Biomechanics of The Eye 1St Edition C J Roberts W J Dupps JR J C Downs Online Ebook Texxtbook Full Chapter PDF

Biomechanics of the Eye 1st Edition C J
Roberts W J Dupps Jr J C Downs

Visit to download the full and correct content document:
https://ebookmeta.com/product/biomechanics-of-the-eye-1st-edition-c-j-roberts-w-j-du
pps-jr-j-c-downs/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
Badlands C J Box
https://ebookmeta.com/product/badlands-c-j-box/
Atone J C Owens
https://ebookmeta.com/product/atone-j-c-owens/
The Cross 1st Edition J. C. Ryle
https://ebookmeta.com/product/the-cross-1st-edition-j-c-ryle/
Snake Skin C J Lyons
https://ebookmeta.com/product/snake-skin-c-j-lyons/
Objects of Desire 1st Edition C J Emerson
https://ebookmeta.com/product/objects-of-desire-1st-edition-c-j-
emerson/
Ehlers Danlos Syndrome a Multidisciplinary Approach 1st

Edition J W G Jacobs L J M Cornelissens M C Veenhuizen
https://ebookmeta.com/product/ehlers-danlos-syndrome-a-
multidisciplinary-approach-1st-edition-j-w-g-jacobs-l-j-m-
cornelissens-m-c-veenhuizen/
The Librarian of Crooked Lane 1st Edition C J Archer
https://ebookmeta.com/product/the-librarian-of-crooked-lane-1st-
edition-c-j-archer/
Eye for an Eye 1st Edition J M Holt
https://ebookmeta.com/product/eye-for-an-eye-1st-edition-j-m-
holt/
The Lost Continent 1st Edition C. J. Cutcliffe Hyne
https://ebookmeta.com/product/the-lost-continent-1st-edition-c-j-
cutcliffe-hyne/
9 789062 992508
ISBN 978-90-6299-250-8
Copyright © 2018. Kugler Publications. All rights reserved.

BIOMECHANICS OF THE EYE

Biomechanics of the Eye
Editors
Cynthia J. Roberts
William J. Dupps Jr.
J. Crawford Downs
Kugler Publications/Amsterdam/The Netherlands

ISBN 978-90-6299-250-8
Kugler Publications
P.O. Box 20538
1001 NM Amsterdam, The Netherlands
www.kuglerpublications.com
© 2018 Kugler Publications, Amsterdam, The Netherlands

All rights reserved. No part of this book may be translated or reproduced in any form by print, photoprint,
microfilm, or any other means without prior written permission from the publisher.
Kugler Publications is an imprint of SPB Academic Publishing bv, P.O. Box 20538, 1001 NM Amsterdam,
The Netherlands
Cover design by: Willem Driebergen, Rijnsburg, The Netherlands

Table of contents
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
About the editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
1. Basics of biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Jesper Hjortdal
2. Corneal stroma: collagen ultrastructure and orientation in health and disease . . . . . . . . . . . . . 15

Keith M. Meek, Sally Hayes
3. Acoustic radiation force elastic microscopy and corneal structural correlation . . . . . . . . . . . . . 31

Eric Mikula, Donald J. Brown, Moritz Winkler, Elena Koudouna, Tibor Juhasz, James V. Jester
4. Cellular micromechanics of corneal stroma: keratocyte and extracellular

matrix interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
W. Matthew Petroll, Miguel Miron Mendoza
5. The electrochemical basis of corneal hydration, swelling, and transparency . . . . . . . . . . . . . . . 63

Peter Pinsky, Xi Cheng
6. Material properties of the human cornea: anisotropy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Ashkan Eliasy, Zhou Dong, Harald Studer, Craig Boote, Ahmed Elsheikh
7. Inflation testing of the cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Thao D. Nguyen, Jun Liu
8. Optical coherence tomography principles and elastography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Matthew R. Ford, Vinicius De Stefano, William J. Dupps Jr.
9. Optical coherence elastography for ocular biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Manmohan Singh, Michael D. Twa, Kirill V. Larin
10. Electronic speckle pattern interferometry and lateral shearing interferometry . . . . . . . . . . 147
Abby Wilson, John Marshall
11. Brillouin microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Giuliano Scarcelli, Seok Hyun Yun
12. Deformation response to an air puff: clinical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Katie Hallahan, William J. Dupps Jr., Cynthia J. Roberts
vi
13. Factors contributing to air-puff derived corneal responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Riccardo Vinciguerra, Renato Ambrósio Jr., Simone Donati, Claudio Azzolini, Paolo Vinciguerra
14. Biomechanics in ectasia detection: ORA and Corvis ST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Renato Ambrósio Jr., Fernando Faria Correia, Bernardo T. Lopes, Rui Carneiro Freitas, Isaac Ramos,
Marcella Q. Salomão, Allan Luz
15. Mechanisms of collagen crosslinking and implications on biomechanics . . . . . . . . . . . . . . . . 217

Eberhard Spoerl, David C. Paik
16. Crosslinking kinetics and alternative techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Michael Mrochen, Rebecca McQuaid, Nicole Lemanski, Bojan Pajic
17. Computational modeling of corneal refractive surgery, ectasia,

and corneal crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Ibrahim Seven, Vinicius Silbiger De Stefano, William J. Dupps Jr.
18. Comparative biomechanics of intrastromal lenticule extraction and LASIK . . . . . . . . . . . . . . 261

Dan Z. Reinstein, Timothy J. Archer, Ibrahim Seven, Cynthia Roberts, William J Dupps Jr.
19. Iris biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Anup Dev Pant, Rouzbeh Amini
20. Accommodation and presbyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Matthew Reilly
21. Biomechanics of the lens and its role in accommodation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Noël M. Ziebarth, Vivian M. Sueiras, Vincent T. Moy, Fabrice Manns, Jean-Marie Parel
22. Biomechanics of the vitreous humor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Rodolfo Repetto, Jennifer H. Tweedy
23. Introduction to posterior pole biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

J. Crawford Downs, Vicky Nguyen
24. Intraocular pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

Daniel C. Turner, Jessica V. Jasien, J. Crawford Downs
25. Collagen anisotropy in scleral mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

Neeraj Vij Jr., Jonathan Vande Geest
26. The dynamic response of the corneoscleral shell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

Jun Liu, Keyton L. Clayson, Elias R. Pavlatos
27. Scleral remodeling in myopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

Rafael Grytz
vii
28. The connective tissue phenotype of glaucomatous cupping in the monkey eye . . . . . . . . . . 405
Hongli Yang, Juan Reynaud, Howard Lockwood, Galen Williams, Christy Hardin, Luke Reyes, Cheri Stowell,
Stuart K. Gardiner, Claude F. Burgoyne
29. Cellular mechanisms of lamina cribrosa remodeling in glaucoma . . . . . . . . . . . . . . . . . . . . . . 431

Reinold K. Goetz, Deborah Wallace, Tabitha Goetz, Colm O’Brien
30. Optic nerve head biomechanics in health, aging, and disease . . . . . . . . . . . . . . . . . . . . . . . . . 443
J. Crawford Downs
31. Cerebrospinal fluid pressure and the translaminar pressure gradient in optic nerve head
biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Julia Raykin, Brian C. Samuels, Andrew J. Feola, C. Ross Ethier
32. Parametric analysis to identify biomechanical risk factors:

taking control of population diversity and experiment variability . . . . . . . . . . . . . . . . . . . . . . . . . 479
Andrew P. Voorhees, Yi Hua, Ian A. Sigal
33. In-vivo characterization of optic nerve head biomechanics for improved glaucoma
management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Xiaofei Wang, Meghna R. Beotra, Liang Zhang, Michaël J.A. Girard
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Foreword: Biomechanics of the eye
To illustrate the explosive growth of biomechanical studies in ophthalmic science,
I checked the 9th and 11th edition of Adler’s Physiology of the Eye, a veritable Bible
of the field. The 1992 edition had not one indexed comment on “biomechanics”,
while the 2011 version had two index entries for its nearly 1,000 pages! The cornea
sections dealt with ultrastructure, light transmission, endothelial pumping, and
neovascularization, but not bending forces, and the sclera was treated anatomical-
ly, but not physiologically. It is fortunate for us that a distinguished group of inter-
national experts contributed to the present volume, enlightening us on a series of
vitally important issues that now occupy an important place in the understanding
of how eyes work and don’t work.
Seeing is believing: Inherent in many of the presentations to follow are new
methods of viewing the ocular tissues. Advancing from the microcosmic window
of transmission electron microscopy, we see the cornea and other ocular tissues
clinically through the useful view of optical coherence tomography. Ex-vivo study methods now include a plethora
of illuminating techniques that show the orientation of fibers, their composition, and their change in inflation
studies: small angle light scattering, wide angle x-ray scattering, magnetic resonance imaging, and microscopy
utilizing polarization, second harmonic generation, and two photon imaging. Many of these use unfixed tissue to
avoid the major processing changes that alter tissue physiology. They permit in many cases the reconstruction of
3-D structure and its response as an in-vivo unit.
Life in a bubble: While past studies put strips of cornea or sclera under uniaxial stretch, the ocular tissues
behave as a 3-D globe, and the work to be presented moves to study ocular tissues in their situation in situ, at
least insofar as is practical given the limitations of methods. From studies that began by speckling the scleral
surface and inflating the globe, we now have microscopic methods of viewing the strain and fiber orientation of
the full thickness of the cornea or sclera under stress. Furthermore, for many diseases, it is the process of aging or
response to change in the tissue that determines whether abnormality is functionally important and how badly
the eye is affected. Thus, disease-simulating experimental models of tissue change in animals are important.
Pretty models: To understand how, and more importantly why, a tissue responds as it does, we benefit from
the expertise of those who can construct model systems that simulate tissue reactions. These not only include
all of the important elements as variables to weigh their relative importance, but permit systematic alteration in
the magnitude of each variable to assess through sensitivity analysis its likely contribution. These models can be
used most effectively when relevant data for each parameter is measured experimentally. Models in animals have
begun to show us that looking only at baseline parameters is insufficient, as remodeling during disease may be
more important than where the tissue started. This shows the value of teams of clinician-scientists and engineers
working forceps to caliper.
Who needs a disease: The book deals not only with diseases and their detrimental effect on quality of life,
but also with more common features of the visual system that affect us: refractive error and presbyopia. Pop-
ulation-based studies now show that the most common causes of visual disability worldwide are the need for
distance and reading glasses. If one wishes to start a career in vision science with the aim of having the maximum
impact on the world, it would be to fix these two. The present book takes on aspects of these troubling problems
and what biomechanics teaches about them.
Softer mechanics: The eye has a variety of tissues that have biomechanical processes other than those that
are classically considered part of the engineering repertoire (cornea and sclera). We are increasingly aware
that collagenous fibers are one aspect of biomechanical response, but their accompanying matrix and cellular
components play important roles as well. Recent research shows that we need to know more about the mechanics
x
of the trabecular meshwork (relevant to glaucoma and newer glaucoma surgeries), of the iris (for contributions to
angle closure mechanisms), of the vitreous (for contribution to retinal detachment), and of the choroid (for rela-
tionships to myopia and age-related macular degeneration).
Who cares? Basic knowledge leads to important future clues for both diagnosis and therapy. Important avenues
for diagnostic biomarkers have been developed for the contributions of corneal hysteresis, central corneal
thickness, iris volume loss on pupil dilation, and optic nerve head flexibility, among many others. The models
point to potential treatments, and in the case of corneal ectasia, making the structure stiffer has shown promise
for avoiding the need for replacement surgery of the cornea. For glaucoma, making the eye stiffer to limit strain
has (at least in mice) made things worse, not better, so one size does not fit all.
This volume has a huge collection of the best presentations by the sharpest minds in this field. Enjoy.
Harry A. Quigley, MD
A. Edward Maumenee Professor, Ophthalmology, Wilmer Institute, Johns Hopkins, Baltimore, MD, USA
Introduction
J. Crawford Downs, William J. Dupps Jr., Cynthia J. Roberts
Biomechanics is the study of the mechanical interaction of solids and/or fluids with internal and external forces in
the context of biology. It has long been a mainstay in the cardiovascular and orthopedic fields, where it has been
used to analyze and predict the mechanical and biological mechanisms underlying bone fractures, hard and soft
tissue remodeling, and blood flow through arterial stents and aneurysms. Biomechanical techniques are critical
in optimizing cardiac and orthopedic implant designs for maximum clinical efficacy and life.
Ocular biomechanics has been primarily focused on diseases of the cornea, trabecular meshwork, sclera, and
optic nerve head, with more limited application in the vitreous, lens, and iris. It has provided insight into disease
processes and surgical outcomes in various eye disorders. For example, in glaucoma, ocular biomechanics has
been used to analyze and predict the importance of the sclera in determining the biomechanics of the lamina
cribrosa, the site of axonal damage in glaucoma. In the cornea, the science of biomechanics has been used to
better understand the structural basis of corneal ectatic diseases and to develop biomechanically mediated
treatments for keratoconus that have already resulted in a global reduction in the number of corneal transplants
required for this disease.
Biomechanical engineers use cutting-edge engineering-based computational and experimental techniques to
investigate the interaction of ocular tissues with their surroundings, as well as the forces that are common in
the eye: intraocular pressure, tensile and torsional muscle tractions, blood flow and vascular pressures, external
traumatic forces, cerebrospinal fluid pressure, and tissue growth pressures. The tools bioengineers use include
finite element modeling, a computational technique to split complex geometries into small regularly shaped
elements, for which loading, mechanical stress (force distribution), and mechanical strain (local deformation) are
calculated individually. The results of each of these simple elemental responses are then added up, or superposed,
into the overall response of the structure. Measures of tissue deformation under load can now be obtained with
imaging techniques, such as ultrasound biomicroscopy, optical coherence tomography, Scheimpflug tomography,
infrared corneal reflection monitoring, and magnetic resonance imaging, and these observations can be used
to generate various approximations of biomechanical properties and validate computational biomechanics
simulations. Many of these measurement technologies are being developed (or are already available) for in vivo
and clinical applications.
The structural geometries in the human body are much more complex than typical engineered structures, such
as bridges and airplane wings. Biological tissue stiffness is inherently complex in that it changes with orientation
(anisotropy), the rate of loading (viscoelasticity), and the level of stretch or compression (hyperelasticity). Com-
putational models require accurate representations of tissue geometry, loading and constraints on the modeled
structure, and compliance or stiffness of the tissue constituents. Whereas certain elements of the ocular anatomy
such as the cornea are very accessible to measurement, measurements are more difficult to obtain in very small
structures and more posterior ocular components. Important factors such as fluid pressures or blood flow are
nearly impossible to measure using current technology. When accurate representations of the model inputs are
unavailable, simple representative geometries coupled with simplifying assumptions on the loading and tissue
material properties can still be used to construct models that reveal fundamental relationships regarding the
responses of tissues to load.
The eye boasts one of nature’s most exquisite relationships between structure and function. Ocular function
is a complex product of the eye’s constitutive elements, their mechanical properties, and a host of biological
processes responsible for normal function, immunological defense, repair, and disease. This book introduces the
eye as a biomechanical entity and surveys emerging efforts to apply biomechanical principles to understanding
mechanisms of ocular disease, enhancing diagnosis, and optimizing treatment.
About the editors
Cynthia J. Roberts
Dr. Roberts received a BS degree in Nursing with Distinction from the University of
Iowa in 1979, and worked as a Registered Nurse for several years at the University
of Iowa Hospitals and Clinics before enrolling in engineering. She received an MS
degree in Electrical Engineering in 1986, and a PhD in Biomedical Engineering in
1989, both from The Ohio State University. Dr. Roberts is currently a Professor in
Ophthalmology & Visual Science, and Biomedical Engineering at The Ohio State
University, and holds the Martha G. and Milton Staub Chair for Research in Oph-
thalmology. Her research focus is ophthalmic engineering, or the application of
engineering principles and problem-solving techniques to the maintenance and
improvement of vision. Corneal topography was her first area of research within
ophthalmology. Her other research interests include ocular biomechanics in
refractive surgery, cornea and glaucoma; intraocular pressure measurement
error; the in-vivo assessment of corneal biomechanical properties using ultrasonic
and dynamic imaging techniques; ophthalmic imaging applications including intraoperative topography-guided
surgery, Scheimpflug tomography, and optical coherence tomography with both corneal and retinal applications.
She is well published in these areas and has many international collaborators. Dr. Roberts serves on the editorial
boards of the Journal of Refractive Surgery, the Journal of Cataract and Refractive Surgery, and the Internation-
al Journal of Keratoconus and Ectatic Corneal Diseases. She has given many invited lectures internationally, and
multiple courses in corneal topography and corneal biomechanics, in both the United States and Europe. Dr.
Roberts received the inaugural Barraquer Medal from the Brazilian Society of Refractive Surgery in 2008 with
a lecture entitled ‘Biomechanical Customization: The Next Generation of Refractive Surgery.’ She was inducted
as a Fellow in the American Institute for Medical and Biological Engineering in 2009, and was recognized by the
American Academy of Ophthalmology with an Achievement Award in 2012.
William J. Dupps Jr., MD, PhD, a native of Catawba Island, Ohio, is Professor of
Ophthalmology at the Cleveland Clinic Lerner College of Medicine of Case Western
Reserve University and Staff in Ophthalmology, Biomedical Engineering and Trans-
plantation at Cleveland Clinic’s Cole Eye Institute and Lerner Research Institute.
He is an Adjunct Professor of Biomedical Engineering at Case Western Reserve
University and adjunct faculty in the Department of Chemical and Biomedical
Engineering at Cleveland State University. After graduating with a BS in Chemical

