IP Library › Granted Patent US 12,453,652
Granted Patent B2
US 12,453,652 · App. 16/575,428 · Granted Oct 28, 2025

Systems and methods treating for corneal ectatic disorders

Inventors: Rajesh K. Rajpal (McLean, VA); Grace Elizabeth Lytle (Boston, MA)
Assignee: Avedro, Inc.
A61F9/0017A61N5/062A61F2009/00872A61F2009/00893A61N2005/0661A61N2005/0662A61N2005/0665
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Quick Facts
Patent No.
US 12,453,652
App. No.
16/575,428
Granted
Oct 28, 2025
Kind
B2
Abstract

To treat corneal ectatic disorders, systems and methods can precisely apply photoactivating light to specified areas of a cornea treated with a cross-linking agent. An example system includes a light source that provides a photoactivating light to photoactivate a cross-linking agent applied to an eye. The system includes optical element(s) that transmit the photoactivating light to the eye according to a pattern defined by a plurality of treatment zones. The treatment zones are delivered to different respective areas on the eye. The plurality of treatment zones includes at least a first treatment zone and a second treatment zone. The first treatment zone provides a first dose of the photoactivating light. The second treatment zone provides a second dose of the photoactivating light. The first dose is greater than the second dose. The first treatment zone is disposed within an inner boundary of the second treatment zone.

Claims (29)

1. A system for treating an eye, comprising:

a light source configured to provide a photoactivating light that photoactivates a cross-linking agent applied to an eye, the light source further configured to pulse the photoactivating light at a pulse rate between approximately 1,000 Hz to 100,000 Hz;

an oxygen delivery device configured to provide a concentration of oxygen from an oxygen source to a cornea of the eye;

one or more optical elements configured to receive the photoactivating light and transmit the photoactivating light to the eye according to a pattern defined by a plurality of treatment zones; and

a controller including one or more processors configured to execute program instructions stored on a one or more computer-readable media, the program instructions causing the one or more processors to determine a location of the plurality of treatment zones and to control at least one of the light source and the one or more optical elements to deliver the pattern of photoactivating light according to the location of the plurality of treatment zones,

wherein the treatment zones are delivered to different respective areas on the eye, the plurality of treatment zones include at least a first treatment zone and a second treatment zone, the at least first treatment zone and the second treatment zone collectively encompassing an entire surface of the cornea of the eye, the first treatment zone configured to provide a first dose of the photoactivating light to a center of an ectatic cone for a first treatment time, the second treatment zone configured to provide a second dose of the photoactivating light offset from the center of the ectatic cone for a second treatment time, the first dose being less than the second dose, and the first treatment zone being disposed within an inner boundary of the second treatment zone, and

wherein the one or more processors control at least one of the light source and the one or more optical elements to deliver the first dose of the photoactivating light as the first treatment zone to the ectatic cone and to deliver the second dose of the photoactivating light as the second treatment zone to areas of the cornea outside the ectatic cone.

2. The system of claim 1 , wherein the plurality of treatment zones includes a third treatment zone providing a third dose of the photoactivating light, the third dose being greater than the first dose, and the third treatment zone being disposed within an inner boundary of the first treatment zone.

3. The system of claim 1 , wherein the program instructions cause the one or more processors to determine the location of the plurality of treatment zones on the cornea based on information associated with at least one of topography, tomography, or pachymetry of a cornea.

4. The system of claim 1 , wherein the plurality of treatment zones includes a third treatment zone providing a third dose of the photoactivating light, the third dose being greater than the first dose, the third treatment zone being disposed within an inner boundary of the first treatment zone, and the one or more processors control at least one of the light source and the one or more optical elements to deliver the first dose of the photoactivating light as the first treatment zone and the third dose of the photoactivating light as the third treatment zone to the ectatic cone and to deliver the second dose of the photoactivating light as the second treatment zone to areas of the cornea outside the ectatic cone.

