IP Library › Granted Patent US 12,293,513
Granted Patent B2
US 12,293,513 · App. 17/689,515 · Granted May 6, 2025

Systems and methods for generating patient-specific corneal cross-linking treatment patterns

Inventors: David Usher (Waltham, MA); Mikhail Smirnov (North Andover, MA); Behrouz Tavakol (Lexington, MA); Grace Lytle (Bedford, MA)
Assignee: AVEDRO, INC.
G06T7/0012A61B3/102A61P27/02G06T2207/10101G06T2207/30041
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Quick Facts
Patent No.
US 12,293,513
App. No.
17/689,515
Granted
May 6, 2025
Kind
B2
Abstract

An automated process receives input tomography data and generates an optimized (customized) treatment pattern for an individual patient without relying on the physician's analysis and judgment. For example, a method for treating a cornea includes receiving tomographic data for a cornea. The method includes identifying a keratoconic defect in the cornea based on the tomographic data. The method includes segmenting the keratoconic defect into treatment zones based on predefined geometric parameters, wherein the treatment zones indicate where a cross-linking agent is to be applied on the cornea and photoactivated to treat the keratoconic defect.

Claims (32)

1. A method for treating a cornea having a cone center, comprising:

receiving tomographic data for a cornea;

identifying a keratoconic defect in the cornea based on the tomographic data; and,

segmenting the keratoconic defect into treatment zones based on predefined geometric parameters, wherein the treatment zones indicate where a cross-linking agent is to be applied on the cornea and photoactivated to treat the keratoconic defect,

wherein segmenting the keratoconic defect into treatment zones includes creating elliptical boundaries for the treatment zones based on segmentation data, wherein the elliptical boundaries are created by evaluating a predefined number of meridians built from the cone center, and

wherein segmenting the keratoconic defect into treatment zones includes post-processing the boundaries for the treatment zones to at least one of: reduce eccentricity of treatment shapes for the treatment zones, scale up or down treatment shapes for the treatment zones, or modify treatment zone areas.

2. The method of claim 1 , further comprising:

applying the cross-linking agent to the cornea; and

delivering, with an illumination system, the illumination to photoactivate the cross-linking agent according to the treatment zones.

3. The method of claim 1 , further comprising specifying different respective doses of photoactivating light to be delivered to the treatment zones.

4. The method of claim 3 , wherein the respective doses of photoactivating light decrease outwardly from an innermost treatment zone.

5. The method of claim 1 , wherein the tomographic data provides topography maps showing at least one of elevation, curvature, or pachymetry.

6. The method of claim 1 , wherein identifying a keratoconic defect in the cornea based on the tomographic data includes generating Zernike coefficients describing deviation of anterior and/or posterior conical surfaces from a reference shape.

7. The method of claim 1 , wherein identifying a keratoconic defect in the cornea based on the tomographic data includes implementing Corneal Location and Magnitude Index (CLMI) analysis to produce estimates for location and severity of the keratoconic defect.

8. The method of claim 1 , wherein segmenting the keratoconic defect into treatment zones includes selecting elevation, curvature, or pachymetry data as a basis for segmentation.

9. The method of claim 1 , wherein segmenting the keratoconic defect into treatment zones includes creating boundaries for the treatment zones based on segmentation data.

10. The method of claim 1 , wherein segmenting the keratoconic defect into treatment zones includes processing boundaries for the treatment zones to at least one of: reduce eccentricity of treatment shapes for the treatment zones, scale up or down treatment shapes for the treatment zones, or modify treatment zone areas.

11. A system for treating a cornea having a cone center, comprising:

an illumination system configured to deliver illumination that activates a photosensitizing agent applied to a cornea; and

a controller configured to control the illumination system, the controller including one or more processors and one or more computer readable media, the one or more processors configured to execute instructions from the computer readable media to cause the controller to:

receive tomographic data for a cornea;

identify a keratoconic defect in the cornea based on the tomographic data;

segment the keratoconic defect into treatment zones based on predefined geometric parameters, wherein the treatment zones indicate where a cross-linking agent is to be applied on the cornea and photoactivated to treat the keratoconic defect, wherein the controller segments the keratoconic defect into treatment zones by creating elliptical boundaries for the treatment zones based on segmentation data, wherein the controller segments the keratoconic defect into treatment zones by post-processing the boundaries for the treatment zones to at least one of: reduce eccentricity of treatment shapes for the treatment zones, scale up or down treatment shapes for the treatment zones, or modify treatment zone areas; and

cause the illumination system to deliver the illumination to photoactivate the cross-linking agent according to the treatment zones,

wherein the elliptical boundaries are created by evaluating a predefined number of meridians built from the cone center.