Engineering from Purdue University, he completed MS and PhD programs in
Biomedical Engineering at The Ohio State University and earned a medical degree
with honors in the Medical Scientist Training Program. He completed a residency
in Ophthalmology at the University of Iowa Department of Ophthalmology and
Visual Sciences and a two-year Cornea and Refractive Surgery Fellowship at the
Cole Eye Institute, a program for which he now serves as Director. His clinical
practice focuses on refractive surgery, corneal disease, and cataract surgery.
With grant support that includes the National Institutes of Health, the Ohio Third Frontier program and Research
xiv
to Prevent Blindness, Dr. Dupps leads an interdisciplinary research team in translational corneal biomechanics.
His research addresses the biomechanics of corneal refractive surgery and corneal ectatic disease as well as the
development of novel approaches to optimizing corneal surgery through computational modeling and biome-
chanical measurement. Dr. Dupps’ has received the Achievement Award for service to the American Academy
of Ophthalmology (AAO), the Kritzinger Award from the International Society of Refractive Surgery and a Dis-
tinguished Alumnus Award from The Ohio State University College of Engineering. He is currently chair of the
AAO Practicing Ophthalmologist Curriculum Refractive Management & Intervention Panel. He is a member of the
American Ophthalmological Society.
Dr. Dupps serves as Associate Editor for the Journal of Cataract and Refractive Surgery and Translational Visual
Science and Technology and served previously as an Executive Editor for Experimental Eye Research. He has
published 120 journal articles and editorials and has delivered over 150 invited lectures. He holds several patents
and received the Cleveland Clinic’s first Early Career Innovation Award in 2009 for founding OptoQuest, a Cleveland
Clinic spin-off for commercializing systems to improve surgical planning through patient-specific computational
simulation. He lives with his wife, Gretchen, and their three children in Bay Village, Ohio.
J. Crawford Downs
J. Crawford Downs received his PhD in Biomedical Engineering in 2002 from

Tulane University in New Orleans, Louisiana, and is now Professor of Ophthalmol-
ogy, Biomedical Engineering, and Computer Science at the University of Alabama
at Birmingham (UAB) in Birmingham, Alabama, USA. He served as Vice Chair of
Research in the Department of Ophthalmology during the department’s building
phase (2013-2017) and as founding Director of the UAB Ocular Biomechanics and
Mechanobiology Program. Prior to joining UAB, Dr. Downs held appointments as a
Research Assistant Professor at the Louisiana State University Eye Center in New
Orleans, Louisiana (2002-2005), and as an Associate Scientist at the Devers Eye
Institute in Portland, Oregon (2005-2012). He has spent his career studying ocular
biomechanics, focusing in particular on biomechanics and mechanobiology of
the optic nerve head (ONH), sclera, and lamina cribrosa to better understand the
pathophysiology of glaucoma, a leading cause of irreversible blindness worldwide.
Dr. Downs uses the unilateral, inducible model of glaucoma in non-human primates, and has developed a novel
wireless telemetry system that measures and records continuous intraocular pressure, arterial blood pressure,
and intracranial pressures in both normal and glaucoma eyes. He uses these data, along with laser-based ocular
inflation testing data and high-resolution 3-D reconstructions of the ONH geometry, as inputs to finite element
models of ONH biomechanics. He also works in human donor eyes when possible. Dr. Downs’ laboratory is funded
by R01 grants from the National Eye Institute of the National Institutes of Health, Bright-Focus Foundation, Research
to Prevent Blindness (departmental support), and the EyeSight Foundation of Alabama. He has authored over 70
peer-reviewed research papers, 12 book chapters, and hundreds of conference abstracts, and he is a frequent
invited lecturer at domestic and international meetings and institutions. Dr. Downs serves on the NASA Research
and Clinical Advisory Panel for Space-associated Neuro-ocular Syndrome (SANS). He also serves on the editorial
board of Current Eye Research and is a frequent reviewer and/or guest editor for a multitude of journals, including
Investigative Ophthalmology and Visual Science, PLoS One, Nature Scientific Reports, Ophthalmology, and JAMA
Ophthalmology. Dr. Downs is a frequent reviewer of grant proposals to NIH, domestic foundations, and foreign
governments.
List of contributors
Renato Ambrósio Jr.
Department for Ophthalmology of the Federal University of The State of Rio de Janeiro (UniRIO) and Federal
University of São Paulo (UNIFESP), Brazil; Rio de Janeiro Corneal Tomography and Biomechanics Study Group, Rio
de Janeiro, Brazil; Instituto de Olhos Renato Ambrósio and VisareRIO, Rio de Janeiro, Brazil
Rouzbeh Amini
Department of Biomedical Engineering, The University of Akron, Akron, OH, USA
Tim Archer
London Vision Clinic, London, UK
Claudio Azzolini
Department of Medicine and Surgery, University of Insubria, Varese, Italy
Meghna R. Beotra
Ophthalmic Engineering & Innovation Laboratory, Department of Biomedical Engineering, Faculty of Engineering,
National University of Singapore, Singapore
Craig Boote
Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
Donald J. Brown
Gavin Herbert Eye Institute, School of Medicine, University of California, Irvine, USA; Department of Biomedical
Engineering, University of California, Irvine, USA
Claude Burgoyne
Devers Eye Institute, Optic Nerve Head Research Laboratory, Legacy Research Institute, Portland, OR, USA; Devers
Eye Institute, Discoveries in Sight Research Laboratories, Legacy Research Institute, Portland, OR, USA
Xi Cheng
Department of Mechanical Engineering, Stanford University, Stanford, California, USA
Keyton L. Clayson
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
Fernando Faria Correia

Rio de Janeiro Corneal Tomography and Biomechanics Study Group, Rio de Janeiro, Brazil; Cornea and Refractive
Department, Hospital de Braga, Braga, Portugal; Cornea and Refractive Department, Instituto CUF, Porto,
Portugal; School of Health Sciences, University of Minho, Braga, Portugal
Vinicius de Stefano
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA; Ophthalmology and Visual Sciences, Federal University
of São Paulo, São Paulo, SP, Brazil
xvi
Simone Donati
St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom
J. Crawford Downs
Department of Ophthalmology, University of Alabama at Birmingham School of Medicine Birmingham, AL, USA

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Ophthalmology, Cleveland Clinic Lerner
College of Medicine of Case Western Reserve University, Cleveland. OH, USA; Department of Biomedical Engineering,
Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Biomedical Engineering, Case
Western Reserve University, Cleveland, OH, USA
Ashkan Eliasy
School of Engineering, University of Liverpool, Liverpool, UK
Ahmed Elsheik
School of Engineering, University of Liverpool, Liverpool, UK; NIHR Biomedical Research Centre for Ophthalmol-
ogy, Moorfields Eye Hospital NHS Foundation Trust, London, UK; Institute of Ophthalmology, University College
London, London, UK
Ross Ethier
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University,
Atlanta, GA, USA George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta,
GA, USA
Andrew J. Feola
Atlanta, GA, USA
Matthew Ford
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
Rui Carneiro Freitas

Rio de Janeiro Corneal Tomography and Biomechanics Study Group, Rio de Janeiro, Brazil; Cornea and Refractive
Department, Hospital de Braga, Braga, Portugal
Stuart K. Gardiner
Devers Eye Institute, Discoveries in Sight Research Laboratories, Legacy Research Institute, Portland, OR, USA
Michaël Girard
National University of Singapore, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre,
Singapore
Tabitha Goetz
Department of Ophthalmology, School of Medicine & Mater Misericordiae University Hospital, University College
Dublin, Dublin, Ireland
xvii
Reinold K. Goetz
Rafael Grytz
Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
Katie Hallahan
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
Christy Hardin
Sally Hayes
Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
Jesper Hjortdal
Department of Ophthalmology, Aarhus University Hospital NBG, Aarhus, Denmark
Yi Hua
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
Jessica V. Jasien
Department of Vision Sciences, School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA
James Jester
Tibor Juhasz
Elena Koudouna
Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales,
UK
Kirill Larin
Department of Biomedical Engineering, University of Houston, Houston, TX, USA; Department of Molecular
Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
Nicole Lemanski
Mabel Cheng MD PLLC, Albany, USA
Jun Liu
xviii
Howard Lockwood
Bernardo T. Lopes
Alan Luz
de Janeiro, Brazil; Hospital de Olhos de Sergipe, Aracaju, Brazil
Fabrice Manns
Department of Biomedical Engineering, University of Miami College of Engineering, Miami, FL, USA; Ophthalmic
Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
John Marshall
Institute of Ophthalmology, University College London, London, UK
Rebecca McQuaid
University College of Dublin, Dublin, Ireland
Keith Meek
Miguel Miron Mendoza

Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Eric Mikula
Gavin Herbert Eye Institute, School of Medicine, University of California, Irvine, USA
Vincent T. Moy
Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA
Michael Mrochen
IROC Science AG, Zürich, Switzerland; Swiss Eye Research Foundation, Reinach AG, Switzerland
Vicki Nguyen
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA
Colm O’Brien
xix
David C. Paik
Paik Laboratory for Tissue Cross-linking, Columbia University Medical Center, New York, NY, USA
Bojan Pajic
Orasis AG, Reinach, Switzerland; Swiss Eye Research Foundation, Reinach AG, Switzerland
Arun Dev Pant

Department of Biomedical Engineering, The University of Akron, Akron, OH, USA
Jean Marie Parel

Department of Biomedical Engineering, University of Miami College of Engineering, Miami, FL, USA; Ophthalmic
Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
Elias R. Pavlatos
Matthew Petroll
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Biomedical
Engineering Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA
Peter Pinsky
Department of Mechanical Engineering, Stanford University, Stanford, California, USA
Isaac Ramos
Rio de Janeiro Corneal Tomography and Biomechanics Study Group, Rio de Janeiro, Brazil; Hospital de Olhos
Santa Luzia, Maceió, Brazil
Julia Raykin
Atlanta, GA, USA
Dan Reinstein
London Vision Clinic, London, UK; Department of Ophthalmology, Columbia University Medical Center, New York,
NY, USA; Centre Hospitalier National d’Ophtalmologie, Paris, France; Biomedical Science Research Institute,
University of Ulster, Coleraine, Northern Ireland
Matthew A. Reilly
Department of Biomedical Engineering, Department of Ophthalmology & Visual Science, The Ohio State University,
Columbus, OH, USA
Rodolfo Repetto
Department of Civil, Chemical and Environmental Engineering, University of Genoa, Genoa, Italy
Luke Reyes
xx
Juan Reynaud
Cynthia Roberts
Department of Ophthalmology & Visual Science, Department of Biomedical Engineering, The Ohio State University,
OH, USA
Marcella Q. Salomão
Brian C. Samuels
Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL, USA
Giuliano Scarcelli
Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
Ibrahim Seven
Ocular Biomechanics & Imaging Lab, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
Ian Sigal
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering,
University of Pittsburgh, Pittsburgh, PA, USA
Manmohan Singh
Department of Biomedical Engineering, University of Houston, Houston, TX, USA
Eberhard Spoerll
Carl Gustav Carus University Hospital, Department of Ophthalmology, Dresden, Germany
Cheri Stowell
Harald Studer
Swiss Eye Research Foundation, Reinach, Switzerland; OCT Research Laboratory, Department of Ophthalmology,
University of Basel, Switzerland
Vivian M. Sueiras
Department of Biomedical Engineering, University of Miami College of Engineering, Miami, FL, USA
Michael Twa
School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA
xxi
Daniel C. Turner
Department of Vision Sciences, School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA
Jennifer H. Tweedy
Department of Bioengineering, Imperial College London, London, UK
Jonathan Vande Geest

Departments of Bioengineering and Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
Neeraj Vij Jr.

Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA
Paolo Vinciguerra
Humanitas University, Department of Biomedical Sciences, Milan, Italy; Humanitas Clinical and Research, Rozzano,
Italy
Riccardo Vinciguerra
St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom
Andrew P. Voorhees
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
Deborah Wallace
Xiaofei Wang
Galen Williams
Abby Wilson
Wolfson School of Mechanical, Manufacturing and Electrical Engineering, Loughborough, UK
Moritz Winkler
Department of Biomedical Engineering, University of California, Irvine, USA
Hongli Yang
Seok Hyun Yun

Wellman Center for Photomedicine, Massachusetts General Hospital, Cambridge, MA, USA; Department of
Dermatology, Harvard Medical School, Boston, MA, USA
xxii
Liang Zhang
Dong Zhou
School of Engineering, University of Liverpool, Liverpool, UK
Noël M. Ziebarth
Department of Biomedical Engineering, University of Miami College of Engineering, Miami, FL, USA
CORNEA
1. Basics of biomechanics
Jesper Hjortdal
Department of Ophthalmology, Aarhus University Hospital NBG, Aarhus, Denmark
1. Introduction
Biomechanics is mechanics applied to biology and cornea as a tissue, which easily imbibes water. Based
seeks to understand the mechanics of living systems.1 on the author’s previous experience with experimental
The term biomechanics can thus be applied to the studies on corneal biomechanics and present position
investigation of a variety of physical and chemical tissue as an anterior segment surgeon, the aim is to keep the
properties. Having a basic understanding of the biome- level basic, trying to ensure that the content is under-
chanical properties of the eye has become increasingly standable for ophthalmology residents and clinicians
important for clinicians working within the ophthalmo- working with refractive and other types of corneal
logical specialty. surgery.
The anterior-most portion of the eye, the cornea, has
unique biomechanical properties which are essential for
preserving a stable refractive state. Corneal refractive 2. Elasticity
procedures all disrupt the anatomical integrity of
the cornea; due to the physical stress of intraocular The basic elements of elasticity are those of strain
pressure, this will result in a secondary deformation. and stress, which are connected through the elastic
The degree of deformation is dependent on the biome- properties of the material.2 When a force is applied to
chanical properties of the cornea. The intrinsic biome- a fixed structure, it will deform to the point where the
chanical properties of the cornea can also be affected developed opposing force in the structure balances
in diseases such as keratoconus and can today be the applied force. For the same size of applied force,
modified using corneal crosslinking. the extent of deformation will depend both on the
In addition to the importance of corneal biomechan- size and shape of the unloaded structure and on the
ics in corneal optics, clinical methods for measurement direction of the applied force. Consequently, absolute
of the intraocular pressure are based on deformation deformations are related to the original undeformed
of the cornea. The degree of deformation will therefore shape of the structure and quantified as strains, and
not only depend on the magnitude of the intraocular forces are converted to stresses (force per unit area).
pressure, but also on the specific biomechanical Deformation and force can be decomposed into
properties of the individual cornea. tensor components acting in parallel or perpendic-
This chapter will give an introductory overview of ular to each other, eventually giving rise to normal as
the basic parameters used for characterizing the bio- well as shear stresses and strains. A Hookean elastic
mechanical properties of tissues. The main focus will solid is a solid that obeys Hooke’s law, which states
be on in-vitro studies and in-vivo studies of the human that the stress tensor is proportional to the strain
cornea by means of an experimental approach, all tensor. The constants that determine how the tissue
taking into account the very special feature of the strains for a certain stress form together the consti-
Correspondence: Jesper Hjortdal, MD, PhD, DrMedSci, Department of Ophthalmology, Aarhus University Hospital NBG, Norrebrogade
44, 8000 Aarhus C, Denmark.
E-mail: jesper.hjortdal@dadlnet.dk
Biomechanics of the Eye, pp. 3-13

Edited by: C.J. Roberts, W.J. Dupps and J.C. Downs
4 J. Hjortdal
3. Measurement of the extensibility of

the cornea
In order to measure the in-plane, or tangential extensi-
bility of the cornea, a force must stress the tissue. Two
principles have been used in the past: either strip exten-
siometry or inflation tests based on pressure loading of
the intact eye or the isolated anterior segment.
3.1. Strip extensiometry

In strip extensiometry, strips of corneal tissue are
excised and grasped by a dedicated biotester (Fig. 2).
Fig. 1. A typical illustration of loading of a biological specimen. The Typically, the tissue is cycled and stretched until the
relation between strain and stress is non-linear. difference between loading and relaxation curves is
reduced as a pre-conditioning procedure. The stress in
tutive properties of the material. A material without the tissue is calculated from the force applied divided by
symmetry with respect to its mechanical properties is the cross-sectional area of the tested strip. The strain is
called anisotropic. On the other hand, in an isotropic calculated as the relative elongation of the tissue strip
material the elastic properties are independent of the from the non-stressed length. Finally, Young’s modulus
orientation of the specimen. From the two constants of elasticity is calculated from the slope of the stress-
(the Lamé constants) necessary to fully characterize an strain curve.
isotropic material, the more commonly used Young’s Several previous studies have investigated the
modulus of elasticity, the shear modulus, and Poisson’s in-plane membrane elasticity of the human cornea using
ratio can be calculated.2 strip extensiometry.4-9 Values for Young’s modulus range
Few biological materials are linearly elastic and from 0.5 to 80 MPa, while those performed at physio-
isotropic. In most cases, biological materials exhibit logical stress levels fall approximately between 0.5 and
a non-linear relationship between the stress and the 5 MPa. The studies have all documented that corneal
strain tensors, that is, the material is non-linearly elastic tissue shows stress-stiffening, as the deformation
(Fig. 1). Biological materials typically show some sort of curve is non-linear. This means that Young’s modulus of
preferential orientation of their fibrillar micro-structur- elasticity becomes greater at higher levels of stress in
al constituents causing anisotropic material properties, the tissue.
but also display symmetry in one or more planes.
Various levels of symmetry thus exist between the two
extremes of anisotropy and isotropy. Considering the
microstructure of the cornea, with ground substance
embedded collagen fibrils mainly running in lamellar
sheets parallel to the corneal surface,3 it is apparent that
the cornea is not an isotropic material. An orthotropic
material exhibits symmetry of its elastic properties

with respect to two orthogonal planes;2 such a model
may, to some basic limits, be considered sufficient to
describe the elastic behavior of the corneal stroma.
Fig. 2. Strip extensiometry of a specimen.

Basics of biomechanics 5
When comparing results, it is of utmost importance moduli of elasticity to be calculated. Values around 5-10
to note which pre-stress level was used. Although this MPa were measured in these studies.
in principle should be zero, a small force is necessary Alternatively, a more indirect approach can be
to make the curved corneal tissue strip straight.10 As used only if the cornea and surrounding limbal tissue
corneal tissue shows stress-stiffening, it is also essential is mounted and fixed in a test chamber. In such a
to refer to a specific stress-level for the determined model, changes in corneal apex position and corneal
Young’s modulus. curvature can be measured, and Young’s moduli can
Quantitatively, the results from these studies vary be calculated.15 Values for Young’s modulus in these
one order of magnitude, possibly due to varying or studies, however, were less than 1 MPa. It is not clear
uncontrolled experimental circumstances. what caused this discrepancy, but fixation of the
peripheral cornea may have affected the fibril organi-
3.2. Inflation tests zation within the tissue.
To avoid the difficulties associated with strip extensi- In inflation tests, Young’s modulus of elasticity of the
ometry, whole-organ setups have also been used for cornea has also been found to increase with increasing
in-vitro experiments. By studying the cornea in situ, load, corresponding to non-linear elasticity.13-15
application of physiological stresses becomes easier as It has been suggested that folding of fibrils in the
the intraocular pressure can be used for setting up the relaxed state is the structural basis for the observed
stress in the tissue. Intraocular pressure gives rise to a non-linearity in mechanical testing of parallel-fibered
wall tension in the cornea, which can be estimated from structures such as tendons and ligaments.16 When the
the corneal curvature and corneal thickness using the specimen is loaded, the folding will gradually disappear
law of Laplace (Fig. 3). The whole-organ in-vitro setup is during the “toe-region” of the stress-strain curve,
also advantageous for comparison of in-vitro and in-vivo active load-bearing fibrils will be sequentially recruited,
experiments, as similar variables may be measured and and in the linear part all fibrils will have straightened.
compared. Whole-organ experiments require, however, Thus, sequential recruitment of fibrils may cause the
application of more complex mechanical theories and observed non-linearity in stress-strain curves obtained
additional assumptions, as loading inevitably becomes in swollen corneas.13,14,17,18 The fibrils of the normo-hy-
multi- rather than uni-directional as in strip extensiome- drated human cornea have not been found to fold or
try experiments.11 In the cornea, the in-plane meridional crimp during unloading, whereas fibrils in the rabbit
and circumferential corneal stresses may be estimated cornea do.19 Stromal striations have, however, been
from the equations for a thin surface of revolution12 as observed in the normal living human cornea.20 If the
mathematical derivatives of the law of Laplace.13,14 In folded or crimped collagen fibrils are assumed to follow
testing, the corneal tissue is stress-loaded by varying a sinusoidal course with an amplitude of a and a period
the intraocular pressure and the resulting deformation of λ, the slack strain due to unfolding of the fibril will be
strain of the cornea can be measured, allowing Young’s (π a / λ)2.19 Thus, it can be calculated that for small slack
strains, for example 1%, the ratio between amplitude
and wave length will be 3%. It appears that such low
amplitudes may easily escape detection using conven-
tional morphometric techniques. Accordingly, low-am-
plitude crimp of the collagen fibrils might contribute

to the observed non-linear elastic response of the nor-
mo-hydrated human cornea. Local reorientation of
fibrils under stress may, however, also be responsible
for the “toe-region” in stress-strain curves.21 Structural
studies of the conformation of collagen molecules
Fig. 3. Inflation testing of the cornea. (A) Side view of the eye.
(B) Frontal view of the eye. Strains in the circumferential and
have also revealed axial regions of alternating “order”
meridional direction can be measured and corresponding stresses and “disorder”.22 Application of stress to a fibril may
can be calculated from (A). then result in preferential unraveling of the regions
6 J. Hjortdal
of disorder, resulting in non-linear elasticity of the regions must be caused by regional differences in
collagen fibril itself. the ultrastructural components responsible for the
mechanical performance of the tissues. From this
viewpoint, it can be considered useful to look on the
4. Regional elastic differences in the cornea as a fiber-reinforced material27 in which the
cornea collagen forms the enhancing fibrillar structure and
the ground substance forms the matrix.14 In this case,
The regional corneal elasticity has been studied in differences in the elastic modulus can be caused by
whole-eye inflation tests.14 The studies revealed that variations in:
the circumferential strain of the corneal limbus is fairly 1. the elastic modulus of the fibrils;
similar to the circumferential strain of the corneal 2. the degree of reinforcement (mix-ratio of fibril to
regions during pressure loading. When calculated for ground substance);
the same intraocular pressure load intervals, the highest 3. the efficacy factor (orientation of the fibrils); and
modulus of elasticity was found at the center and the 4. the sequential recruitment of fibrils.
para-central region in the meridional direction, and From considerations on the ultrastructure of the
at the limbus in the circumferential direction. A higher cornea, it can be hypothesized that the difference in
modulus of elasticity in a certain direction and region elasticity in the meridional direction is possibly caused
corresponds to an increased resistance to deformation, by a variable recruitment of collagen fibrils, whereas
and suggests that these particular regional directions the circumferential limbal enhancement is caused by
behave like functional ligaments. In order to investigate preferential circumferential orientation of fibrils in this
whether these functional enhancements were due region.
to higher stress levels or to localized higher elastic Today, advanced studies on transverse depth colla-
moduli, the stress-normalized elastic moduli were gen-fibril orientation and distribution28 combined with
also evaluated. In the circumferential direction, the advanced mathematical models of the biomechani-
stress-controlled elastic modulus of the limbus was cal properties of the cornea29,30 are used to refine our
found to be significantly higher than that of the other understanding of corneal elastic properties.
regions, whereas the elasticity of the corneal periphery
was not significantly different from that of the central
or para-central regions. In the meridional direction, it 5. Shear-force resistance of the cornea
was found that the stress-controlled elastic moduli of
the center and para-center were higher than those of The resistance of the human cornea to in-plane shear
the periphery and the limbus. A similar tendency was deformation is small,31 but little is known about
observed by Shin et al.23 its actual size due to methodological difficulties
The fine microstructure of the human cornea has in measuring it (Fig. 4).31,32 In preliminary shearing
been studied using wide-angle X-ray scattering (WAXS), experiments in rabbit31 and human corneas,32 the
which has detailed the anisotropic arrangement of
collagen fibrils in the human cornea and quantified
typical characteristics, including:
1. a preferred orthogonal orientation in the central

cornea in temporal–nasal (T–N) and superior–
inferior (S–I) directions;
2. circumferentially arranged fibrils in the limbus
and corneal periphery;
3. a transition zone between 1. and 2.; and
4. a greater total quantity of fibrils in the peripheral
region compared to the central cornea.24-26
The variability in elastic moduli between the corneal Fig. 4. Shear testing of a cornea at a defined thickness, t.
shear modulus (shear stiffness) has been found to be in

the order of 1 and 2 kPa, respectively. Petsche et al.33
measured the torsional shear throughout the stromal
depth of the human cornea. They found the transversal,
torsional shear modulus to be depth-dependent and its
magnitude to be greatest in the anterior third stroma.
Elsheikh et al.34 also measured the shear modulus of the
human cornea, and found values in the range of 20 kPa.
Further recent studies of the shear-force resistance
of human corneas found values of 2 kPa and have also
documented that the shear-resistance is higher in the Fig. 5. Swelling pressure measurement of an excised cornea at a
anterior corneal stroma than in the posterior stroma.35 defined thickness, t.
At low shear strain, the shear stiffness of an individual
lamella is proposed to result from the gel properties the tissue has free access to a physiologic aqueous
of the interaction of stromal ground substance with medium.” (Fig. 5).39,40 The swelling pressure depends
the fixed charges of the glycosaminoglycans (GAG). on the degree of compression of the tissue,41 the ionic
The transverse shear modulus resulting from this strength of the bathing medium,42 temperature,40 and
interaction is expected to be small compared to the pH.43
tensile modulus from direct testing of collagen fibrils on From experimental studies, differential swelling in
tension tests. A significant dependency of shear moduli different compartments of the corneal stroma have
on the axial compression of the tissue has also been been described.44 The cornea swells predominantly
observed. This agrees with the finding that increased in the anterior-posterior direction (orthogonal to its
compression results in the fixed charges of the GAG faces).45 However, the lattice of fibrils swells equally
moving closer together. An increased fixed charge in all directions, whereas the tissue as a whole swells
density may then result in increased shear modulus.35 predominantly in one direction. This means that a rear-
rangement of the fibrils in two dimensions may occur as
the cornea swells.46
6. Swelling pressure From diffraction studies on highly swollen corneas, it
was concluded that the swollen cornea is essentially a
The corneal stroma has an innate tendency to imbibe system of mutually repelling cylinders and the existence
fluid and a swelling capacity that exceeds any other of interfibrillar crosslinking is unlikely.47 When swelling,
connective tissue in the body. This high swelling however, the corneal stroma does not separate even
capacity and its transparency in vivo are both unusual when shear force is applied. Thus, the stroma possesses
properties for a connective tissue.36 The biophysical self-cohesion between corneal lamellae.48 The inter-
properties of the cornea therefore depend on precise weaving varies with depth, appearing maximally at the
maintenance of tissue hydration, and the heterogeneity anterior surface and reducing posteriorly.49
of the stroma suggests that the swelling properties are Thus, corneal swelling and hydration can greatly
not uniformly distributed. The less interwoven posterior influence the alignment of collagen fibrils in the stroma,
stroma can swell more than the anterior stroma,37 and and thereby influence the in-plane, tangential elastic
at a given swelling pressure, the posterior stroma is properties of the cornea.
more hydrated than the anterior stroma.38 Several investigators have measured the stromal
Maurice described the corneal stroma as a sponge, swelling pressure in different mammalian species, but
which behaves as if consisting of two separate phases: the swelling pressures of human corneas have only been
one rigid structural phase and one fluid phase. The scarcely investigated. At normal corneal thickness, the
gel pressure or swelling pressure (SP) of a tissue can swelling pressure in humans has been measured as 84
be defined as: “the mechanical pressure applied to mmHg.41
its surfaces which is needed to prevent swelling when
8 J. Hjortdal
corneal stroma, decreased epithelial surface strain,