5. The system of claim 1 , wherein at least one of the light source and the one or more optical elements are configured to deliver the first dose of the photoactivating light and the second dose of the photoactivating light by:

simultaneously initiating delivery of the first treatment zone and the second treatment zone to the eye,

ceasing delivery of the second treatment zone after the second dose has been delivered, and

ceasing delivery of the first treatment zone after the first dose has been delivered, wherein the delivery of the second treatment zone ceases before the delivery of the first treatment zone ceases.

6. The system of claim 1 , wherein at least one of the light source and the one or more optical elements are configured to deliver the photoactivating light to one or more depths along an axis extending under a surface of the eye by adjusting an irradiance of the photoactivating light in each of the plurality of treatment zones, and the pattern of photoactivating light is defined along a plane transverse to the axis.

7. A method for treating an eye, comprising:

determining a location of a treatment area on the eye;

providing a concentration of oxygen from an oxygen source to a cornea of the eye; and

operating at least one of a light source for photoactivating light or one or more optical elements coupled to the light source to deliver a pattern of photoactivating light according to the location of the treatment area, the light source further configured to pulse the photoactivating light at a pulse rate between approximately 1,000 Hz to 100,000 Hz, the photoactivating light photoactivating a cross-linking agent applied to the eye, the pattern of photoactivating light defined by a plurality of treatment zones, the treatment zones being delivered to different respective areas on the eye, the plurality of treatment zones including at least a first treatment zone and a second treatment zone, the at least first treatment zone and the second treatment zone collectively encompassing an entire surface of a cornea of the eye, the first treatment zone configured to provide a first dose of the photoactivating light to a center of an ectatic cone for a first treatment time, the second treatment zone configured to provide a second dose of the photoactivating light offset from the center of the ectatic cone for a second treatment time, the first dose being less than the second dose, and the first treatment zone being disposed within an inner boundary of the second treatment zone.

8. The method of claim 7 , wherein the plurality of treatment zones includes a third treatment zone providing a third dose of the photoactivating light, the third dose being greater than the first dose, the third treatment zone being disposed within an inner boundary of the first treatment zone.

9. The method of claim 7 , wherein determining a location of a treatment area on the eye includes determining the location of the treatment area on the cornea based on information associated with at least one of topography, tomography, or pachymetry of the cornea.

10. The method of claim 7 , wherein at least one of the light source and the one or more optical elements is operated to deliver the first dose of the photoactivating light as the first treatment zone to the ectatic cone and to deliver the second dose of the photoactivating light as the second treatment zone to areas of the cornea outside the ectatic cone.

11. The method of claim 10 , wherein the plurality of treatment zones includes a third treatment zone providing a third dose of the photoactivating light, the third dose being greater than the first dose, the third treatment zone being disposed within an inner boundary of the first treatment zone, and at least one of the light source and the one or more optical elements is operated to deliver the first dose of the photoactivating light as the first treatment zone and the third dose of the photoactivating light as the third treatment zone to the ectatic cone and to deliver the second dose of the photoactivating light as the second treatment zone to areas of the cornea outside the ectatic cone.

12. The method of claim 7 , wherein at least one of the light source and the one or more optical elements is operated to deliver the first dose of the photoactivating light and the second dose of the photoactivating light by:

simultaneously initiating delivery of the first treatment zone and the second treatment zone to the eye,

ceasing delivery of the second treatment zone after the second dose has been delivered, and

ceasing delivery of the first treatment zone after the first dose has been delivered, wherein delivery of the second treatment zone ceases before delivery of the first treatment zone ceases.

13. The method of claim 7 , wherein at least one of the light source and the one or more optical elements are further operated to deliver the photoactivating light to one or more depths along an axis extending under a surface of the eye by adjusting an irradiance of the photoactivating light in each of the plurality of treatment zones, the pattern of photoactivating light being defined along a plane transverse to the axis.

