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FIFTH EDITION
CORNEA
Mark J. Mannis, MD, FACS
Natalie Fosse Endowed Chair in
Vision Science Research
Professor and Chair
Department of Ophthalmology & Vision Science
University of California Davis Eye Center
Sacramento, CA, United States
Edward J. Holland, MD
Director of Cornea
Cincinnati Eye Institute
Professor of Ophthalmology
University of Cincinnati
Cincinnati, OH, United States
For additional online content visit ExpertConsult.com
London New York Oxford Philadelphia St Louis Sydney 2022

© 2022, Elsevier Inc. All rights reserved.
First edition 1997

Second edition 2005
Third edition 2011
Fourth edition 2017
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions
This book and the individual contributions contained in it are protected under copyright by the Publisher (other
than as may be noted herein).
Csaba L. Mártonyi retains copyright of his original figures in Chapter 7.

Michael E. Snyder retains copyright of his original figures and video clips in Chapter 150.
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid advances in
the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for
any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
ISBN:
Print: 978-0-323-67240-5
E-book: 978-0-323-67472-0
Content Strategist: Kayla Wolfe

Content Development Specialist: Sharon Nash
Project Manager: Joanna Souch
Design: Ryan Cook
Illustration Manager: Narayanan Ramakrishnan
Marketing Manager: Claire McKenzie
Printed in Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1

P R E FA C E
The contemporary specialist in cornea and external disease has at their dis-
posal a broad range of medical and surgical treatments for the management
of diseases of the cornea and external eye. This burgeoning repertoire of
therapeutic options is clearly based on our enhanced understanding of the
biology and physiology of the cornea and the ocular surface. As a result,
we are blessed with many new therapeutic options but, at the same time,
are also challenged with a flood of new medical and technical knowledge
to master.
In this volume, we have provided a comprehensive and updated com-
pilation of the most current knowledge in our subspecialty. Despite the
easy availability of information on the internet, a single source of the most
current knowledge in the field is an invaluable tool for general ophthalmol-
ogists and corneal specialists at all levels.
We sincerely hope that this edition will serve as a comprehensive resource
that blends the newest science with the best clinical practice.
Mark J. Mannis
Edward J. Holland
xiii
ACKNOWLED GMENTS
First and foremost, we wish to thank the many contributors to this book.
This edition is a compilation of the collective knowledge of the finest minds
in our specialty. Producing a book chapter is a laborious task, requiring
rigorous attention to detail, the ensuring of accuracy and authenticity,
and painstaking documentation of source materials. Without the hard
work of the contributors, there would be no book. They have our lasting
appreciation.
The process of producing a book of this scope is complicated. We thank
the fine editorial staff at Elsevier—Sharon Nash, Kayla Wolfe, and Joanna
Souch, who painstakingly shepherded the Fifth Edition from its concep-
tion to publication.
Of course, we thank our families who accompanied us through this
task with unfailing support and grace.
And finally, we want to thank you, our reader, for acquiring what we hope
will be a useful tool in your continuing education and in your practice.
Mark J. Mannis
Edward J. Holland
xiv
To Christopher J. Murphy, DVM, PhD and Karla Zadnik OD, PhD, who have
exceeded their mentors and have brought excellence to vision science.
To Daniel J. Douglas, MD and Richard L. Lindstrom, MD who have both guided

and motivated me at critical times in my academic career.
ACKNOWLED GMENTS TO THE
FOUNDING EDITORS
Jay H. Krachmer, MD
First published in 1997, Cornea established itself as the market-leading

comprehensive title covering fundamentals, diagnosis, and medical and
surgical treatment of cornea and related external disorders. Continually
used by practitioners and trainees throughout the world, what started out
as a three-volume book-set has now evolved into a complete multimedia
resource delivering content in print, online, ebook, and video formats. We
acknowledge the founding editorial team who brought this project to frui-
tion through their tireless efforts, expertise, and devotion that started over
20 years ago.
Elsevier
xvi
LIST OF CONTRIBUTORS
The editor(s) would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new
edition would not have been possible.
Richard L. Abbott, MD Lênio Souza Alvarenga, MD, Mohammad Anwar, FRCS, FRCOphth
Thomas W. Boyden and Kathleen Rydar MSc, PhD Former Chief of Cornea Unit
Professor Emeritus Country Medical Director-Brazil Eye Department
UCSF Department of Ophthalmology Roche Pharmaceuticals Magrabi Eye Center
Research Associate São Paulo, Brazil Dubai, United Arab Emirates
Francis I. Proctor Foundation
San Francisco, CA, United States Wallace L.M. Alward, MD Sruthi Arepalli, MD
Professor Fellow
Nisha R. Acharya, MD, MS Department of Ophthalmology & Visual Uveitis
Professor Sciences Casey Eye Institute
Department of Ophthalmology and University of Iowa Portland, OR, United States
Department of Epidemiology Iowa City, IA, United States
University of California, San Francisco Penny A. Asbell, MD, FACS, MBA,
San Francisco, CA, United States Renato Ambrósio Jr., MD, PhD FARVO
Director, Uveitis Service Adjunct Professor Barrett G. Haik Endowed Chair
F.I. Proctor Foundation Ophthalmology Department of Ophthalmology
University of California, San Francisco Federal University of the State of Rio de Director, Hamilton Eye Institute
San Francisco, CA, United States Janeiro, Professor of Ophthalmology
Rio de Janeiro, Brazil University of Tennessee Health Science
Shruti Aggarwal, MD Affiliated Professor Center
Department of Ophthalmology Ophthalmology Memphis, TN, United States
University of Miami Miller School of Medicine Federal University of São Paulo,
Miami, FL, United States São Paulo, Brazil Irit Bahar, MD, MHA
Katzen Eye Institute Founder and Research Director Professor
Baltimore, MD, United States Rio de Janeiro Corneal Tomography and Ophthalmology
Biomechanics Study Group Rabin Medical Center
Anthony J. Aldave, MD Rio de Janeiro, Brazil Petach Tiqva, Israel
Professor of Ophthalmology Clinical Director
The Stein Eye Institute Cornea and Refractive Surgery Annie K. Baik, MD
University of California, Los Angeles Instituto de Olhos Renato Ambrosio Associate Clinical Professor
Los Angeles, CA, United States Rio de Janeiro, Brazil Ophthalmology and Vision Science
University of California, Davis
Eduardo C. Alfonso, MD Sacramento, CA, United States
Chairman Andrea Y. Ang, MBBS, MPH, FRANZCO
Department of Ophthalmology Consultant Shaunak K. Bakshi, BS
University of Miami Miller School of Ophthalmology Medical Student, Research Fellow
Medicine Lions Eye Institute Ophthalmology
Miami, FL, United States Perth, WA, Australia Harvard Medical School, Massachusetts
Director Consultant Eye and Ear
Bascom Palmer Eye Institute Ophthalmology Boston, MA, United States
University of Miami Royal Perth Hospital
Miami, FL, United States Perth, WA, Australia Michael W. Belin, MD
Kathleen and Stanley Glaser Distinguished Professor of Ophthalmology & Vision
Chair in Ophthalmology Marcus Ang, MBBS, MCI, MMED, Science
University of Miami FAMS, FRCSEd, PhD Ophthalmology
Miami, FL, United States Consultant University of Arizona
Cornea and External Eye Diseases Tucson, AZ, United States
Zaina Al-Mohtaseb, MD Singapore National Eye Centre
Assistant Professor and Associate Residency Singapore
Program Director Associate Professor
Ophthalmology Ophthalmology
Baylor College of Medicine DUKE-NUS
Houston, TX, United States Singapore
xvii
xviii LIST OF CONTRIBUTORS
Beth A. Benetz, MA Cat N. Burkat, MD, FACS Clara C. Chan, MD, FRCSC, FACS
Professor Professor Assistant Professor
Ophthalmology and Visual Sciences Oculoplastics, Orbital, & Cosmetic Facial Ophthalmology and Vision Sciences
Case Western Reserve University Surgery University of Toronto
Cleveland, OH, United States Department of Ophthalmology and Visual Toronto, ON, Canada
Scientific Director Sciences
Cornea Image Analysis Reading Center University of Wisconsin-Madison Bernard H. Chang, MD
CWRU Department of Ophthalmology and Madison, WI, United States Partner Physician
Visual Sciences Ophthalmology
University Hospitals Eye Institute Massimo Busin, MD Cornea and Cataract Consultants of
Cleveland, OH, United States Department of Morphology, Surgery and Nashville
Experimental Medicine Nashville, TN, United States
Joseph M. Biber, MD University of Ferrara
Cornea, Cataract, and Refractive Specialist Ferrara, Italy Jenny Chen, MD
Partner Ospedali Privati Forlì Assistant Clinical Professor
Horizon Eye Care Department of Ophthalmology Ophthalmology & Vision Sciences
Charlotte, NC, United States Forlì, Italy University of California, Davis
Sacramento, CA, United States
J. Douglas Cameron, MD, MBA
Erin A. Boese, MD
Department of Ophthalmology and Visual
Clinical Assistant Professor Michael C. Chen, MD
Neurosciences,
Department of Ophthalmology & Visual Assistant Professor of Ophthalmology
University of Minnesota
Sciences Penn State Eye Center
Minneapolis, MN, United States
University of Iowa Penn State Milton S. Hershey Medical
Iowa City, IA, United States Mauro Campos, MD, PhD Center
Professor of Ophthalmology Hershey, PA, United States
Kelley J. Bohm, MD Ophthalmology
Ophthalmology Resident Federal University of São Paulo Kenneth C. Chern, MD, MBA
Ophthalmology and Visual Sciences São Paulo, Brazil Assistant Clinical Professor
University of Illinois at Chicago Clinical Director Ophthalmology
Chicago, IL, United States Hospital de Olhos Paulista University of California, San Francisco
São Paulo, Brazil San Francisco, CA, United States
Clemence Bonnet, MD, FEBO Clinical Instructor
Cornea Fellow Danmin Cao, MD Francis I. Proctor Foundation
The Stein Eye Institute Department of Ophthalmology San Francisco, CA, United States
University of California, Los Angeles Baylor College of Medicine
Los Angeles, CA, United States Houston, Texas TX, United States Albert Y. Cheung, MD
Aier Eye Hospital of Wuhan University Assistant Professor
Charles S. Bouchard, MD, MA Wuhan, China Department of Ophthalmology
Professor and Chairman Eastern Virginia Medical School
Ophthalmology Emmett F. Carpel, MD Norfolk, VA, United States
Loyola University Medical Center Adjunct Professor Cornea/External Disease
Maywood, IL, United States Ophthalmology Virginia Eye Consultants
University of Minnesota Norfolk, VA, United States
James D. Brandt, MD Minneapolis, MN, United States
Professor & Director, Glaucoma Service Chief James Chodosh, MD, MPH
Department of Ophthalmology & Vision Division of Ophthalmology Edith Ives Professor of Ophthalmology
Science Minneapolis VA Health Care System Massachusetts Eye and Ear—Harvard
University of California, Davis Minneapolis, MN, United States Medical School
Sacramento, CA, United States Boston, MA, United States
H. Dwight Cavanagh, MD, PhD
Ashley R. Brissette, MD, MSc Clinical Professor and Vice Chair Emeritus Michael B. Choi, MD
Assistant Professor of Ophthalmology Ophthalmology Fellow
Weill Cornell Medicine and New York UT Southwestern Medical Center Ophthalmology
Presbyterian Hospital Dallas, TX, United States Ophthalmic Consultants of Long Island
New York, NY, United States Rockville, NY, United States
Jean S.M. Chai, MBBS, MMed (Ophth),
Cassandra C. Brooks, MD Mazen Y. Choulakian, MD, FRCSC
FAMS, FRCSEd
Resident Physician Assistant Professor of Ophthalmology
Senior Consultant
Ophthalmology University of Sherbrooke Faculty of
Corneal and External Eye Disease
Duke University Eye Center Medicine
Singapore National Eye Centre
Durham, NC, United States Sherbrooke, QC, Canada
Singapore
Adjunct Assistant Professor
Duke-NUS Medical School
Singapore
LIST OF CONTRIBUTORS xix
Gary Chung, MD Mahshad Darvish-Zargar, MDCM, MBA Steven P. Dunn, MD

Cornea Specialist Assistant Professor Section Head
Private Practice Department of Ophthalmology Cornea and External Diseases
Evergreen Eye Center McGill University Department of Ophthalmology
Federal Way, WA, United States Montreal, QC, Canada Oakland University William Beaumont
School of Medicine
Joseph B. Ciolino, MD Richard S. Davidson, MD Royal Oak, MI, United States
Associate Professor of Ophthalmology Professor and Vice Chair for Quality and
Ophthalmology Clinical Affairs Ralph C. Eagle Jr., MD
Massachusetts Eye and Ear Infirmary Department of Ophthalmology Chief of the Pathology Service
Boston, MA, United States University of Colorado School of Medicine Wills Eye Hospital
Aurora, CO, United States Professor of Ophthalmology and Pathology
Jessica B. Ciralsky, MD Sidney Kimmel Medical College
Associate Clinical Professor Denise de Freitas, MD Thomas Jefferson University
Ophthalmology Associate Professor Philadelphia, PA, United States
Weill Cornell Medical College Department of Ophthalmology and Visual
Allen O. Eghrari, MD, MPH
New York, NY, United States Sciences
Assistant Professor
Paulista School of Medicine
Department of Ophthalmology
Kathryn A. Colby, MD, PhD Federal University of São Paulo
Johns Hopkins University School of Medicine
Louis Block Professor and Chairman São Paulo, Brazil
Baltimore, MD, United States
Department of Ophthalmology and Visual
Science Jose de la Cruz, MD Maryam Eslami, MD
University of Chicago Assistant Professor of Ophthalmology Department of Ophthalmology and Visual
Chicago, IL, United States Department of Ophthalmology and Visual Sciences
Sciences University of British Columbia
Minas T. Coroneo, BSc (Med), MBBS, University of Illinois at Chicago Vancouver, BC, Canada
MSc, MD, MS Illinois Eye and Ear Infirmary
Professor and Chairman Chicago, IL, United States Medi Eslani, MD
Department of Ophthalmology Shiley Eye Institute
UNSW at Prince of Wales Hospital Jennifer DeMatteo, MCM, CIC Viterbi Family Department of Ophthalmology
Sydney, NSW, Australia Director of Regulations and Standards University of California San Diego
Eye Bank Association of America La Jolla, CA, United States
Maria Soledad Cortina, MD Washington, DC, United States
Associate Professor of Ophthalmology Mark D. Ewald, BS, MD
Department of Ophthalmology and Visual Ali R. Djalilian, MD Partner
Sciences Professor of Ophthalmology Ophthalmology
University of Illinois Eye & Ear Infirmary Ophthalmology and Visual Sciences Cornea and Cataract Consultants of Nashville
Chicago, IL, United States University of Illinois at Chicago Nashville, TN, United States
Chicago, IL, United States
Dennis E. Cortés, MD Mina A. Farahani, MD, MS, MS
Assistant Professor of Ophthalmology Eric D. Donnenfeld, MD Cornea, Cataract, Refractive, Ocular Surface
Department of Ophthalmology Clinical Professor Ophthalmic Consultants of Boston
Pontificia Universidad Católica de Chile Ophthalmology Boston, MA, United States
Santiago, Chile New York University
New York, NY, United States Neil Farbman, MD, JD
Alexandra Z. Crawford, BA, MBChB, MD Trustee Cornea, Cataract, and Refractive Surgeon
Cornea and Anterior Segment Fellow Dartmouth Medical School Kremer Eye Center
Department of Ophthalmology Hanover, NH, United States King of Prussia, PA, United States
University of Auckland
Auckland, New Zealand Donna C. Drury, BS, MBA Marjan Farid, MD
Director Professor of Ophthalmology
Melissa B. Daluvoy, MD Transplant Services Center Gavin Herbert Eye Institute
Assistant Professor of Ophthalmology UT Southwestern Medical Center University of California, Irvine
Duke University Dallas, TX, United States Irvine, CA, United States
Durham, NC, United States
Grace E. Dunbar, MD Asim V. Farooq, MD
Paulo Elias C. Dantas, MD, PhD Clinical Lecturer Assistant Professor
Corneal and External Disease Cornea, Cataract and Refractive Surgery Department of Ophthalmology and Visual
Hospital Oftalmológico de Sorocaba, Department of Ophthalmology and Visual Science
Sorocaba Sciences University of Chicago
São Paulo, Brazil University of Michigan Kellogg Eye Center Chicago, IL, United States
Oftalmologistas Associados, São Paulo Ann Arbor, MI, United States
São Paulo, Brazil
xx LIST OF CONTRIBUTORS
Robert S. Feder, MD, MBA Prashant Garg, MD Steven A. Greenstein, MD

