US 5885275A
· Muller
· 1999
[cited by applicant]
US 5891131A
· Rajan et al.
· 1999
[cited by applicant]
US 5910110A
· Bastable
· 1999
[cited by applicant]
US 6033396A
· Huang et al.
· 2000
[cited by applicant]
US 6099521A
· Shadduck
· 2000
[cited by applicant]
US 6101411A
· Newsome
· 2000
[cited by applicant]
US 6104959A
· Spertell
· 2000
[cited by applicant]
US 6139876A
· Kolta
· 2000
[cited by applicant]
US 6161544A
· DeVore et al.
· 2000
[cited by applicant]
US 6162210A
· Shadduck
· 2000
[cited by applicant]
US 6188500B1
· Rudeen et al.
· 2001
[cited by applicant]
US 6218360B1
· Cintron et al.
· 2001
[cited by applicant]
US 6223075B1
· Beck et al.
· 2001
[cited by applicant]
US 6270221B1
· Liang et al.
· 2001
[cited by applicant]
US 6280436B1
· Freeman et al.
· 2001
[cited by applicant]
US 6293938B1
· Muller et al.
· 2001
[cited by applicant]
US 6319273B1
· Chen et al.
· 2001
[cited by applicant]
US 6322557B1
· Nikolaevich et al.
· 2001
[cited by applicant]
US 6325792B1
· Swinger et al.
· 2001
[cited by applicant]
US 6334074B1
· Spertell
· 2001
[cited by applicant]
US 6342053B1
· Berry
· 2002
[cited by applicant]
US 6394999B1
· Williams et al.
· 2002
[cited by applicant]
US 6402739B1
· Neev
· 2002
[cited by applicant]
US 6413255B1
· Stern
· 2002
[cited by applicant]
US 6478792B1
· Hansel
· 2002
[cited by applicant]
US 6520956B1
· Huang
· 2003
[cited by applicant]
US 6520958B1
· Shimmick et al.
· 2003
[cited by applicant]
US 6537545B1
· Karageozian et al.
· 2003
[cited by applicant]
US 6571118B1
· Utzinger et al.
· 2003
[cited by applicant]
US 6572849B2
· Shahinian, Jr.
· 2003
[cited by applicant]
US 6617963B1
· Watters et al.
· 2003
[cited by applicant]
US 6673067B1
· Peyman
· 2004
[cited by applicant]
US 6918904B1
· Peyman
· 2005
[cited by applicant]
US 6946440B1
· DeWoolfson et al.
· 2005
[cited by applicant]
US 7001374B2
· Peyman
· 2006
[cited by applicant]
US 7004902B2
· Luce
· 2006
[cited by applicant]
US 7044945B2
· Sand
· 2006
[cited by applicant]
US 7073510B2
· Redmond et al.
· 2006
[cited by applicant]
US 7130835B2
· Cox et al.
· 2006
[cited by applicant]
US 7141049B2
· Stern et al.
· 2006
[cited by applicant]
US 7192429B2
· Trembly
· 2007
[cited by applicant]
US 7237898B1
· Hohla et al.
· 2007
[cited by applicant]
US 7270658B2
· Woloszko et al.
· 2007
[cited by applicant]
US 7302189B2
· Kawahata
· 2007
[cited by applicant]
US 7331350B2
· Kochevar et al.
· 2008
[cited by applicant]
US 7402562B2
· DeWoolfson et al.
· 2008
[cited by applicant]
US 7753943B2
· Strong
· 2010
[cited by applicant]
US 7871378B1
· Chou et al.
· 2011
[cited by applicant]
US 7898656B2
· Yun et al.
· 2011
[cited by applicant]
US 7935058B2
· Dupps, Jr. et al.
· 2011
[cited by applicant]
US 8111394B1
· Borysow et al.
· 2012
[cited by applicant]
US 8115919B2
· Yun et al.
· 2012
[cited by applicant]
US 8366689B2
· Marshall
· 2013
[cited by examiner]
US 8414911B2
· Mattson et al.
· 2013
[cited by applicant]
US 8475437B2
· Mrochen et al.
· 2013
[cited by applicant]
US 8574277B2
· Muller
· 2013
[cited by examiner]
US 8715273B2
· Thyzel
· 2014
[cited by applicant]
US 8870934B2
· Muller et al.
· 2014
[cited by applicant]
US 8995618B2
· Gertner
· 2015
[cited by applicant]
US 9005261B2
· Brinkmann
· 2015
[cited by applicant]
US 9498642B2
· Muller
· 2016
[cited by examiner]
US 9707126B2
· Friedman
· 2017
[cited by examiner]
US 20010041856A1
· McDaniel
· 2001
[cited by applicant]
US 20010047012A1
· Desantis, Jr.