14. The method of claim 7 , further comprising applying the cross-linking agent to the eye.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 3, 2021
From: LYTLE, GRACE ELIZABETH
To: AVEDRO, INC.
Reel/Frame 056430/0199 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2020
From: RAJPAL, RAJESH K.
To: AVEDRO, INC.
Reel/Frame 051450/0163 →
Continuity (2)
Provisional Application 62733617 · Sep 19, 2018
Related Publication 20200085617A1 · Mar 19, 2020
References Cited (249)
US 4034750A · Seiderman · 1977 [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 4891043A · Zelmer 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 5019074A · Muller · 1991 [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 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 5624437A · Freeman et al. · 1997 [cited by applicant]
US 5779696A · Berry et al. · 1998 [cited by applicant]
US 5786893A · Fink et al. · 1998 [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 6139876A · Kolta · 2000 [cited by applicant]
US 6161544A · DeVore et al. · 2000 [cited by applicant]
US 6188500B1 · Rudeen et al. · 2001 [cited by applicant]
US 6218360B1 · Cintron 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 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 6394999B1 · Williams et al. · 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 6617963B1 · Watters et al. · 2003 [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 7331350B2 · Kochevar et al. · 2008 [cited by applicant]
US 7402562B2 · DeWoolfson et al. · 2008 [cited by applicant]
US 7731362B2 · Gerlach · 2010 [cited by applicant]
US 7753943B2 · Strong · 2010 [cited by applicant]
US 7898656B2 · Yun et al. · 2011 [cited by applicant]
US 7935058B2 · Dupps 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 et al. · 2013 [cited by applicant]
US 8414911B2 · Mattson et al. · 2013 [cited by applicant]
US 8475437B2 · Mrochen et al. · 2013 [cited by applicant]
US 20010055095A1 · D'Souza et al. · 2001 [cited by applicant]
US 20020013577A1 · Frey 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 20030175259A1 · Karageozian et al. · 2003 [cited by applicant]
US 20030189689A1 · Rathjen · 2003 [cited by applicant]
US 20030231285A1 · Ferguson · 2003 [cited by applicant]
US 20040002694A1 · Pawlowski et al. · 2004 [cited by applicant]
US 20040093046A1 · Sand · 2004 [cited by applicant]
US 20040199079A1 · Chuck et al. · 2004 [cited by applicant]
US 20050038471A1 · Chan et al. · 2005 [cited by applicant]
US 20050096515A1 · Geng · 2005 [cited by applicant]
US 20050149006A1 · Peyman · 2005 [cited by applicant]
US 20050271590A1 · Schwartz et al. · 2005 [cited by applicant]
US 20060135957A1 · Panescu · 2006 [cited by applicant]
US 20060149343A1 · Altshuler et al. · 2006 [cited by applicant]
US 20060195076A1 · Blumenkranz et al. · 2006 [cited by applicant]
US 20060276777A1 · Coroneo · 2006 [cited by applicant]
US 20070024860A1 · Tobiason et al. · 2007 [cited by applicant]
US 20070048340A1 · Bran 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 20070265603A1 · Pinelli · 2007 [cited by examiner]
US 20080009901A1 · Redmond et al. · 2008 [cited by applicant]
US 20080015660A1 · Herekar · 2008 [cited by applicant]
US 20080063627A1 · Stucke et al. · 2008 [cited by applicant]
US 20080114283A1 · Mattson et al. · 2008 [cited by applicant]
US 20080139671A1 · Herekar · 2008 [cited by applicant]
US 20080208177A1 · Mrochen et al. · 2008 [cited by applicant]
US 20090116096A1 · Zalevsky et al. · 2009 [cited by applicant]
US 20090149842A1 · Muller et al. · 2009 [cited by applicant]
US 20090149923A1 · Herekar · 2009 [cited by applicant]
US 20090171305A1 · El Hage · 2009 [cited by applicant]
US 20090234335A1 · Yee · 2009 [cited by applicant]