Professor of Ophthalmology Director, Kallam Anji Reddy Campus Cornea and Laser Eye Institute
Feinberg School of Medicine L V Prasad Eye Institute Hersh Vision Group
Northwestern University Hyderabad, Telangana, India Teaneck, NJ, United States
Chicago, IL, United States Assistant Clinical Professor
Chief, Cornea and External Disease Sumit Garg, MD Rutgers University—New Jersey Medical
Feinberg School of Medicine Vice Chair and Medical Director School
Northwestern University Ophthalmology Newark, NJ, United States
Chicago, IL, United States Gavin Herbert Eye Institute
Irvine, CA, United States Darren G. Gregory, MD
Sergio Felberg, MD, PhD Associate Professor
Professor of Ophthalmology David B. Glasser, MD Ophthalmology
Department of Ophthalmology, Corneal and Assistant Professor University of Colorado School of Medicine
External Disease Service Ophthalmology Denver, CO, United States
Santa Casa of São Paulo Johns Hopkins University School of
São Paulo, Brazil Medicine Mark A. Greiner, MD
State of São Paulo Public Server Hospital Baltimore, MD, United States Robert and Joell Brightfelt Professor of
São Paulo, Brazil Cornea Research
Julie Goldman, MD Cornea and External Diseases
Matthew T. Feng, MD Visiting Clinical Assistant Professor Department of Ophthalmology and Visual
Private Practice Department of Ophthalmology and Visual Sciences
Price Vision Group Sciences Carver College of Medicine
Indianapolis, IN, United States University of Illinois at Chicago University of Iowa
Co-Medical Director Chicago, IL, United States Iowa City, IA, United States
Vision First Associate Ophthalmologist
Indianapolis, IN, United States Chicago Glaucoma Consultants Oscar Gris, MD, PhD
Board of Directors Glenview, IL, United States Anterior Segment Diseases Specialist
Cornea Research Foundation of America Cornea and Refractive Surgery Unit
Indianapolis, IN, United States Debra A. Goldstein, MD, FRCSC Instituto de Microcirugía Ocular
Magerstadt Professor of Ophthalmology Barcelona, Spain
Luigi Fontana, MD, PhD Director, Uveitis Service
Director Northwestern University Feinberg School of Erich B. Groos Jr., MD
Ophthalmic Unit Medicine Partner
Azienda Ospedaliera Santa Maria Chicago, IL, United States Private Practice
Nuova—IRCCS Cornea and Cataract Consultants of Nashville
Reggio Emilia, Italy Jeffrey R. Golen, MD Nashville, TN, United States
Ophthalmology Medical Director
Gary N. Foulks, MD Magruder Eye Institute Eye Surgery Center of Nashville
Emeritus Professor Orlando, FL, United States Nashville, TN, United States
Ophthalmology and Vision Sciences Medical Director
University of Louisville School of Medicine John A. Gonzales, MD Tennessee Eye Bank
Louisville, KY, United States Assistant Professor DCI Donor Services
Department of Ophthalmology Nashville, TN, United States
Nicole R. Fram, MD F.I. Proctor Foundation
Clinical Instructor of Ophthalmology University of California, San Francisco William D. Gruzensky, MD
Ophthalmology San Francisco, CA, United States Cornea and Refractive Surgeon
Stein Eye Institute Surgery
University of California, Los Angeles John D. Gottsch, MD Pacific Cataract and Laser Institute
Los Angeles, CA, United States Professor Anchorage, AK, United States
Managing Partner Department of Ophthalmology
Advanced Vision Care Johns Hopkins Wilmer Eye Institute Jose L. Güell, MD, PhD
Los Angeles, CA, United States Baltimore, MD, United States Director of Cornea and Refractive Surgery Unit
Instituto Microcirugia Ocular of Barcelona
Anat Galor, MD, MSPH Enrique O. Graue-Hernández, MD, MSc Barcelona, Spain
Staff Physician Head, Cornea & Refractive Surgery Professor of the IMO Master Program
Miami VAMC Universidad Nacional Autónoma de México Autonoma University of Barcelona
VA Instituto de Oftalmología Barcelona, Spain
Miami, FL, United States Fundación Conde de Valenciana Lead Professor and Coordinator
Associate Professor of Ophthalmology Mexico City, Mexico Anterior Segment Diseases
Bascom Palmer Eye Institute European School for Advanced Studies
University of Miami in Ophthalmology (ESASO)
Miami, FL, United States Lugano, Switzerland
LIST OF CONTRIBUTORS xxi
Frederico P. Guerra, MD Justin Hellman, MD Christopher T. Hood, MD

Chief of the Cornea Department Oculoplastic Surgery Clinical Associate Professor
Ipanema Federal Hospital Rocky Mountain Eye Center Department of Ophthalmology and Visual
Rio de Janeiro, Brazil Colorado Springs, CO, United States Sciences
W.K. Kellogg Eye Center
Arushi Gupta, DOMS, DNB, FICO (UK) Maria A. Henriquez, MD, MSc, PhD University of Michigan Medical School
Senior Resident Chair of Research Department Ann Arbor, MI, United States
Department of Ophthalmology Oftalmosalud Instituto de Ojos
AIIMS Jodhpur Professor in Ophthalmology Eliza N. Hoskins, MD
Jodhpur, Rajasthan, India Post GCRST Harvard Medical School Department of Ophthalmology
Lima, Peru The Permanente Medical Group
Nidhi Gupta, MBBS, DNB Walnut Creek, CA, United States
Consultant Cornea and Ocular Surface Peter S. Hersh, MD
Cornea Director Joshua H. Hou, MD
Dr. Shroff ’s Charity Eye Hospital Cornea and Laser Eye Institute Assistant Professor of Ophthalmology
Delhi, India Hersh Vision Group Ophthalmology & Visual Neurosciences
Teaneck, NJ, United States University of Minnesota
Preeya K. Gupta, MD Clinical Professor Minneapolis, MN, United States
Associate Professor of Ophthalmology Ophthalmology
Cornea & Refractive Surgery Rutgers Medical School Andrew J.W. Huang, MD, MPH
Department of Ophthalmology Newark, NJ, United States Professor of Ophthalmology
Duke University Eye Center Department of Ophthalmology and Visual
Durham, NC, United States Ana Luisa Hofling-Lima, MD, PhD Sciences
Head Professor Washington University
M. Bowes Hamill, MD Department of Ophthalmology St. Louis, MO, United States
Professor Escola Paulista de Medicina
Department of Ophthalmology UNIFESP David Huang, MD, PhD
Baylor College of Medicine, Cullen Eye São Paulo, Brazil Peterson Professor of Ophthalmology
Institute and Professor of Biomedical Engineering
Houston, TX, United States Edward J. Holland, MD Casey Eye Institute
Director of Cornea Oregon Health & Science University
D. Rex Hamilton, MD, MS, FACS Cincinnati Eye Institute Portland, OR, United States
Cataract and Refractive Surgery Specialist Professor of Clinical Ophthalmology
Medical Director and Founder University of Cincinnati Jennifer I. Hui, MD, FACS
Hamilton Eye Institute Cincinnati, OH, United States Founder
Los Angeles, CA, United States Ophthalmic Plastic and Reconstructive
Gary N. Holland, MD Surgery
Kristin M. Hammersmith, MD Jack H. Skirball Professor of Ocular The Eyelid Institute
Associate Professor of Ophthalmology Inflammatory Diseases Palm Desert, CA, United States
Sidney Kimmel Medical College at Department of Ophthalmology Assistant Professor
Thomas Jefferson University David Geffen School of Medicine at Ophthalmology
Philadelphia, PA, United States University of California, Los Angeles Loma Linda University Eye Institute
Los Angeles, CA, United States Loma Linda, CA, United States
Sadeer B. Hannush, MD
Attending Surgeon Augustine R. Hong, MD Kyle Huynh, MD
Cornea Service Assistant Professor Fellow
Wills Eye Hospital Department of Ophthalmology and Visual Gavin Herbert Eye Institute
Philadelphia, PA, United States Sciences Irvine, CA, United States
Professor of Ophthalmology Washington University
Sidney Kimmel Medical College at Thomas St. Louis, MO, United States Alfonso Iovieno, MD, PhD, FRCS, FACS
Jefferson University Department of Ophthalmology and Visual
Philadelphia, PA, United States Marc A. Honig, MD Sciences
Instructor University of British Columbia
David R. Hardten, MD Ophthalmology Vancouver, BC, Canada
Director of Refractive Surgery Wilmer Eye Institute
Department of Ophthalmology The Johns Hopkins University School of Matthew H. Ip, MD, MS
Minnesota Eye Consultants Medicine Department of Ophthalmology
Minnetonka, MN, United States Baltimore, MD, United States Prince of Wales Hospital
Adjunct Associate Professor of Assistant Professor Sydney, NSW, Australia
Ophthalmology Department of Ophthalmology and Visual
Department of Ophthalmology Sciences
University of Minnesota University of Maryland School of Medicine
Minneapolis, MN, United States Baltimore, MD, United States
xxii LIST OF CONTRIBUTORS
Joseph D. Iuorno, MD Carol L. Karp, MD Shigeru Kinoshita, MD, PhD

Ophthalmologist/Cornea Specialist Professor of Ophthalmology Professor and Chair
Cornea Richard K. Forster Chair in Ophthalmology Frontier Medical Science and Technology for
Commonwealth Eye Care Associates Dr. Ronald & Alicia Lepke Endowed Ophthalmology
Richmond, VA, United States Professorship in Cornea and Ocular Kyoto Prefectural University of Medicine
Surface Diseases Kyoto, Japan
Luis Izquierdo Jr., MD, PhD Bascom Palmer Eye Institute
Professor in Ophthalmology University of Miami Miller School of Colin M. Kirkness†
Cornea and External Disease Medicine Formerly Tennent Professor of
Oftalmosalud Instituto de Ojos Miami, FL, United States Ophthalmology
Lima, Peru Department of Ophthalmology
Associate Professor in Ophthalmology Stephen C. Kaufman, MD, PhD Faculty of Medicine
Cornea and External Disease Professor and Vice-Chairman of University of Glasgow
Universidad Nacional Mayor de San Marcos Ophthalmology Glasgow, United Kingdom
Lima, Peru Director of Cornea and Refractive Surgery
University of Minnesota Stephen D. Klyce, PhD, FARVO
Sayena Jabbehdari, MD Minneapolis, MN, United States Adjunct Professor of Ophthalmology
Department of Ophthalmology and Visual Icahn School of Medicine at Mount Sinai
Sciences Jeremy D. Keenan, MD, MPH New York, NY, United States
University of Illinois at Chicago Professor
Chicago, IL, United States Francis I. Proctor Foundation and Douglas D. Koch, MD
Department of Ophthalmology Professor and Allen, Mosbacher, and Law
Deborah S. Jacobs, MD University of California, San Francisco Chair in Ophthalmology
Associate Professor of Ophthalmology San Francisco, CA, United States Department of Ophthalmology
Massachusetts Eye & Ear Baylor College of Medicine
Harvard Medical School Robert C. Kersten, MD Houston, TX, United States
Boston, MA, United States Professor of Clinical Ophthalmology
Department of Ophthalmology Thomas Kohnen, MD, PhD, FEBO
Frederick A. Jakobiec, MD, DSc University of California, San Francisco Professor and Chair
Emeritus Director, David G. Cogan San Francisco, CA, United States Department of Ophthalmology
Ophthalmic Pathology Laboratory Goethe-University
Ophthalmology Rohit C. Khanna, MD Frankfurt, Hessen, Germany
Massachusetts Eye and Ear Infirmary Director Gullapalli Pratibha Rao
Boston, MA, United States International Centre for Advancement of Noriko Koizumi, MD, PhD
Rural Eye Care Professor
Bennie H. Jeng, MD, MS L V Prasad Eye Institute Department of Biomedical Engineering
Professor and Chair Hyderabad, Telangana, India Faculty of Life and Medical Sciences
Department of Ophthalmology and Visual Doshisha University
Sciences Eric J. Kim, MD Kyoto, Japan
University of Maryland School of Medicine Resident Physician
Baltimore, MD, United States Department of Ophthalmology Daniel Kook, MD, PhD
Baylor College of Medicine Prof. Dr. Medicine
James V. Jester, PhD Houston, TX, United States Ophthalmology
Professor Prof. Kook & Partner
Ophthalmology and Biomedical Engineering Stella K. Kim, MD Private Practice
University of California, Irvine Joe M. Green Jr. Professor of Clinical Graefelfing, Bavaria, Germany
Irvine, CA, United States Ophthalmology
Ruiz Department of Ophthalmology and Regis P. Kowalski, MS, M(ASCP)
David R. Jordan, MD Visual Science Professor
Professor of Ophthalmology University of Texas Health, Medical School Ophthalmology
Ophthalmology Houston, TX, United States University of Pittsburgh
University of Ottawa Ee Institute and the Pittsburgh, PA, United States
Ottawa Hospital Terry Kim, MD
Ottawa, ON, Canada Professor of Ophthalmology Friedrich E. Kruse, MD
Department of Ophthalmology Professor and Chair of Ophthalmology
Raageen Kanjee, MD, FRCSC Duke University Eye Center Department of Ophthalmology
Department of Ophthalmology Durham, NC, United States University of Erlangen-Nuremberg
Max Rady College of Medicine Erlangen, Germany
University of Manitoba
Winnipeg, MB, Canada †Deceased
LIST OF CONTRIBUTORS xxiii
Priyanka Kumar, MD Michael A. Lemp, MD Thomas D. Lindquist, MD, PhD

Assistant Professor of Clinical Clinical Professor Formerly Director, Cornea and External
Ophthalmology Ophthalmology Disease Service
Perelman School of Medicine, University of Georgetown University Department of Ophthalmology
Pennsylvania Washington, DC, United States Group Health Cooperative
Attending Surgeon Bellevue, WA, United States
Children’s Hospital of Philadelphia Jennifer Y. Li, MD Clinical Professor
Philadelphia, PA, United States Professor Department of Ophthalmology
Department of Ophthalmology University of Washington School of
Khaliq Kurji, MD, MSc, FRCSC University of California, Davis Medicine
Ophthalmologist and Clinical Lecturer Sacramento, CA, United States Seattle, WA, United States
Department of Ophthalmology and Visual Medical Director
Sciences Yan Li, PhD SightLife
University of Alberta Research Assistant Professor Seattle, WA, United States
Edmonton, AB, Canada Ophthalmology
Oregon Health and Science University Richard L. Lindstrom, BA, BS, MD
Edward Lai, MD Portland, OR, United States Adjunct Clinical Professor Emeritus
Associate Clinical Professor Ophthalmology
Ophthalmology Thomas M. Lietman, MD University of Minnesota
Weill Cornell Medical College Director Minneapolis, MN, United States
New York, NY, United States Francis I Proctor Foundation
University of California, San Francisco Jennifer J. Ling, MD
Jonathan H. Lass, MD San Francisco, CA, United States Assistant Professor
Charles I Thomas Professor Professor Cornea and External Diseases
Department of Ophthalmology and Visual Departments of Ophthalmology and Department of Ophthalmology and Visual
Sciences Epidemiology & Biostatistics Sciences
Case Western Reserve University University of California, San Francisco Carver College of Medicine
Cleveland, OH, United States San Francisco, CA, United States University of Iowa
Medical Director Iowa City, IA, United States
Cornea Image Analysis Reading Center Michele C. Lim, MD
CWRU Department of Ophthalmology and Professor of Ophthalmology Yu-Chi Liu, MD
Visual Sciences Ophthalmology & Vision Sciences Clinician Scientist
University Hospitals Eye Institute University of California, Davis Cornea and Refractive Surgery
Cleveland, OH, United States Sacramento, CA, United States Singapore Eye Research Institute
Medical Director Singapore
Eversight Ohio Lily Koo Lin, MD
Cleveland, OH, United States Professor, Ophthalmic Plastic and Orbital Allan Luz, MD, PhD
Surgery Corneal Director of Hospital de Olhos de
Hong-Gam Le, MD Department of Ophthalmology Sergipe
Resident Physician University of California Davis Health Department of Ophthalmology
Ophthalmology Sacramento, CA, United States Federal University of São Paulo
Northwestern University São Paulo, Brazil
Chicago, IL, United States Shawn R. Lin, MD, MBA
Assistant Professor of Ophthalmology Marian S. Macsai, MD
Samuel H. Lee, MD University of California Los Angeles Clinical Professor of Ophthalmology
Cornea Service Stein Eye Institute Department of Ophthalmology and Visual
Sacramento Eye Consultants Los Angeles, CA, United States Science
Sacramento, CA, United States University of Chicago Medical Center
T. Peter Lindquist, MD Chicago, IL, United States
W. Barry Lee, MD, FACS Director Chief
Partner Cornea and Refractive Service Division of Ophthalmology
Cornea, External Disease & Refractive SouthEast Eye Specialists Northshore University Health Systems
Surgery Chattanooga, TN, United States Evanston, IL, United States
Eye Consultants of Atlanta/Piedmont Hospital Associate Medical Director
Atlanta, GA, United States Georgia Eye Bank Francis Mah, MD
Medical Director Atlanta, GA, United States Director of Cornea and External Disease
Georgia Eye Bank Co-Director of Refractive Surgery
Atlanta, GA, United States Department of Ophthalmology
Scripps Clinic Medical Group
La Jolla, CA, United States
xxiv LIST OF CONTRIBUTORS
Gabriel N. Mannis, MD Jodhbir S. Mehta, MBBS, PhD Steven M. Naids, MD