· 2001
[cited by applicant]
US 20010055095A1
· D'Souza et al.
· 2001
[cited by applicant]
US 20020002369A1
· Hood
· 2002
[cited by applicant]
US 20020013577A1
· Frey et al.
· 2002
[cited by applicant]
US 20020042638A1
· Iezzi et al.
· 2002
[cited by applicant]
US 20020049437A1
· Silvestrini
· 2002
[cited by applicant]
US 20020099363A1
· Woodward et al.
· 2002
[cited by applicant]
US 20020159618A1
· Freeman et al.
· 2002
[cited by applicant]
US 20020164379A1
· Nishihara et al.
· 2002
[cited by applicant]
US 20030018255A1
· Martin et al.
· 2003
[cited by applicant]
US 20030030908A1
· Cheng et al.
· 2003
[cited by applicant]
US 20030135122A1
· Bambot et al.
· 2003
[cited by applicant]
US 20030175259A1
· Karageozian et al.
· 2003
[cited by applicant]
US 20030208190A1
· Roberts et al.
· 2003
[cited by applicant]
US 20030231285A1
· Ferguson
· 2003
[cited by applicant]
US 20040002694A1
· Pawlowski et al.
· 2004
[cited by applicant]
US 20040071778A1
· Bellmann et al.
· 2004
[cited by applicant]
US 20040199158A1
· Hood et al.
· 2004
[cited by applicant]
US 20040204707A1
· Hood et al.
· 2004
[cited by applicant]
US 20040254520A1
· Porteous et al.
· 2004
[cited by applicant]
US 20050096515A1
· Geng
· 2005
[cited by applicant]
US 20050149006A1
· Peyman
· 2005
[cited by applicant]
US 20050187599A1
· Sharkey et al.
· 2005
[cited by applicant]
US 20060135957A1
· Panescu
· 2006
[cited by applicant]
US 20060149343A1
· Altshuler et al.
· 2006
[cited by applicant]
US 20060177430A1
· Bhushan et al.
· 2006
[cited by applicant]
US 20060276777A1
· Coroneo
· 2006
[cited by applicant]
US 20060287662A1
· Berry et al.
· 2006
[cited by applicant]
US 20070027509A1
· Eisenberg et al.
· 2007
[cited by applicant]
US 20070048340A1
· Ferren et al.
· 2007
[cited by applicant]
US 20070055227A1
· Khalaj et al.
· 2007
[cited by applicant]
US 20070074722A1
· Giroux et al.
· 2007
[cited by applicant]
US 20070123845A1
· Lubatschowski
· 2007
[cited by applicant]
US 20070135805A1
· Peyman
· 2007
[cited by applicant]
US 20070142828A1
· Peyman
· 2007
[cited by applicant]
US 20070203478A1
· Herekar
· 2007
[cited by applicant]
US 20070203547A1
· Costello et al.
· 2007
[cited by applicant]
US 20070244496A1
· Hellenkamp
· 2007
[cited by applicant]
US 20070265603A1
· Pinelli
· 2007
[cited by applicant]
US 20080009901A1
· Redmond et al.
· 2008
[cited by applicant]
US 20080015660A1
· Herekar
· 2008
[cited by applicant]
US 20080027328A1
· Klopotek et al.
· 2008
[cited by applicant]
US 20080063627A1
· Stucke et al.
· 2008
[cited by applicant]
US 20080139671A1
· Herekar
· 2008
[cited by applicant]
US 20080208177A1
· Mrochen et al.
· 2008
[cited by applicant]
US 20090130176A1
· Bossy-Nobs et al.
· 2009
[cited by applicant]
US 20090149923A1
· Herekar
· 2009
[cited by examiner]
US 20090171305A1
· El Hage
· 2009
[cited by applicant]
US 20090192437A1
· Soltz et al.
· 2009
[cited by applicant]
US 20090275929A1
· Zickler
· 2009
[cited by applicant]
US 20090276042A1
· Hughes et al.
· 2009
[cited by applicant]
US 20100028407A1
· Del Priore et al.
· 2010
[cited by applicant]
US 20100057060A1
· Herekar
· 2010
[cited by applicant]
US 20100082018A1
· Panthakey et al.
· 2010
[cited by applicant]
US 20100286156A1
· Pinelli
· 2010
[cited by applicant]
US 20100318017A1
· Lewis et al.
· 2010
[cited by applicant]
US 20110044902A1
· Weiner et al.