US 20090275929A1 · Zickler · 2009 [cited by applicant]
US 20100028407A1 · Del Priore et al. · 2010 [cited by applicant]
US 20100057060A1 · Herekar · 2010 [cited by applicant]
US 20100069894A1 · Mrochen et al. · 2010 [cited by applicant]
US 20100082018A1 · Panthakey et al. · 2010 [cited by applicant]
US 20100094197A1 · Marshall et al. · 2010 [cited by applicant]
US 20100114109A1 · Peyman · 2010 [cited by applicant]
US 20100149487A1 · Ribak · 2010 [cited by applicant]
US 20100173019A1 · Paik et al. · 2010 [cited by applicant]
US 20100189817A1 · Krueger et al. · 2010 [cited by applicant]
US 20100204584A1 · Omberg et al. · 2010 [cited by applicant]
US 20100210996A1 · Peyman · 2010 [cited by applicant]
US 20100318017A1 · Lewis et al. · 2010 [cited by applicant]
US 20110077624A1 · Brady et al. · 2011 [cited by applicant]
US 20110098790A1 · Daxer · 2011 [cited by applicant]
US 20110118654A1 · Muller et al. · 2011 [cited by applicant]
US 20110152219A1 · Stagni et al. · 2011 [cited by applicant]
US 20110190742A1 · Anisimov · 2011 [cited by applicant]
US 20110202114A1 · Kessel et al. · 2011 [cited by applicant]
US 20110208300A1 · Eugene et al. · 2011 [cited by applicant]
US 20110237999A1 · Muller et al. · 2011 [cited by applicant]
US 20110264082A1 · Mrochen · 2011 [cited by applicant]
US 20110288466A1 · Muller et al. · 2011 [cited by applicant]
US 20110301524A1 · Bueler et al. · 2011 [cited by applicant]
US 20120083772A1 · Rubinfield et al. · 2012 [cited by applicant]
US 20120203161A1 · Herekar · 2012 [cited by applicant]
US 20120215155A1 · Muller · 2012 [cited by examiner]
US 20120289886A1 · Muller et al. · 2012 [cited by applicant]
US 20120302862A1 · Yun et al. · 2012 [cited by applicant]
US 20120303008A1 · Muller et al. · 2012 [cited by applicant]
US 20120310083A1 · Friedman et al. · 2012 [cited by applicant]
US 20120310223A1 · Knox et al. · 2012 [cited by applicant]
US 20130060187A1 · Friedman et al. · 2013 [cited by applicant]
US 20130085370A1 · Friedman et al. · 2013 [cited by applicant]
US 20130116757A1 · Russmann · 2013 [cited by applicant]
US 20140194957A1 · Rubinfield et al. · 2014 [cited by applicant]
US 20140249509A1 · Rubinfield et al. · 2014 [cited by applicant]
US 20160310319A1 · Friedman et al. · 2016 [cited by applicant]
US 20160338588A1 · Friedman · 2016 [cited by examiner]
US 20180235808A1 · Muller et al. · 2018 [cited by applicant]
CN 105682620A · 2016 [cited by applicant]
JP 2014519866A · 2014 [cited by applicant]
JP 2017532180A · 2017 [cited by applicant]
RU 2086215 · 1997 [cited by applicant]
RU 2420330 · 2011 [cited by applicant]
RU 2456971 · 2012 [cited by applicant]
WO 2000074648 · 2000 [cited by applicant]
WO 2001058495 · 2001 [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 2007120457 · 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 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 2010093908 · 2010 [cited by applicant]
WO 2011019940 · 2011 [cited by applicant]
WO 2011116306 · 2011 [cited by applicant]
WO 2012004726 · 2012 [cited by applicant]
WO 2012149570 · 2012 [cited by applicant]
WO 2012174453 · 2012 [cited by applicant]
WO 2013148713 · 2013 [cited by applicant]
WO 2013148895 · 2013 [cited by applicant]
WO 2013148896 · 2013 [cited by applicant]
WO 2013149075 · 2013 [cited by applicant]
WO 2014202736 · 2014 [cited by applicant]
WO 2016069628A1 · 2016 [cited by applicant]
Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized Corneal Cross-linking: One-Year Results. Am J Ophthalmol. Jun. 2016;166:14-21. doi: 10.1016/j.ajo.2016.02.029. Epub Mar. 2, 2016. PMID: 26944278.… [cited by examiner]
Shetty R, Pahuja N, Roshan T, Deshmukh R, Francis M, Ghosh A, Sinha Roy A. Customized Corneal Cross-linking Using Different UVA Beam Profiles. J Refract Surg. Oct. 1, 2017;33(10):676-682. doi: 10.3928/1081597X-20170621-… [cited by examiner]