Assistant Professor of Medicine Professor Ophthalmologist
Hematology Cornea Ophthalmology
Stanford Cancer Institute Singapore National Eye Centre Advanced Vision Care
Stanford University Singapore Los Angeles, CA, United States
Stanford, CA, United States
Shahzad I. Mian, MD Afshan A. Nanji, MD, MPH
Mark J. Mannis, MD, FACS Professor and Vice-Chair Assistant Professor of Ophthalmology
Department of Ophthalmology & Vision Department of Ophthalmology and Visual Casey Eye Institute
Science Sciences Oregon Health and Science University
University of California Davis Health W.K. Kellogg Eye Center Portland, OR, United States
System University of Michigan
Sacramento, CA, United States Ann Arbor, MI, United States Kristiana D. Neff, MD
Partner
Tova Mannis, MD Darlene Miller, DHSc, MPH, MA, CIC Carolina Cataract & Laser Center
Eye Physician and Surgeon Research Professor Charleston, SC, United States
Kaiser Permanente Ophthalmology
Oakland, CA, United States University of Miami Sarah M. Nehls, MD
Miami, FL, United States Professor
Carlos E. Martinez, MD, MS Research Professor Department of Ophthalmology & Visual
Chairman of Ophthalmology Microbiology and Immunology Sciences
Long Beach Memorial Hospital University of Miami University of Wisconsin
Long Beach, CA, United States Miami, FL, United States Madison, WI, United States
Technical Director of Ocular Microbiology
Csaba L. Mártonyi, FOPS Laboratory Patrick W. Nelson, OD
Emeritus Associate Professor Bascom Palmer Eye Institute Clinical Director
Department of Ophthalmology and Visual Miami, FL, United States Midwest
Sciences TLC Laser Eye Centers
University of Michigan Medical School Naoyuki Morishige, MD, PhD Brookfield, WI, United States
Ann Arbor, MI, United States Director
Division of Cornea and Ocular Surface Jeffrey A. Nerad, MD
Maite Sainz de la Maza, MD, PhD Ohshima Eye Hospyal Partner
Associate Professor Fukuoka, Japan Oculoplastic Surgery
Department of Ophthalmology Cincinnati Eye Institute
Hospital Clinic, Barcelona Melina I. Morkin, MD Cincinnati, OH, United States
Barcelona, Spain Assistant Professor of Ophthalmology
Cornea, External Disease, Cataract, Ken K. Nischal, MD, FRCOphth
Hall T. McGee, MD, MS Refractive Surgery Professor
Ophthalmologist New England Eye Center Ophthalmology
Cornea and External Disease Tufts University School of Medicine UPMC Children’s Hospital of Pittsburgh
Everett & Hurite Ophthalmic Association Boston, MA, United States Pittsburgh, PA, United States
Pittsburgh, PA, United States
Mercè Morral, MD, PhD Teruo Nishida, MD, DSc
Charles N.J. McGhee, MBChB, PhD, Cornea, Cataract and Refractive Surgery Professor Emeritus
DSc, FRCS, FRCOphth, FRANZCO Specialist Department of Ophthalmology
Professor and Chair of Ophthalmology Cornea and Refractive Surgery Yamaguchi University Graduate School of
Department of Ophthalmology Institut de Microcirugia Ocular, Barcelona Medicine
University of Auckland Barcelona, Spain Ube City, Yamaguchi, Japan
Auckland, New Zealand Honorary Director
Adam Moss, MD, MBA Cornea Service
Beeran Meghpara, MD Cornea and External Disease Ohshima Eye Hospital
Co-Director of Refractive Surgery McCannel Eye Clinic Fukuoka City, Fukuoka, Japan
Wills Eye Hospital Minneapolis, MN, United States
Philadelphia, PA, United States Adjunct Assistant Professor
Assistant Professor Department of Ophthalmology and Visual
Department of Ophthalmology Neurosciences
Sidney Kimmel Medical College at Thomas University of Minnesota
Jefferson University Minneapolis, MN, USA
Philadelphia, PA, United States
LIST OF CONTRIBUTORS xxv
Maria Cristina Nishiwaki-Dantas, MD, Matthew R. Parsons, MD Kasey L. Pierson, BS, MD

PhD Excel Eye Center Anterior Segment and Cornea Fellow
Former Chief and Chair Provo, UT, United States Ophthalmology
Department of Ophthalmology Cincinnati Eye Institute
Santa Casa of São Paulo, Brazil Sirichai Pasadhika, MD Cincinnati, OH, United States
São Paulo, Brazil Vitreoretinal and Uveitis Services
Collaborating Professor of Ophthalmology, Ophthalmology Francis W. Price, Jr., MD
Corneal and External Disease Service Legacy Devers Eye Institute President of the Board
Federal University of São Paulo, Brazil Portland, OR, United States Cornea Research Foundation of America
São Paulo, Brazil Affiliate Instructor Indianapolis, IN, United States
Corneal and External Disease Ophthalmology Price Vision Group
Hospital Oftalmológico de Sorocaba and Oregon Health and Science University Indianapolis, IN, United States
Oftalmologistas Associados Portland, OR, United States
São Paulo, Brazil Marianne O. Price, PhD, MBA
Dipika V. Patel, PhD, MRCOphth Executive Director
Nour Nofal, MD Professor Cornea Research Foundation of America
Department of Ophthalmology Department of Ophthalmology Indianapolis, IN, United States
McGill University University of Auckland
Montreal, QC, Canada Auckland, New Zealand Louis E. Probst, MD
TLC The Laser Eye Centers
Daniel Ofori, MD Eric S. Pearlstein, MD Chicago, IL, United States
Cornea Fellow Clinical Assistant Professor
Hamilton Eye Institute Department of Ophthalmology Sana Qureshi, MD
University of Tennessee Health Science Center SUNY Downstate Medical Center Resident in Ophthalmology
Memphis, TN, United States Brooklyn, NY, United States Department of Ophthalmology and Visual
Sciences
Hon Shing Ong, MSc, MBBS, Jay S. Pepose, MD, PhD W.K. Kellogg Eye Center
FRCOphth, FAMS, FRCS(Ed) Professor of Clinical Ophthalmology University of Michigan
Consultant Ophthalmologist Department of Ophthalmology and Visual Ann Arbor, MI, United States
Corneal and External Diseases Department Sciences
Singapore National Eye Centre/Singapore Washington University School of Sam Ramos, BS, CEBT, CTBS
Eye Research Institute Medicine Executive Director
Ophthalmology and Visual Sciences St. Louis, MO, United States Sierra Donor Services Eye Bank
Academic Clinical Program Duke-NUS Founder and Medical Director West Sacramento, CA, United States
Medical School Pepose Vision Institute
Singapore St. Louis, MO, United States Gullapalli N. Rao, MD
Chairman
David A. Palay, MD Robert J. Peralta, MD L V Prasad Eye Institute
Associate Clinical Professor Ophthalmic Plastic & Reconstructive Hyderabad, Telangana, India
Department of Ophthalmology Surgery
Emory University The Permanente Medical Group Christopher J. Rapuano, MD
Atlanta, GA, United States Oakland, CA, United States Chief
Cornea Service
Deval R. Paranjpe, MD ScB Victor L. Perez, MD Wills Eye Hospital
Assistant Professor of Ophthalmology Professor of Ophthalmology Philadelphia, PA, United States
Drexel University College of Medicine Duke University Professor of Ophthalmology
Pittsburgh, PA, United States Durham, NC, United States Sidney Kimmel Medical College
Thomas Jefferson University
Mansi Parikh, MD Mauricio A. Perez Velasquez, MD Philadelphia, PA, United States
Ophthalmology Cornea, Cataract & Refractive Surgeon
Eye Care Center of Northern Colorado Fundación Oftalmológica Los Andes Ellen F. Redenbo, CDOS
Longmont, CO, United States Santiago, Chile Manager of Ophthalmic Imaging and Ultrasound
Ocular Trauma Surgeon Casey Eye Institute
Jennifer Park, MD Unidad de Trauma Ocular/Hospital Oregon Health Sciences University
Assistant Professor Salvador Portland, OR, United States
Department of Ophthalmology Santiago, Chile
SUNY Downstate Health Sciences University James J. Reidy, MD
Brooklyn, NY, United States W. Matthew Petroll, PhD Associate Professor
Professor Ophthalmology & Visual Science
Ophthalmology University of Chicago Medicine
UT Southwestern Medical Center Chicago, IL, United States
Dallas, TX, United States
xxvi LIST OF CONTRIBUTORS
Charles D. Reilly, MD Eric D. Rosenberg, DO, MSE Caterina Sarnicola, MD

Managing Partner Cornea and Refractive Fellow Consultant
Cornea/External Disease and Refractive Department of Ophthalmology Department of Ophthalmology
Surgery Weill Cornell Medicine Corneal and External Disease Service
Rashid, Rice, Flynn and Reilly Eye Associates New York, NY, United States Ospedale Oftalmico and Ospedale San
San Antonio, TX, United States Giovanni Bosco
Adjunct Assistant Professor Bryan M. Roth, MD Turin, Italy
Ophthalmology Associate Staff Ophthalmologist
University of Texas Health Science Center, San Cole Eye Institute Clinica degli Occhi Sarnicola
Antonio Cleveland Clinic Grosseto, Italy
San Antonio, TX, United States Cleveland, OH, United States
Enrica Sarnicola, MD
Bibiana Jin Reiser, MD Aravind Roy, MD Consultant
Assistant Professor Cornea and Anterior Segment Services Department of Ophthalmology
Ophthalmology KVC Campus Corneal and External Disease Service
Director L V Prasad Eye Institute Ospedale Oftalmico and Ospedale San
Cornea and Glaucoma Services Vijayawada, Andhra Pradesh, India Giovanni Bosco
Children’s Hospital, Los Angeles Turin, Italy
Los Angeles, CA, United States Alan E. Sadowsky, MD Ophthalmologist
Department of Ophthalmology Clinica degli Occhi Sarnicola
Andri K. Riau, PhD M Health Fairview Grosseto, Italy
Research Fellow Minneapolis, MN, United States
Tissue Engineering and Cell Therapy Group Vincenzo Sarnicola, MD
Singapore Eye Research Institute Shizuya Saika, MD, PhD Director of Ophthalmology
Singapore Professor and Chairman Clinica degli Occhi Sarnicola
Department of Ophthalmology Grosseto, Italy
Lorena Riveroll-Hannush, MD Wakayama Medical University School of
Asociación Para Evitar La Ceguera en México Medicine Gregory A. Schmidt, MBA, CEBT
Cornea Service Wakayama, Japan Iowa Lions Eye Bank
Mexico City, Mexico Coralville, IA, United States
C. Drew Salisbury, MD
Allison E. Rizzuti, MD Associate Samantha L. Schockman, MD
Clinical Assistant Professor Cornea, External Disease & Refractive Attending Surgeon
Ophthalmology Surgery Cincinnati Eye Institute
SUNY Downstate Premier Medical Volunteer Assistant Professor of
Brooklyn, NY, United States Mobile, AL, United States Ophthalmology
University of Cincinnati
Danielle M. Robertson, OD, PhD James Salz, MD Cincinnati, OH, United States
Associate Professor of Ophthalmology Clinical Professor
Graduate Programs in Immunology and Cell Ophthalmology Miriam T. Schteingart, MD
and Molecular Biology University of Southern California Clinical Assistant Professor
UT Southwestern Medical Center Roski Eye Institute Department of Ophthalmology
Dallas, TX, United States Los Angeles, CA, United States Central Michigan University School of
Medicine
Mario J. Rojas, MD Simrenjeet Sandhu, MD Andersen Eye Associates
Ocular Surface Directory Department of Ophthalmology & Visual Saginaw, MI, United States
Aran Eye Associates Sciences
Miami, FL, United States University of Alberta Ivan R. Schwab, MD, FACS
Edmonton, AB, Canada Professor of Ophthalmology
David S. Rootman, MD, FRCSC Ophthalmology
Professor Virender S. Sangwan, MBBS, MS University of California, Davis
Ophthalmology and Vision Sciences (Ophthal) Sacramento, CA, United States
University of Toronto Director, Innovations
Toronto, ON, Canada Dr. Shroff ’s Charity Eye Hospital Brian L. Schwam, MD
Delhi, India Vice President and Chief Medical Officer
James T. Rosenbaum, AB, MD Johnson and Johnson Vision Care
Professor Gisella Santaella, MD Jacksonville, FL, United States
Ophthalmology, Medicine, and Cell Biology Ophthalmologist
Oregon Health & Science University Department of Ophthalmology and Vision
Portland, OR, United States Science
Chair of Ophthalmology Emeritus University of Toronto
Legacy Devers Eye Institute Toronto, ON, Canada
Portland, OR, United States
LIST OF CONTRIBUTORS xxvii
Gary S. Schwartz, MD, MHA Patricia B. Sierra, MD Sathish Srinivasan, FRCSEd,

Adjunct Associate Professor Cornea, Cataract and Refractive Surgery FRCOphth, FACS
Ophthalmology Sacramento Eye Consultants Consultant Cornea Surgeon
University of Minnesota Sacramento, CA, United States University Hospital Ayr
Minneapolis, MN, United States Ayr, Scotland, United Kingdom
President Megan R. Silas, MD
Associated Eye Care Resident Physician Anna M. Stagner, MD
Stillwater, MN, United States Department of Ophthalmology and Visual Director, David G. Cogan Ophthalmic
Science Pathology Laboratory
Vincenzo Scorcia, MD University of Chicago Medical Center Massachusetts Eye and Ear Infirmary
Professor Chicago, IL, United States Dermatopathologist
Department of Medical and Surgical Sciences Massachusetts General Hospital
University of Magna Graecia Ophthalmology Craig A. Skolnick, MD Boston, MA, United States
Department President
Catanzaro, Italy Cornea, External Disease, Cataract Christopher E. Starr, MD
Skolnick Eye Institute Associate Professor
Craig W. See, MD Jupiter, FL, United States Ophthalmology
Associate Staff Director, Refractive Surgery Service
Cole Eye Institute Allan R. Slomovic, MSc, MD, FRCSC Director, Ophthalmic Education
Cleveland Clinic Professor of Ophthalmology Weill Cornell Medicine
Cleveland, OH, United States Department of Ophthalmology and Vision New York, NY, United States
Science
Boris Severinsky, OD, FAAO, FSLS University of Toronto Raymond Stein, MD, FRCSC
Chief, Contact Lens Service Toronto, ON, Canada Medical Director
Assistant Professor of Ophthalmology Bochner Eye Institute
Emory University School of Medicine Michael E. Snyder, MD Toronto, ON, Canada
Atlanta, GA, United States Member, Board of Clinical Governance Associate Professor of Ophthalmology
Chair, Clinical Research Steering Committee and Vision Sciences
Kevin J. Shah, MD Cincinnati Eye Institute University of Toronto
Physician CEI Vision Partners Toronto, ON, Canada
Cornea, Cataract and External Disease Professor of Ophthalmology
Eye Consultants of Pennsylvania University of Cincinnati Roger F. Steinert†
Reading, PA, United States Cincinnati, OH, United States Professor and Chair of Ophthalmology
Director of the Gavin Herbert Eye Institute
Mehdi Shajari, MD Jonathan C. Song, MD, MBA University of California, Irvine
Department of Ophthalmology Associate Irvine, CA, United States
University Hospital Ophthalmology
Basil T.L. Stoica
Goethe University Kaiser Permanente South Bay
Ophthalmic Surgeon
Frankfurt, Germany Harbor City, CA, United States
Centro Oftalmologico y Oculoplastico de
Madrid
Neda Shamie, MD Nir Sorkin, MD
Hospital Universitario Madrid Norte
Cataract, LASIK and Corneal Surgeon Clinical and Research Fellow
Sanchinarro
Maloney-Shamie Vision Institute Ophthalmology
Hospital Universitario de Fuenlabrada
Los Angeles, CA, United States University of Toronto
Madrid, Spain
Toronto, ON, Canada
Elizabeth Shen, MD Cornea, Cataract and Refractive Surgeon Michael D. Straiko, MD
Resident Physician Department of Ophthalmology Associate Director
Ophthalmology Tel Aviv Medical Center and Sackler Faculty Corneal Service
Gavin Herbert Eye Institute of Medicine Devers Eye Institute
Irvine, CA, United States Tel Aviv University Portland, OR, United States
Tel Aviv, Israel
Shigeto Shimmura, MD, PhD Alan Sugar, MD
Department of Ophthalmology Chie Sotozono, MD, PhD Professor of Ophthalmology
Keio University School of Medicine Professor and Chair Department of Ophthalmology and Visual
Shinjuku-ku, Tokyo Department of Ophthalmology Sciences
Kyoto Prefectural University of Medicine W.K. Kellogg Eye Center
Afua A. Shin, BS, MD Kyoto, Japan University of Michigan
Eye Clinic of Wisconsin Ann Arbor, MI, United States
Wausau, WI, United States Luciene Barbosa de Sousa, MD
Head of Cornea Section
Federal University of São Paulo †Deceaed
São Paulo, Brazil