and increased endothelial surface strain.13,18
The observation of viscoelastic behavior in the intact
human cornea may be explained by the influence of
corneal hydration on the stress distribution between
the corneal lamellae. In the swollen cornea, only the
anterior corneal lamellae are able to take up tension,
whereas the posterior lamellae will be slack. Clinically,
this can be observed as folds in Descemet’s membrane.
During the pressure-induced reduction in corneal
Fig. 6. (A) Stress relaxation at constant strain. (B) Creep at constant volume, the posterior lamellae elongate and take up
stress. some of the corneal stress and the stress on the anterior
lamellae will decrease. This is consistent with obser-
vations by Eliasson and Maurice,51 who after studying
7. Viscoelasticity the displacement of the corneal surfaces induced by
corneal thinning, concluded that the stress distribution
If a material is suddenly strained to a constant level, across the corneal stroma is even in the normo-hydrat-
the stresses induced in the material may decrease ed human cornea in vivo.31
with time, that is, the material shows stress relaxation
(Fig. 6A). Similarly, if a constant force suddenly stresses
a material, the material may continue to deform with 8. Changes in corneal curvature induced
time, and the material is said to show creep (Fig. 6B). by intraocular pressure
These phenomena are features of viscoelasticity.1 The
cornea does show viscoelastic changes when tested The adult human cornea is very stable and fluctua-
in vitro. In swelling pressure experiments, it takes tions in intraocular pressure do not result in clinically
typically one to two hours before a steady state level significant changes in the radius of curvature of the
is reached.41,50 In biological materials, the viscoelas- cornea and the refractive state of the eye.
tic response is probably caused mainly by overall In vitro, studies have revealed that in swollen corneas
hydration changes of the tissue or by a redistribution the change in central corneal radius of curvature parallel
of water within the tissue.1 Elsheikh et al.10 studied the change in central epithelial side corneal strain: when
in detail creep and stress-relaxation behavior of the the corneal stroma stretched, the radius of curvature
human cornea in pressure-chamber inflation and strip became larger, and vice versa.18 During corneal thinning
extensiometry tests, respectively, and found that creep and subsequent epithelial side shortening, the cornea
and stress-relaxation went on for hours. thus became steeper. Other authors have found
In inflation tests of whole human eye globes, it has slight corneal steepening in association with corneal
been shown that the creep observed in human corneas dehydration in vitro as well.52 Corneal hydration has
can be partly or fully explained by a change in corneal also been found to influence corneal radius of curvature
hydration.18 Corneas with increased thickness, cor- in vivo. Associated with an overnight 2.4% increase in
responding to increased hydration, strained approx- corneal thickness, the radius of curvature increased
imately 1% on the central epithelial side and 3% 0.04 mm, and with eyelid opening, the cornea was
on the endothelial side when intraocular pressure found to thin and steepen slightly.53
was increased from 2 to 100 mmHg. In comparison, The pressure-induced corneal curvature changes in
corneas which had been thinned in Dextran to normal normal human eyes have been found to be very small. In
hydration, strained approximately 0.5% on the vivo, 0.2 diopters (0.04 mm) of central corneal flattening
epithelial as well as the endothelial side for the same was observed when the pressure was increased from
pressure increment.13,14 Continuous pressure loading 14 to 30 mmHg.54 Previous in-vivo studies have similarly
of a swollen cornea induced significant thinning of the not been able to detect significant changes in kerato-
metric-measured corneal curvature during pressure in the posterior layers of the cornea, which make the
loading.55 In studies of the corneal radius of curvature cornea easier to bend.61,62
before and after treatment for acute glaucoma,
Poinoosawmy and Roth56 found, however, that the
keratometric measured corneal radius of curvature 10. Basic biomechanics in corneal
decreased 0.07 mm when the pressure was lowered disease
from 27 to 20 mmHg. This change in curvature could,
however, also be due to changes in corneal hydration. The basic biomechanics of only few corneal diseases
In summary, increasing intraocular pressure in the have been studied in vitro, as most corneal diseases
normal human eye changes the curvature of the cornea are uncommon and tissue specimens typically can
very little. It appears, however, that in vivo the cornea only be acquired post-mortem after donation from the
tends to flatten slightly when the pressure increases. deceased.
Although keratoconus corneas are believed to be
“softer” and more susceptible to deformation, the only
9. Basic biomechanics in tonometry two experimental studies based on strip extensiometry
measurements could only show a difference between
All types of clinical tonometry involve corneal bending. keratoconus and control corneal tissues at stress-lev-
Factors which alter the bending rigidity of the cornea els much higher than those encountered in vivo.5,6 It
will therefore affect the readings of tonometry may be that the mechanical characteristic of corneas
instruments. In normal subjects, there is a positive with keratoconus may be a type of abnormal viscoelas-
correlation between corneal thickness and intraocular tic creep: a difference between normal corneas and
pressure, as a thick cornea is more difficult to bend.57 corneas with keratoconus can be observed only over
The change in corneal radius of curvature may also months or years.63
affect tonometry readings. The necessary bending
force is larger, and the displaced intraocular volume is
larger in an eye with a steep cornea than in an eye with 11. Basic biomechanics in refractive
a flat cornea to achieve the same amount of corneal surgery
flattening. Both factors will tend to falsely increase the
measured intraocular pressure.58,59 11.1. Radial keratotomy
After refractive surgery for myopia, the cornea Although radial keratotomy for myopia is not
becomes thinner and flatter. Extrapolation from performed any longer, earlier studies of incised
observations in normal corneas suggests that this corneas give some information about the basic bio-
will lead to artifactually low pressure measurements mechanics of corneal tissue. Inflation studies of the
in eyes treated for myopia. Many clinical studies have local deformation pattern of human corneas with a
documented that thinning and flattening keratorefrac- radial keratotomy have revealed that the mechanical
tive procedures falsely lower the reading of tonometry behavior of the incised human cornea is a complex
instruments based on applanation and air-puff combination of tissue extension, tissue compression,
indentation.60 The clinical importance of the possible and internal shear.64 Early microstructural studies only
small errors in tonometry may become more important documented that radial keratotomy incisions gape
when the growing population of corneal refractive during pressure loading.65-67 More detailed studies
individuals becomes older and develops open-angle revealed that pressure loading of radially incised
glaucoma. If the pressure is falsely measured as too human corneas induced:
low in these patients, the diagnosis may be missed or 1. epithelial surface wound gape of 44 μm (2-100
delayed. mmHg pressure increment);
On the other hand, increased corneal thickness due 2. epithelial surface circumferential tissue
to corneal edema results in inaccurately low readings compression between incisions;
of tonometers, possibly due to slack corneal fibrils 3. considerable epithelial surface meridional tissue
10 J. Hjortdal
elongation at and between incisions; eyes, a 7-mm diameter superficial central keratectomy
4. little endothelial surface circumferential strain induced central corneal strains 5-10% higher in corneas
across incisions; and without Bowman’s layer compared with intact corneas.74
5. little endothelial surface meridional strain at and The epithelial surface tangential corneal strains in
between incisions.64 eyes with a 70% deep keratectomy increased twice as
Thus, the peripheral “tissue addition” seen after radial much as those of intact corneas, but the endothelial
keratotomy is a net result of wound gape and circum- surface strains were similar. From considerations on
ferential tissue compression. The negative circum- the possible stress distribution in the keratectomized
ferential strains between radial incision have also cornea, it can be argued that the difference between
been confirmed using confocal microscopy in rabbit the epithelial surface strain and the endothelial surface
corneas.68 The presence of tissue compression between strain is a function of the shear force resistance between
the four radial incisions can explain why additional the stromal lamellae.74 The differences in average
incisions do not induce much additional corneal corneal strains between the three groups could be
flattening.69 explained by changes in central corneal thickness, as
there were no statistically significant differences in the
11.1.1. Pressure induced curvature changes after radial stress-normalized Young’s moduli of elasticity between
keratotomy the three groups. Corresponding with this, strip exten-
In vitro, radial keratotomy results in considerable siometry studies of the cornea did not detect a statis-
corneal flattening (2.3 diopters) even at very low loading tically significant difference in elastic or viscoelastic
pressures, and in the physiological pressure range the properties between excised full-thickness corneal
central cornea flattens around 0.05 diopters for each strip samples and paired samples with Bowman’s layer
mmHg increment in intraocular pressure.64 Similar removed.75 When removed, the underlying lamellae
central curvature changes have been found in other of the otherwise unaltered corneal stroma possibly
in-vitro studies.70 In vivo, in studies of patients that have take up the mechanical functions of the outer limiting
previously undergone radial keratotomy, increasing the connective tissue layer.
intraocular pressure from 14 to 30 mmHg induced 0.5 Measurements of the surface profile inside and
diopters of central corneal flattening, corresponding to outside the ablation zone of treated patients have
0.03 diopters for each mmHg increment in intraocular documented that cutting of the anterior lamellae
pressure.54 Similar pressure-induced changes in central actually results in outward bulging of the cornea
curvature have been found by Feldman et al.55 outside the ablated area.76
A significant proportion of patients previously
operated on with radial keratotomy experience 11.2.1. Pressure induced curvature changes after kera-
continued diurnal fluctuations in visual acuity, and tectomy
these changes are associated with corneal steepening After a keratectomy, corneal thickness decreases. The
during the day.71,72 Corneal hydration and intraocular remaining corneal fibrils will therefore be exposed
pressure also exhibit diurnal changes. In vitro, to higher levels of membrane stresses inducing some
increased corneal hydration has been found to increase elongation of the fibrils. If the edge of the ablation zone
the flattening effect of a radial keratotomy;70 diurnal is considered fixed it would be expected that the central
variations in corneal hydration have also been found to cornea steepens in response to pressure loading.
correlate with diurnal changes in corneal power.73 In vitro, it has been observed that the central radius of
curvature does not change significantly with increasing
11.2. Surface ablation pressure in intact eyes or in eyes without Bowman’s
After photorefractive or phototherapeutic keratectomy, layer.74 In deeply ablated corneas, the corneal radius of
the corneal stroma is thinned and Bowman’s layer is curvature decreased in vitro approximately 1% when
removed. Overall, these changes in corneal structure the intraocular pressure was increased from 2 to 100
should result in a biomechanical weakening. In in-vitro mmHg.74 Similar central bulging has been reported
studies of excimer laser ablations in human cadaver in cadaver eyes when 150 μm or more of the outer
surface was excised with excimer laser.77 In patients side-cut angulations, and the relative contribution of
who had undergone excimer laser ablation (approxi- the lamellar and side cuts have been evaluated using a
mately 70 μm ablation), no significant central corneal femtosecond laser and radial shearing speckle pattern
steepening or flattening was observed with increasing interferometry in human corneas in vitro.78 The study
pressure, although normal control eyes flattened sig- documented that vertical side cuts through corneal
nificantly due to pressure loading.54 In the study, a lamellae rather than horizontal delamination incisions
significant correlation between the pressure-induced contribute to the loss of structural integrity during
change in central curvature and the postoperative time LASIK flap creation. This finding supports the possible
was, however, found. Patients investigated during the biomechanical advantage of the small incision lenticule
first months after surgery steepened more centrally extraction procedure (SMILE),79 although this has not
than patients investigated one year or more after laser been documented experimentally.80
ablation. Thus, the wound healing response of the
cornea somehow influences the corneal stability of
excimer laser-ablated patients. It can be hypothesized 12. Conclusion and perspectives
that the recovery of stability is due to an increasing
stromal shear force resistance, induced by scar tissue Although simple in nature, the biomechanical
in the superficial cornea. properties of the human cornea are still a matter of
debate. Recently, very advanced biomechanical models
11. 3. Intrastromal procedures (LASIK, SMILE) of the corneal tissue have been developed. The models
Today, intrastromal corneal refractive procedures are based on the microstructural composition of the
are increasingly used to correct refractive errors. tissue and mechanical properties of collagen fibrils and
Although a biomechanically mediated corneal ground substance. These models will possibly further
protrusion (ectasia) can develop after any photoabla- advance simulations of the corneal response to surgery
tive procedure, the procedures have only been scarcely and disease. However, further laboratory and clinical
evaluated in terms of basic biomechanical studies. testing of human corneal tissue is necessary to provide
The corneal biomechanical effects of varying laser-as- valid empirical data for such models.
sisted in situ keratomileusis (LASIK) flap-depth and
References
8. Zeng Y, Yang J, Huang K, Lee Z, Lee X. A comparison of biome-
1. Fung, YC. Biomechanics. Mechanical properties of living chanical properties between human and porcine cornea. J
tissues. New York: Springer-Verlag 1981. Biomech. 2001;34:533–537
2. Bisplinghoff RL, Marr JW, Pian THH. Statics of deformable 9. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of
solids. New York: Dover Publications Inc. 1965. human and porcine corneas after riboflavin–ultraviolet-A-in-
3. Maurice DM. The cornea and sclera. In: Davson H (ed). The Eye, duced cross-linking. J Cataract Refract Surg. 2003;29:1780–1785.
Vol 1B, pp. 303-351. New York: Academic Press:1984. 10. Elsheikh A, Anderson K. Comparative study of corneal strip exten-
4. Woo S L-Y, Kobayashi AS, Schlegel WA, Lawrence C. Nonlinear siometry and inflation tests. J R Soc Interface. 2005;2:177-185.
material properties of intact cornea and sclera. Exp Eye Res. 11. Jue B, Maurice DM. The mechanical properties of the rabbit and
1972;14:29-39. human cornea. J Biomech.anics 1986;19:847-853.
5. Andreassen TT, Hjorth Simonsen A, Oxlund H. Biomechanical 12. Roark RJ. Formulas for stress and strain. New York: McGraw-Hill,
properties of keratoconus and normal corneas. Exp Eye Res. Inc. 1965.
1980;31:435-441. 13. Hjortdal J. Extensibility of the normo-hydrated human cornea.
6. Nash IS, Greene PR, Foster CS. Comparison of mechanical Acta Ophthal Scand. 1995;73:12-17.
properties of keratoconus and normal corneas. Exp Eye Res. 14. Hjortdal J. Regional elastic performance of the human cornea.
1982;35:413-424. J Biomech. 1996;29:931–942.
7. Hoeltzel DA, Altman P, Buzard K, Choe K. Strip extensiometry 15. Elsheik A, Wang D, Brown M, Rama P, Campanelli M, Pye D. As-
for comparison of the mechanical response of bovine, rabbit, sessment of corneal biomechanical properties and their vari-
and human corneas. J Biomech Eng. 1992;114:202-215. abtion with age. Current Eye Research. 2007;32:11–19.
12 J. Hjortdal
16. Viidik AA. Functional properties of collagenous tissues. In: 35. Søndergaard AP, Ivarsen A, Hjortdal J. Corneal resistance to
David A Hall & DS Jackson (eds.). International review of con- shear force after UVA-riboflavin cross-linking. Invest Ophthal-
nective tissue research, Vol. 6, pp. 127-211 Academic Press: mol Vis Sci. 2013;54:5059–5069.
London 1973. 36. Hart RW, Farrell RA. Structural theory of swelling pressure of
17. Hatami-Marbini H. Hydration dependent viscoelastic tensile corneal stroma in saline. Bull Math Biophys. 1971;33:165–186.
behavior of cornea. Ann Biomech Eng. 2014;42:1740-1748. 37. Kikkawa Y, Hirayama K. Uneven swelling of the corneal stroma.
18. Hjortdal JØ, Jensen PK. In vitro measurement of corneal strain, Invest Ophthalmol. 1970;9:735-741.
thickness, and curvature using digital image processing. Acta 38. Lee D, Wilson G. Non-uniform swelling properties of the corneal
Ophthalmol Scand. 1995;73:5-11 stroma. Curr Eye Res. 1981;1:457-461.
19. Gallagher B, Maurice DM. Striations of light scattering in the 39. Dohlman CH, Hedbys BO, Mishima S. The swelling pressure of
corneal stroma. J Ultrastruc Res. 1977;61:100-114. the corneal stroma. Invest Ophthalmol. 1962;1:158–162.
20. Bron AJ. Superficial fibrillary lines. A feature of the normal 40. Fatt I. The coefficient of thermal expansion of stroma. Exp Eye
cornea. Brit J Ophthalmol. 1975;59:133-135. Res. 1971;12:254–260.
21. Parry DAD, Craig AS. Collagen fibrils during development and 41. Olsen T, Sperling S. The swelling pressure of the human
maturation and their contribution to the mechanical attributes corneal stroma as determined by a new method. Exp Eye Res.
of connective tissue. In: Nimni ME (ed.): Collagen, Vol. II, pp 1987;44:481-490.
1-24. Boca Raton: CRC Press 1988. 42. Huang Y, Meek KM. Swelling studies on the cornea and sclera: the
22. Fraser RDB, MacRae TP, Miller A, Suzuki E. Molecular conforma- effects of pH and ionic strength. Biophys J. 1999;77:1655-1665.
tion and packing in collagen fibrils. J Mol Biol. 1983;167:497- 43. Ehlers N. Studies on hydration of cornea with special reference
521. to acid hydration. Acta Ophthalmol (Copenh). 1966;44:924-931.
23. Shin TJ, Vito RP, Johnson LW, McCarey BE. The distribution of 44. Wilson G, O’Leary DJ, Vaughan W. Differential swelling in com-
strain in the human cornea. J Biomech. 1997;30:497-503. partments of the corneal stroma. Invest Ophthalmol Vis Sci.
24. Aghamohammadzadeh H, Newton RH, Meek KM. X-ray scat- 1984;25:1105-1108.
tering used to map the preferred collagen orientation in the 45. Hedbys BO, Mishima S. Flow of water in the corneal stroma. Exp
human cornea and limbus. Structure. 2004;2:249–256. Eye Res. 1962;1:262–275.
25. Meek KM, Boote C. The organization of collagen in the corneal 46. Meek KM, Quantock AJ. The use of X-ray scattering techniques
stroma. Exp Eye Res. 2004;78:503–512. to determine corneal ultrastructure. Prog Retin Eye Res.
26. Boote C, Hayes S, Abahussin M, Meek KM. Mapping collagen or- 2001;20:95-137.
ganization in the human cornea: left and right eyes are structur- 47. Elliott GF, Sayers Z, Timmins PA. Neutron diffraction studies of
ally distinct. Invest. Ophthalmol Vis Sci. 2006;47: 901–908. the corneal stroma. J Mol Biol. 1982;155:389-393.
27. Krenchel H. Fibre Reinforcement. Theoretical and practical in- 48. Maurice DM. Some puzzles in the microscopic structure of the
vestigations of the elasticity and strength of fibre-reinforced stroma. J Refract Surg. 1999;15: 692-694.
materials. Copenhagen: Akademisk Forlag 1964. 49. Smolek MK. Interlamellar cohesive strength in the vertical
28. Abass A, Hayes S, White N, Sorensen T, Meek KM. Transverse meridian of human eye bank corneas. Invest Ophthalmol Vis
depth-dependent changes in corneal collagen lamellar orienta- Sci. 1993;34:2962-2969.
tion and distribution. J R Soc Interface. 2015;12(104):20140717 50. Fatt I. Dynamics of water transport in the corneal stroma. Exp
29. Petsche SJ, Pinsky PM. The role of 3-D collagen organization in Eye Res. 1968;7:402-412.
stromal elasticity: a model based on X-ray diffraction data and 51. Eliasson J, Maurice DM. Stress distribution across the in vivo
second harmonic-generated images. Biomech Model Mechano- human cornea. Invest Ophthalmol Vis Sci 20 (Suppl.) 1981;156.
biol. 2013;12:1101–1113. 52. Simon G, Ren Q. Biomechanical behavior of the cornea and
30. Whitford C, Studer H, Boote, Meek KM, Elsheikh A. Biomechani- its response to radial keratotomy. J Refract Corneal Surg.
cal model of the human cornea: Considering shear stiffness and 1994;10:343-356.
regional variation of collagen anisotropy and density. J Mech 53. Kiely PM, Carney LG, Smith G. Diurnal variations of corneal to-
Beh Biomed Mat. 2015;42:76-87. pography and thickness. Am J Optom Physiol Opt 1982;59:976-
31. Maurice DM. Mechanics of the cornea. In: Cavanagh HD (ed). 982.
The Cornea: Transactions of the World Congress on the Cornea 54. Hjortdal JØ, Böhm A, Kohlhaas M, et al. Mechanical stability of
III. New York: Raven Press, Ltd. 1988. the cornea after radial keratotomy and photorefractive keratec-
32. Wollensak J, Ihme A, Seiler T. Neue Befunde bei Keratoconus. tomy. J Refract Surg 1996;12:459-466.
Fortschr Ophthalmol. 1987;84:28-32. 55. Feldman ST, Frucht-Perry J, Weinreb RN, Chayet A, Dreher AW,
33. Petsche SJ, Chernyak D, Martiz J, Levenston ME, Pinsky PM. Brown SI. The effect of increased intraocular pressure on visual
Depth-dependent transverse shear properties of the human acuity and corneal curvature after radial keratotomy. Am J
corneal stroma. Invest Ophthalmol Vis Sci. 2012;53:873–880. Ophthalmol. 1989;108:126-129.
34. Elsheikh A, Ross S, Rama P, Alhasso D. Numerical study of the 56. Poinoosawmy D, Roth JA. Variations in visual acuity, refraction,
effect of corneal layered structure on ocular biomechanics. and corneal curvature with changes in applanation tension. Br
Curr Eye Res. 2009;34:26-35. J Ophthalmol. 1974;58:523-528.
57. Ehlers N, Bramsen T, Sperling S. Applanation tonometry 70. Maloney RK. Effect of corneal hydration and intraocular
and central corneal thickness. Acta Ophthalmol (Copenh.) pressure on keratometric power after experimental radial kera-
1975;53:34-43. totomy. Ophthalmology. 1990;97:927-933.
58. Whitacre MM, Stein R. Sources of error with use of Gold- 71. Santos VR, Waring GO, Lynn MJ, et al. Morning-to-evening
mann-type tonometers. Surv Ophthalmol 1993;38:1-30. change in refraction, corneal curvature, and visual acuity 2 to 4
59. Kohlhaas M, Lerche R, Draeger J, et al. The influence of corneal years after radial keratotomy in the PERK Study. Ophthalmolo-
thickness and corneal curvature on tonometry readings after gy. 1988;95:1487-1493.
corneal refractive surgery. Eur J Implant Ref Surg. 1995;7:84-88. 72. Schanzlin DJ, Santos VR, Waring GO, et al. Diurnal change in
60. Yao WJ, Crossan AS. An update on post-refractive surgery in- refraction, corneal curvature, visual acuity, and intraocular
traocular pressure determination. Curr Opin Ophthalmol. pressure after radial keratotomy in the PERK Study. Ophthal-
2014;25(4):258-263. mology. 1986;93:167-175.
61. Ahearne M, Yang Y, Then KY, Liu K-K. An indentation technique 73. MacRae S, Rich L, Phillips D, Bedrossian R. Diurnal variation in
to characterize the mechanical and viscoelastic properties of vision after radial keratotomy. Am J Ophthalmol. 1989;107:262-
human and porcine corneas. Ann Biomech Eng. 2007;35:1608- 267.
1616. 74. Hjortdal JØ, Ehlers N. Effect of excimer laser keratectomy on
62. Clemmensen K, Hjortdal J. Intraocular pressure and corneal the mechanical performance of the human cornea. Acta Oph-
biomechanics in Fuchs’ endothelial dystrophy and after poste- thalmol Scand. 1995;73:18-24.
rior lamellar keratoplasty. Acta Ophthalmol. 2014;92:350-354. 75. Seiler T, Matallana M, Sendler S, Bende T. Does Bowman’s layer
63. Vellara HR, Patel DV. Biomechanical properties of the kerato- determine the biomechanical properties of the cornea? Refract
conic cornea: a review. Clin Exp Optom. 2015;98:31–38 Corneal Surg. 1992;8:139-142.
64. Hjortdal JØ, Ehlers N. Acute tissue deformation patterns of 76. Dupps WJ Jr, Roberts C. Effect of acute biomechanical changes
the human cornea after radial keratotomy. J Refract Surg. on corneal curvature after photokeratectomy. J Refract Surg.
1996;12:391-400. 2001;17:658-669.
65. Buzard KA, Ronk JF, Friedlander MH, Tepper DJ, Hoeltzel DA, 77. Litwin K, Moreira H, Odahi C, McDonnell P. Changes in corneal
Choe KI. Quantitative measurement of wound spreading in curvature at different excimer laser ablative depths. Am J Oph-
radial keratotomy. Refract Corneal Surg. 1992;8:217-223. thalmol. 1991;111:382-384.
66. Petroll WM, New K, Sachdev M, Cavanagh HD, Jester JV. 78. Knox Cartwright NE, Tyrer JR, Jaycock PD, Marshall J. Effects of
Radial keratotomy. III. Relationship between wound gape and variation in depth and side cut angulations in LASIK and thin-
corneal curvature in primate eyes. Invest Ophthalmol Vis Sci. flap LASIK using a femtosecond laser: a biomechanical study. J
1992;33(12):3283-91. Refract Surg. 2012;28:419-425.
67. Petroll WM, Roy P, Choung CJ, Hall B, Cavanagh HD, Jester JV. 79. Hjortdal JØ, Vestergaard AH, Ivarsen A, Ragunathan S, Asp
Measurement of surgically induced corneal deformations using S. Predictors for the outcome of small-incision lenticule ex-
three-dimensional confocal microscopy. Cornea. 1996;15:154- traction for Myopia. J Refract Surg. 2012;28:865-871.
164. 80. Pedersen IB, Bak-Nielsen S, Vestergaard AH, Ivarsen A, Hjortdal
68. Henninghausen H, Feldman ST, Bille JF, McCulloch AD. Effect of J. Corneal biomechanical properties after LASIK, ReLEx flex,
swelling and refractive surgery on regional strains in the rabbit and ReLEx smile by Scheimpflug-based dynamic tonometry.
cornea. Invest Ophthalmol Vis Sci. 1996;37:S314. Graefes Arch Clin Exp Ophthalmol. 2014;252:1329-1335.
69. Jester JV, Venet T, Lee J, Schanzlin DJ, Smith RE. A statistical
analysis of radial keratotomy in human cadaver eyes. Am J
Ophthalmol. 1981;92:172-177.
2. Corneal stroma: collagen ultrastructure and
orientation in health and disease
Keith M. Meek, Sally Hayes
1. Introduction and V co-localize within the fibrils, whereas type VI

