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The Contact Lens and Tear Film Laboratory, The Ohio State University College of Optometry
Institutional Personal Profile Profile The Contact Lens and Tear Film Laboratory, The Ohio State University College of Optometry KELLY K. NICHOLS, OD, MPH, PHD, AND JASON J. NICHOLS, OD, MPH, PHD
ounded in 1914, The Ohio State University’s College of Optometry ranks as the oldest university-based optometry program in the nation, with a long tradition of combining research, clinical patient care, and education. The ocular surface research of the Contact Lens and Tear Film Laboratory grows out of a longstanding interest in corneal physiology and contact lens wear dating to the pioneering work of faculty members Richard Hill, John Schoessler, Gerald Lowther, Joe Barr, and Barbara Fink in the 1970s and 1980s. They were joined by Karla Zadnik in the 1990s. The college’s strong contact lens fellowship and clinical program likewise lends support to our work in dry eye disease, a field of research we introduced to the school as PhD students in the mid-1990s. In Kelly’s case, her interest stems from her clinical residency in Denver, where virtually everyone has dry eye to some degree due to its infamously parched, thin air. Jason’s research derives from his longstanding interest in contact lenses. The laboratory’s early research focused on tear film and dry eye (led by Kelly) and contact lens, tear film, and ocular surface interactions (led by Jason). Four early findings were that dry eye symptoms don’t correlate with the results of standard dry eye tests, that the results of different diagnostic tests don’t correlate with each other, that doctors favor a symptom assessment over any other diagnostic test, and that even
F
©2007 Ethis Communications, Inc. All rights reserved.
physiology in normal and the results of a dry eyes, as well as in consingle test (eg, tact lens wear. Lisa Jones, staining) may not PhD, is the director of the be consistent or Optometry Coordinating correlate with the Center, and leads a team disease state over of biostatisticians who are time. This lack instrumental in more of of correlation our clinical research activiand reproducties. We are assisted by two ibility forces us staff optometrists, Katherine to question our Weibel and Kathleen Reuter, understanding of and a progression of maspatients’ sympters and doctoral students. toms and the Research associate Beth way we evaluate Oglevee coordinates all dry eye disease. of our efforts (Figure 1). Jason’s early work Outside the College showed how the of Optometry, our most precorneal tear The new addition of three floors important collaborators film is altered to Fry Hall, site of the Contact include analytic chemist during contact Lens and Tear Film Laboratory. Kari Green-Church, PhD, lens wear and director of The Ohio State University’s how this is associated with numerous Mass Spectrometry and Proteomics ocular surface symptoms in contact Facility, and The Ohio State Medical lens wear. These questions now drive Center endocrinologist Rebecca our laboratory’s research, in particular Jackson, MD, a principal investigator our interest in forging a deeper unfor the Women’s Health Initiative of derstanding of tear film stability and the National Institutes of Health and the etiology —likely multiple etiolothe National Heart, Lung and Blood gies—of dry eye disease. Institute. Our collaborations with THE LABORATORY TEAM Green-Church and Jackson reflect the Our group consists of four College wealth of resources available to us at of Optometry faculty members. Kelly Ohio State, one of the largest and most is an associate professor interested in comprehensive health sciences centers tear film physiology and dry eye. Jason in the world. Our research funding is an assistant professor interested continues to flow from both industry primarily in the interaction between (pharmaceutical and contact lens) and a contact lens and the tear film and government agencies. ocular surface. Professor Ewen KingAgainst this backdrop, our lab has Smith is a Cambridge-trained physicist several primary foci: 1) the use of high and physiologist who has designed and resolution, noninvasive interferometbuilt several noninvasive interferometry ric methods for studying the tear film systems for studying human tear film and developing advanced diagnostics;
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
259
INSTITUTIONAL PROFILE / Ohio State University, College of Optometry
2) the identification and analysis of the lipid and protein fractions of human tears as potential biomarkers of ocular surface disease states; 3) the effect of contact lens wear on tear film stability and dry eye; and 4) the
of Prydal’s benchmark of 40 microns. Dr. King-Smith has developed two interferometers for studying the cornea and tear film in our lab (Figure 2). The spectral interferometer is used to measure the thickness of pre-corneal, pre-lens, and post-lens tear films, the corneal epithelium, and the complete corneal thickness. Advantages of this method, in addition to its being noninvasive, include fine resolution (less than 1 micron), Figure 1. The Contact Lens and Tear Film Laboratory team. good signal-tonoise ratio, rapidetiology, diagnosis, and treatment of ity (up to 36 measurements per second), postmenopausal dry eye disease. and higher precision than is possible with competing technologies, such as INTERFEROMETRY AND DRY EYE optical coherence tomography. This has A knowledge of normal tear film facilitated our recent findings of relathickness is crucial to understanding tively rapid and steady thinning rates of the structure of healthy tear film laythe pre-corneal and pre-lens tear layers ers, tear film formation and redistribubetween blinks—up to 10 microns tion, and the occurrence of dry spots. per minute