xxviii LIST OF CONTRIBUTORS
Joel Sugar, MD Taíse Tognon MD, PhD Edmund Tsui, MD

Professor Ophthalmologist Uveitis Fellow
Department of Ophthalmology and Visual Cornea, External Diseases and Refractive Francis I. Proctor Foundation
Sciences Surgery University of California, San Francisco
University of Illinois at Chicago Instituto Penido Burnier San Francisco, CA, United States
Chicago, IL, United States Campinas, São Paulo, Brazil
Coordinator Professor Elmer Y. Tu, MD
Christopher N. Ta, MD Cornea and External Diseases Director, Cornea and External Disease
Professor of Ophthalmology Fundação Dr. João Penido Burnier Department of Ophthalmology and Visual
Ophthalmology Campinas, São Paulo, Brazil Sciences
Stanford University University of Illinois College of Medicine
Palo Alto, CA, United States C. Maya Tong, BSc, MD Chicago, IL, United States
Resident
Khalid F. Tabbara, MD Department of Ophthalmology & Visual Julie Vadboncoeur, MD, FRCSC
Clinical Professor of Ophthalmology Sciences Department of Ophthalmology
King Saud University College of Medicine University of Alberta University of Montreal
Riyadh, Saudi Arabia Edmonton, AB, Canada Montreal, QC, Canada
The Eye Center
Riyadh, Saudi Arabia Emilio A. Torres-Netto, MD
Felipe A. Valenzuela, MD
Cornea, Cataract and Refractive Surgeon
Clinical Fellow
Donald T.H. Tan, FRCSG, FRCSE, Escola Paulista de Medicina
FRCOphth, FAMS UNIFESP
Bascom Palmer Eye Institute
Adjunct Professor São Paulo, Brazil
University of Miami
Singapore National Eye Centre ELZA Institute
Miller School of Medicine
Singapore Dietikon, Zurich, Switzerland
Miami, FL, United States
Ophthalmology and Visual Sciences University of Zurich
Academic Clinical Program Zurich, Switzerland
Caroline W. Vargason, MD, PhD
Duke-NUS Graduate Medical School Oculofacial Plastic & Reconstructive
Singapore Elias I. Traboulsi, MD, MEd
Surgeon
Jensen Eye Associates
Jeremy C.K. Tan, MD, BSc Cole Eye Institute
Nampa, ID, United States
Ophthalmology Registrar Cleveland Clinic
Prince of Wales Hospital Cleveland, OH, United States
David D. Verdier, MD
Sydney, NSW, Australia
Clinical Professor
William Trattler, MD
Hassan N. Tausif, MD Department of Surgery
Director of Cornea
Resident Physician Ophthalmology Division
Ophthalmology
Ophthalmology Michigan State University College of Human
Center for Excellence in Eye Care
Beaumont Eye Institute Medicine
Royal Oak, MI, United States Grand Rapids, MI, United States
Director
Tanya Trinh, BAppSc, MBBS,
Shabnam Taylor, MD Verdier Eye Center, PLC
FRANZCO
The Permanente Medical Group Grand Rapids, MI, United States
Cornea, External Diseases and Refractive
Folsom, CA, United States
Fellow
Ana Carolina Vieira, MD, PhD
Mark A. Terry, MD Department of Ophthalmology
Director, Corneal Services University of Toronto
Devers Eye Institute Toronto, ON, Canada
Universidade Federal Fluminense
Portland, OR, United States Rio de Janiero, Brazil
Professor of Clinical Ophthalmology David T. Tse, MD
Cornea and External Diseases Specialist
Oregon Health Sciences University Vice Chair of Administration and Strategic
Portland, OR, United States Planning
Federal University of São Paulo
Medical and Scientific Director Professor of Ophthalmology, Dermatology,
São Paulo, Brazil
Eye Bank and Research Laboratory Otolaryngology, and Neurosurgery
Lions VisionGift Dr. Nasser Ibrahim Al-Rashid Chair in
Elizabeth T. Viriya, MD
Portland, OR, United States Ophthalmic Plastic, Orbital Surgery and
Clinical Assistant Professor
Oncology
Director, Dr. Nasser Ibrahim Al-Rashid
NYU Langone Health,
Orbital Vision Research Center
New York University School of Medicine
Bascom Palmer Eye Institute
New York, NY, United States
University of Miami Health System
LIST OF CONTRIBUTORS xxix
Jesse M. Vislisel, MD Jayne S. Weiss, MD Elizabeth Yeu, MD

Medical Director Professor and Chair Partner
Cornea & External Disease Department of Ophthalmology Virginia Eye Consultants
Associated Eye Care Associate Dean of Clinical Affairs Norfolk, VA, United States
Stillwater, MN, United States Herbert E. Kaufman MD Endowed Assistant Professor of Ophthalmology
Professor Eastern Virginia Medical School
John A. Vukich, MD Professor of Pathology and Pharmacology Norfolk, VA, United States
Director Louisiana State University School of
Department of Ophthalmology Medicine Charles Q. Yu, MD
Davis Duehr Dean Chief Medical Officer Assistant Professor
Madison, WI, United States Louisiana State University Health Care Ophthalmology
Network Stanford University
Matthew Wade, MD New Orleans, LA, United States Palo Alto, CA, United States
Associate Clinical Professor
Department of Ophthalmology Michael T. Wildes, MD Fatma Zaguia, MDCM, MSc
Gavin Herbert Eye Institute Fellow in Cornea, External Disease, and Department of Ophthalmology
University of California Refractive Surgery McGill University
Irvine, CA, United States Department of Ophthalmology Montreal, QC, Canada
University of Colorado School of Medicine
Michael A. Warner, MD Aurora, CO, United States Lucy Y. Zhang, MD, MEng
Oculoplastic Surgeon Ophthalmology
Ophthalmology Kirk R. Wilhelmus, MD, PhD Bay Area Eye Specialists
Pasadena, CA, United States Emeritus Professor of Ophthalmology Greenbrae, CA, United States
Clinical Instructor Cullen Eye Institute, Baylor College of
Ophthalmology Medicine Hui Zhao, MD, PhD
Oregon Health and Sciences University Houston, TX, United States Department of Ophthalmology & Visual
Portland, OR, United States Sciences
Samantha Williamson, MD Washington University/Barnes-Jewish
Mitchell P. Weikert, MD, MS Cornea and Anterior Segment Surgery Hospital
Associate Professor Select Eye Care St. Louis, MO, United States
Department of Ophthalmology Baltimore, MD, United States
Baylor College of Medicine Dagny Zhu, MD
Houston, TX, United States Steven E. Wilson, MD, FARVO Cornea, Cataract, and Refractive Surgeon
Professor of Ophthalmology Medical Director and Partner
Jessica E. Weinstein, MD, MS Staff Refractive Surgeon NVISION Eye Centers/HyperSpeed LASIK
Assistant Instructor Director of Corneal Research Rowland Heights, CA, United States
Ophthalmology PBC Cole Eye Institute
Wake Forest School of Medicine Cleveland Clinic
Winston-Salem, NC, United States Cleveland, OH, United States
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PART I Basic Science: Cornea, Sclera, Ocular Adnexa Anatomy,
Physiology, and Pathophysiologic Responses
1
Cornea and Sclera: Anatomy and Physiology
Teruo Nishida, Shizuya Saika, Naoyuki Morishige
KEY CONCEPTS
• Th
e principal physiologic role of the cornea is to allow external Collagen fibrils are homogeneous in diameter and are aligned
light to enter the eye and to contribute to its focusing on the at a constant distance from each other to maintain tissue
retina. Thus transparency and refractive power are essential for transparency. Keratocytes are the resident cells of the stroma,
this function. and although relatively few in number, they play important roles
• The cornea consists of the epithelium, Bowman layer, stroma, in the maintenance of stromal structure through synthesis and
Descemet membrane, and endothelium. secretion, as well as degradation, of collagen and proteoglycans.
• The functions of the corneal epithelium are regulated by various • The cornea is one of the most sensitive tissues in the body as
biologically active agents such as growth factors, cytokines, and a result of its abundant sensory nerve endings. Thus neural
chemokines in tear fluid, whereas those of the endothelium are regulation is another important factor in the maintenance of
regulated by factors in aqueous humor. corneal structure and function.
• Dynamic homeostasis of the corneal epithelium is maintained • Morphogenesis of the eye is achieved by cell lineages of various
by the generation of new epithelial cells from limbal stem cells, origins, including the surface and neural ectoderm during
centripetal cell movement, differentiation of basal cells into wing embryonic development. Characterization of the development
cells and then superficial cells, and cell desquamation via apoptosis. of ocular tissues during embryogenesis is important for
• The corneal stroma is composed primarily of extracellular understanding the pathogenesis of congenital anomalies of the
matrix, predominantly type I collagen and proteoglycans. cornea and anterior eye segment.
The smooth surface of the cornea contributes to visual clarity. The

INTRODUCTION regular arrangement of collagen fibrils in the corneal stroma accounts
The avascular cornea is not an isolated tissue. It forms, together for the transparency of this tissue.3–6 Maintenance of corneal shape
with the sclera, the outer shell of the eye, occupying one-third of the and transparency is critical for light refraction, with the cornea
ocular tunic. Although most of both the cornea and sclera consist accounting for more than two-thirds of the total refractive power of
of dense connective tissue, the physiologic roles of these two com- the eye. A functionally intact corneal endothelium is important for
ponents of the eye shell differ. The cornea serves as the transparent maintenance of stromal transparency as a result of regulation by the
“window” of the eye that allows the entry of light, whereas the sclera endothelium of corneal hydration. The cornea thus plays a central
provides a “dark box” that allows the formation of an image on the role in vision as a result of its transparency and refractive power, and
retina. The cornea is exposed to the outer environment, whereas the it maintains the eye shell. Each part of the cornea contributes to its
anterior portion of the opaque sclera is covered with the semitrans- transparency and shape, and its anatomy is closely related to its phys-
parent conjunctiva and has no direct exposure to the outside. The iology and function. Any change in corneal shape or function may
differences in the functions of the cornea and sclera reflect those in thus impair the formation of a clear image on the retina.
their microscopic structures and biochemical components (Fig. 1.1). The maintenance of corneal function is dependent on precise and
Interwoven fibrous collagen is responsible for the mechanical delicate regulatory mechanisms, with humoral and neural regula-
strength of both the cornea and sclera, protecting the inner compo- tion playing key roles.
nents of the eye from physical injury and maintaining the ocular con- Various hormones, cytokines, and growth factors regulate the
tour.1 The corneal epithelium forms an effective mechanical barrier various cellular components of the cornea,7 and such humoral
as a result of the interdigitation of cell membranes and the formation regulatory factors are present in tear fluid and aqueous humor.8,9
of junctional complexes such as tight junctions and desmosomes Although the cornea itself lacks a vasculature, rich vascular systems
between adjacent cells.2 Together with the cellular and chemical in the limbus and conjunctiva are a source of humoral regulatory
components of the conjunctiva and tear film, the corneal surface factors that reach the corneal surface via tear fluid or the corneal
protects against potential pathologic agents and microorganisms. stroma by diffusion. Furthermore, the cellular components of the
1
2 PART I Basic Science
(1)
(2)
(3)
(4)
A B
(5)
Fig. 1.1 Anatomy of the human cornea. (A) Slit lamp microscopic view of the cornea. (B) Histology of the cor-
nea showing the epithelium (1), Bowman layer (2), stroma (3), Descemet membrane (4), and endothelium (5).
cornea and conjunctiva—including epithelial cells, stromal keratocytes

and conjunctival fibroblasts, and endothelial cells—influence each
other through the production and secretion of cytokines and growth
*
factors,10–12 although the precise mechanisms of these reciprocal inter- *
actions remain to be fully clarified. On the other hand, the cornea and
adnexa are innervated by the ophthalmic division of the trigeminal
nerve, with such neural regulation also being important for mainte-
nance of the physiologic functions of the cornea.13,14
Any disturbance in these humoral or neural regulatory mecha-
nisms, such as might arise as a result of infection, dry eye syndrome, or
trigeminal nerve dysfunction, can lead to defects in corneal structure
and function that manifest clinically.
ANATOMY AND PHYSIOLOGY

Structure of the Cornea and Sclera
The ocular surface is composed of the cornea, conjunctiva, lacrimal
glands, and other adnexa. The outermost portion of the cornea and
conjunctiva is an epithelium that directly faces the environment. The
anterior corneal surface is covered by tear fluid, which protects the
cornea from dehydration and helps to maintain a smooth epithelial
surface. Tear fluid contains many biologically important ions and mol-
A B
ecules, including electrolytes, glucose, immunoglobulins, lactoferrin,
lysozyme, albumin, and oxygen. Moreover, it contains a wide range Fig. 1.2 Histology of the human sclera. (A) Hematoxylin and eosin
of biologically active substances such as histamine, prostaglandins, staining of a cross-section of the sclera. Blood vessels (asterisks) are
growth factors, and cytokines.10 The tear film thus serves not only as largely restricted to the episclera (upper region of section). (B) Higher-
a lubricant and source of oxygen and nutrients for the corneal epithe- magnification view of the conjunctiva and episclera as well as of stromal
lium but also as a source of regulatory factors required for epithelial fibroblasts (arrows) in the sclera. Bar: 100 μm.
maintenance and repair. The posterior surface of the cornea is bathed
directly by the aqueous humor. The highly vascularized limbus, which nontransparency of the sclera prevents light from reaching the retina
is thought to contain a reservoir of pluripotent stem cells, constitutes other than through the cornea, and, together with the pigmentation of
the transition zone between the cornea and the sclera or conjunctiva. the choroid and retinal pigment epithelium, the sclera provides a dark
The structure and function of the corneal epithelium and endothelium box for image formation. The scleral spur is a projection of the anterior
are therefore regulated by biologically active factors present in tear scleral stroma toward the angle of the anterior chamber and is the site
fluid and aqueous humor, respectively. of insertion for the anterior ciliary muscle. Contraction of this mus-
The sclera, a tough and nontransparent tissue, shapes the eye shell, cle thus opens the trabecular meshwork. At the posterior pole of the
which is approximately 24 mm in diameter in the emmetropic eye. The eyeball, where the optic nerve fibers enter the eye, the scleral stroma
sclera is the continuation of the corneal stroma and does not directly is separated into outer and inner layers. The outer layer fuses with the
face the environment. The anterior part of the sclera is covered with sheath of the optic nerve, dura, and arachnoid, whereas the inner layer
the bulbar conjunctiva and Tenon capsule, which consists of loose contains the sieve-like structure of the lamina cribrosa. The rigidity
connective tissue and is located beneath the conjunctiva (Fig. 1.2). The of the lamina cribrosa accounts for the susceptibility of retinal nerve
CHAPTER 1 Cornea and Sclera: Anatomy and Physiology 3
fibers to damage during the development of chronic open-angle glau-

coma. The sclera contains six insertion sites of the extraocular muscles, Corneal Epithelium
as well as the inputs of arteries (anterior and posterior ciliary arteries) The corneal and conjunctival epithelia are continuous and together
and outputs of veins (vortex veins) that circulate blood through the form the ocular surface. They are both composed of nonkeratinized,
uveal tissues. stratified, squamous epithelial cells. The thickness of the corneal epi-
thelium is approximately 50 μm, which is approximately 10% of the
Dimensions and Optical Properties of the Cornea total thickness of the cornea (see Fig. 1.1), and it is constant over the
The anterior corneal surface is convex and aspheric (see Fig. 1.1), entire corneal surface. The corneal epithelium consists of five or six
and it is transversely oval as a result of scleralization superiorly and layers of three different types of epithelial cells: superficial cells, wing
inferiorly. The adult human cornea measures 11–12 mm horizon- cells, and columnar basal cells, the latter of which adhere to the base-
tally and 9–11 mm vertically. It is approximately 0.5 mm thick at the ment membrane adjacent to the Bowman layer (Figs. 1.1, 1.3 and 1.4).
center, with the thickness increasing gradually toward the periphery, Although their characteristics differ, both corneal and conjunctival
where it is approximately 0.7 mm thick.15 The curvature of the cor- epithelia cooperate to provide the biodefense system of the anterior sur-
neal surface is not constant, being greatest at the center and smallest face of the eye.6,7,16,17 The characteristics of the different types of junc-
at the periphery. The radius of curvature is between 7.5 and 8.0 mm tional complexes present in the corneal epithelium (Figs. 1.4 and 1.5)
at the 3 mm central optical zone of the cornea, where the surface is are summarized in Table 1.1. Tight junctions (zonula occludens) are
almost spherical. The refractive power of the cornea is 40–44 diop- present mostly between cells of the superficial cell layers and provide
ters, constituting approximately two-thirds of the total refractive a highly effective barrier to prevent the penetration of tear fluid and its
power of the eye. chemical constituents. Desmosomes and adherens junctions are pres-
The optical properties of the cornea are determined by its trans- ent in all layers of the corneal epithelium, whereas gap junctions, which
parency, surface smoothness, contour, and refractive index of the allow the passage of small molecules between cells, are present in wing
tissue.3 Given that the spherocylindrical surface of the cornea has cells and basal cells; and hemidesmosomes are localized to basal cells.
both minor and major axes, changes in corneal contour caused either After damage to the corneal epithelium, actively migrating epithelial
by pathologic conditions such as scarring, thinning, or keratoconus cells no longer manifest junctional complexes in the wounded region
or by refractive surgery render the surface regularly or irregularly lacking a basement membrane. Reestablishment of the continuity of the
astigmatic. corneal epithelium is accompanied by the synthesis of basement mem-
The total refractive index of the cornea is determined by the sum of brane proteins and reconstruction of the basement membrane and by
refraction at the anterior and posterior interfaces, as well as by the trans- the reassembly of the various types of junctional apparatus, suggesting
mission properties of the tissue. The refractive indices of air, tear fluid, that the presence of the basement membrane may be required for re-
corneal tissue, and aqueous humor are 1.000, 1.336, 1.376, and 1.336, formation of cell-cell junctions in the corneal epithelium (see Fig. 1.5).18
respectively. The refractive power of a curved surface is determined by In corneal epithelial cells, intermediate filaments of the cytoskel-
the refractive index and the radius of curvature. The refractive power at eton are formed by specific types of acidic (type I) and basic (type II)
the central cornea is approximately +43 diopters, being the sum of that keratin molecules.19 Basal cells of the corneal epithelium express ker-
at the air–tear fluid (+44 diopters), tear fluid–cornea (+5 diopters), and atin 5/14, like basal epidermal cells of the skin. However, keratin 3/12
cornea–aqueous humor (−6 diopters) interfaces. Most keratometry and (64-kDa keratin) is specifically expressed in the epithelium of the cor-
topography measurements assume a standard refractive index of 1.3375. nea, not being found in that of the conjunctiva or in the epidermis,20,21
TABLE 1.1 Characteristics of the Various Types of Corneal Epithelial Cells