forms a random network of filaments that may help
The cornea is the only connective tissue that must stabilize the fibrillar array, but may also prolong the
combine tensile strength with a perfectly defined life of corneal cells by preventing anti-beta 1 integ-
shape and almost 100% transparency. For nearly rin-based cell apoptosis.4 Table 1 lists typical values
a century, it has been known that these properties for a number of structural,5-12 biomechanical,13,14 and
derive from the arrangement of the constituents of the optical properties5,15 of corneal collagen that have been
stroma.1,2 The corneal stroma has a lamellar structure, obtained from the literature.
with most layers running approximately parallel to
the corneal surface, and lying at an angle to their 2.1. Collagen fibril structure
neighbors. Therefore, throughout the full thickness of Corneal collagen fibrils are the principal load-bearing
the 200 or so lamellae (in the central human cornea) constituents of the lamellae. The fibrils must resist
all radial angles are occupied; this arrangement results the tensile forces due to the intraocular pressure and
in a high tensile strength within the plane of the tissue protect the inner ocular tissue from external trauma
that can withstand the intraocular pressure. With the while, at the same time, remaining narrow to allow
advent of electron microscopy, it was clear that each tissue transparency. These competing requirements
lamella contains parallel collagen fibrils which have are achieved by their rather complex structure.
a narrow diameter and a high degree of regularity in The basic unit of the collagen fibril is the triple helical
their lateral packing. It is these structural properties collagen molecule containing two identical alpha 1
that confer strength and transparency to the tissue. In helices and one alpha 2 helix (each with left-handed
this chapter, we describe the structure of the corneal coiling), in a right-handed supercoiled arrangement.
stroma in detail, discussing the hierarchical architec- The molecule contains over 3000 amino acids (>1000 in
ture of collagen from the molecules to the lamellae and each alpha chain) and measures ~300 nm in length by
showing how aspects of this can change in disease and about 1.6 nm in diameter (Table 1). The alpha chains are
following surgery. enzymatically crosslinked in the non-helical terminal
regions.16 These molecules self-assemble in a staggered
arrangement with a gap region between one molecule
2. Collagen hierarchical structure: and the one in front (Fig. 1), which then gives the fibril
molecules to fibrils an axial periodicity, D. The stagger is 234.2 amino acid
residues,17 which leads to a value of D of close to 67 nm

Most of the collagen in the corneal stroma is types in most connective tissues. The immediate subunit of
I, V, and VI, though numerous other collagen types the fibril is the five-stranded microfibril.18
such as XIII, XV, and XVIII are also present.3 Types I Within the microfibril constituent, molecules have a
Correspondence: Keith M. Meek, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ, UK.
E-mail: MeekKM@cardiff.ac.uk
Biomechanics of the Eye, pp. 15-30

Edited by: C.J. Roberts, W.J. Dupps and J.C. Downs
16 K.M. Meek and S. Hayes
Fig. 1. The hierarchical structure of collagen fibrils. Triple helical collagen molecules (top) assemble in an axially staggered array, with
gaps between one molecule and the one in front to form five-stranded microfibrils (middle). The microfibrils aggregate in a coiled manner
to produce the collagen fibril (bottom). The electron micrographs of the microfibrils are reproduced from Baldock et al.18 (bottom left) and
Ottani et al.31 (bottom right) with permission of the copyright holders. Images are not shown to scale.
to the fibrils in the adjacent sclera, which are wider and