· 2011
[cited by applicant]
US 20110098790A1
· Daxer
· 2011
[cited by applicant]
US 20110152219A1
· Stagni
· 2011
[cited by applicant]
US 20110190742A1
· Anisimov
· 2011
[cited by applicant]
US 20110202114A1
· Kessel et al.
· 2011
[cited by applicant]
US 20110237999A1
· Muller
· 2011
[cited by examiner]
US 20110288466A1
· Muller et al.
· 2011
[cited by applicant]
US 20120083772A1
· Rubinfeld et al.
· 2012
[cited by applicant]
US 20120203161A1
· Herekar
· 2012
[cited by applicant]
US 20120215155A1
· Muller et al.
· 2012
[cited by applicant]
US 20120283621A1
· Muller
· 2012
[cited by applicant]
US 20120289886A1
· Muller et al.
· 2012
[cited by applicant]
US 20120302862A1
· Yun et al.
· 2012
[cited by applicant]
US 20130085370A1
· Friedman et al.
· 2013
[cited by applicant]
US 20130245536A1
· Friedman et al.
· 2013
[cited by applicant]
US 20130310732A1
· Foschini et al.
· 2013
[cited by applicant]
US 20140066835A1
· Muller et al.
· 2014
[cited by applicant]
US 20140276361A1
· Herekar et al.
· 2014
[cited by applicant]
US 20140277431A1
· Herekar et al.
· 2014
[cited by applicant]
US 20140343480A1
· Kamaev et al.
· 2014
[cited by applicant]
US 20160175442A1
· Kamaev
· 2016
[cited by examiner]
DE 102008046834
· 2010
[cited by applicant]
EP 1285679
· 2003
[cited by applicant]
EP 1561440
· 2005
[cited by applicant]
EP 1790383
· 2007
[cited by applicant]
EP 2253321
· 2010
[cited by applicant]
EP 4241748A2
· 2023
[cited by examiner]
IT MI2010A001236
· 2010
[cited by applicant]
JP 2000262476
· 2000
[cited by applicant]
KG 1376
· 2011
[cited by applicant]
RU 2086215
· 1997
[cited by applicant]
RU 2098057
· 1997
[cited by applicant]
RU 2121825
· 1998
[cited by applicant]
RU 2127099
· 1999
[cited by applicant]
RU 2127100
· 1999
[cited by applicant]
RU 2309713
· 2007
[cited by applicant]
RU 2359716
· 2009
[cited by applicant]
RU 2420330
· 2011
[cited by applicant]
RU 2428152
· 2011
[cited by applicant]
RU 2456971
· 2012
[cited by applicant]
WO 9316631
· 1993
[cited by applicant]
WO 9403134
· 1994
[cited by applicant]
WO 0074648
· 2000
[cited by applicant]
WO 0158495
· 2001
[cited by applicant]
WO 03061696
· 2003
[cited by applicant]
WO 2004052223
· 2004
[cited by applicant]
WO 2005110397
· 2005
[cited by applicant]
WO 2006012947
· 2006
[cited by applicant]
WO 2006128038
· 2006
[cited by applicant]
WO 2007001926
· 2007
[cited by applicant]
WO 2007053826
· 2007
[cited by applicant]
WO 2007081750
· 2007
[cited by applicant]
WO 2007120457
· 2007
[cited by applicant]
WO 2007128581
· 2007
[cited by applicant]
WO 2007139927
· 2007
[cited by applicant]
WO 2007143111
· 2007
[cited by applicant]
WO 2008000478
· 2008
[cited by applicant]
WO 2008052081
· 2008
[cited by applicant]
WO 2008095075
· 2008
[cited by applicant]
WO 2009042159
· 2009
[cited by applicant]
WO 2009073213
· 2009
[cited by applicant]
WO 2009114513
· 2009
[cited by applicant]
WO 2009146151
· 2009
[cited by applicant]
WO 2010011119
· 2010
[cited by applicant]
WO 2010015255
· 2010
[cited by applicant]
WO 2010023705
· 2010
[cited by applicant]
WO 2010039854
· 2010
[cited by applicant]
WO 2010093908
· 2010
[cited by applicant]
WO 2011019940
· 2011
[cited by applicant]
WO 2011050360
· 2011
[cited by applicant]
WO 2011116306
· 2011
[cited by applicant]
WO 2012004726
· 2012
[cited by applicant]
WO 2012047307
· 2012
[cited by applicant]
WO 2012149570
· 2012
[cited by applicant]
WO 2012158991
· 2012
[cited by applicant]
WO 2012174453
· 2012
[cited by applicant]
WO 2013062910
· 2013
[cited by applicant]
WO 2013148713
· 2013
[cited by applicant]
WO 2013148895
· 2013
[cited by applicant]
WO 2013149075
· 2013
[cited by applicant]
WO 2014081875
· 2014
[cited by applicant]
WO 2014145666
· 2014
[cited by applicant]
WO 2014202736
· 2014
[cited by applicant]
Abahussin, M. “3D Collagen Orientation Study of the Human Cornea Using X-ray Diffraction and Femtosecond Laser Technology” Investigative Ophthalmology & Visual Science, Nov. 2009, vol. 50, No. 11, pp. 5159-5164.