12. The system of claim 11 , wherein the illumination is ultraviolet (UV) light.

13. The system of claim 11 , wherein the instructions from the computer readable media further cause the controller to specify different respective doses of photoactivating light to be delivered to the treatment zones.

14. The system of claim 13 , wherein the respective doses of photoactivating light decrease outwardly from an innermost treatment zone.

15. The system of claim 11 , wherein the tomographic data provides topography maps showing at least one of elevation, curvature, or pachymetry.

16. The system of claim 11 , wherein the controller identifies the keratoconic defect in the cornea by generating Zernike coefficients describing deviation of anterior and/or posterior corneal surfaces from a reference shape.

17. The system of claim 11 , wherein the controller identifies the keratoconic defect in the cornea by implementing Corneal Location and Magnitude Index (CLMI) analysis to produce estimates for location and severity of the keratoconic defect.

18. The system of claim 11 , wherein the controller segments the keratoconic defect into treatment zones by selecting elevation, curvature, or pachymetry data as a basis for segmentation.

Continuity (2)
Provisional Application 63158023 · Mar 8, 2021
Related Publication 20220284575A1 · Sep 8, 2022
References Cited (250)
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 10468142B1 · Abou Shousha · 2019 [cited by examiner]
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 applicant]
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 · Ornberg 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 20120215155A1 · Muller et al. · 2012 [cited by applicant]
US 20120203161A1 · Herekar · 2012 [cited by applicant]
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 20140113009A1 · Muller · 2014 [cited by examiner]
US 20140194957A1 · Rubinfield et al. · 2014 [cited by applicant]
US 20140249509A1 · Rubinfield et al. · 2014 [cited by applicant]
US 20160151202A1 · Scarcelli · 2016 [cited by examiner]
US 20160364543A1 · Dupps, Jr. · 2016 [cited by examiner]
US 20180014725A1 · Bagherinia · 2018 [cited by examiner]
US 20180193188A1 · Vukelic · 2018 [cited by examiner]
US 20180206719A1 · Adler · 2018 [cited by examiner]
US 20200085617A1 · Rajpal et al. · 2020 [cited by applicant]
US 20200187771A1 · Yun · 2020 [cited by examiner]
US 20210379397A1 · Epstein · 2021 [cited by examiner]
CN 110559087A · 2019 [cited by applicant]
DE 102008046834 · 2010 [cited by applicant]
EP 1561440 · 2005 [cited by applicant]
EP 1790383 · 2007 [cited by applicant]
IT MI2010A001236 · 2010 [cited by applicant]
KG 1376 · 2011 [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]
Ilker et al., “Investigation of the Efficacy of the Cone Location and Magnitude Index in the Diagnosis of Keratoconus”, Seminars in Ophthalmology, Early Online, 1-7, 2014 (Year: 2014). [cited by examiner]
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]
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]
Averianova, O. S., “Nastoyaschee I buduschee kross-linkage.” Mir Ofalmologii, 2010, [online] [retrieved on Feb. 13, 2014] Retrieved from the internet: http:/ /miroft.org.ualpublications/.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 (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., “Therapeutische Quervernetzung der Hornhaut mittels UVA und Riboflavin: Therapeutic Cross-Linking of the Cornea Using Riboflavin/UVA,” Klinische Monatsblatter fur Augenheilkunde, val. 224, No. 9, pp. … [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]
Kornilovsky, I. M. “Novye neinvazivnye tekhnologii lazernoy modifikatsii optiko-refraksionnykk struktur glaza. Refraktsionnaya khirurgiya I oftalmologiya.” vol. 9, No. 3, 2006 (pts. 17-26). [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 3° 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]
International Search Report and Written Opinion for related International Application No. PCT/US2022/019314; action dated Jun. 15, 2022; (33 page). [cited by applicant]