Misconception 1: There are other interme- have a more parallel arrangement of microfibrils within
diate structures within the collagen fibril them.24 At present, it is not certain if the collagen fibrils
in the cornea are crimped in vivo as in other connective
There have been reports over many years of tissues, but recent publications claim there is a small
larger subunits within collagen fibrils.19-21 At the crimp.25-27 This crimp would add another level of
time of writing, these larger subunit structures protection to the fibrils, allowing small extensions and
have not been universally accepted as their distortion of lamellae without fibril sliding.
measured dimensions seem to be technique- Corneal collagen fibril diameters vary between
specific. species.7, 28 Electron microscopy showed the existence of
an 8 nm step in diameter measurements from a number
of corneal specimens belonging to different species,29

left-handed twist. These molecules are enzymatically suggesting that fibrils grow by addition of discrete
crosslinked at several axial locations. In some tissues concentric radial shells of microfibrils.30,31 The variation
such as the cornea, these microfibrils also coil (with a of fibril diameter between species is accompanied by a
right-handed twist),22 and this leads to a reduction in similar variation in the center-to-center fibril spacings28
the axially-projected D-period to 65 nm (Table 1).12,23,24 such that there is a constant collagen fibril area
This crosslinked rope-like structure, with an alternating fraction.7 The fibril diameter in the center of the human
twist at each hierarchical level, conveys considerable cornea as determined by x-ray diffraction is approxi-
strength to the narrow corneal fibrils and is in contrast mately 31-34 nm, depending on age (Table 1).
Corneal stroma: collagen ultrastructure and orientation in health and disease 17
Table 1. Some properties of human corneal collagen fibrils
Property37 Value Data sources
Inter-molecular Bragg spacing 1.63 nm Leonard and Meek7

Diameter of microfibrils* 4 nm Holmes et al.6
Fibril diameter 31–34 nm Meek and Leonard;7 Daxer et al.;8 Boote et al.9
Number of molecules in fibril cross-section 263 Meek and Leonard7
Number of microfibrils in fibril cross-section* ∼70 (64 type I and 6 type V) Holmes and Kadler10
Tilt angle of microfibrils with respect to fibril axis* 15˚ Holmes et al.6
Collagen fibril D-periodicity 65 nm Meek et al.12
Inter-fibrillar Bragg spacing 55–57 nm Leonard and Meek;7 Boote et al.9
Fibril area fraction 0.34 Freund et al.11
Fibril cross-section number density 509 fibrils/µm2 Freund et al.11
Young’s modulus of collagen molecule 4.8 GPa Gautieri et al.14
Young’s modulus of fibrils along fibril direction ∼ 1.0 GPa Pinsky and Datye13
Form birefringence of fibrils 0.00218–0.0027 Worthington15
Fibril refractive index 1.411–1.454 Leonard and Meek;5 Worthington15
*Data from bovine corneas has been included where human data are not available.
an increase in the fibril area fraction with position across

Misconception 2: The diameter of corneal the cornea.9 This, coupled with increasing peripheral
collagen is about 24 nm corneal thickness, probably contributes to differences
in the biomechanical properties between the center
The values close to 24 nm often found in and the periphery of the human cornea.38,39 The area
the literature are obtained from electron fraction of fibrils is proportional to the mechanical
microscopy, a technique which involves strength of connective tissues.9,40 For example, the
fixation and dehydration procedures that are ability to resist creep and crack propagation, as well as
likely to reduce the intermolecular spacing, flexibility, are directly related to the amount of smaller
and hence the fibril diameter. 20,32 Furthermore, diameter fibrils, but tensile strength is greater in wider
it is believed that there is a fractal coating of fibrils.41 Thus, it is possible that the presence of smaller
proteoglycans surrounding each collagen diameter fibrils near the visual axis requires closer
fibril.33 The thickness of this coating is likely to packing in order to promote transparency and provide
be hydration sensitive,34 so it is possible that strength in a region where the cornea is thinner. These
the diameters obtained from x-ray diffraction7 smaller fibrils in the center may also confer greater
and low temperature electron microscopy flexibility, maintaining tissue integrity while allowing
processing35 are larger because they include deformation that may occur, for example, during eye
the coating that is preserved in a hydrated rubbing.
state. Several factors are involved in the control of fibril

diameters, each one of them probably exerting
Within the human cornea, fibril diameters are an influence at a different hierarchical level.42 The
constant within the central 8 mm,9 do not vary with presence of hydroxylysine-linked mono- and di-saccha-
tissue depth,11,36 and increase rapidly toward the rides43 and covalent collagen crosslinking by transglu-
limbus.9,37 Average interfibrillar distances remain taminase-244 may be involved at the molecular level.
constant within the central 4 mm (horizontally) and 3 The presence of type V collagen molecules, which have
mm (vertically), and then start to rise in the periphery, substantial globular domains, appears to limit the
increasing steeply at the limbus. These changes lead to accretion of additional microfibrillar shells and thus
ultimately controls the diameter of individual fibrils.45,46

The association of proteoglycans with the surfaces of
fibrils (see Section 2.2) has been shown to be essential
to prevent adjacent fibrils from fusing together to form
larger fibrillar structures.47-50
2.2. Fibril organization and the interfibrillar matrix

When developing his theory of corneal transparency,
Maurice51 assumed that the corneal collagen fibrils
were packed in a crystalline lattice. This lattice was not
observed in electron micrographs, and x-ray scattering
Fig. 2. Banded collagen fibrils are surrounded by a matrix containing
confirmed that fibril packing was more “liquid-like”.52 two main proteoglycan types. Decorin consists of a protein core
The x-ray data indicated that fibril order extended (green) that is attached to the collagen via hydrogen bonds at two
to three fibril diameters from a given fibril, and this possible sites within the gap region of the collagen fibrils. These
core proteins tend to form duplexes. The associated dermatan
degree of order is sufficient for destructive interference sulphate glycosaminoglycans (red) appear to wrap around the
of any scattered light so long as adjacent fibrils do not surfaces of the fibrils and many interconnect, possibly via their gly-
approach each other too closely.53 Reported values cosaminoglycan chains, to dermatan sulfate and keratan sulfate
chains on adjacent fibrils. Keratan sulphate-containing proteo-
for the area fraction (and hence the volume fraction)
glycans such as lumican are attached via their protein cores at the
occupied by the fibrils depends on the technique used, gap/overlap boundaries. Up to three glycosaminoglycan chains
with x-ray studies yielding an average value close to (orange) are attached to their single protein cores (also in green).
30% for many species.7 These appear to be shorter than the dermatan sulphate glycosami-
noglycans and run either around or along the fibril axis or protrude
The lamellar structure of the cornea appears to into the interfibrillar space, sometimes forming links with other
derive from the stromal cells themselves,54,55 and glycosaminoglycans attached to adjacent fibrils.
may be directed by long cellular projections termed
keratopodia.56 Recently, it has been shown that there is neighbor, which then provides an increased Donnan
an early influence on lamellar stacking by the presence restoring force because the interstitial GAGs become
of covalent collagen crosslinking by lysyl oxidases.44 more concentrated, and this pushes the displaced fibril
The control of fibril packing within the lamellae is back to its equilibrium position.59,61 These ideas are
provided by the interfibrillar proteoglycans (PGs) and discussed in detail in Chapter 5.
their associated glycosaminoglycan chains (GAGs). Pro- The interfibrillar matrix has an elastic modulus some
teoglycans bind to collagen fibrils via their protein cores 10,000 times lower than the collagen fibrils,62 and thus
at specific axial locations.57,58 The proteoglycans and plays no significant role in the tensile properties of the
their GAGs form a fractal coating on the surface of the mature cornea. However, interactions between decorin
collagen fibrils33 and GAGs also extend out to associate proteoglycan and type I collagen during fibrillogen-
with GAGs whose proteoglycans are attached to other esis increase the tensile strength of collagen gels63 so
fibrils (Fig. 2). The fractal coating limits aggregation if may be involved in the mechanical response by means
fibrils get too close by exerting a repulsive force due to of their influence on fibril aggregation. The hydrated
the Donnan effect associated with their high negative proteoglycan matrix also plays a vital role in resisting
charge.59 It was suggested that thermal motion of the tissue compression as well as in providing viscoelastici-
GAG chains provides a counterbalancing attractive ty to the cornea. It has been suggested that PGs in some
force, and these two opposing forces cause the fibrils tissues contribute to mechanical properties by allowing
to oscillate about their equilibrium positions.60 Alterna- fiber sliding or by crosslinking collagen fibrils, thereby
tively, modelling has shown that the GAGs that connect contributing to load sharing.64
adjacent fibrils can supply the necessary restoring force The human cornea contains elastic fibers that are
due to the constraining boundary conditions on the abundant in the limbus and peripheral posterior
tissue as a whole. In other words, when a fibril moves stroma65 and extend across the cornea above
further away from a neighbor, it moves closer to another Descemet’s membrane.66 These fibers are present in the
fetus and are thought to persist throughout life. They With an average density of 456 fibrils per µm2 (Table 1),
are elastin-rich at the limbus, but lose their elastin core there are thus of the order of 200,000 fibrils within a
as they progress across the cornea, becoming bundles typical lamella and of the order of 50 million throughout
of fibrillin rich microfibrils.66 Although their mechanical the whole central cornea. The anterior lamellae are
role in the adult cornea, if any, is not yet known, elastic interwoven and insert into Bowman’s layer, whereas the
fibers generally provide restoring forces when a tissue posterior lamellae are stacked rather like plywood (see
is extended, so they may be involved with restoring Chapter 3). It is the arrangement of these lamellae, both
equilibrium when the cornea is distorted, for example within and out of plane, which ultimately determines
by the intraocular pulse. the mechanical properties of the tissue.
Corneal stromal cells (keratocytes) reside between In 1938, Kokott71 observed stress lines in the cornea
the collagen lamellae, and are responsible for secreting that suggested a preferential arrangement of lamellae
extracellular matrix components required to maintain in the vertical and horizontal directions. The existence
normal corneal structure and function. From a of this arrangement was later confirmed using x-ray
mechanical standpoint, resting corneal keratocytes are scattering — a powerful technique that allows quan-
considered quiescent; they do not express stress fibers titative measurements of collagen fibril parameters
or generate substantial contractile forces.67 However, without the need for tissue processing.72 The x-ray
they do interact with the extracellular matrix, and this beam is passed through a specific region of the cornea,
is discussed in Chapter 4. from anterior to posterior, and the scatter is recorded
and analyzed to provide data on several structural
parameters (intermolecular spacing, fibril spacing,
3. Collagen lamellar organization and etc.). In this way, the observed scattered x-ray beam is
distribution in the healthy cornea the sum of the scattering from all of the 50 million or
so collagen fibrils that it encounters. This technique
The microscopic organization of collagen in the cornea has been used to obtain much of the numerical data
is in the form of lamellae that run roughly parallel to presented in Table 1. In addition to the data shown
the surface of the eye like flattened fibers which, in the in Table 1, the angular distribution of the scattered
deeper layers, appear to cross the cornea from limbus x-rays may be used to determine the angular distribu-
to limbus.
Misconception 3: A structural unit exists

between the fibril and the lamella
Some techniques appear to reveal fibers that

are much wider than those seen in electron
micrographs. For example, the fibers seen
within lamellae using second harmonic
generation (SHG) non-linear microscopy are
too wide to be the same as those seen using
electron microscopy. However, the exact

source of the signals generated using SHG is
still not completely understood.
In humans, the number of lamellae through the