[cited by applicant]
Acosta A. et al., “Corneal Stroma Regeneration in Felines After Supradescemetic Keratoprothesis Implantation,” Cornea, vol. 25, No. 7, pp. 830-838; Aug. 2006.
[cited by applicant]
Averianova, O. S., “Nastoyaschee I buduschee kross-linkage.” Mir Ofalmologii, 2010, [online] [retrieved on Feb. 13, 2014] Retrieved from the internet: http://miroft.org.ua/publications/.html.
[cited by applicant]
Baier J. et al., “Singlet Oxygen Generation by UVA Light Exposure of Endogenous Photosensitizers,” Biophysical Journal, vol. 91(4), pp. 1452-1459; Aug. 15, 2006.
[cited by applicant]
Ballou, D. et al., “Direct Demonstration Of Superoxide Anion Production During The Oxidation Of Reduced Flavin And Of Its Catalytic Decomposition By Erythrocuprein,” Biochemical And Biophysical Research Communications v…
[cited by applicant]
Barbarino, S. et al., “Post-LASIK ectasia: Stabilization and Effective Management with Riboflavin / ultraviolet A-induced collagen cross-linking,” Association for Research in Vision and Ophthalmology, 2006.
[cited by applicant]
Berjano E., et al., “Radio-Frequency Heating of the Cornea: Theoretical Model and In Vitro Experiments,” IEEE Transactions on Biomedical Engineering, vol. 49, No. 3, pp. 196-205; Mar. 2002.
[cited by applicant]
Berjano E., et al., “Ring Electrode for Radio-frequency Heating of the Cornea: Modelling and in vitro Experiments,” Medical & Biological Engineering & Computing, vol. 41, pp. 630-639; Jun. 2003.
[cited by applicant]
Bruel, A., “Changes In Biomechanical Properties, Composition Of Collagen And Elastin, And Advanced Glycation Endproducts Of The Rat Aorta In Relation To Age,” Atherosclerosis 127, Mar. 14, 1996.
[cited by applicant]
Burke, JM et al., Abstract for “Retinal proliferation in response to vitreous hemoglobin or iron”, Investigative Ophthalmology & Visual Science, May 1981, 20(5), pp. 582-592.
[cited by applicant]
Chai, D. et al., “Quantitative Assessment of UVA-Riboflavin Corneal Cross-Linking Using Nonlinear Optical Microscopy,” Investigative Ophthalmology & Visual Science, Jun. 2011, vol. 52, No. 7, 4231-4238.
[cited by applicant]
Chan B.P., et al., “Effects of photochemical crosslinking on the microstructure of collagen and a feasibility study on controlled protein release;” Acta Biomaterialia, vol. 4, Issue 6, pp. 1627-1636; Jul. 1, 2008.
[cited by applicant]
Chandonnet, “CO2 Laser Annular Thermokeratoplasty: A Preliminary Study,” Lasers in Surgery and Medicine, vol. 12, pp. 264-273; 1992.
[cited by applicant]
Chace, KV. et al., Abstract for “The role of nonenzymatic glycosylation, transition metals, and free radicals in the formation of collagen aggregates”, Arch Biochem Biophys., Aug. 1, 1991, 288(2), pp. 473-480.
[cited by applicant]
Clinical Trials.gov, “Riboflavin Mediated Corneal Crosslinking for Stabilizing Progression of Keratoconus (CCL),” University Hospital Freiburg, Feb. 20, 2008; retrieved from http://www.clinicaltrials.gov/ct2/show/NCT006…
[cited by applicant]
Corbett M., et al., “Effect of Collagenase Inhibitors on Corneal Haze after PRK,” Exp. Eye Res., vol. 72, Issue 3, pp. 253-259; Jan. 2001.
[cited by applicant]
Coskenseven E. et al., “Comparative Study of Corneal Collagen Cross-linking With Riboflavin and UVA Irradiation in Patients With Keratoconus,” Journal of Refractive Surgery, vol. 25, issue 4, pp. 371-376; Apr. 2009.