Mitotic Inter Junctional Cytoplasmic Microfila Micro
Shape Layers Size Activity digitation Complexes Organelles Keratin ments (Actin) tubules
Superficial Flat 2–4 40–60 μm in − Entire surface Desmosomes Sparse + + ±
cells Microvilli diameter Tight junc-
Microplicae 4–6 μm thick tions
at the Adherens
nucleus junctions
2 μm thick
at the
periphery
Wing cells Wing-like 2–3 − Entire surface Desmosomes Sparse +++ + ±
processes Gap junctions
Adherens
junctions
Basal Columnar Mono- 18–20 μm + Apical surface Desmosomes More than superfi- +++ + +
cells layer high Gap junctions cial cells
8–10 μm in Adherens Large numbers
diameter junctions of glycogen
Flat at poste- Hemidesmo- granules
rior surface somes Prominent mito-
chondria and
Golgi apparatus
$ % &
' ( )
* + ,
Fig. 1.3 Confocal biomicroscopy of the human cornea. (A–C) Superficial, wing, and basal cell layers of the cor-
neal epithelium, respectively. (D) Subepithelial nerve plexus. (E) Shallow layer of the stroma, containing a high
density of polygonal keratocytes. (F) Midlayer of the stroma, containing thick, nonbranching nerve fibers. (G)
Deep layer of the stroma, containing a lower density of keratocytes. (H) Amorphous appearance of Descemet
membrane. (I) Endothelium, comprising hexagonal endothelial cells of uniform size.
and it is essential for the normal architecture of corneal epithelial cells. by dynamic equilibrium (Fig. 1.6). Only the basal cells of the corneal
Deletion of the keratin 12 gene results in fragility of the corneal epithe- epithelium proliferate, with the daughter cells instead differentiating
lium in mice.22 In humans, genetic mutation of the keratin 12 gene is into wing cells and subsequently into superficial cells and gradually
responsible for Meesmann dystrophy of the corneal epithelium.23 emerging at the corneal surface.28 The differentiation process requires
Replacement of most organs or tissues by transplantation from approximately 7 to 14 days, after which the superficial cells undergo
a genetically nonidentical individual is associated with an immune desquamation into the tear film.29 Mechanical friction associated with
response that may lead to rejection. In contrast, the cornea is “immune blinking, ultraviolet radiation, and hypoxia induces apoptosis (pro-
privileged,” a characteristic that is critical for the success of corneal grammed cell death) and desquamation of corneal epithelial cells.30–32
transplantation. Dendritic Langerhans cells, specialized macrophages Thoft and Friend proposed that an equilibrium, represented by the
derived from the bone marrow that are implicated in antigen process- equation X + Y = Z, exists between the proliferation of basal epithelial
ing, are abundant at the periphery of the corneal epithelium but are cells and their differentiation into superficial cells (X), the centripe-
not present in the central region of the normal cornea.24,25 These cells tal movement of peripheral epithelial cells (Y), and epithelial cell loss
express human leukocyte antigen (HLA) class II molecules and are from the corneal surface (Z).33 This X, Y, Z hypothesis explains well the
thought to function in the afferent arm of the ocular immune response dynamic equilibrium of epithelial cells in the cornea. Given the con-
by presenting antigens to T lymphocytes.26,27 Injury to the central cor- tinuous desquamation of surface epithelial cells, it is essential that new
nea results in the rapid migration of peripheral Langerhans cells to the epithelial cells be supplied not only by mitosis of basal cells but also by
damaged area. the emergence of epithelial cells from the periphery.
The function of stem cells is to replenish cells lost in normal or
Limbal Stem Cells and Lineage of Corneal Epithelial Cells damaged tissue. The asymmetric division of each stem cell generates
Corneal epithelial cells are renewed continuously to maintain the a new stem cell and a transit amplifying cell that initially proliferates
normal layered structure of the epithelium in a process characterized and then gives rise to terminally differentiated cells. As in other tissues,
% '
$ & (
Fig. 1.4 Transmission electron microscopy of the human corneal epithelium. (A) The epithelium comprises
five or six layers of epithelial cells. The electron-dense cell is about to undergo desquamation. (B) Basal
cells. Note the numerous junctional complexes. (C) Basement membrane and anterior portion of Bowman
layer. Note hemidesmosomes at the basal surface of the epithelial cells. (D) Interdigitation and junctional
complexes at the lateral surface of basal epithelial cells. (E) Gap junction at the lateral surface of basal cells.
the existence of stem cells to maintain homeostasis of the corneal epi- central cornea in vitro.41 Centripetal movement of corneal epithelial
thelium has been postulated.34–39 Although keratin 3/12 (64-kDa ker- cells has also been well documented.42–45 These observations suggested
atin) is expressed in all layers of corneal epithelial cells, it is present that stem cells for corneal epithelial cells reside at the limbus, the tran-
only in the suprabasal epithelial cells at the limbus.22 The presence of sitional zone between the cornea and conjunctiva.35,46,47
slowly cycling cells in the basal cell layer at the limbus was demon- The palisades of Vogt, richly vascularized papillae at the transition
strated by cell labeling with [3H]thymidine,40 and basal cells at the lim- zone between the cornea and conjunctiva, have been identified as the
bus were found to have a higher mitotic potential than those of the likely location of limbal stem cells for corneal epithelial cells.48,49 These
$ % & '
( ) * + , -
AF AF AF AF
AF AF
c-AMP KF KF
Ca2+ AF
P120
AF
zo-2 DP I/II
Cx Cx PG E-cad
Ca2+ Cx Cx
7H6
PG β-ctn a-ctn
zo-1
Cx Cx Ca2+ zo-1 PG α-ctn β-ctn
7H6 PG E-cad
zo-2 DP I/II
c-AMP Ca2+ AF KF
AF KF P120 AF
Oc/Cld Dsg/Dsc Dsg/Dsc
. / AF AF 0 AF 1
AF AF
Fig. 1.5 Intercellular junctions in the corneal epithelium. (A–D) Transmission electron micrographs of the
human corneal epithelium. Scale bars: 50 nm. (E–J) Immunofluorescence micrographs of the rat corneal epi-
thelium stained with antibodies to the indicated proteins. Scale bars: 20 μm. (K–N) Schematic representation
of intercellular junctions in the corneal epithelium. 7H6, 7H6 antigen; AF, actin filament; AJ, adherens junc-
tion; α- and β-ctn, α- and β-catenin; c-AMP, cyclic adenosine monophosphate; Cld, claudin; Cx43, connexin
43; DP I/II, desmoplakin I or II; DS, desmosome; Dsc, desmocollin; Dsg 1+2, desmogleins 1 and 2; E-cad,
E-cadherin; GJ, Gap junction; KF, keratin filament; Oc, occludin; P120, P120 catenin; PG, plakoglobin; TJ, tight
junction; zo-1 and -2, zonula occludens-1 and -2. (Modified from Suzuki K, Saito J, Yanai R, et al. Cell–matrix
and cell–cell interactions during corneal epithelial wound healing. Prog Retin Eye Res 2003;22:113–33. Copy-
right Elsevier.)
structures are able to provide a protective environment for stem cells, as direct evidence for the existence of limbal stem cells has been obtained
well as to supply them with growth factors, extracellular matrix (ECM), to date, ABCG2 appears to be the most promising surface marker for
and neural signals to maintain their nature as stem cells. Limbal epi- the identification of such cells.
thelial crypts, anatomic structures that extend from the palisades of Limbal stem cell deficiency has been recognized as a complex
Vogt, have been proposed to be the actual site of the stem cell niche.34 corneal disorder resulting from functional or structural loss of
The putative stem cells in the basal layer of the limbus have unique the limbus. Deficiency of limbal stem cells has been suggested to
characteristics in that they cycle slowly and therefore retain DNA labels lead to impairment of corneal epithelial homeostasis in individuals
such as [3H]thymidine, they are poorly differentiated with primitive with aniridia, inflammatory disorders of the ocular surface such as
cytoplasm, they have a high proliferative potential without undergo- Stevens-Johnson syndrome, or severe alkali burn of the ocular sur-
ing maturation, they are small with a high nucleus-to-cytoplasm ratio, face.55 No medical treatment for limbal stem cell deficiency is cur-
they are capable of generating a large number of differentiated progeny, rently available. Transplantation of stem cells is a potential approach
and they reside in close contact with a subset of mesenchymal niche to the treatment of limbal stem cell deficiency. However, such an
cells.50,51 approach requires sorting of limbal stem cells from explants of lim-
Although many markers for limbal stem cells have been pro- bus tissue, given that the stem cells are thought to constitute less
posed,49,52 there is no single positive marker that distinguishes these than 1% of cells in the basal layer of the limbus. The lack of a defin-
cells. The expression of p63 (a marker of cell proliferative ability), itive stem cell marker has thus impeded the sorting process. Sorting
α-enolase, keratin 19, and the hepatocyte growth factor (HGF) recep- based on the presence of stem cell–associated markers (ABCG2,
tor has been shown to be higher in the limbal epithelium than in the vimentin, keratin 19) and the absence of differentiation markers
corneal epithelium.49 The transporter protein ABCG2 is also expressed (keratin 3/12, connexin 43, involucrin) might be the best current
specifically in the basal layer of the limbal epithelium.53,54 Although no approach.49
Conjunctiva Limbus Cornea Terminally

differentiated
cells Z
Basal
Transient cells
amplifying
cells
Centripetal
Limbal stem cells movement
X
Palisades of Vogt
Limbus
ZXY
X: Proliferation of Y: Centripetal movement of cells Z: Cell loss from the surface
basal cells (supply from limbal stem cells) (desquamation via apoptosis)
Fig. 1.6 Lineage of corneal epithelial cells. Stem cells thought to reside in the basal cell layer at the limbus
proliferate asymmetrically to yield a daughter stem cell and a transit amplifying cell, the progeny of which
move centripetally toward the center of the cornea to become basal corneal epithelial cells. These newly gen-
erated basal cells proliferate symmetrically and then differentiate consecutively into wing cells and superficial
cells, the latter of which undergo apoptosis and consequent desquamation.
Layered Structure of the Corneal Epithelium composed of keratin (see Table 1.1). The cell membranes of adjacent
Superficial cells. The surface of the corneal epithelium contains two wing cells are interdigitated (see Fig. 1.5).
to four layers of terminally differentiated superficial cells. In contrast Basal cells. The single layer of columnar basal cells of the
to the epidermis of the skin, the corneal epithelium is not normally corneal epithelium rests on the basement membrane. Basal cells,
keratinized, although it may become so under pathologic conditions unlike superficial and wing cells, possess mitotic activity, and they
such as vitamin A deficiency. These cells are flat and polygonal with a differentiate consecutively into wing and superficial cells (see Table
diameter of 40–60 μm and a thickness of 2–6 μm (see Table 1.1). Their 1.1). Neighboring basal cells interdigitate laterally and are joined by
surface is covered with microvilli.56 Given that superficial cells are well desmosomes, gap junctions, and adherens junctions (see Fig. 1.5).
differentiated, they do not proliferate. The posterior surface of basal cells is flat and abuts the basement
Numerous glycoprotein (mucin) and glycolipid molecules are membrane.
embedded in the cell membrane of corneal epithelial cells.57 Mucins Basal cells adhere to the basement membrane via hemidesmosomes
include both membrane-bound and secreted molecules, with the for- that are linked to anchoring fibrils of type VII collagen (see Fig. 1.4).60
mer in humans including MUC1, MUC4, and MUC16, all of which The anchoring fibrils penetrate the basement membrane and course
have been detected in superficial epithelial cells of the cornea and con- into the stroma, where they form anchoring plaques together with type
junctiva.58 In mice, MUC16 is expressed in the conjunctiva but not in I collagen, a major component of the stroma. The adherens junctions
the cornea.57 These glycoproteins and glycolipids form floating parti- are present at the lateral surface of the basal cells of the corneal epithe-
cles in the cell membrane that are collectively termed the glycocalyx lium and are thought to mediate cell-cell interaction.61
and which confer hydrophilic properties on the anterior surface of the Basement membrane. As in epithelia in other parts of the body,
superficial epithelial cells. The glycocalyx interacts with the mucinous basal cells of the corneal epithelium are anchored to a basement
layer of the tear film and helps to maintain the layered structure of the membrane. The presence of the basement membrane between the basal
latter.59 Loss either of the glycocalyx of corneal epithelial cells or of epithelium and the underlying stroma fixes the polarity of epithelial
goblet cells in the conjunctival epithelium results in tear film instability cells. Ultrastructurally, the basement membrane, which is 40–60 nm
and the mucin-deficiency form of dry eye. thick, is composed of a pale layer (the lamina lucida) immediately
Wing cells. Beneath the superficial cells lie two or three layers of posterior to the cell membrane of the basal epithelial cells as well as an
wing cells, so called because of their characteristic wing-like shape. electron-dense layer (the lamina densa) (see Fig. 1.4). Type IV collagen
Wing cells are in an intermediate state of differentiation between and laminin are major components of the basement membrane
basal and superficial cells and are rich in intracellular tonofilaments (Fig. 1.7).62
$ % & '
Fig. 1.7 Immunofluorescence analysis of the expression of matrix proteins in the rat corneal epithelium.
(A) Type I collagen. (B) Type IV collagen. (C) Laminin. (D) Fibronectin. Bar: 50 μm.
The basement membranes of the corneal and conjunctival epithe- Hyaluronan. Hyaluronan is also recognized as a biologic signaling
lia contain different type IV collagen chains, although the functional molecule and, like fibronectin, plays an important role in inflammation
relevance of this difference is unknown. Collagen α5 (IV) is present and wound healing.75 Unlike other glycosaminoglycans, a core protein
in the corneal basement membrane, whereas collagen α2 (IV) is pres- for hyaluronan binding has not yet been identified. Hyaluronan is not
ent in the conjunctival basement membrane (as well as in the amniotic present in the normal cornea, but it is transiently expressed in the
membrane).63 rabbit cornea during wound healing.76 These observations suggest
that hyaluronan might play a role in the late stages of corneal wound
Physiology of the Corneal Epithelium healing. Exogenous hyaluronan also increases the rate of corneal
Maintenance of corneal structure is crucial for the physiologic roles epithelial wound healing. The administration of hyaluronan eye
of this tissue in refraction and biodefense. A smooth epithelium, a drops thus promotes corneal epithelial wound closure after epithelial
transparent stroma, and a functioning endothelium are all essential for debridement in rabbits and in diabetic rats.77,78
clear vision. The cornea is vulnerable to various chemical or biologic Proteolytic enzymes. Proteolytic enzymes also play an important
agents, as well as to physical events in the outside world. It is therefore role in wound healing. Cellular motility thus depends not only on the
equipped with an active maintenance system responsible for renewal of interaction of cells with the underlying ECM but also on the termination
the corneal epithelium and wound healing. of such interaction by degradation of matrix proteins. Proteases,
The widespread application of corneal surgery, including kerato- including plasminogen activator, have been detected in tear fluid.79,80
plasty and refractive surgery, has necessitated a more detailed under- Mechanical wounding induces upregulation of urokinase-type
standing of the cellular and molecular biology of corneal wound healing. plasminogen activator (uPA) at both the protein and mRNA levels in
In most parts of the body, wound healing is initiated by the extravasa- corneal epithelial cells, suggesting that this protease may contribute to
tion of blood constituents that accompanies disruption of blood vessels. epithelial cell migration by degrading fibronectin during corneal epi-
However, the cornea is an avascular tissue. The mechanism of wound thelial wound healing and thereby promoting cell detachment from the
healing in the cornea thus differs from that elsewhere in the body. ECM.81,82 In addition to mediating pericellular proteolysis, uPA pro-
Epithelial movement. Injury to the corneal surface is not uncom- motes leukocyte infiltration during corneal inflammation.83
mon and results in an epithelial defect, the rapid resurfacing of which It may therefore be a critical player in inflammatory responses in
is required for restoration of the continuity of the corneal epithelium. the cornea. Matrix metalloproteinase (MMP)-9 is also implicated in the
Repair of epithelial defects occurs in three distinct phases characterized early stages of wound healing in the corneal epithelium.84,85 MMP-9 is
by epithelial cell migration, proliferation, and differentiation, resulting thus the major MMP synthesized and secreted by basal corneal epithe-
in restoration of the stratified structure of the epithelium. lial cells during their migration to resurface a wound.86,87
Epithelial migration is thus the initial step in the resurfacing of epi- Cytokines and growth factors. The roles of various cytokines and
thelial defects.64 Trauma to the corneal epithelium induces the sliding growth factors in the regulation of corneal epithelial migration have
and migration of the remaining epithelial cells adjacent to the injury also been investigated.88 In general, these molecules modulate corneal
site toward the defective area.65–68 Dynamic changes in cell-cell and epithelial wound healing by regulating the various healing-related
cell-matrix (fibronectin-integrin system) interactions, upregulation of systems described earlier.7,8
hyaluronan (hyaluronic acid), and modulation of the ECM by newly Epidermal growth factor (EGF) was first isolated from the mouse
expressed proteolytic enzymes play important roles in these two types submaxillary gland as a factor that stimulates eye opening and incisory
of epithelial cell movement in response to injury. Such changes are tooth eruption in newborn mice.89 This 53-amino acid polypeptide is
under the overall control of growth factors and cytokines. a potent stimulator of proliferation in a variety of cell types, including
Fibronectin-integrin system. The fibronectin-integrin system corneal epithelial cells.90,91 EGF is synthesized in lacrimal glands92,93
plays a central role in corneal epithelial wound healing.69 Fibronectin and is present in tear fluid.94,95 It influences the physiology of the cor-
provides a provisional matrix during the first phase of epithelial wound neal epithelium and promotes corneal epithelial wound closure in
healing. It appears at the newly exposed corneal surface soon after animals.96
epithelial or stromal injury,70,71 and epithelial cells then attach to and The continuous exposure of the corneal epithelium to EGF present
spread over the fibronectin matrix in an integrin-dependent manner.72 in tear fluid suggests that the stimulatory effect of this growth factor on
The integrin family includes 24 different α subunits and nine dif- epithelial cell proliferation must be counteracted if the normal thick-
ferent β subunits. The integrin subunits α2, α3, α5, α6, αv, β1, β4, and ness and function of the epithelium are to be maintained. In addition to
β5 have been detected in the human cornea.73 The appearance and its stimulatory effect on cell proliferation, EGF exerts a variety of other
disappearance of the integrin β1 chain and fibronectin during corneal actions in corneal epithelial cells, including promotion of cell migra-
epithelial wound healing are well coordinated (Fig. 1.8).74 tion and cell adhesion to a fibronectin matrix.97,98
Normal Integrin β1 Fibronectin Laminin
$ % & '
12H
( ) * +
1D
, - . /
1W
0 1 2 3
1M
4 5 6 7
Fig. 1.8 Changes in the localization of the integrin β1 chain, fibronectin, and laminin after a nonpenetrating
incision in the rat cornea. Phase-contrast microscopy (A, E, I, M, Q) and immunofluorescence microscopy
for the integrin β1 chain (B, F, J, N, R), fibronectin (C, G, K, O, S), and laminin (D, H, L, P, T) are shown for
the intact rat cornea (A–D) as well as at 12 hours (E–H), 1 day (I–L), 1 week (M–P), and 1 month (Q–T) after
incision. Immediately after the incision, fibronectin was detected at the surface of the V-shaped defect in the
stroma. Epithelial cells expressing the integrin β1 subunit then began to migrate over and to fill in the defect.
With the exception of that in basal cells, expression of the integrin β1 chain in epithelial cells was down-
regulated coincident with the completion of wound healing. The abundance of fibronectin at the interface
between the new epithelium and the stroma also markedly decreased at this time.
Corneal epithelial cells express transforming growth factor (TGF)-β1.93