Cassagne M, Pierné K, Galiacy SD, Asfaux-Marfaing MP, Fournié P, Malecaze F. Customized Topography-Guided Corneal Collagen Cross-linking for Keratoconus. J Refract Surg. May 1, 2017;33(5):290-297. doi: 10.3928/1081597X-… [cited by examiner]
Malecaze F. and Peirne K. “Concentrate on the Cone”. Cataract & Refractive Surgery Today Europe (CRSTR). Mar. 2017; 52-54 (Year: 2017). [cited by examiner]
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 (6 pages… [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 (8 pages). [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 Managmeent with Riboflavin / ultraviolet A-induced collagen cross-linking,” Association for Research in Vision and Ophthalmology, 2006 (1 page). [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 (11 pages). [cited by applicant]
Chace, K.V. 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 (1 page). [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 (8 pages). [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 (10 pa… [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]
Coskenseven E. et al., “Comparative Study of Corneal Collagen Cross-linking With Riboflaving and UVA Irradiation in Patients With Keratoconus,” Journal of Refractive Surgery, vol. 25, issue 4, pp. 371-376; Apr. 2009 (6 … [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 (10 pages). [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 (6 pages). [cited by applicant]
Gibson, Q. et al., “The Oxidation Of Reduced Flavin Mononucleotide By Molecular Oxygen,” Biochem. J. (1962) 83, 368-377 (10 pages). [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 (11… [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 (4 pages). [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 (5 pages). [cited by applicant]
IMEX, “KXL System: Crosslinking Para Cirugia Corneal Bibliografia Cientifica,” Product Literature, Nov. 23, 2010 (24 pages). [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 Opthalmology & Visual Science, vol. 51, No. 8, pp. 3929-3934; Aug. 201… [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: UV A-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 p… [cited by applicant]
Kissner Anja, et al., “Pharmacological Modification of the Epithelial Permeability by Benzalkonium Chloride in UVNRiboflavin 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]
Krueger Ronald R., “Rapid VS Standard Collagen CXL with Equivalent Energy Dosing,” presentation slides, (26 pages); available at http://www.slideshare.net/logen/krueger-kerekar-rapid-cross-linking (date unknown, prior t… [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]
Marzouky, et al., Tensioactive-mediated Transepithelial Corneal Cross-linking-First Laboratory Report, European Ophthalmic Review, 2009, 3(2), pp. 67-70. [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]
Meek, K.M. et al. “The Cornea and Sclera”, Collagen: Structure and Mechanics, Chapter 13, pp. 359-396, 2008 (38 pages). [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]
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]
Pinelli R., et al., “C3-Riboflaving 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. “Corneal Cross-Linking with Riboflavin: Entering a New Era in Ophthalmology.” Ophthalmology Times Europe. vol. 2, No. 7, Sep. 1, 2006 (3 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]
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 Measurement and Intrepretation of Brillouin Scattering in the Lens of the Eye,” The Royal Society, Abstract only, published 2013 [available online at http:/ /rspb.royalsocietypublishing.org/cont… [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]