[cited by applicant]
“DEFINITY (perflutren) injection, suspension [Bristol-Myers Squibb Medical Imaging],” http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8338, revised Sep. 2008, retrieved via the internet archive from http://web.arch…
[cited by applicant]
Ehlers W., et al., “Factors Affecting Therapeutic Concentration of Topical Aminocaproic Acid in Traumatic Hyphema,” Investigative Ophthalmology & Visual Science, vol. 31, No. 11, pp. 2389-2394; Nov. 1990.
[cited by applicant]
Erskine H., “Avedro Becomes Sponsor of US FDA Clinical Trials of Corneal Collagen Crosslinking,” Press Release, Mar. 16, 2010 (1 page).
[cited by applicant]
Fite et al., “Noninvasive Multimodal Evaluation of Bioengineered Cartilage Constructs Combining Time-Resolved Fluorescence and Ultrasound Imaging.” Tissue Eng: Part C vol. 17, No. 4, 2011.
[cited by applicant]
Friedman, M. et al. “Advanced Corneal Cross-Linking System with Fluorescence Dosimetry”, Journal of Ophthalmology, vol. 2012, Article ID 303459, dated May 7, 2012.
[cited by applicant]
Frucht-Pery, et al. “Iontophoresis-gentamicin delivery into the rabbit cornea, using a hydrogel delivery probe,” Jun. 20, 2003.
[cited by applicant]
Gibson, Q. et al., “The Oxidation Of Reduced Flavin Mononucleotide By Molecular Oxygen,” Biochem. J. (1962) 83, 368-377.
[cited by applicant]
Givens et al. “A Photoactivated Diazpryruvoyl Cross-Linking Agent for Bonding Tissue Containing Type-I Collagen.” Photochemistry and Photobiology. vol. 78, No. 1, 2003 (pp. 23-29).
[cited by applicant]
Glenn J.V., et al., “Advanced Glycation End Product (AGE) Accumulation on Bruch's Membrane: Links to Age-Related RPE Dysfunction;” Investigative Ophthalmology & Visual Science, vol. 50, No. 1, pp. 441-451; Jan. 2009.
[cited by applicant]
Gravitz L., “Laser Show in the Surgical Suite: Lasers and a century-old dye could supplant needles and thread;” technology review, MIT, Mar./Apr. 2009; retrieved from http://www.technologyreview.com/biomedicine/22088/?h…
[cited by applicant]
Hafezi F., et al., “Collagen Crosslinking with Ultraviolet-A and Hypoosmolar Riboflavin Solution in Thin Corneas,” J. Catract Refract. Surg., vol. 35, No. 1, pp. 621-624; Apr. 2009.
[cited by applicant]
Hammer Arthur et al., “Corneal Biomechanical Properties at different Corneal Cross-Linking (CXL) Irradiances,” IOVS, May 2014, vol. 55, No. 5, pp. 2881-2884.
[cited by applicant]
Hitzenberger et al., “Birefringence Properties Of The Human Cornea Measured With Polarization Sensitive Optical Coherence Tomography,” Bull. Soc. Beige Ophtalmol., 302, 153-168, 2006.
[cited by applicant]
Holmstrom, B. et al., “Riboflavin As An Electron Donor In Photochemical Reactions,” 1867-1871, Nov. 29, 1960.
[cited by applicant]
How to Use DEFINITY: “Frequently Asked Questions;” retrieved from http://www.definityimaging.com/how-faq.html, on Sep. 26, 2011 (3 pages) (date unknown, prior to Apr. 26, 2010).
[cited by applicant]
IMEX, “KXL System: Crosslinking Para Cirugia Corneal Bibliografia Cientifica,” Product Literature, Nov. 23, 2010.
[cited by applicant]
Kamaev et al., “Photochemical Kinetics Of Corneal Cross-Linking With Riboflavin,” Investigative Ophthalmology & Visual Science, Apr. 2012, vol. 53, No. 4, pp. 2360-2367 (8 pages).
[cited by applicant]
Kampik D. et al., “Influence of Corneal Collagen Crosslinking With Riboflavin and Ultraviolet-A Irradiation on Excimer Laser Surgery,” Investigative Ophthalmology & Visual Science, vol. 51, No. 8, pp. 3929-3934; Aug. 20…
[cited by applicant]
Kanellopoulos, A. J., “Collagen Cross-linking in Early Keratoconus With Riboflavin in a Femtosecond Laser-created Pocket: Initial Clinical Results”, Journal of Refractive Surgery, Aug. 18, 2009.
[cited by applicant]
Kanellopoulos, A. J., “Keratoconus management: UVA-induced collagen cross-linking followed by a limited topo-guided surface excimer ablation,” American Academy of Ophthalmology, 2006 (25 pages).