or greater. We now believe Our early studies, reported in 2000, that evaporation drives this provided some of the first reliable steady thinning and repremeasurements—previous measuresents the major cause of tear ments employed fairly invasive methfilm breakup. ods that lacked resolution, and which, We use a second, “imnot surprisingly, produced wide aging” interferometer to variations in estimated tear film thickrecord video of pre-corneal nesses, ranging from 4 to 40 microns. and pre-lens tear films. We Because microscopy has not yet simultaneously record two been applied to tear film study with videos, one using a narrow much success, interferometry offers the band of spectral light and most promising noninvasive method one using a broad band. for advancing our understanding. In By comparing these two this method, interference from light reimages, we can study the flected from the corneal surface leads to three-dimensional distribuoscillations across the reflectance spection of the pre-corneal tear trum, and the frequency of these oscilfilm—a first in vision relations is proportional to the thickness search. Through these and of the layers associated with the reflecother studies, we continue Figure 2. tions. By measuring reflectance specto see the great potential tra from the human cornea, we have for interferometry in the evaluation garnered data consistently supporting of tear film flow and evaporation and a human tear film thickness value of in the analysis of dry eye disease. approximately 3 microns. In doing so, DRY EYE AND CONTACT LENS WEAR our studies force a rethinking of both Our group has a major interest Danjo’s value of 11 microns (except in evaluating the effect of contact in cases of reflex tears) and certainly 260
lens wear on the ocular surface and tear film stability. In particular, we continue to study contact lens-related dry eye, a problem that our studies show affects up to half of all contact lens wearers. We’ve identified several initiating factors, including the use of high-water content contact lenses, abnormally rapid pre-lens tear film thinning, and a significant increase in osmolality of the tear film. In other studies using our noninvasive imaging methods, we have shown that contact lenses significantly change tear film flow and distribution. We continue to pursue basic and clinical research into tear film dynamics and the etiology of dry eye in contact lens wearers, with particular emphasis on the changes in tear film proteins and lipids and the polymer surface modifications that occur during lens wear. TEAR FILM LIPIDS AND PROTEINS
The meibomian glands secrete a complex mixture of triglycerides, free fatty acids, peptides, proteins, polar lipids, and other organic molecules that together protect and maintain the ocular surface and provide a smooth refractive
Two views of the interferometer.
interface. Yet we are far from a thorough understanding of the individual constituents of this intricate and vitally important solution. In collaboration with Dr. Green-Church, we are working to identify unique proteins and lipids in meibomian gland secretions and tear film.
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
INSTITUTIONAL PROFILE / Ohio State University, College of Optometry
Most recently we have used mass spectrometry to show that the fatty acid amides are associated with meibomian gland secretions. This finding may lead to additional insights into their role in tear film stability and/or in ocular surface signaling. It is interesting to note that this class of compounds is often referred to as “signaling lipids,” in recognition of their role in modulating pain and locomotor activity. Oleamide, in particular, has been reported to have a potential role in wound healing and neurotransmitter-mediated cell communication, suggesting that it may play a crucial, albeit still mysterious, role in ocular surface health and disease. Our lipid work may also produce useful new biomarkers to aid in diagnosis and monitoring of ocular surface disease. In coming years, we strongly believe, further understanding of the molecular structure of tear film and an in-depth evaluation of its components will prove key to greater understanding of ocular surface disease. Using state-of-the-art mass spectrometry techniques, we have also shown approximately 100 proteins associated with the human tear film. We are also showing that many of these proteins are post-translationally modified, usually undergoing glycosylation or phosphorylation. DRY EYE AND MENOPAUSE
Hormone status, in particular levels of estrogen and androgens, may play a profound role in tear film stability and ocular surface health. In a culmination of our group’s research interests, we are currently launching a landmark study that will explore the factors associated with dry eye in postmenopausal women. Our funding comes as part of a $1.7 million grant from the National Eye Institute’s Women’s Health Initiative Sight Examination, a national evaluation of the effect of hormone replacement on cataracts and macular degeneration. This will enable our team and our Ohio State University collaborators to follow 500 women over 5 years in one of the largest research efforts ever to
uncover the multiple causes that we suspect underlie dry eye disease. In this effort, we will apply our advanced measurement and analytical techniques to the clinical evaluation of the ocular surfaces of older women both with and without dry eye. In particular, we will evaluate abnormalities in relation to concentrations of tear film lipids, changes in tear film thickness, and aging-related alterations in the structure of the meibomian glands. Our collaboration with endocrinologist Rebecca Jackson will enable us to further explore the previously observed effects of hormones on meibomian glands and their secretions. Figure 3.