central stromal thickness is reported as 242 ± 4. In the Fig. 3. A vector plot map, created using x-ray scattering data, shows
more anterior region of the stroma, the density of the the predominant direction of collagen across the cornea, limbus,
and sclera. In the montage display, the largest vector plots (which
lamellae is 50% greater than in the posterior stroma.68 represent regions of greatest collagen alignment) have been scaled
The lamellae are about 0.2 mm wide and 2 µm thick.69,70 down by the factors shown in the color key.
tion of lamellae at specific points in the tissue.73 The studies described above. However, mathematically,
scatter intensity also allows the relative distribution the origin of corneal birefringence is more complicated
of collagen mass to be mapped. By separating the than the origin of x-ray scatter, which arises only from
scatter into isotropic and non-isotropic components, the collagen fibrils or the molecules within them. The
it is thus possible to separate out contributions from preferentially aligned vertical and horizontal lamellae
the lamellae that are, on average, equally populating identified by x-ray scattering studies may produce bire-
all angles within the plane of the cornea, from the fringence that tends to cancel out, resulting in only
sub-population that have a preferred orientation.74 an excess of one fibril orientation being detected.84 In
Observations of the angular scatter distribution addition to this, it is not known what effect non-collage-
across the human cornea and limbus confirmed that nous components, such as the extensive network of cell
there is a preferred orientation of lamellae close to processes85 and the presence of elastic fibers within the
the vertical and horizontal directions (Fig. 3).74-76 On cornea,86 may have on the overall birefringence.
average, the two directions are equally populated, but In the human cornea, this arrangement of lamellae
there are significant differences between individuals changes within the peripheral couple of millimeters to
that have been proposed to affect corneal shape.77 a pseudo annulus at the limbus76,87,88 that appears to be
necessary to support the change in curvature between
Misconception 4: Lamellae are orthogo- the cornea and sclera.89 Such an annulus seems to
nally arranged in the human cornea occur in most mammalian species.82,90,91 The distribu-
tion of mass of the preferentially aligned collagen fibrils
The word “orthogonal” is used in many also suggested the presence of “anchoring lamellae”
research papers to describe the vertical and containing wider collagen fibrils that enter the cornea
horizontal preferred orientations of lamellae. from the direction of the inferior, superior, medial, and
In fact, lamellae make many different angles lateral rectus muscles. These lamellae do not traverse
with their neighbours in the human cornea,78 the optical zone,37 and may insert into Bowman’s layer.92
so adjacent lamellae are not orthogonal. X-ray scattering has also been used to quantify the
out-of-plane angles made by lamellae at different
depths in the tissue. This is an alternative approach to
The structural reinforcement provided by these pref- second harmonic generation non-linear microscopy
erentially aligned lamellae in the center of the cornea (see Chapter 3). At the center of the cornea, the out-of-
may help balance the stress exerted by the extraocular plane angle (inclination angle) falls from an average of
muscles,74 particularly in the horizontal direction.79 11˚ at the anterior surface to about 7.5˚ at the posterior
Moving the eyelids and squeezing the eyeball would surface.93 The current models of preferred lamella ori-
exert stress principally in the vertical direction.77,80 A entations within and through the depth of the cornea
preferential alignment of lamellae in the central cornea are schematically illustrated in Figure 4.
is confined to the posterior two thirds of the stroma, with
the anterior stroma possessing an essentially isotropic
angular distribution of lamellae.75,81 This arrangement 4. The role of collagen in keratoconus
seems to be species-specific, with animals that require
intermediate to high levels of visual acuity possessing Keratoconus, first described by Nottingham in 1854,94
an excess of collagen directed towards one or both sets is an ocular disorder whereby the cornea thins and
of opposing rectus muscles.82 weakens to such an extent that it can no longer maintain
Studies of corneal birefringence have shown that the its normal curvature. The progressive deterioration in
central human cornea acts as a birefringent retarder in tissue strength causes the cornea to bulge outward to
the supero-temporal to infero-nasal direction.83 This assume a conical shape which results in severe, irregular
information has often been interpreted as evidence of a astigmatism (Fig. 5). Although the effects of keratoconus
preferred orientation of collagen in that direction, and on corneal tissue are well documented,95 its cause and
therefore seen to be at odds with the x-ray scattering the mechanism that leads to the progressive thinning
Fig. 4. A contour map showing the intensity of x-ray scatter (arbitrary units) from preferentially aligned collagen in a typical human cornea.
The predominant direction of collagen has been superimposed using solid black lines (in the central and peripheral cornea) and a broken
black line (limbus). In the peripheral stroma and limbus, anchoring lamellae (probably of scleral origin) are thought to reinforce the tissue
in the mid-posterior layers without entering the central stroma. X-ray data from transverse sections show an increase in total scatter
intensity between the central, peripheral and limbal regions (B) and a decrease in lamellar inclination angle between the anterior and
posterior cornea (C). The presumed location of anchoring lamellae (solid black lines) and lamellae cut in cross-section (solid black circles)
at the limbal pseudo annulus (broken black line) have been superimposed onto the contour plot in (B).
Fig. 5. Side profile of a normal cornea and a keratoconus cornea. Images courtesy of Ellen Hayes and Ken Pullum.
and weakening of the cornea remain uncertain.96 This pathway, of many different pathological processes.
uncertainty may be attributed in part to the lack of Although changes in the epithelium and breaks
biomechanical and structural studies focused on the in Bowman’s layer are a well-known occurrence in
early stages of the disease and the possibility that keratoconus,97 neither layer is considered to play a
keratoconus may be the end result, or final common significant role in the strength of the cornea.98,99 The
Fig. 6. Vector plot maps showing the predominant orientation of stromal collagen in the central 7 mm of a normal and a keratoconic
cornea have been superimposed onto videokeratography images taken from the same specimens prior to surgery. In the apical region of
the keratoconic cornea, the normal preferred alignment of collagen in the vertical and horizontal directions is absent.
collagenous stroma, on the other hand, accounts for shown heightened levels of proteolytic enzymes110-113
about 90% of total corneal thickness and is considered and decreased levels of proteinase inhibitors114
the primary load-carrying layer of the cornea. The role within the affected tissue. Similarly, a mechanism
of basement membrane and stromal collagen in the of lamellar slippage may be readily envisaged when
pathogenesis is supported by reports of abnormalities one considers the reduced levels of inter-lamellar
in collagen types XIII, XV, an XVIII within keratoconic adhesion115 and lamellar interlacing in the apex of
corneas100-102 and the association of keratoconus with keratoconic corneas116,117 along with the diminished
certain connective tissue disorders, such as Marfan number of lamellar insertions into Bowman’s layer.116
syndrome, osteogenesis imperfecta (brittle bone Further strong evidence for a mechanism of lamellar
disease), mitral valve prolapse,103 and Ehlers-Dan- slippage has been provided by X-ray scattering
los syndrome (hyper-mobility of joints and increased studies, which have shown gross lamellar rearrange-
elasticity of skin).104 In this respect it is also interesting ment to occur in keratoconus corneas74,118 not only at
to note that advanced post-surgical keratoconus the apex but also, in some cases, in the surrounding
buttons show an abnormal elastic fiber network, which peripheral cornea (Fig. 6).119,120 Such a change in fibril
it has been postulated, may impede the recovery of the orientation would be difficult to explain on the basis
tissue following distortion and contribute to the patho- of tissue degradation alone, since collagen loss would
genesis of the disease.105 be unlikely to give rise to a systematic realignment of
Although there is general agreement that the stromal fibrils. In addition to this, Edmund121 demonstrated
thinning observed in keratoconus is caused by a that, except in advanced keratoconus, the cross-sec-
reduction in the number of lamellae within the affected tional area of corneas in optical section did not differ
region106 and not by the compaction of collagen fibrils from that of normal corneas, implying that ectasia
within individual lamellae,107 the precise mechanism occurs by a redistribution of stromal mass rather than
by which the thinning occurs is not clear. Some have by a loss from extensive tissue degradation. However,
attributed the stromal thinning to collagen degradation more recent 3-D analyses of corneal volumes in normal
instigated by the release of unspecific enzymes from and keratoconic eyes have demonstrated lower corneal
a defective epithelium108 while others have favored volumes in earlier disease stages122,123 and suggest that
a view that collagen is not lost, but simply redistrib- some combination of tissue degradation and lamellar
uted within the cornea via a mechanism of lamellar slippage may be required to explain the morphological
slippage.104,109 Evidence supporting the involvement features of keratoconus.
of collagen degradation in keratoconus progression One theory is that the loss of structural integrity in the
has been provided by biochemical studies which have keratoconus cornea is caused not only by the presence
Another random document with
no related content on Scribd:
Tabitha and told her the bad news, which personally did not alarm
her. She inquired where Dick was, and he replied that he had gone
on a hunting expedition, but luckily left his medicine book behind him
open at the article which gave him a clue. Next she asked to see the
letter which Dick had written to Rupert, and taking it from his pocket,
he handed it to her. Tabitha read it attentively.
“I see, Rupert, you have quarrelled with him at last,” she said.
“Ach! what a coward that man is!” then a light flashed in her eyes,
and she added: “No, I understand now. It is a little trick of dear
Dick’s; he knows it is the plague, he runs away, he sends for you, he
hopes that you will catch it. Mein Gott! he is not only a coward, he is
a murderer; you quarrel with him—what you say?—you beat him?
Well, he hit you back with the plague, or try to.”
Rupert began to laugh, then checked himself and said: “No,
Tabitha, he would scarcely be such a brute as that. Why!
assassination is nothing to it. Anyhow, I am not afraid; I do not catch
things.”
“You do not know the dear Dick; I do,” she replied grimly. “Go
home, Rupert, at once, burn the clothes you are wearing, sit in
smoke, wash yourself all over with soaps, do everything you can.”
“All right,” he answered, “don’t frighten Edith; I will take
precautions.”
He did, with the result that it was past two o’clock before he could
find time for food, he who had eaten nothing since seven on the
previous night.
For the next three days, knowing her terror of infectious diseases,
every morning he sent a message to Edith that she must not see
him, but with Tabitha and, of course, with Mea, he associated as
before, since neither of them would listen to his warnings. There had
been no further cases amongst Dick’s people, or elsewhere, and
although his camels were now ready, Dick himself had not yet
returned. It was reported that he was enjoying excellent sport on the
hills.
Rupert thought very little more about the plague, however, for he
had other things on his mind. Within four days the month would be
up, and he must give his answer to the great question. Edith, whom
for her own sake he still refused to see, had taken a desperate step;
she had sent him a letter.
Why do you keep me away from you? (she wrote). Of

course I know that I used to be afraid of illnesses, but I
don’t care any more about them now. Sometimes I
think it would be a good thing if I did catch the plague
and it made an end of me and my wretched life.
Rupert, I know you forbade me to speak to you about
these matters until next week, but you never said that I
mightn’t write, and I will write upon the chance that you
may read. Rupert, I am a miserable woman, as I
deserve to be, for I have been very wicked. I
acknowledge it all now. Dick has been my curse. When
I was still quite a child, he began to make love to me;
you know how handsome and taking he was then, and
I fell under his influence, which for years I could never
shake off. I tried to, for I knew that he was bad, but it
was no good, he attracted me, as a magnet attracts a
bit of iron. Then you came home, and I really did
admire you and respect you, and I was very flattered
that you should care for me. Also, I will tell you all the
truth, I thought that you were going to be a peer and
wealthy, and that you had a great career before you,
and I wished to be the wife of such a man. Dick of
course was furiously jealous; he insulted me upon the
very day that you proposed to me, and because I
would not be turned from my purpose, he set to work
to avenge himself upon us both. It was he who gave
the War Office the idea of sending you out on that
wretched mission, and who afterwards took away your
good name.
But, Rupert, I did not know all this at the time when you
were supposed to be dead. I let Dick, who seemed to
be turning out better then, regain his influence over
me. That day on which you came home I had become
secretly engaged to him. This will help to explain what
followed. Really, I was out of my mind and not
responsible. Afterwards, in my distress, I wrote Dick
some foolish letters, which he has held over my head
ever since I refused to have anything more to do with
him. Also, I would have asked your pardon and tried to
make it up with you if I had known where you were
gone. But I did not know, and I was afraid to inquire for
fear of betraying the shameful facts.
Rupert, it is true that I have grown to hate Dick, as

much as I once loved him, if I ever did love him. Since I
have found out how vile and treacherous he is, that it
was he who set to work to blacken your reputation, as
afterwards he has done by mine, and the rest of it, I
have loathed him; but he follows me like my shadow
and threatens me. I cannot cast him off, and if he says
things about me, and shows those letters, who will
believe that I am innocent—I with whom my own
husband will have nothing to do? I shall be a ruined
woman. Even here he has followed me; yes, and the
wicked wretch tried to murder you, I am sure, by giving
you that sickness. Well, thank Heaven! he seems to
have failed there.
Rupert, my husband, before the God that made me, I

tell you the honest truth. I love you now, body and soul;
it was only Dick that stood between us, and he is gone
from me for ever. I am miserable because I may not be
near you, and, if you will forgive all the past, and come
back to me, no man in the world shall have a better
wife, or one more obedient to his wishes. I know it is
much to ask; I know I do not deserve it, and I know,
too, that this beautiful lady Mea loves you, and that she
is as true and good as you are. Oh! Rupert, Rupert,
don’t break my heart; don’t turn me out to wander
again in the wilderness alone. If so, I do not know what
will happen to me, but I think that I shall go to the bad,
like many another poor creature. At any rate, it may be
amusing while it lasts. Rupert, be merciful, as you
hope for mercy.—Your wife (for I suppose that I still
have a right to sign myself so),
EDITH.
This letter produced a great effect upon Rupert, as its writer had
hoped that it would do. When he received it he was already low-
spirited, but after reading it his depression became acute. The
piteous way in which Edith made the best of a bad case; her evident
and honest repentance, and the curious heart-change which, as she
declared and as he half believed, now inclined her towards himself,
all touched him deeply, especially the repentance.
Yet he could not but see that almost every argument she used
might be urged with even greater effect upon behalf of Mea, who
wrote no letters and made no prayer. Why should Mea’s heart be
broken? Why should Mea be left to wander in that lonely wilderness
whereof Edith spoke, or perhaps to take to those common courses of
despair—Mea, who had never offended, who had always played an
angel’s part towards him?
Of course the only answer was that he was married to Edith, and
that he was not married to Mea; that he had taken Edith for better or
for worse, and that to them applied the ancient saying: “Those whom
God has joined together, let no man put asunder.” He knew well
enough in which direction his own feelings lay. Yet, what right had he
to thrust her out, his wife, whom he had asked to marry him? On the
other hand, what right had he to desert Mea, the woman who had
saved and sheltered him?
Rupert was sore perplexed; he could find no answer to these
problems. He wrote a note to Edith thanking her for her letter, the
contents of which he said he was considering, adding that he was
quite well, but she had better still keep away from him for a while.
Then he took a sudden resolution. He would go to Mea, and lay the
whole matter before her.
Once again they sat in that room in which, after weeks of
blindness, he had recovered his sight. His story had been told, the
letter had been read, there it lay upon the ground beside them.
“And now, Rupert,” asked Mea quietly, “what shall you do?”
“I don’t know,” he answered passionately. “I have come to ask
you.”
She looked at him and asked again: “Which is it that you love, your
wife or me?”
“You know well,” he replied. “It is you, and no other woman, you
now and for ever. Why do you make me tell you so again?”
“Because I like to hear it, Rupert,” she said, with her slow smile.
“But it does not make the choice easier, does it? On the one side,
love; on the other your law. Which will win, love or your law?”
“I have come to you to tell me, Mea.”
She looked upwards as though seeking an inspiration, then spoke
again.
“I will be no stumbling-block in your path of righteousness. Was it
for this that I was given to you? Love is longer than your law, Rupert,
and is not that doctrine which we practise named Renunciation? It
seems that those who would reap must sow.”
“What do you mean?” he asked.
“I mean, Rupert, that this woman who has behaved so ill repents,
and what says our Book—the Book you taught me to believe?
‘Judge not, that ye be not judged!’ I mean that since she has kept its
letter, that oath still stands between you and her.”
“Then I must leave you?” he muttered hoarsely.
“Yes, Rupert, I suppose so.”
“And what will become of you then?”
“I,” she replied, with another of her sweet smiles, “oh! what does it
matter? But if you wish to know, I will tell you. I think that I shall die,
and go to wait for you where love remains, and your law is finished.
Shall we agree that together, my Rupert?”
His hands trembled, and the veins swelled upon his forehead.
“I can’t,” he said hoarsely, “God forgive me, I can’t—yet. You are
nobler than I, Mea.”
“Then, Rupert, what?”
“Mea,” he said, “we have still four days. Something might happen
in those four days. Perhaps God may be pleased to help us in some
manner unforeseen. If not, at the end of them I will accept your
counsel, however cruel it may be; yes, even if it kills us both.”
“Good!” she answered, with a flash of her eyes, “such words I
looked to hear you speak, for shall the preacher of a faith fly before
its fires? The sooner we are dead, the sooner will there be an end—
and a beginning.”
“Aye,” he echoed, breaking into English, “an end and a beginning.”
Another two days had gone by, and once more Rupert and Mea
sat together. They were making arrangements for the forthcoming
gathering in the temple; also, he was giving her an account of his
stewardship, he who it seemed must so soon depart. He was ill; he
was troubled. He faltered in his speech, forgetting the Arabic words,
his head bent forwards over the book of accounts. Then suddenly he
placed his hands upon the edge of the table and raised himself with
a smothered exclamation of pain.
“What is it?” she asked wildly, as he sank back into his seat.
“Nothing,” he answered, in a faint voice. “It was as though a sword
passed through me, that is all.”
“Oh! Rupert,” she cried, “you are ill.”
“Yes, Mea,” he said presently, “I am ill. I think that God has shown
us a way out of our troubles, and for that blessed be His name. Mea,
I have the plague. Leave me; leave me at once.”
“Aye,” she answered, setting her lips, “when they take you from
me dead, but never before.”
Two more days and Rupert was dying with the dawn. By his side
knelt Mea, and in a chair at the end of the shadowed room, tears
streaming down her placid face, and the grey-haired Bakhita
crouched crooning at her feet, sat Tabitha. Edith was not there.
Rupert had refused to allow her to be admitted, lest she also should
contract the plague. Sometimes he was conscious, and sometimes
he sank into sleep. His eyes opened, he woke again and turned to
Mea.
“Beloved,” she whispered in his ear, “I have hidden it from all save
Bakhita, but I have that which I must tell you at last. Our merciful
God has called me—I die also. Before midday I follow on your road.
Wait for me, Rupert.”
He smiled, and whispered: “I understand. I will wait—surely,
surely!”
Then he stretched up his arms. She sank into them, and for the
first time their lips met. It was their kiss of farewell—and of greeting.
“Bakhita,” said Mea presently in a clear and ringing voice, “it is
done. Come; tire me in those robes that I have made ready, my
bridal robes. Be swift now, for my lord calls me.”
The stern-faced, aged woman rose and obeyed. Tabitha knelt in
prayer by the corpse of Rupert, and messengers swiftly spread the
news that Zahed had departed from his people. A while later, as high
and shrill the Eastern death-wail broke upon the silence, a door burst
open and in rushed Edith.
“Oh! is it true, is it true?” she sobbed.
Tabitha pointed to the shrouded form of Rupert.
“Come no nearer,” she said, “lest you should die also—you who
are not ready to die.”
The two women, Edith and Mea, stood face to face with each
other; Edith, dishevelled, weeping; Mea, a strange and glorious sight
in the rays of the rising sun that struck on her through the open
window-place. She was clad in silvery robes that flowed about her; in
her weak hand swayed the ancient sceptre of her race, upon her
breast lay a pectoral of Isis and Nepthys weeping over dead Osiris;
above her outspread hair was set that funeral crown worked in thin
gold and enamelled flowers which once she had shown to Rupert.
Her wide eyes shone like stars, and the fever that burned upon it
seemed to give to her mysterious face a richer beauty.
“I greet you, lady,” she said to Edith. “Well have I nursed our lord,
but now he has passed from us—home, and I—I follow him,” and
she pointed over the shattered temple and the wall of mountains
upwards to the splendid sky.
“You follow him; you follow him?” gasped Edith? “What do you
mean?”
By way of answer, Mea tore open her white wrappings and
showed her bosom marked with those spots of plague that appear
only just before the end.
“It was his last and best gift to me,” she cried in Arabic.
“Soon, very soon we two shall have done with separations and
with griefs. Hearken you, his lady according to your law. He had
determined that to-morrow he would have gone back with you whom
he forgave, as I do. But we prayed, he and I—yes, knee by knee we
prayed to our God that He would save us from this sacrifice, and He
has answered to our prayer. Behold! we who have followed the way
of the Spirit inherit the Spirit; and we who renounced, renounce no
more. To me it was given to save his life; to me it is given to share
his death and all beyond it through light, through dark—forever and
forever.
“Way now, make way for Tama who comes to her lord’s bed!”
Then while they gazed and wondered, with slow steps Mea reeled
to the couch upon which the corpse of Rupert lay; uttering one low
cry of love and triumph, she cast herself beside him, and there she
died.
“Now,” said the quiet voice of Tabitha, as she looked upward to
heaven over the ruined temples of a faith fulfilled and the cruel
mountains of our world—“now, who will deny there dwells One
yonder that rewards the righteous and smites the wicked with His
sword?”
FINIS
WORKS BY H. RIDER HAGGARD