Endogenous TGF-β also promotes corneal epithelial cell migration.99 Stroma of the Cornea and Sclera
The stimulatory effects of EGF on corneal epithelial cell proliferation, Bowman Layer
attachment to fibronectin, and migration are modulated by TGF-β.100,101 An acellular, membrane-like zone known as Bowman layer, or Bowman
Although TGF-β alone inhibits corneal epithelial cell proliferation, it has membrane, is detectable by light microscopy at the interface between
no effect on cell attachment to a fibronectin matrix in the absence of EGF. the corneal epithelium and stroma in humans and certain other mam-
Nerve growth factor (NGF) was first isolated from sarcoma cells mals (but not in rodents). Given that this structure, which is 12 μm
and snake venom.102,103 NGF is a 26-kDa protein that plays key roles in thick, is not a membrane but rather a random arrangement of collagen
morphogenesis, homeostasis, repair, and inflammation in both neural fibrils and proteoglycans, the term Bowman layer is preferable. The col-
and nonneural tissues including the corneal epithelium.104,105 Sensory lagen fibrils in the Bowman layer are primarily collagen types I and III.
nerves in the corneal and limbal epithelium are essential for the pro- The diameter of these fibrils is 20–30 nm, which is smaller than that of
liferative activity of the basal epithelial cells.106 Investigations into the the collagen fibrils present in the corneal stroma (22.5–35 nm).
action of NGF in corneal homeostasis and wound healing107 resulted The Bowman layer is considered to be the anterior portion of the
in the development of eye drops containing NGF for the treatment of corneal stroma. The anterior surface of this layer, which faces the base-
corneal epithelial disorders.108 ment membrane, is smooth. Given that the collagen fibrils in the Bow-
Interleukins are cytokines that regulate the function of the immune man layer are synthesized and secreted by stromal keratocytes, they
system, inflammation, and other reactions of tissue to external stim- appear continuous with those in the stroma.
uli.109 They modulate the activities of immune or inflammatory cells Biologic functions originally attributed to the Bowman layer are
both locally in tissue and systemically in the circulation and in bone currently thought to be mediated by the basement membrane. The
marrow. Although 36 members of the interleukin family (IL-1 to Bowman layer does not regenerate after injury. Clinical experience
IL-36) have been identified to date, the roles of many of these proteins with excimer laser photoablation demonstrates that a normal epithe-
in corneal wound healing remain to be investigated. lium is formed and maintained even in the absence of the Bowman
5 µm 1 µm
$ %
Fig. 1.9 Transmission electron microscopy of the human corneal stroma. (A) A keratocyte localized between
stromal lamellae. (B) A higher-magnification view showing a keratocyte in relation to collagen fibrils coursing
in various directions.
layer. Furthermore, many mammals do not have a Bowman layer but Keratocytes are similar to fibroblasts and possess an extensive intra-
still exhibit a well-organized epithelial structure. The physiologic role cellular cytoskeleton, including prominent actin filaments. They are
of the Bowman layer therefore remains unclear. quiescent in the healthy cornea and express water-soluble transketo-
lase, aldehyde dehydrogenase, CD34, and CD133.115,116 However, they
Structure of the Stroma are readily activated and undergo transformation into myofibroblasts
The stroma constitutes the largest portion, more than 90%, of the that express α-smooth muscle actin in response to various types of
thickness of the cornea. The peripheral portion of the cornea connects insult to the stroma.117,118 CD34 is downregulated during myofibro-
to the anterior sclera at the limbus, where the tissue loses its trans- blasts differentiation.119 Myofibroblasts produce ECM, MMPs and
parency. Many characteristics of the cornea, including its physical other collagen-degrading enzymes, and cytokines that facilitate stro-
strength, stability of shape, and transparency, are largely attributable mal tissue repair, and their ability to contract contributes to wound
to the anatomic and biochemical properties of the stroma. The uni- closure. Keratocytes thus play key roles in the response to corneal
form arrangement and continuous slow turnover (production and infection and in tissue repair.120
degradation) of collagen fibrils in the stroma are essential for corneal Although stem cells for corneal epithelial cells are thought to be
transparency. located at the limbus of the cornea, those for keratocytes are localized to
The sclera is also composed mostly of collagen fibrils and other the peripheral corneal stroma.121–124 These stem cells for keratocytes iso-
matrix macromolecules, but nonuniformity in the arrangement of lated from the limbal stroma express stem cell markers such as ABCG2
these fibrils accounts for its lack of transparency.110 The thickness of the and PAX6, and they possess a multipotent differentiation potential.125
scleral stroma ranges from approximately 0.5 to 1.0 mm depending on Corneal stromal stem cells may also serve as niche cells to support epi-
the area, with the exception of the sites of insertion for the rectus mus- thelial stem cells in the basal cell layer of the limbal epithelium. These
cle, where the sclera is thinnest. The toughness of the scleral stroma stromal stem cells are immunosuppressive, and they limit scarring by
is essential for its role as a container of the intraocular tissues. Scleral promoting neutrophil infiltration during stromal wound healing.126–128
fibroblasts are embedded within the collagen lamellae. In addition to keratocytes, bone marrow–derived cells are present in
Cells. The cellular components (predominantly keratocytes) occupy the corneal stroma. Approximately 6% of cells that reside in the normal
only 2%–3% of the total volume of the corneal stroma,111 with the human corneal stroma express the hematopoietic cell marker CD45,129
remaining portion comprising mostly the ECM components collagen and 7.58% of stromal cells were found to express this marker in a
and proteoglycans. Keratocytes are thought to turn over approximately mouse bone marrow transplantation model.130 However, in response
every 2–3 years. The spindle-shaped keratocytes are scattered among to infection or injury, many inflammatory cells infiltrate the corneal
the lamellae of the stroma (Fig. 1.9). These cells extend long processes, stroma from the limbal vessels surrounding the cornea.
and the processes of neighboring cells are connected at their tips by gap Although scleral fibroblasts are not as well characterized as ker-
junctions (Fig. 1.10).112 The three-dimensional network structure of atocytes, they are thought to be similar to fibroblasts in other parts of
keratocytes can be observed by light microscopy in flat preparations of the body. As in the corneal stroma, a slow turnover of collagen fibrils
the corneal stroma, by confocal biomicroscopy, and, after digestion of by scleral fibroblasts is required for connective tissue homeostasis.
stromal collagen, by scanning electron microscopy (see Fig. 1.10).113,114 Matrix degradation by scleral fibroblasts is promoted by prostaglandin
$ % 10 µm
Fig. 1.10 Electron microscopy of the corneal stroma. (A) Lamellar structure of collagen fibrils and elec-
tron-dense gap junctions (1) between the cellular processes of keratocytes in the human cornea. (B) Three-
dimensional view of keratocytes in the rat cornea after digestion of collagen. Note the cellular network formed
by keratocytes.
derivatives, which accounts in part for the increase in uveoscleral collagen lamellae in the human corneal stroma vary in width from 0.5
outflow of aqueous humor and the reduction in intraocular pressure to 250 μm and in thickness from 0.2 to 2.5 μm, and they interweave
induced by such drugs.131 Activation of scleral fibroblasts by external with each other at various angles.143–145 They change direction as they
stimuli, such as injury or surgery, also results in their transdifferentia- course from the center to the outer zone of the cornea.141
tion into myofibroblasts and consequent tissue fibrosis. Three-dimensional analysis by second harmonic generation imag-
Collagen. Collagen constitutes more than 70% of the dry weight ing microscopy has revealed that the anatomic characteristics of colla-
of the cornea. Collagen in the corneal stroma is mostly type I, with gen lamellae are not uniform throughout the normal human corneal
smaller amounts of types III, V, VI, XII, and XIV also present.132–138 stroma (Fig. 1.11).146,147 Lamellae at the anterior stroma manifest an
Proteoglycans are distributed among the major collagen fibrils. interwoven structure with an angle of approximately 21 degrees rela-
Both the mean diameter of collagen fibrils and the mean distance tive to the Bowman layer, whereas those in the middle and posterior
between such fibrils in the corneal stroma are relatively homogeneous regions of the stroma are parallel.145 The width of collagen lamellae also
and are less than half of the wavelength of visible light (400–700 nm). gradually increases from the anterior to posterior stroma.145 Given that
This anatomic arrangement is thought to be responsible for the fact dense and interwoven collagen lamellae confer a more rigid structure
that scattering of an incident ray of light by each collagen fibril is can- compared with parallel lamellae, this organization of stromal collagen
celed by interference from other scattered rays,3,5 allowing light to pass lamellae is thought to contribute to maintenance of anterior stromal
through the cornea. If the diameter of or the distance between collagen curvature. The collagen lamellae immediately below the Bowman layer
fibrils becomes heterogeneous (as occurs in fibrosis or edema), inci- adhere evenly to it. The width of collagen lamellae adherent to the
dent rays are scattered randomly and the cornea loses its transparency. Bowman layer is slightly larger than that of those located immediately
Procollagen molecules are secreted into the extracellular space posteriorly,145 likely facilitating strong adherence. Similar adherence of
by keratocytes, after which the propeptides at both ends are cleaved collagen lamellae to Descemet membrane in the posterior region of the
to yield the mature collagen molecules. The collagen molecules self- stroma has not been observed. The turnover of collagen molecules in
assemble into fibrils with a diameter of 10–300 nm, and these fibrils the cornea is slow, requiring 2–3 years.148
subsequently further assemble into collagen fibers.5 Individual colla- The histologic features of the scleral stroma are similar to those of the
gen fibrils in the corneal stroma can be observed by transmission elec- corneal stroma, with the scleral stroma also being composed largely of
tron microscopy (see Fig. 1.9). As mentioned earlier, both the diameter major collagen fibrils and proteoglycans.149 The collagen types detected
of (22.5–35 nm) and distance between (41.4 ± 0.5 nm) collagen fibrils in the scleral stroma are also similar to those in the corneal stroma.
in the corneal stroma are highly uniform, with this regular arrange- In contrast, the matrix components present in the spaces between the
ment being a major determinant of corneal transparency.139–141 Such a major collagen fibrils in the scleral stroma differ from those in the
uniform alignment of the collagen fibrils is maintained by association corneal stroma. This difference in the noncollagenous matrix largely
with other ECM components such as small leucine-rich proteoglycans accounts for the difference in ultrastructure between the cornea and
(SLRPs) and type V collagen.142 At high magnification, each collagen sclera. The collagen fibrils in the corneal stroma are highly uniform in
fibril exhibits a characteristic cross-striation pattern with a periodic- diameter, whereas those in the scleral stroma range in diameter from
ity of 67 nm. In the corneal stroma, the collagen fibrils align with the 25 to 250 nm. Furthermore, collagen fibrils are arranged regularly with
same orientation to form approximately 300 lamellae. Each lamella a relatively uniform interfiber distance in the corneal stroma, whereas
courses parallel to the surface of the cornea from limbus to limbus. The the distance between collagen fibrils in the scleral stroma varies. The
provided some insight. Mutation of the keratocan gene was recently

shown to result in cornea plana, an anomaly characterized by abnor-
mal corneal curvature, but it did not affect the transparency of the cor-
neal stroma.156,157
Recent studies with transgenic or knockout mice have also provided
insight into the roles of proteoglycan core proteins. A lumican-null
mouse was shown to undergo age-dependent opacification of the cor-
$ neal stroma.158,159 Transmission electron microscopy revealed an irreg-
ular arrangement of collagen fibrils in the posterior stroma of these
animals, indicating that lumican is required for the regular organiza-
tion of collagen fibrils and that its distribution is not uniform through-
out the thickness of the stroma.5 Similar to the effect of keratocan gene
mutation in humans,157 keratocan-deficient mice show a change in the
shape of the eye shell, but the transparency of the corneal stroma is not
affected.156 These observations indicate that two major keratan sulfate
proteoglycans (those based on lumican or keratocan) do not similarly
% influence collagen fibril organization in the corneal stroma.155 Mice
lacking decorin exhibit abnormal collagen fibrillogenesis in the tail
tendon but not in the corneal stroma,160 indicating that decorin may
not play an important role in maintenance of corneal stromal transpar-
ency, despite its abundance in the stroma. Such genetically modified
mice not only shed light on the functions of specific molecules but also
provide models of human genetic disorders of the cornea.
The main difference between the proteoglycan composition of
& ' the sclera and that of the cornea is the absence of keratocan, a spe-
cific marker of keratocyte differentiation,154 in the sclera. However,
Fig. 1.11 Second harmonic generation imaging microscopy of the this difference alone does not explain the lack of uniformity in the
human cornea. Note the difference in alignment of collagen fibers in size and arrangement of collagen fibrils in the sclera. The eyeball of
anterior (A), middle (B), and posterior (C) regions of the stroma. Recon- lumican-null mice is larger than that of wild-type animals, whereas
structed projection image of collagen lamellae in the normal corneal
that of keratocan-deficient mice is smaller.156,158,159 Although humans
stroma are also shown (D). Note that interwoven collagen lamellae
with a mutated lumican gene have not yet been described, recent stud-
were observed at the anterior stroma. Bar: 50 μm.
ies suggest that high myopia due to an increased axial length of the eye
globe is associated with lumican gene polymorphisms.161 The relative
ECM of the scleral stroma, including both collagen and noncollage- amounts of proteoglycan components in the sclera are changed in an
nous components, is produced by the stromal fibroblasts. animal model of myopia.162 Recent studies thus suggest that matrix
Proteoglycans. Proteoglycans, the major matrix components located components of the cornea or sclera play specific roles in regulation of
in the spaces among major collagen fibrils in the stroma of the cornea the shape or size of the eye shell.
and sclera, are composed of a core protein and glycosaminoglycan
chains and are thought to modulate collagen fibrillogenesis.150,151 Physiology of the Stroma
Glycosaminoglycans comprise repeating disaccharide units and Extracellular matrix and stromal repair. Structural and biochemical
play important roles regardless of the core protein to which they are homeostasis of the ECM in the corneal stroma is maintained by a balance
attached. The functions of proteoglycans can thus be considered from in the synthesis and degradation of ECM components by keratocytes.
the points of view of both the core protein and glycosaminoglycans. In response to corneal injury, keratocytes transdifferentiate into
With the exception of hyaluronan, the glycosaminoglycans of the myofibroblasts and actively produce matrix components for healing
corneal stroma are present in the form of proteoglycans. The most of the injured stroma, with each newly expressed macromolecule
abundant glycosaminoglycan in the cornea is keratan sulfate,152 consti- appearing to play an important role in the repair process.
tuting about 65% of the total glycosaminoglycan content. The remain- During infectious ulceration of the corneal stroma, enzymes that
ing glycosaminoglycans include chondroitin sulfate and dermatan degrade the ECM of the stroma are released by both host cells and
sulfate. Glycosaminoglycans have the ability to absorb and retain large the infecting bacteria. Bacterial corneal ulcers have different clini-
amounts of water. cal manifestations that depend on the type of bacterium and may be
In terms of core proteins, the corneal stroma contains lumican, ker- attributable to differences in the types of enzyme released from the
atocan, and mimecan (osteoglycin) as keratan sulfate proteoglycans, as bacteria. Pseudomonas elastase degrades collagen directly as well as
well as decorin and biglycan as chondroitin sulfate or dermatan sulfate promoting collagen degradation by keratocytes, in part via activa-
proteoglycans (Table 1.2).153,154 These core proteins are members of the tion of pro-MMPs.163 Thus there appear to be at least three different
family of SLRPs, which contain a common central domain consisting pathways for the degradation of stromal collagen fibrils in individu-
of approximately 10 leucine-rich repeats.155 They first accumulate as als with pseudomonas corneal ulceration: (1) direct degradation by
low-sulfate glycoproteins in the embryonic stroma and subsequently bacterial collagenase, (2) degradation by MMPs released from ker-
bind glycosaminoglycans to form proteoglycans typical of the adult atocytes (or myofibroblasts) and activated by bacterial factors such
cornea. Although the roles of specific proteoglycans in the mainte- as elastase, and (3) degradation by proteases released from infiltrated
nance of corneal transparency or shape under physiologic conditions inflammatory cells. On the other hand, Staphylococcus aureus releases
or in the development of corneal haziness under pathologic condi- certain proteases but does not appear to produce factors that degrade
tions remain unclear, spontaneous mutation of a core protein gene has collagen directly. Instead, plasminogen seems to be essential for
TABLE 1.2 Glycosaminoglycans and Proteoglycan Core Proteins in the Cornea