[cited by applicant]
Kanellopoulos, A. J., “ Ultraviolet A cornea collagen cross-linking, as a pre-treatment for surface excimer ablation in the management of keratoconus and post-LASIK ectasia,” American Academy of Ophthalmology, 2005 (28 …
[cited by applicant]
Kissner Anja, et al., “Pharmacological Modification of the Epithelial Permeability by Benzalkonium Chloride in UVA/Riboflavin Corneal Collagen Cross-Linking,” Current Eye Research 35(8), pp. 715-721; Mar. 2010 (7 pages).
[cited by applicant]
Koller, T. et al., “Complication and failure rates after corneal crosslinking,” Journal Cataract and refractive surgery, vol. 35, No. 8, Aug. 2009, pp. 1358-1362.
[cited by applicant]
Koller T., et al., “Therapeutische Quervernetzung der Hornhaut mittels UVA und Riboflavin: Therapeutic Cross-Linking of the Comea Using Riboflavin/UVA,” Klinische Monatsblatter fur Augenheilkunde, vol. 224, No. 9, pp. 7…
[cited by applicant]
Kornilovsky, I. M. “Novye neinvazivnye tekhnologii lazernoy modifikatsii optiko-refraksionnykk struktur glaza. Refraktsionnaya khirurgiya I oftalmologiya.” vol. 9, No. 3, 2006 (pp. 17-26).
[cited by applicant]
Krueger, Ronald R., “Rapid VS Standard Collagen CXL with Equivalent Energy Dosing,” presentation slides; available at http://www.slideshare.net/logen/krueger-herekar-rapid-cross-linking (date unknown, prior to Nov. 9, 2…
[cited by applicant]
Massey, V., “Activation Of Molecular Oxygen By Flavins And Flavoproteins,” The Journal of Biological Chemistry vol. 269, No. 36, Issue of Sep. 9, pp. 22459-22462, 1994 (4 pages).
[cited by applicant]
Marzouky, et al., Tensioactive-mediated Transepithelial Corneal Cross-linking—First Laboratory Report, European Ophthalmic Review, 2009, 3(2), pp. 67-70.
[cited by applicant]
Lee et al., “Spectrally filtered Raman / Thomson scattering using a rubidium Vapor filter”, AIAA J. 40, pp. 2504-2510 (2002).
[cited by applicant]
Li, C. et al. “Elastic Properties of Soft Tissue-Mimicking Phantoms Assessed by Combined Use of Laser Ultrasonics and Low Coherence Interferometry.” Optics Express. vol. 19, No. 11, May 9, 2011 (pp. 10153-10163).
[cited by applicant]
Li, C. et al. “Noncontact All-Optical Measurement of Corneal Elasticity.” Optics Letters. vol. 37, No. 10, May 15, 2012 (pp. 1625-1627).
[cited by applicant]
Li, P. et al. “In Vivo Microstructural and Microvascular Imaging of the Human Corneo-Scleral Limbus Using Optical Coherence Tomography.” Biomedical Optics Express. Vol. 2, No. 11, Oct. 18, 2011 (pp. 3109-3118).
[cited by applicant]
Meek, K.M. et al. “The Cornea and Scleera”, Collagen: Structure and Mechanics, Chapter 13, pp. 359-396, 2008 (38 pages).
[cited by applicant]
Korean Office Action for related Korean Application No. 10-2022-7022431; action dated Sep. 22, 2022; (6 pages).
[cited by applicant]
Wollensak G., et al., “Cross-linking of Scleral Collagen in the Rabbit Using Riboflavin and UVA,” Acta Ophtalmologica Scandinavica, vol. 83(4), pp. 477-482; Aug. 2005 (6 pages).
[cited by applicant]
Wollensak G., “Crosslinking Treatment of Progressive Keratoconus: New Hope,” Current Opinion in Ophthalmology, vol. 17(4), pp. 356-360; Aug. 2006 (5 pages).
[cited by applicant]
Wollensak G., et al., “Hydration Behavior of Porcine Cornea Crosslinked with Riboflavin and Ultraviolet,” A.J. Cataract Refract. Surg., vol. 33, Issue 3, pp. 516-521; Mar. 2007 (6 pages).
[cited by applicant]
Wollensak G., et al., “Riboflavin/Ultraviolet-A-induced Collagen Crosslinking for the Treatment of Keratoconus,” American Journal of Ophthalmology, vol. 135, No. 5, pp. 620-627; May 2003 (8 pages).