NEW FACILITIES, FUTURE PROSPECTS
In February of 2007, our Contact Lens and Tear Film Laboratory began moving into the third and fifth floors of the newly built E.F. Wildermuth Optometric Research Clinic (Figures 3 and 4). A matching-fund grant from the National Institutes of Health, along with funds raised by college alumni, The Ohio State University, the state of Ohio, and private foundations, made this three-story addition possible. It represents the College of Optometry’s largest building project in 40 years. The rapid growth of the college’s research program demanded this major expansion. For our team, it Figure 4. has brought an increase in bench-science space that will allow us to greatly expand our basic science work with cell culture, immunoassays, histology, and other laboratory techniques. Our new facilities also include greater space for clinical research, including new exam rooms and office space that will allow us to bring in new collaborators to expand our team and its expertise. In particular, we see ourselves increasing our work in proteomics and lipidomics and branching out in our clinical
work to include other ocular surface diseases like allergy, as well as contact lens wearers and women. Foremost among our goals is to deepen our understanding of dry eye disease. We have yet to fully define the mechanisms underlying the pathophysiology of dry eye disease or develop a sufficient appreciation of its multifactorial nature. Clearly, contact
The Contact Lens and Tear Film Laboratory.
lens wear, age, hormonal status, genes, gender, immune status, innervation, pathogens, and environmental stresses all can affect the cellular and molecular structure and function of the ocular surface. The coming years promise an exciting combination of advances in basic and clinical research that will, we hope, result in more effective diagnostics and treatment. With expanded
The biological science lab area.
facilities and the impressive collaborative resources of the university’s medical center, we look forward to being a key part of this endeavor at The Ohio State University College of Optometry. Kelly K. Nichols, OD, MPH, PhD, is an associate professor of optometry and vision science and Jason J. Nichols, OD, MPH, PhD, is an assistant professor of optometry and vision science at the Ohio State University College of Optometry, Columbus, OH.
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
261
ounded in 1914, The Ohio State University’s College of Optometry ranks as the oldest university-based optometry program in the nation, with a long tradition of combining research, clinical patient care, and education. The ocular surface research of the Contact Lens and Tear Film Laboratory grows out of a longstanding interest in corneal physiology and contact lens wear dating to the pioneering work of faculty members Richard Hill, John Schoessler, Gerald Lowther, Joe Barr, and Barbara Fink in the 1970s and 1980s. They were joined by Karla Zadnik in the 1990s. The college’s strong contact lens fellowship and clinical program likewise lends support to our work in dry eye disease, a field of research we introduced to the school as PhD students in the mid-1990s. In Kelly’s case, her interest stems from her clinical residency in Denver, where virtually everyone has dry eye to some degree due to its infamously parched, thin air. Jason’s research derives from his longstanding interest in contact lenses. The laboratory’s early research focused on tear film and dry eye (led by Kelly) and contact lens, tear film, and ocular surface interactions (led by Jason). Four early findings were that dry eye symptoms don’t correlate with the results of standard dry eye tests, that the results of different diagnostic tests don’t correlate with each other, that doctors favor a symptom assessment over any other diagnostic test, and that even
F
©2007 Ethis Communications, Inc. All rights reserved.