PARLIAMENTARY BLUE-BOOK
Report to H.M.’s Government on the Salvation Army colonies
in the United States, with Scheme of National Land
Settlement. [Cd. 2562.]
POLITICAL HISTORY
Cetewayo and his White Neighbours
WORKS ON AGRICULTURE, COUNTRY LIFE, AND SOCIOLOGY

Rural England (2 vols.)
A Farmer’s Year
The Poor and the Land
A Gardener’s Year
BOOK OF TRAVEL
A Winter Pilgrimage
NOVELS
Dawn
Beatrice
The Witch’s Head
Joan Haste
Jess
Doctor Therne
Colonel Quaritch, V.C.
Stella Fregelius
ROMANCES
King Solomon’s Mines
She
Allan Quatermain
Maiwa’s Revenge
Mr. Meeson’s Will
Allan’s Wife
Cleopatra
Eric Brighteyes
Nada the Lily
Montezuma’s Daughter
The People of the Mist
Heart of the World
Swallow
Black Heart and White Heart
Lysbeth
Pearl Maiden
The Brethren
Ayesha: The Return of She
(In collaboration with Andrew Lang):
The World’s Desire
*** END OF THE PROJECT GUTENBERG EBOOK THE WAY OF
THE SPIRIT ***
Updated editions will replace the previous one—the old editions will
be renamed.
Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright in
these works, so the Foundation (and you!) can copy and distribute it
in the United States without permission and without paying copyright
royalties. Special rules, set forth in the General Terms of Use part of
this license, apply to copying and distributing Project Gutenberg™
electronic works to protect the PROJECT GUTENBERG™ concept
and trademark. Project Gutenberg is a registered trademark, and
may not be used if you charge for an eBook, except by following the
terms of the trademark license, including paying royalties for use of
the Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is very
easy. You may use this eBook for nearly any purpose such as
creation of derivative works, reports, performances and research.
Project Gutenberg eBooks may be modified and printed and given
away—you may do practically ANYTHING in the United States with
eBooks not protected by U.S. copyright law. Redistribution is subject
to the trademark license, especially commercial redistribution.
START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK
To protect the Project Gutenberg™ mission of promoting the free

distribution of electronic works, by using or distributing this work (or
any other work associated in any way with the phrase “Project
Gutenberg”), you agree to comply with all the terms of the Full
Project Gutenberg™ License available with this file or online at
www.gutenberg.org/license.
Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand, agree
to and accept all the terms of this license and intellectual property
(trademark/copyright) agreement. If you do not agree to abide by all
the terms of this agreement, you must cease using and return or
destroy all copies of Project Gutenberg™ electronic works in your
possession. If you paid a fee for obtaining a copy of or access to a
Project Gutenberg™ electronic work and you do not agree to be
bound by the terms of this agreement, you may obtain a refund from
the person or entity to whom you paid the fee as set forth in
paragraph 1.E.8.
1.B. “Project Gutenberg” is a registered trademark. It may only be

used on or associated in any way with an electronic work by people
who agree to be bound by the terms of this agreement. There are a
few things that you can do with most Project Gutenberg™ electronic
works even without complying with the full terms of this agreement.
See paragraph 1.C below. There are a lot of things you can do with
Project Gutenberg™ electronic works if you follow the terms of this
agreement and help preserve free future access to Project
Gutenberg™ electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright law in
the United States and you are located in the United States, we do
not claim a right to prevent you from copying, distributing,
performing, displaying or creating derivative works based on the
work as long as all references to Project Gutenberg are removed. Of
course, we hope that you will support the Project Gutenberg™
mission of promoting free access to electronic works by freely
sharing Project Gutenberg™ works in compliance with the terms of
this agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms of
this agreement by keeping this work in the same format with its
attached full Project Gutenberg™ License when you share it without
charge with others.
1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside the
United States, check the laws of your country in addition to the terms
of this agreement before downloading, copying, displaying,
performing, distributing or creating derivative works based on this
work or any other Project Gutenberg™ work. The Foundation makes
no representations concerning the copyright status of any work in
any country other than the United States.
1.E. Unless you have removed all references to Project Gutenberg:
1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project Gutenberg™
work (any work on which the phrase “Project Gutenberg” appears, or
with which the phrase “Project Gutenberg” is associated) is
accessed, displayed, performed, viewed, copied or distributed:
This eBook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this eBook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.
1.E.2. If an individual Project Gutenberg™ electronic work is derived

from texts not protected by U.S. copyright law (does not contain a
notice indicating that it is posted with permission of the copyright
holder), the work can be copied and distributed to anyone in the
United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must
comply either with the requirements of paragraphs 1.E.1 through
1.E.7 or obtain permission for the use of the work and the Project
Gutenberg™ trademark as set forth in paragraphs 1.E.8 or 1.E.9.
1.E.3. If an individual Project Gutenberg™ electronic work is posted

with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works posted
with the permission of the copyright holder found at the beginning of
this work.
1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files containing a
part of this work or any other work associated with Project
Gutenberg™.
1.E.5. Do not copy, display, perform, distribute or redistribute this

electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.
1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if you
provide access to or distribute copies of a Project Gutenberg™ work
in a format other than “Plain Vanilla ASCII” or other format used in
the official version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.
1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.
1.E.8. You may charge a reasonable fee for copies of or providing

access to or distributing Project Gutenberg™ electronic works
provided that:
• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”
• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.
• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.
• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.
1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

electronic work or group of works on different terms than are set
forth in this agreement, you must obtain permission in writing from
the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.
1.F.
1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on, transcribe
and proofread works not protected by U.S. copyright law in creating
the Project Gutenberg™ collection. Despite these efforts, Project
Gutenberg™ electronic works, and the medium on which they may
be stored, may contain “Defects,” such as, but not limited to,
incomplete, inaccurate or corrupt data, transcription errors, a
copyright or other intellectual property infringement, a defective or
damaged disk or other medium, a computer virus, or computer
codes that damage or cannot be read by your equipment.
1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

for the “Right of Replacement or Refund” described in paragraph
1.F.3, the Project Gutenberg Literary Archive Foundation, the owner
of the Project Gutenberg™ trademark, and any other party
distributing a Project Gutenberg™ electronic work under this
agreement, disclaim all liability to you for damages, costs and
expenses, including legal fees. YOU AGREE THAT YOU HAVE NO
REMEDIES FOR NEGLIGENCE, STRICT LIABILITY, BREACH OF
WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE
FOUNDATION, THE TRADEMARK OWNER, AND ANY
DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE LIABLE
TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL,
PUNITIVE OR INCIDENTAL DAMAGES EVEN IF YOU GIVE
NOTICE OF THE POSSIBILITY OF SUCH DAMAGE.
1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

discover a defect in this electronic work within 90 days of receiving it,
you can receive a refund of the money (if any) you paid for it by
sending a written explanation to the person you received the work
from. If you received the work on a physical medium, you must
return the medium with your written explanation. The person or entity
that provided you with the defective work may elect to provide a
replacement copy in lieu of a refund. If you received the work
electronically, the person or entity providing it to you may choose to
give you a second opportunity to receive the work electronically in
lieu of a refund. If the second copy is also defective, you may
demand a refund in writing without further opportunities to fix the
problem.
1.F.4. Except for the limited right of replacement or refund set forth in
paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.
1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of damages.
If any disclaimer or limitation set forth in this agreement violates the
law of the state applicable to this agreement, the agreement shall be
interpreted to make the maximum disclaimer or limitation permitted
by the applicable state law. The invalidity or unenforceability of any
provision of this agreement shall not void the remaining provisions.
1.F.6. INDEMNITY - You agree to indemnify and hold the
Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and distribution
of Project Gutenberg™ electronic works, harmless from all liability,
costs and expenses, including legal fees, that arise directly or
indirectly from any of the following which you do or cause to occur:
(a) distribution of this or any Project Gutenberg™ work, (b)
alteration, modification, or additions or deletions to any Project
Gutenberg™ work, and (c) any Defect you cause.
Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers.
It exists because of the efforts of hundreds of volunteers and
donations from people in all walks of life.
Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a
secure and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help,
see Sections 3 and 4 and the Foundation information page at
www.gutenberg.org.
Section 3. Information about the Project

Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg
Literary Archive Foundation are tax deductible to the full extent
permitted by U.S. federal laws and your state’s laws.
The Foundation’s business office is located at 809 North 1500 West,

Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact
Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can
be freely distributed in machine-readable form accessible by the
widest array of equipment including outdated equipment. Many small
donations ($1 to $5,000) are particularly important to maintaining tax
exempt status with the IRS.
The Foundation is committed to complying with the laws regulating

charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and
keep up with these requirements. We do not solicit donations in
locations where we have not received written confirmation of
compliance. To SEND DONATIONS or determine the status of
compliance for any particular state visit www.gutenberg.org/donate.
While we cannot and do not solicit contributions from states where

we have not met the solicitation requirements, we know of no

Biomechanics of The Eye 1St Edition C J Roberts W J Dupps JR J C Downs Online Ebook Texxtbook Full Chapter PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Biomechanics of The Eye 1St Edition C J Roberts W J Dupps JR J C Downs Online Ebook Texxtbook Full Chapter PDF

Uploaded by

Copyright:

Available Formats

Biomechanics of the Eye 1st Edition C J

Roberts W J Dupps Jr J C Downs

The Cross 1st Edition J. C. Ryle

Snake Skin C J Lyons

Ehlers Danlos Syndrome a Multidisciplinary Approach 1st

The Librarian of Crooked Lane 1st Edition C J Archer

Eye for an Eye 1st Edition J M Holt

The Lost Continent 1st Edition C. J. Cutcliffe Hyne

Copyright © 2018. Kugler Publications. All rights reserved.

BIOMECHANICS OF THE EYE

Kugler Publications/Amsterdam/The Netherlands

© 2018 Kugler Publications, Amsterdam, The Netherlands

Cover design by: Willem Driebergen, Rijnsburg, The Netherlands

About the editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

2. Corneal stroma: collagen ultrastructure and orientation in health and disease . . . . . . . . . . . . . 15

3. Acoustic radiation force elastic microscopy and corneal structural correlation . . . . . . . . . . . . . 31

4. Cellular micromechanics of corneal stroma: keratocyte and extracellular

5. The electrochemical basis of corneal hydration, swelling, and transparency . . . . . . . . . . . . . . . 63

6. Material properties of the human cornea: anisotropy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

7. Inflation testing of the cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

8. Optical coherence tomography principles and elastography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

9. Optical coherence elastography for ocular biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

11. Brillouin microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

12. Deformation response to an air puff: clinical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

13. Factors contributing to air-puff derived corneal responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

14. Biomechanics in ectasia detection: ORA and Corvis ST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

15. Mechanisms of collagen crosslinking and implications on biomechanics . . . . . . . . . . . . . . . . 217

16. Crosslinking kinetics and alternative techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

17. Computational modeling of corneal refractive surgery, ectasia,

18. Comparative biomechanics of intrastromal lenticule extraction and LASIK . . . . . . . . . . . . . . 261

19. Iris biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

20. Accommodation and presbyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

21. Biomechanics of the lens and its role in accommodation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

22. Biomechanics of the vitreous humor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

23. Introduction to posterior pole biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

24. Intraocular pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

25. Collagen anisotropy in scleral mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

26. The dynamic response of the corneoscleral shell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

27. Scleral remodeling in myopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

29. Cellular mechanisms of lamina cribrosa remodeling in glaucoma . . . . . . . . . . . . . . . . . . . . . . 431

32. Parametric analysis to identify biomechanical risk factors:

William J. Dupps Jr.

Engineering at Cleveland State University. After graduating with a BS in Chemical

J. Crawford Downs received his PhD in Biomedical Engineering in 2002 from

Fernando Faria Correia

William J. Dupps Jr.

Rui Carneiro Freitas

Miguel Miron Mendoza

Arun Dev Pant

Jean Marie Parel

Columbus, OH, USA

University of Basel, Switzerland

Jonathan Vande Geest

Neeraj Vij Jr.

Department of Biomedical Engineering, University of California, Irvine, USA

Seok Hyun Yun

Department of Ophthalmology, Aarhus University Hospital NBG, Aarhus, Denmark

Biomechanics of the Eye, pp. 3-13

3. Measurement of the extensibility of

3.1. Strip extensiometry

material exhibits symmetry of its elastic properties

Fig. 2. Strip extensiometry of a specimen.

plitude crimp of the collagen fibrils might contribute