[cited by applicant]
Wollensak, G. et al. “Laboratory Science: Stress-Strain Measurements of Human and Porcine Corneas after Riboflavin-Ultraviolet-A-Induced Cross-Linking.” Journal of Cataract and Refractive Surgery. vol. 29, No. 9, Sep. 2…
[cited by applicant]
Wong, J. et al., “Post-Lasik ectasia: PRK following previous stablization and effective management with Riboflavin / ultraviolet A-induced collagen cross-linking,” Association for Research in Vision and Ophthalmology, 2…
[cited by applicant]
Yang H., et al., “3-D Histomorphometry of the Normal and Early Glaucomatous Monkey Optic Nerve Head: Lamina Cribrosa and Peripapillary Scleral Position and Thickness,” Investigative Ophthalmology & Visual Science, vol. …
[cited by applicant]
Yang N., Oster G. Dye-sensitized photopolymerization in the presence of reversible oxygen carriers. J. Phys. Chem. 74, 856-860 (1970) (5 pages).
[cited by applicant]
Zhang, Y. et al., “Effect of the Synthetic NC-1059 Peptide on Diffusion of Riboflavin Across an Intact Corneal Epithelium”, May 6, 2012, ARBO 2012 Annual Meeting Abstract, 140 Stroma and Keratocytes, program No. 1073, p…
[cited by applicant]
Zhang, Y. et al., “Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking”, Journal of Biological Chemistry, vol. 286, No. 15, dated Apr. 15, 2011 (pp. 1301…
[cited by applicant]
Zderic V., et al., “Drug Delivery Into the Eye With the Use of Ultrasound,” J. Ultrasound Med, vol. 23(10), pp. 1349-1359; Oct. 2004 (11 pages).
[cited by applicant]
Zderic V., et al., “Ultrasound-enhanced Transcorneal Drug Delivery,” Cornea vol. 23, No. 8, pp. 804-811; Nov. 2004 (8 pages).
[cited by applicant]
International Search Report PCT/US 2016/029559, mailed Aug. 18, 2016.
[cited by applicant]
Mi S., et al., “The adhesion of LASIK-like flaps in the cornea: effects of cross-linking, stromal fibroblasts and cytokine treatment,” presented at British Society for Matrix Biology annual Meeting, Cardiff, UK, Sep. 8-…
[cited by applicant]
Muller L., et al., “The Specific Architecture of the Anterior Stroma Accounts for Maintenance of Corneal Curvature,” Br. J. Opthalmol., vol. 85, pp. 437-443; Apr. 2001 (8 pages).
[cited by applicant]
Mulroy L., et al., “Photochemical Keratodesmos for repair of Lamellar corneal Incisions;” Investigative Ophthalmology & Visual Science, vol. 41, No. 11, pp. 3335-3340; Oct. 2000 (6 pages).
[cited by applicant]
Naoumidi T., et al., “Two-Year Follow-up of Conductive Keratoplasty for the Treatment of Hyperopic Astigmatism,” J. Cataract Refract. Surg., vol. 32(5), pp. 732-741; May 2006 (10 pages).
[cited by applicant]
Nesterov, A. P. “Transpalpebralny Tonometr Dlya Izmereniya Vnutriglaznogo Davleniya.” Feb. 2, 2006. [online] [Retrieved Dec. 17, 2012] Retrieved from the Internet: <URL: http://grpz.ru/images/publication_pdf/27.pdf>.
[cited by applicant]
O'Neil A.C., et al., “Microvascular Anastomosis Using a Photochemical Tissue Bonding Technique;” Lasers in Surgery and Medicine, vol. 39, Issue 9, pp. 716-722; Oct. 2007 (7 pages).
[cited by applicant]
O.V. Shilenskaya et al., “Vtorichnaya katarakta posle implantatsii myagkikh IOL,” [online] Aug. 21, 2008 [retrieved Mar. 4, 2013] Retrieved from the Internet: <URL:http://www.reper.ru/rus/index.php?catid=210> (4 pages).
[cited by applicant]
Paddock C., Medical News Today: “Metastatic Melanoma PV-10 Trial Results Encouraging Says Drug Company;” Jun. 9, 2009; retrieved from http://www.medicalnewstoday.com/articles/153024.php, on Sep. 26, 2011 (2 pages).
[cited by applicant]
Pallikaris I., et al., “Long-term Results of Conductive Keratoplasty for low to Moderate Hyperopia,” J. Cataract Refract. Surg., vol. 31(8), pp. 1520-1529; Aug. 2005 (10 pages).