Glycosaminoglycan Size (kDa) Constituent Disaccharide
Heparan sulfate 5–12 N-acetylgalactosamine, glucuronic acid
Heparin 6–25 N-acetylgalactosamine, glucuronic acid
Dermatan sulfate 15–49 N-acetylgalactosamine, iduronic acid
Chondroitin 4,6-sulfate 5–50 N-acetylgalactosamine, glucuronic acid
Keratan sulfate 4–19 N-acetylgalactosamine, galactose
Hyaluronan 4–8000 N-acetylgalactosamine, glucuronic acid
Core Protein Glycosaminoglycan Function
Lumican Keratan sulfate Interaction with corneal epithelial cells
Regulation of collagen fibril diameter and distance
between individual collagen fibrils
Keratocan Keratan sulfate Mutation causes cornea plana
Mimecan Keratan sulfate Unknown
Decorin Chondroitin sulfate or dermatan sulfate Wound healing
In the normal cornea, proteoglycans are synthesized by stromal keratocytes. They are transiently synthesized by corneal epithelial cells during the
early phase of wound healing.
collagen degradation induced by S. aureus infection.164 Two possible Descemet membrane is composed primarily of collagen types IV
pathways for collagen degradation associated with S. aureus infection and VIII and laminin174 but also contains fibronectin.70,71 Type VIII
are thus the direct degradation mediated by plasmin and degradation collagen, which is produced by the corneal endothelium, forms a hex-
mediated by MMP-1 released from corneal myofibroblasts and acti- agonal lattice quite different from the structure of type IV collagen in
vated by plasmin. the epithelial basement membrane. Collagen fibers in the stroma are
Cytokines and growth factors. Both keratocytes and infiltrated cells, continuous with those in the Bowman layer but not with those in the
such as lymphocytes, neutrophils, and macrophages, secrete cytokines Descemet membrane. The Descemet membrane adheres tightly to the
and growth factors and thereby modulate the behavior of cells in posterior surface of the corneal stroma and reflects any change in the
the healing corneal stroma. Each cytokine or growth factor activates shape of the stroma. Rupture of the Descemet membrane by physi-
signal transduction pathways that regulate the expression of specific cal stress, such as compression birth injury, results in the penetration
genes that contribute to the inflammatory response. Targeting of such of aqueous humor into the corneal stroma and consequent stromal
regulation at the ligand or signaling level may provide new strategies edema. The Descemet membrane does not regenerate after endothelial
for treatment of wound-related pathology. TGF-β is thought to play a cells re-cover the ruptured area. Diseases such as Fuchs dystrophy are
key role in the healing of the corneal stroma.165,166 It is expressed by associated with an atypical striated pattern of collagen deposition in
both epithelial cells and stromal cells (keratocytes or scleral fibroblasts), the Descemet membrane.175 A patient with early-onset Fuchs dystro-
as well as by inflammatory cells that activate stromal cells and phy was found to harbor a mutation in COL8A2,176 which encodes the
promote their transdifferentiation into myofibroblasts. Myofibroblasts α2 chain of type VIII collagen.
contribute not only to wound repair but also to postinjury stromal
scarring in the cornea and sclera as a result of the overproduction of Endothelial Cells
matrix components. Blockade of TGF-β signaling effectively reduces A single layer of corneal endothelial cells covers the posterior surface of
the fibrogenic reaction and consequent scarring and opacification in a the Descemet membrane in a well-arranged mosaic pattern (Fig. 1.12).
mouse model of corneal alkali burn.165,166 In humans, these cells are uniformly 5 μm in thickness and 20 μm in
The proinflammatory cytokine tumor necrosis factor (TNF)-α is width and are polygonal (mostly hexagonal) in shape. The uniformity
also upregulated in response to tissue injury.167 TNF-α induces vari- of endothelial cell size has been evaluated by statistical analysis based
ous effects in the cornea under pathologic conditions such as injury, on photographs taken by a wide-field specular microscope.177–179 In
allergy, and infection.168–171 However, the complete loss of TNF-α in young adults, the cell density is approximately 3500 cells/mm2. The
the cornea of knockout mice results in enhancement of post–alkali coefficient of variation (standard deviation/mean) for cell area is a clin-
burn inflammation, suggesting that the role of TNF-α in the cornea ically valuable marker and is approximately 0.25 in the normal cornea.
might depend on the specific condition.172 An increase in the variability of cell area is termed polymegethism.
Another morphometric parameter of the state of the endothelium is
hexagonality. In the normal healthy cornea, approximately 70%–80%
Endothelium of endothelial cells are hexagonal. However, endothelial damage can
Descemet Membrane result in a decrease in the hexagonality value and an increase in the
Descemet membrane, the basement membrane of the corneal endothe- variability of cell area (see Fig. 1.12). Deviation from hexagonality is
lium, gradually increases in thickness from birth (3 μm) to adulthood referred to as pleomorphism.
(8–10 μm) in humans. Histologic analysis reveals it to be stratified into Corneal endothelial cells contain a large nucleus and abundant
a thin (0.3 μm), nonbanded layer adjacent to the stroma, an anterior cytoplasmic organelles, including mitochondria, endoplasmic reticu-
banded zone (2–4 μm), and a posterior, amorphous, nonbanded zone lum, free ribosomes, and Golgi apparatus (see Fig. 1.12), suggesting
(>4 μm), the latter of which can represent up to two-thirds of the thick- that they are metabolically active. The endothelial cells interdigitate
ness of the membrane and is laid down over time.173 and contain various junctional complexes, including zonula occludens,
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ARGUMENTO
DEL SEPTIMO
CANTO DEL
GALLO
En el septimo canto que se sigue

el auctor concluyendo la
parabola del hijo prodigo finge
lo que comunmente suele
aconteçer en los mançebos
que aburridos de vn viçio dan
en meterse frayles; y en el fin
del canto se descriue vna
famosa cortesana ramera[480].
Gallo.—Despierta Miçilo, oye y