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]
Spoerl E. et al., “Safety of UVA-Riboflavin Cross-Linking of the Cornea,” Cornea, vol. 26, No. 4, pp. 385-389; May 2007 (5 pages). [cited by applicant]
Spoerl E., et al., “Artificial Stiffening of the Cornea by Induction of Intrastromal Cross-links,” Oer Ophthalmologe, vol. 94, No. 12, pp. 902-906; Dec. 1997 (5 pages). [cited by applicant]
Spoerl E., et al., “Induction of Cross-links in Corneal Tissue,” Experimental Eye Research, vol. 66, Issue 1, pp. 97-103; Jan. 1998 (7 pages). [cited by applicant]
Spoerl E., et al., “Techniques for Stiffening the Cornea,” Journal of Refractive Surgery, vol. 15, Issue 6, pp. 711-713; Nov.-Dec. 1999 (4 pages). [cited by applicant]
Tessier FJ, et al., “Rigidification of Corneas Treated in vitro with Glyceraldehyde: Characterization of Two Novel Crosslinks and Two Chromophores,” Investigative Opthalmology & Visual Science, vol. 43, E-Abstract; 2002… [cited by applicant]
Thorton, I. et al., “Biomechancial Effects of Intraocular Pressure Elevation on Optic Berve/Lamina Cribrosa before and after Peripapillary Scleral Collagen Cross-Linking.” Invest. Ophthalmol. Vis. Sci., Mar. 2009, 50(3)… [cited by applicant]
UV-X: Radiation System for Treatment of Keratokonus, PESCHKE Meditrade GmbH; retrieved from http://www.peschkemed.ch/ on Sep. 27, 2011 (1 page) (date unknown, prior to Sep. 16, 2008). [cited by applicant]
Vasan S., et al., “An agent cleaving glucose-derived protein crosslinks in vitro and in vivo;” Letters to Nature, vol. 382, pp. 275-278; Jul. 18, 1996 (4 pages). [cited by applicant]
Verzijl et al. Crosslinking by Advanced Glycation End Products Increases the Stiffness of the Collagen Network in Human Articular Cartilage. Arthritis & Rheumatism vol. 46, No. 1, Jan. 2002, pp. 114-123 (10 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., “Biomechanical and Histological Changes After Corneal Crosslinking With and Without Epithelial Debridement,” J. Cataract Refract. Surg., vol. 35, Issue 3, pp. 540-546; Mar. 2009 (7 pages). [cited by applicant]
Wollensak G., et al., “Collagen Crosslinking of Human and Porcine Sclera,” J. Cataract Refract. Surg., vol. 30, Issue 3, pp. 689-695; Mar. 2004 (7 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., 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 I 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). [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. 5, 2011 (pp. 13011… [cited by applicant]
International Patent Application No. PCT/US2019/051876, International Search Report, Dec. 19, 2019 (2 pages). [cited by applicant]
International Patent Application No. PCT/US2019/051876, Written Opinion of the ISA, Dec. 19, 2019 (3 pages). [cited by applicant]
Extended European Search Report for related European Application No. 19861900.9; action dated May 11, 2022; (7 pages). [cited by applicant]
Office Action for related Japanese Application No. 2021-515067; action dated Nov. 1, 2022; (9 pages). [cited by applicant]
Chinese Office Action from corresponding Chinese Patent Application No. 201980068841.7, mailed Feb. 13, 2023. [cited by applicant]
Seiler et al, “Customer Corneal Cross linking: One Year Results ”, American Journal of Ophthalmology, p. 14 20, Jun. 2016. [cited by applicant]
Notification of Reasons for Rejection for Japanese Patent Application No. 2021-515067 dated Mar. 23, 2023. [cited by applicant]
Notification of Reasons for Rejection and English Translation from corresponding Japanese Patent Application No. 2021-515067, dated Dec. 5, 2023. 5 pages. [cited by applicant]
Australian Examination Report No. 1 for corresponding Australian Patent Application No. 2019345061, mailed May 6, 2024. 3 pages. [cited by applicant]