physiology in normal and the results of a dry eyes, as well as in consingle test (eg, tact lens wear. Lisa Jones, staining) may not PhD, is the director of the be consistent or Optometry Coordinating correlate with the Center, and leads a team disease state over of biostatisticians who are time. This lack instrumental in more of of correlation our clinical research activiand reproducties. We are assisted by two ibility forces us staff optometrists, Katherine to question our Weibel and Kathleen Reuter, understanding of and a progression of maspatients’ sympters and doctoral students. toms and the Research associate Beth way we evaluate Oglevee coordinates all dry eye disease. of our efforts (Figure 1). Jason’s early work Outside the College showed how the of Optometry, our most precorneal tear The new addition of three floors important collaborators film is altered to Fry Hall, site of the Contact include analytic chemist during contact Lens and Tear Film Laboratory. Kari Green-Church, PhD, lens wear and director of The Ohio State University’s how this is associated with numerous Mass Spectrometry and Proteomics ocular surface symptoms in contact Facility, and The Ohio State Medical lens wear. These questions now drive Center endocrinologist Rebecca our laboratory’s research, in particular Jackson, MD, a principal investigator our interest in forging a deeper unfor the Women’s Health Initiative of derstanding of tear film stability and the National Institutes of Health and the etiology —likely multiple etiolothe National Heart, Lung and Blood gies—of dry eye disease. Institute. Our collaborations with THE LABORATORY TEAM Green-Church and Jackson reflect the Our group consists of four College wealth of resources available to us at of Optometry faculty members. Kelly Ohio State, one of the largest and most is an associate professor interested in comprehensive health sciences centers tear film physiology and dry eye. Jason in the world. Our research funding is an assistant professor interested continues to flow from both industry primarily in the interaction between (pharmaceutical and contact lens) and a contact lens and the tear film and government agencies. ocular surface. Professor Ewen KingAgainst this backdrop, our lab has Smith is a Cambridge-trained physicist several primary foci: 1) the use of high and physiologist who has designed and resolution, noninvasive interferometbuilt several noninvasive interferometry ric methods for studying the tear film systems for studying human tear film and developing advanced diagnostics;
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
259
INSTITUTIONAL PROFILE / Ohio State University, College of Optometry
2) the identification and analysis of the lipid and protein fractions of human tears as potential biomarkers of ocular surface disease states; 3) the effect of contact lens wear on tear film stability and dry eye; and 4) the
of Prydal’s benchmark of 40 microns. Dr. King-Smith has developed two interferometers for studying the cornea and tear film in our lab (Figure 2). The spectral interferometer is used to measure the thickness of pre-corneal, pre-lens, and post-lens tear films, the corneal epithelium, and the complete corneal thickness. Advantages of this method, in addition to its being noninvasive, include fine resolution (less than 1 micron), Figure 1. The Contact Lens and Tear Film Laboratory team. good signal-tonoise ratio, rapidetiology, diagnosis, and treatment of ity (up to 36 measurements per second), postmenopausal dry eye disease. and higher precision than is possible with competing technologies, such as INTERFEROMETRY AND DRY EYE optical coherence tomography. This has A knowledge of normal tear film facilitated our recent findings of relathickness is crucial to understanding tively rapid and steady thinning rates of the structure of healthy tear film laythe pre-corneal and pre-lens tear layers ers, tear film formation and redistribubetween blinks—up to 10 microns tion, and the occurrence of dry spots. per minute or greater. We now believe Our early studies, reported in 2000, that evaporation drives this provided some of the first reliable steady thinning and repremeasurements—previous measuresents the major cause of tear ments employed fairly invasive methfilm breakup. ods that lacked resolution, and which, We use a second, “imnot surprisingly, produced wide aging” interferometer to variations in estimated tear film thickrecord video of pre-corneal nesses, ranging from 4 to 40 microns. and pre-lens tear films. We Because microscopy has not yet simultaneously record two been applied to tear film study with videos, one using a narrow much success, interferometry offers the band of spectral light and most promising noninvasive method one using a broad band. for advancing our understanding. In By comparing these two this method, interference from light reimages, we can study the flected from the corneal surface leads to three-dimensional distribuoscillations across the reflectance spection of the pre-corneal tear trum, and the frequency of these oscilfilm—a first in vision relations is proportional to the thickness search. Through these and of the layers associated with the reflecother studies, we continue Figure 2. tions. By measuring reflectance specto see the great potential tra from the human cornea, we have for interferometry in the evaluation garnered data consistently supporting of tear film flow and evaporation and a human tear film thickness value of in the analysis of dry eye disease. approximately 3 microns. In doing so, DRY EYE AND CONTACT LENS WEAR our studies force a rethinking of both Our group has a major interest Danjo’s value of 11 microns (except in evaluating the effect of contact in cases of reflex tears) and certainly 260
lens wear on the ocular surface and tear film stability. In particular, we continue to study contact lens-related dry eye, a problem that our studies show affects up to half of all contact lens wearers. We’ve identified several initiating factors, including the use of high-water content contact lenses, abnormally rapid pre-lens tear film thinning, and a significant increase in osmolality of the tear film. In other studies using our noninvasive imaging methods, we have shown that contact lenses significantly change tear film flow and distribution. We continue to pursue basic and clinical research into tear film dynamics and the etiology of dry eye in contact lens wearers, with particular emphasis on the changes in tear film proteins and lipids and the polymer surface modifications that occur during lens wear. TEAR FILM LIPIDS AND PROTEINS
The meibomian glands secrete a complex mixture of triglycerides, free fatty acids, peptides, proteins, polar lipids, and other organic molecules that together protect and maintain the ocular surface and provide a smooth refractive
Two views of the interferometer.
interface. Yet we are far from a thorough understanding of the individual constituents of this intricate and vitally important solution. In collaboration with Dr. Green-Church, we are working to identify unique proteins and lipids in meibomian gland secretions and tear film.