ten atençion, que ya te quiero
mostrar el fin, suçeso y remate
que suelen tener todas las cosas
desta vida: cómo todos los
deleytes y plazeres van a la
contina a parar en el hondo
pielago del arrepentimiento, verás
la poca dura que los plazeres
desta vida tienen, y cómo quando
el hombre buelve sobre si halla
auer perdido mucho mas sin
comparaçion que pudo ganar.
Miçilo.—Di, gallo; que muy
atento me tienes a tu graçiosa
cançion.
Gallo.—Pues vibiendo yo aqui
en tanto deleyte, tanto plazer, tan
amado, tan seruido y tan contento
que pareçia que en el parayso no
se podia el gozo y alegria más
comunicar, de noche toda la
passaua abraçado con mi diosa; y
de dia yuamonos a estanques,
riberas de rios y muy agraçiadas y
suaues fuentes, a bosques,
xardines, huertos y vergeles, y
todo genero de deleyte, á pasear
y solazar en el entretanto que se
llegauan las horas del çenar y
comer. Porque para esto tenia por
su arte en sus huertas y tierra
grandes estanques y lagunas en
las quales juntaua todos quantos
generos de pescados ay en el
mar. Delfines, atunes, rodaballos,
salmones, lampreas, sabalos,
truchas, mulos marinos, congrios,
marraxos, coraçinos, y otros
infinitos generos de pescados: los
quales puestos alli a punto
echando los ançuelos o redes, los
hazia façilmente caer para dar
plazer a los amantes. Demas
desto tenia muy deleytosos
vosques de laureles, palmas,
çipreses, platanos, arrayanes,
çedros, naranjos y frescos chopos
y muy poderosos y sombrios
nogales y otras espeçies de
arboles de gran rama y
ocupaçion. Y todos estos estauan
entretexidos y rodeados de rosas,
jazmines, azuçenas, yedras, lilios
y de otras muy graçiosas flores y
olorosas que junto a vnas
perenales y vibas fuentes hazian
vnas suaues carçeles y unos
deleytosos escondrixos
aparejados para encubrir
qualquier desman que entre
damas y caualleros hiziesse el
amor. Por aqui corrian muy
mansos conejos, liebres, gamos,
çieruos: que con manos, sin
corrida, los caçaba cada qual. En
estos plazeres y deleytes me tubo
çiego y encantado esta maga un
mes o dos: no teniendo acuerdo,
cuenta, ni memoria de mi honrra y
fe deuida a mi prinçipe y Señor, el
tiempo perdido, mi viaje y
compañia, ni de la ocasion que
me truxo alli; y ansi vn dia entre
otros (porque muchos dias, ni lo
podia ni osaua haçer) me bajé
solo a vn jardin por me solazar
con alguna libertad, y de alli
guiado no sé por qué buen
destino que me dio, traspuesto
fuera de mí, sin tener miramiento
ni cuenta con la tierra, ni con el
çielo, con el sereno, nublo, ni sol,
el alma sola traspuesta en si
mesma yua traçando en manera
de eleuamiento y contenplaçion la
ventaja que los deleytes del çielo
tenían a los de por acá; y ansi
passé de aquel jardin a vn espeso
y çerrado vosque sin mirar por mi;
y por vna angosta senda caminé
hasta llegar a vna apazible y
deleytosa fuente que con vn
graçioso corriente yua haciendo
vn sonido por entre las piedras y
yernas que sacaua los honbres
de si: y con el descuydo que
llegué alli me arrimé a vn alto y
fresco arrayan, el qual como los
mienbros descuydados y algo
cansados derroqué sobre el
començo a gemir; y como quien
soñando que se ahoga, o está en
algun peligro despierta, ansi con
gran turbaçion bolui sobre mí.
Pero torneme a sosegar quando
consideré estar en tierra y casa
donde todas las cosas causan
admiraçion, y el manjar en el plato
acontece hablar; y como sobre el
arrayan mas el cuerpo cargué,
tornó con habla humana a se
quexar diziendo: tente sobre ti, no
seas tan cruel; y yo como le oy
que tan claro habló leuantéme de
sobre él y él me dixo: no temas ni
te marauilles, Señor, que en tierra
estas donde has visto cosas de
mas espanto que verme hablar á
mi; y yo le dixe: deesa, o ninpha
del voscaxe, o quien quiera que tu
seas, perdona mi mal
comedimiento; que bien creo que
tienes entendido de mi que no he
hecho cosa por te ofender. Que la
inorançia y poca esperiençia que
tengo de ver espiritus humanos
cubiertos de cuerpos y corteças
de árboles me han hecho injuriar
con mis descuydados mienbros tu
diuinidad. Ansi los buenos hados
en plazer contino effectuen tu
dichoso querer, y las çelestiales
estrellas se humillen a tu
voluntad, que me hables y
comuniques tu humana boz, y me
digas si agora o en algun tiempo
yo puedo con algun beneffiçio
purgar la offensa que han hecho
mis miembros a tu diuino ser. Que
yo juro por vida de mi amiga
aquella que morir me haze, de no
reusar trabajo en que te pueda
seruir. Declarame quien eres y
qué hazes aqui. Respondiome él:
No soy, señor, yo deesa, ni
ninpha del vosque; no sé cómo
me has tan presto desconoçido,
que soy tu escudero Palomades.
Pero no me marauillo que no me
conozcas, pues tanto tienpo ha
que no te acuerdas de mi ni te
conoçes a ti. Como yo oy que era
mi escudero quedé confuso y sin
ser, y ansi con aquella mesma
confusion me le fue abraçar
deseoso de le tener con quien a
solas razonar, como con él solia
yo tener otros tiempos en mi mas
contina conuersaçion. Pero ansi
abraçando ramas y hojas y
troncos de arrayan le dixe; ¿que
es esto mi Palomades? ¿quien te
encarceló ay? Respondióme:
mira, señor, que esta tierra donde
estás los arboles que ves todos
son como yo. Tal costumbre tiene
la señora que te tiene aqui, y
todas las damas y dueñas que en
su compañia estan. Sabe que
esta es vna maga encantadora,
treslado y trasumpto de Venus y
otras rameras famosas de la
antigüedad. Ni pienses que obo
otra Cyrçes, ni Morganda, ni
Medea; porque a todas estas
exçede en laçiuia y engaños que
en el arte magica se pueden
saber. Esta es la huespeda que
bajando la sierra nos hospedó; y
con la guia nos enbió á este
castillo y vosque fingiendo nos
enbiar a su sobrina la doncella
Saxe. Pero engañonos, que ella
mesma es; que por gozar de tu
moçedad y loçana juuentud haze
con sus artes que te parezca su
vejez tan hermosa y moça como
agora está. Y ansi como me
dexaste en el patio quando
entramos, aqui fue depositado en
poder de otra vieja hechizera que
con regalos quiso gozar de mi; y
ansi la primera noche ençendida
en su luxuria me descubrio todo
este engaño y su dañada y
peruersa intinçion; çiega y
desuenturada pensando que yo
nunca della me auia de partir. No
pretenden estas maluadas sino
hartar su laçiuia con los honbres
que pueden auer; y luego los
dexan y vuscan otros de quien de
nueuo gozar, y hartas, porque los
honbres no publiquen su torpeza
por allá conuiertenlos en arboles y
en cosas que ves por aqui; y para
effectuar su peruersa suçiedad
tienen demonios ministros que de
çien leguas se los traen quando
saben ser conuenientes para su
mal proposito; y ansi viendome mi
encantadora desgraçiado y
descontento de sus corruptas
costumbres y que andaua
deseoso para te auisar, trabajaron
por me apartar de ti, y avn porque
no huyesse me conuertieron
desuenturado en esta mata de
arrayan que aqui ves, sin
esperança de salud; y ansi han
hecho a otros valerosos
caualleros con los quales ya con
sus artes y engaños satisfizieron
su suçiedad, y despues los
conuertieron en arboles aqui. Ves
alli el que mandó la casa de
Guevara conuertido en aquel
çipres; y aquel nogal alto que está
alli es el que mandó la casa de
Lemos despues del de Portogal; y
aquel chopo hermoso es el que
gouernó la casa de Cenete antes
del de Nasao. Y aquel platano
que da alli tan gran sonbra es uno
de los prinçipales Osorios. Aqui
verás Mendoças, Pimenteles,
Enrriques, Manrriques, Velascos,
Stuñigas y Guzmanes; que
despues de largos años han
quedado penitençiados por aqui.
Buelue, buelue, pues, señor, y
abre los ojos del entendimiento;
acuerdate de tu nobleza y linaxe.
Trabaja por te libertar; no pierdas
tan gran ocasion. No bueluas allá;
huye de aqui. Estuue por gran
pieza aqui confuso y enbobado,
que no sabia qué hablar a lo que
me dezia mi escudero
Palomades; y como al fin en mí
bolui y con los ojos del
entendimiento aduerti sobre mí,
echeme de ver; y hallé que en mi
habito y natural era estrañado de
mi ser. Halleme todo afeminado
sin pareçer en mi ni semejança de
varon: lleno de luxuria y de viçio;
untado el rostro y las manos con
vnguentos, colores y açeites con
que las rameras se suelen
adornar para atraer a si a la
diuersidad de amantes,
principalmente si en la mesma
calle y vezindad ay dos que la vna
está con la otra en porfia. Traya
vn delicado y polido vestido que a
su modo y plazer me auia texido
la mi maga por más se agradar,
con muy gentil aparato y labor.
Lleuaua vn collar rico de muy
preçiadas piedras de Oriente y
esmaltes que de ambos hombros
cuelga hasta el pecho; llenos de
anillos los dedos, y dos braçaletes
en cada braço que pareçian
axorcas de muger. Traya los
cabellos encrespados y
anillados[481] ruçiados y vntados
con aguas y açeytes olorosos y
muy preçiados. Traya el rostro
muy amoroso y bello, afeytado a
semejanza de los mançebos que
en Valençia se vsan y quieren
festejar. En conclusion por el
rostro, semblante y dispusiçion no
huuiera honbre que me
conoçiesse sino fuera por el
nombre; tan trocado y mudado
tenia todo mi ser. Luego como
mirandome vital y de capitan fiero
estimado me hallé conuertido en
viçiosa y delicada muger, de
verguença me quise morir; y se
me cayeron las hazes en el suelo
sin osar leuantar los ojos avn a
mirar el sol; marchicho[482],
confuso y sin saber qué dezir; y
en verdad te digo que fue tanta la
verguença que de mi tenia y el
arrepentimiento y pessar que en
mi spiritu entró que mas quisiera
estar so tierra metido que
ofreçerme a ojos de alguno que
ansi me pudiera ver. Pensaua
dónde yria; quién me acogeria;
quien no se reyria y vurlaria de
mi. Lastimauame mi honrra
perdida; mis amigos que me
aborreçerian; mis parientes que
me huyrian. Comienço en esto tan
miserable y cuytadamente a llorar,
que en lagrimas me pensaua
conuertir. Dezia: ¡o malditos y
miserables[483] placeres del
mundo, qué pago tan
desuenturado dais. ¡O pluguiera a
Dios que fuera yo a la guerra y mil
vezes muriera yo allá antes que
auer yo quedado en este deleyte
acá! Porque con la muerte
hubiera yo hecho la xornada
mucho a mi honrra; y ansi
quedando acá muero çien mil
vezes de muerte vil sin osar
pareçer. He faltado a mí, a mi
prinçipe y señor. Por muchas
vezes miré por el rededor de
aquella fuente por ver si auria
alguna arma, o instrumento de
fuerça con que me poder matar;
porque la mi maga de armas y de
animo me pribó; y ansi con esta
cuyta me bolui al arrayan por
preguntar a mi compañero si auia
dexado sus armas por alli,
siquiera por poder con ellas
caminar y por me defender si
alguna de aquellas malas
mugeres saliesse a mi; y como
junto a si me vio començo a
darme grandes bozes; huye,
huye, señor, que ya aparejado el
yantar anda la tu maga muy
cuydadosa a te vuscar; y si te
halla aqui sospechosa de tu fe
tomará luego vengança cruel de
ti. Porque esto vsan estas
malauenturadas de mugeres por
más que amen; si alguno les falta
y hierra no fian del honbre más, y
nunca se acaban de satisfazer;
porque sienpre quieren muy
hartas de todos trihunfar; y ansi
alçando mis faldas al rededor
començe con grande esfuerço a
correr cara donde sale el sol; yua
huyendo, sudando, cansado y
caluroso, boluiendo a cada passo
el rostro atras. Plugo a los mis
bienauenturados hados que
auiendo corrido dos horas,
avnque con gran fatiga y dolor por
aquel vosque espeso çerrado de
aspereça y matorral, en fin, sali
de la tierra de aquella mala
muger; porque a qualquiera
honbre que con efficaz voluntad
quiere huyr de los viçios le ayuda
luego Dios; y como fuera me vi,
humillado de rodillas, puestas las
manos al çielo, con animo
verdadero demandé perdon
dando infinitas graçias a Dios por
tan soberana merçed. Senteme a
vna fuente que vi alli; la qual
avnque no tenia al rededor
aquella deleytosa sombra de
aquellas arboledas y rosas que
estauan en el vosque de la
encantadora, me dio a mi mayor
deleyte y plazer, por ofreçerseme
a mayor neçesidad; y tomando
con las manos agua me començé
á labar el rostro, cabeza y boca
por echar de las venas y huesos
el calor inmenso que me
abrasaua; y ansi desnudandome
de todas aquellas delicadas ropas
y atauios me ayreé y refresqué,
proponiendo de en toda mi vida
más me las vestir. Arrojé por
aquel suelo collar, oro y joyas que
saqué de aquel Babilon;
pareçiendome que ningun dia por
mí pasó mas bienauenturado que
aquel en que ansi me vi muerto
de hambre y sed. Temia aquellos
arreos y delicadeças no me
tornassen otra vez a encantar;
pareçiendome tener en si vn no
sé que, que aun no me
dexauan[484] del todo boluer en
mi; y ansi lo mas pobre y sençillo
que pude començe á caminar
poniendo mil protestaçiones y
juras sobre mí de nunca yr donde
honbre me pudiesse conoçer;
yendo por aquellos caminos y
soledad me deparó Dios vn pastor
que de pura piedad con pan de
çenteno y agua de vn barril me
mato hambre y sed; y por acabar
de echar de mi del todo aquellos
enbeleñados vestidos hize
trueque con algunos andraxos
que él me quiso dar. Pues con
aquella pobre refeçion llegué ya
casi que anocheçia a vn
monesterio de frayles de San
Bernardo que estaua alli en vn
graçioso y apazible valle; donde
apiadandome el portero, lo mejor
que pude me albergué, y luego a
la mañana trabajé con toda
afabilidad y sabor a los comunicar
y conuersar, pareçiendome a mi
que de buena voluntad me
quedaria aqui si me quisiesen
reçebir. Pero como las guerras
acabauan en aquella sazon en
aquella tierra, pareçiendoles que
yo huuiese sido soldado y que por
no ser bueno venia yo ansi, no se
osauan por algunos dias del todo
fiar; pero por pareçerme que
aquel lugar y estado era
conveniente para mi proposito y
neçesidad, trabajé con mucha
humildad y bajeza a los asegurar
continuando en ellos mi seruiçio
quanto pude; y ansi passados
algunos dias, ya que se
començaron a fiar me obligué a
los seruir. Barriales las claustras y
iglesia; y tanbien seruia al comer
en[485] la mesa de compaña
porque luego no pude mas; y
despues andando el tiempo
pedíles el habito y como me
vieron algo bien inclinado
plugoles de me le dar con
intinçion que fuesse para los
seruir.
Miçilo.—De manera que te
obligauas por sclauo de tu
voluntad.
Gallo.—Por çierto de mayor
seruidunbre me libró Dios quando
de poder de la maga me
escapó[486]. Que lo que peor es
que entrando los hombres alli
luego se comiençan a peruertir.
Que todos quantos en aquella
orden ay todos entran ansi; y
luego tienen pensamiento y
esperança de venir a mandar.
Miçilo.—Buena intinçion lleuais
de seruir a Dios.
Gallo.—¿Pues qué piensas?
Todo es ansi quanto en el mundo
ay. Luego me dieron cargo de la
limpieça del refitorio, compañero
del refitolero.
Miçilo.—Entonces holgarte yas
mucho en gozar de los relieues
de todos los vasos de los frayles.
Gallo.—Pues como yo aprobé
algunos años en este offiçio
començaron me a ordenar. En fin,
me hizieron de misa.
Miçilo.—Grandes letras lleuauas.
Gallo.—Lleuaua todas las que
aquellos vsan entre si; y yo luego
començe a desemboluerme y
endereçar la cresta y fue
subiendo por sus grados, que
quando ubo vn año que fue de
misa me dieron la porteria; y a
otro año me dieron el cargo de
zillerero.
Miçilo.—¿Que offiçio es esse?
Gallo.—Proueer todo el
mantenimiento de casa.
Miçilo.—Gran offiçio era ese,
gallo, para te faltar; a osadas que
no estuuiesses atado a nuestra
pobre raçion.
Gallo.—Entonces cobré yo en la
casa muchos amigos: y gané
mucho credito con todos de
liberal; porque a ninguno negué
nada de todo quanto pidiesse.
Porque siempre trabajé que a
costa ajena ninguno se quexasse
de mi; y ansi me hizieron prior.
Miçilo.—Fuera de todas esas
cosas; en lo que tocaua a la
orden mucho trabajo se deue de
tener.
Gallo.—Antes te digo que no ay
en el mundo estado donde más
sin cuydado ni trabajo se goze lo
bueno que el mundo tiene; si algo
tiene que bueno se pueda dezir.
Porque tres cosas que en el
mundo se estiman las tienen alli
los frayles mejores que las gozan
todos los hombres. La primera es
el comer ordinario; la segunda
son los aposentos en que viben, y
la terçera es el credito y buena
opinion. Porque a casa de
qualquiera prinçipe, o señor que
vays, todos los honbres han de
quedar a la puerta aguardando
para negoçiar; y el frayle ha de
entrar hasta la cama; y a ningun
honbre dará vn señor vna silla, ni
le sentará a su mesa sino vn
frayle quanto quiera que sea de
todo el monesterio el mas vil.
Miçilo.—Tú tienes mucha razon;
y ansi me marauillo como ay
honbre cuerdo que no se meta
frayle.
Gallo.—Al fin mis amigos me
eligieron por abbad.
Miçilo.—¡O cómo gozarias de
aquel su buen comer y beber y de
toda su bienauenturança! Pero
dime ¿en que te ocupauas siendo
abbad?
Gallo.—Era muy amigo de
edificar y ansi hize dos arcos de
piedra muy fuertes en la bodega;
porque estaua cada dia para se
nos hundir; y porque vn refitorio
que teniamos bajo era frio, hize
otro alto de muy ricos y hermosos
artesones y molduras; y vna sala
muy sunptuosa en que comiessen
los huespedes.
Miçilo.—¿Pues no tenias alguna
recreacion?
Gallo.—Para eso tenia la casa
muchas casas en riberas de
plazer, donde auia muy
poderosos cañales y hazeñas.
Miçilo.—Dime gallo ¿con los
ayunos tienen los frayles mucho
trabajo?
Gallo.—Engañais os; porque en
ninguna orden ay mas ayunos
que vosotros teneis seglares[487],
sino el auiento; y este ayuno es
tal que siempre le deseamos que
venga; porque vn mes antes y
aun dos tenemos de recreaçion
para auerle de ayunar. Vamonos
por las granjas, riberas, deesas y
huertas que para esto tiene la
orden muy granjeado y
adereçado; y despues venido el
auiento a ningun frayle nunca
mataron avnque no le ayunasse.
Que a todo esto dizen: tal por ti
qual por mi[488].
Miçilo.—El contino coro de
maytines y otras horas no daua
passion?
Gallo.—El contino coro por
pasatiempo le teniamos y a los
maytines con vn dolor de cabeza
que se fingiesse no van a ellos en
vn mes. Que hombres son como
vosotros acá.
Miçilo.—Por çierto eso es lo peor
y lo que mas es de llorar. Pues si
eso es ansi, que ellos son
honbres como yo ¿de qué tienen
presunçion? ¿De solo el habito
han de presumir?
Gallo.—Calla, Miçilo, que
muchos dellos pueden presumir
de mucha sanctidad y religion que
en ellos ay. Que en el mundo de
todo ha de auer; que no puede
estar cosa en toda perfeçion.
Miçilo.—Espantado me tienes,
Gallo, con lo mucho que has
passado, lo mucho que has visto,
y la mucha esperiençia que
tienes; y prinçipalmente con este
tu cuento[489] me has dado
mucho plazer y admiraçion; yo te
ruego no me dexes cosa por
dezir. Dime agora ¿en qué estado
y naturaleza viuiste después?
Gallo.—Quiero te dezir del que
más me acordare conforme á mi
memoria; porque como es la
nuestra mas flaca que ay en el
animal no te podre guardar orden
en el dezir. Fue monja, fue ximio,
fue auestruz, fue vn pobre Timon,
fue vn perro, fue un triste y
miserable seruidor[490], y fue vn
rico mercader; fue Icaro Menipo el
que subió al çielo y vió allá a
Dios.
Miçilo.—Dese Icaro Menipo he
oido mucho dezir, y de ti deseo
saber más del, porque mejor que
ninguno sabras la verdad.
Gallo.—Pues mira agora de
quién quieres que te diga, que en
todo te quiero complazer.
Miçilo.—Aunque al presente
vurles de mí ¡o ingeniossissimo
gallo! con tu admirable y fingido
cuento[491] te ruego me digas:
luego como te desnudaste del
cuerpo de frayle, de cúyo cuerpo
te vestiste?
Gallo.—El de vna muy honrrada
y reuerenda monja; avnque vana
como es el natural de todas las
otras.
Miçilo.—¡O valame Dios! que
conueniençia tienen entre si
capitan, frayle y monja? De
manera que fue tiempo en el qual
tú, generosissimo gallo, te
atauiauas y lauauas y ungias
como muger; y tenias aquellas
pesadunbres, purgaçiones y
miserias que tienen todas las
otras. Marauillome como pudiste
subjetar aquella braueza y orgullo
de animo con que regias la
fiereza de tus soldados, a la
cobardia y flaqueza de la mujer; y
no de qualquiera, pero de vna tan
afeminada y pusilanime como una
monja; que demas de su natural,
tiene profesada cobardia y
paçiençia.
Gallo.—¿Y deso te marauillas?
Antes te hago saber que yo fue
aquella famosa ramera Cleopatra
egipçia hermana de aquel barbaro
Tholomeo que hizo cortar la
cabeça al gran Pompeo quando
vençido de Julio Cesar en la
Farsalia se acogió á su ribera; y
otro tienpo fue en Roma vna
cortesana llamada Julia Aspassia
mantuana en tienpo del papa
Leon deçimo. Que en loçania y
aparato exçedia a las cortesanas
de mi tienpo; y ansi tuve debajo
de mi dominio y subjeçion a todos
quantos cortesanos auia en Roma
desde el mas graue y ançiano
cardenal, hasta el camarero de
monseñor. Pues cómo te
marauillaras si vieras el brío y
desdeño con que solia yo a todos
tratar! Pues qué si te dixesse los
engaños, fingimientos y cautelas
de que yo vsaua para los atraer; y
despues quanto injeniaua para los
sacar la moneda que era mi
vltimado[492] fin. Solamente
querria que el tienpo nos diese
lugar a te contar quando fue vna
ramera de Toledo en España.
Que te quisiera contar las
costunbres y vida que tuue desde
que naci; y prinçipalmente como

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Cornea: Fundamentals, Diagnosis and

Management - eBook PDF

London New York Oxford Philadelphia St Louis Sydney 2022

First edition 1997

Csaba L. Mártonyi retains copyright of his original figures in Chapter 7.

Content Strategist: Kayla Wolfe

Last digit is the print number: 9 8 7 6 5 4 3 2 1

To Daniel J. Douglas, MD and Richard L. Lindstrom, MD who have both guided

First published in 1997, Cornea established itself as the market-leading

Gary Chung, MD Mahshad Darvish-Zargar, MDCM, MBA Steven P. Dunn, MD

Robert S. Feder, MD, MBA Prashant Garg, MD Steven A. Greenstein, MD

Frederico P. Guerra, MD Justin Hellman, MD Christopher T. Hood, MD

Joseph D. Iuorno, MD Carol L. Karp, MD Shigeru Kinoshita, MD, PhD

Priyanka Kumar, MD Michael A. Lemp, MD Thomas D. Lindquist, MD, PhD

Gabriel N. Mannis, MD Jodhbir S. Mehta, MBBS, PhD Steven M. Naids, MD

Maria Cristina Nishiwaki-Dantas, MD, Matthew R. Parsons, MD Kasey L. Pierson, BS, MD

Charles D. Reilly, MD Eric D. Rosenberg, DO, MSE Caterina Sarnicola, MD

Gary S. Schwartz, MD, MHA Patricia B. Sierra, MD Sathish Srinivasan, FRCSEd, ­

São Paulo, Brazil

Joel Sugar, MD Taíse Tognon MD, PhD Edmund Tsui, MD

Jesse M. Vislisel, MD Jayne S. Weiss, MD Elizabeth Yeu, MD

The smooth surface of the cornea contributes to visual clarity. The

cornea and conjunctiva—including epithelial cells, stromal keratocytes

ANATOMY AND PHYSIOLOGY

fibers to damage during the development of chronic open-angle glau-

TABLE 1.1 Characteristics of the Various Types of Corneal Epithelial Cells

Conjunctiva Limbus Cornea Terminally

Normal Integrin β1 Fibronectin Laminin

Corneal epithelial cells express transforming growth factor (TGF)-β1.93

provided some insight. Mutation of the keratocan gene was recently

TABLE 1.2 Glycosaminoglycans and Proteoglycan Core Proteins in the Cornea

En el septimo canto que se sigue

Gallo.—Despierta Miçilo, oye y

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Gary S. Schwartz, MD, MHA Patricia B. Sierra, MD Sathish Srinivasan, FRCSEd,