[cited by applicant]
Pinelli, R. “Corneal Cross-Linking with Riboflavin: Entering a New Era in Ophthalmology.” Ophthalmology Times Europe. vol. 2, No. 7, Sep. 1, 2006, [online], [retrieved on May 20, 2013]. Retrieved from the Internet: <URL…
[cited by applicant]
Pinelli R., et al., “C3-Riboflavin Treatments: Where Did We Come From? Where Are We Now?” Cataract & Refractive Surgery Today Europe, Summer 2007, pp. 36-46; Jun. 2007 (10 pages).
[cited by applicant]
Pinelli, R., “Panel Discussion: Epithelium On/Off, Corneal abrasion for CCL contra”, presented at the 3º International Congress of Corneal Cross Linking on Dec. 7-8, 2007 in Zurich (36 pages).
[cited by applicant]
Roberto Pinelli et al, “Transepithelial Tensioactive Mediated CXL”, Cataract & Refractive Surgery Today Europe, p. 1, URL: http://bmctoday.net/crstodayeurope/pdfs/0409_09/pdf, XP055158069.
[cited by applicant]
Pinelli R., “Resultados de la Sociedad de Cirugia Refractiva Italiana (SICR) utilizando el C3-R” presented at the Istitutor Laser Microchirurgia Oculare in 2007 in Italy (23 pages).
[cited by applicant]
Pinelli et al., “Tensioactive-mediated Transepithelial Corneal Cross-linking—First Laboratory Report”, 2009, European Ophthalmic Review, 3(2), pp. 67-70.
[cited by applicant]
Pinelli R., “The Italian Refractive Surgery Society (SICR) results using C3-R” presented Jun. 22-23, 2007 in Italy (13 pages).
[cited by applicant]
Ponce C., et al., “Central and Peripheral Corneal Thickness Measured with Optical Coherence Tomography, Scheimpflug Imaging, and Ultrasound Pachymetry in Normal, Keratoconus-suspect and Post-laser in situ Keratomileusis…
[cited by applicant]
Proano C.E., et al., “Photochemical Keratodesmos for Bonding Corneal Incisions;” Investigative Ophthalmology & Visual Science, vol. 45, No. 7, pp. 2177-2181; Jul. 2004 (5 pages).
[cited by applicant]
Randall, J. et al., “The Measurementand Intrepretation of Brillouin Scattering in the Lens of the Eye,” The Royal Society, Abstract only, published 2013 [available online at http://rspb.royalsocietypublishing.org/conten…
[cited by applicant]
Reinstein, D. Z. et al. “Epithelial Thickness Profile as a Method to Evaluate the Effectiveness of Collagen Cross-Linking Treatment After Corneal Ectasis.” Journal of Refractive Surgery. vol. 27, No. 5, May 2011 (pp. 35…
[cited by applicant]
Reiss, S. et al., “Non-Invasive, ortsaufgeloeste Bestimmung von Gewebeeigenschaften derAugenlinse, Dichte undProteinkonzentration unter Anwendung der Brillouin-spektroskopie”, Klin Monatsbl Augenheilkd, vol. 228, No. 12…
[cited by applicant]
Reiss, S. et al., “Spatially resolved Brillouin Spectroscopy to determine the rheological properties of the eye lens”, Biomedical Optics Express, vol. 2, No. 8, p. 2144, Aug. 1, 2011 (1 page).
[cited by applicant]
Rocha K., et al., “Comparative Study of Riboflavin-UVA Cross-linking and “Flash-linking” Using Surface Wave Elastometry,” Journal of Refractive Surgery, vol. 24 Issue 7, pp. S748-S751; Sep. 2008 (4 pages).
[cited by applicant]
Rolandi et al., “Correlation of Collagen-Linked Fluorescence and Tendon Fiber Breaking Time.” Gerontology 1991;27:240-243 (4 pages).
[cited by applicant]
RxList: “Definity Drug Description;” The Internet Drug Index, revised Jun. 16, 2008, retrieved from http://www.rxlist.com/definity-drug.htm, on Sep. 26, 2011 (4 pages).
[cited by applicant]
Saleh et al. “Fundamentals of Photonics” 1991, pp. 74-77.
[cited by applicant]
Scarcelli, G. et al., “Brillouin Optical Microscopy for Corneal Biomechanics”, Investigative Ophthalmology & Visual Science, Jan. 2012, vol. 53, No. 1, pp. 185-190 (6 pages).
[cited by applicant]
Sheehan M., et al., “Illumination System for Corneal Collagen Crosslinking,” Optometry and Vision Science, vol. 88, No. 4, pp. 512-524; Apr. 2011 (13 pages).
[cited by applicant]
Shell, J., “Pharmacokinetics of Topically Applied Ophthalmic Drugs,” Survey of Ophthalmology, vol. 26, No. 4, pp. 207-218; Jan.-Feb. 1982 (12 pages).
[cited by applicant]