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
INSTITUTIONAL PROFILE / Ohio State University, College of Optometry
Most recently we have used mass spectrometry to show that the fatty acid amides are associated with meibomian gland secretions. This finding may lead to additional insights into their role in tear film stability and/or in ocular surface signaling. It is interesting to note that this class of compounds is often referred to as “signaling lipids,” in recognition of their role in modulating pain and locomotor activity. Oleamide, in particular, has been reported to have a potential role in wound healing and neurotransmitter-mediated cell communication, suggesting that it may play a crucial, albeit still mysterious, role in ocular surface health and disease. Our lipid work may also produce useful new biomarkers to aid in diagnosis and monitoring of ocular surface disease. In coming years, we strongly believe, further understanding of the molecular structure of tear film and an in-depth evaluation of its components will prove key to greater understanding of ocular surface disease. Using state-of-the-art mass spectrometry techniques, we have also shown approximately 100 proteins associated with the human tear film. We are also showing that many of these proteins are post-translationally modified, usually undergoing glycosylation or phosphorylation. DRY EYE AND MENOPAUSE
Hormone status, in particular levels of estrogen and androgens, may play a profound role in tear film stability and ocular surface health. In a culmination of our group’s research interests, we are currently launching a landmark study that will explore the factors associated with dry eye in postmenopausal women. Our funding comes as part of a $1.7 million grant from the National Eye Institute’s Women’s Health Initiative Sight Examination, a national evaluation of the effect of hormone replacement on cataracts and macular degeneration. This will enable our team and our Ohio State University collaborators to follow 500 women over 5 years in one of the largest research efforts ever to
uncover the multiple causes that we suspect underlie dry eye disease. In this effort, we will apply our advanced measurement and analytical techniques to the clinical evaluation of the ocular surfaces of older women both with and without dry eye. In particular, we will evaluate abnormalities in relation to concentrations of tear film lipids, changes in tear film thickness, and aging-related alterations in the structure of the meibomian glands. Our collaboration with endocrinologist Rebecca Jackson will enable us to further explore the previously observed effects of hormones on meibomian glands and their secretions. Figure 3.
NEW FACILITIES, FUTURE PROSPECTS
In February of 2007, our Contact Lens and Tear Film Laboratory began moving into the third and fifth floors of the newly built E.F. Wildermuth Optometric Research Clinic (Figures 3 and 4). A matching-fund grant from the National Institutes of Health, along with funds raised by college alumni, The Ohio State University, the state of Ohio, and private foundations, made this three-story addition possible. It represents the College of Optometry’s largest building project in 40 years. The rapid growth of the college’s research program demanded this major expansion. For our team, it Figure 4. has brought an increase in bench-science space that will allow us to greatly expand our basic science work with cell culture, immunoassays, histology, and other laboratory techniques. Our new facilities also include greater space for clinical research, including new exam rooms and office space that will allow us to bring in new collaborators to expand our team and its expertise. In particular, we see ourselves increasing our work in proteomics and lipidomics and branching out in our clinical
work to include other ocular surface diseases like allergy, as well as contact lens wearers and women. Foremost among our goals is to deepen our understanding of dry eye disease. We have yet to fully define the mechanisms underlying the pathophysiology of dry eye disease or develop a sufficient appreciation of its multifactorial nature. Clearly, contact
The Contact Lens and Tear Film Laboratory.
lens wear, age, hormonal status, genes, gender, immune status, innervation, pathogens, and environmental stresses all can affect the cellular and molecular structure and function of the ocular surface. The coming years promise an exciting combination of advances in basic and clinical research that will, we hope, result in more effective diagnostics and treatment. With expanded
The biological science lab area.
facilities and the impressive collaborative resources of the university’s medical center, we look forward to being a key part of this endeavor at The Ohio State University College of Optometry. Kelly K. Nichols, OD, MPH, PhD, is an associate professor of optometry and vision science and Jason J. Nichols, OD, MPH, PhD, is an assistant professor of optometry and vision science at the Ohio State University College of Optometry, Columbus, OH.
THE OCULAR SURFACE / JULY 2007, VOL. 5, NO. 3 / www.theocularsurface.com
261