ARTICLE

Functional Morphology of the

Lipid Layer of the Tear Film
Reiko Arita, MD, PhD,*† Shima Fukuoka, MD,†‡ and Naoyuki Morishige, MD, PhD†§

characterized by terminal duct obstruction or qualitative/

Abstract: Meibomian glands secrete the oily layer of the tear film,
which prevents excessive evaporation of tear fluid. Dysfunction of
meibomian glands is not only one of the causes of evaporative dry
eye but also one of the main causes of entire dry eye. To understand
the pathophysiology of meibomian gland dysfunction, it is important
to evaluate both the morphology and function of the meibomian gland.
We previously reported that meibography enabled visualization of
the morphology of the meibomian gland. Meanwhile, tear interfer-
ometry was introduced as an evaluation method for the function of
the meibomian gland. We combined observations of the oily layer
and the aqueous layer of the tear film and found that a tear film
compensatory system may work toward maintenance of tear film
homeostasis. In this review, we describe both morphological
evaluation systems for the meibomian gland, including noninvasive
meibography, and functional evaluation systems, including tear
interferometry. We further describe the morphological changes of
the meibomian glands in various ocular surface diseases. Finally, we
demonstrate the concept of a tear film compensatory system and
propose a method for tear film component-oriented diagnosis.
Key Words: meibomian gland, meibomian gland dysfunction,
noninvasive meibography, tear interferometry, dry eye, tear film
(Cornea 2017;36:S1–S7)
quantitative changes in glandular secretion.6 The oily layer
of the tear film in patients with MGD is unstable, resulting in
ocular discomfort, ocular surface inflammatory reactions, and
ocular surface diseases. Therefore, adequate evaluation of the
morphology and function of meibomian glands is an impor-
tant factor in diagnosing MGD.
MORPHOLOGY OF THE MEIBOMIAN GLAND
VISUALIZED BY NONINVASIVE MEIBOGRAPHY
Meibography was introduced as a method for visuali-
zation of the meibomian gland. However, a previous obser-
vation system involving meibography had several
disadvantages, such as pain, heat sensation, and limited
visualization area, thus making it inadequate for regular
clinical examinations.7–11 We previously described a non-
invasive meibography system as a novel method for visual-
ization of the meibomian gland.12 This noninvasive
meibography system enabled us to observe the entire
meibomian gland, from the nasal part to the temporal part

T he meibomian gland was named after the German

physician Heinrich Meibom, who discovered the exis-
tence of secretory glands inside the tarsal plates in the 17th
century. Meibomian glands secrete oily components called
meibum that form the oily layer of the tear film.1 The oily
layer of the tear film prevents evaporation of the tear fluid,1 and
thus meibomian gland dysfunction (MGD) mainly causes
evaporative dry eye.2–4 The number of patients with evapo-
rative dry eye is currently larger than the number with
aqueous-deficient dry eye.5 The International Workshop on
Meibomian Gland Dysfunction defines MGD as a chronic
diffuse abnormality of the meibomian glands, commonly

Received for publication July 7, 2017; revision received July 19, 2017;
accepted July 20, 2017.
From the *Itoh Clinic, Saitama, Japan; †Lid and Meibomian Gland Working
Group, Tokyo, Japan; ‡Omiya Hamada Eye Clinic, Saitama, Japan; and
§Department of Cornea and Ocular Surface, Ohshima Eye Hospital,
Fukuoka, Japan.
R. Arita has received consulting fees from Kowa. The remaining authors have
no funding or conflicts of interest to disclose.
Reprints: Reiko Arita, MD, PhD, Itoh Clinic, 626-11 Minaminakano,
Minuma-ku, Saitama 337-0042, Japan (e-mail: ritoh@za2.so-net.ne.jp).
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 1. Representative images of meibomian glands in the
upper and lower eyelids of a normal subject obtained by
noninvasive meibography. Reprinted with permission from the
Association for Research in Vision and Ophthalmology from
Efron et al63. Copyright Association for Research in Vision and
Ophthalmology, Rockville, MD. All permission requests for this
image should be made to the copyright holder.

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Arita et al Cornea  Supplement to Volume 36, Number 11, November 2017

TABLE 1. Types of Noninvasive Meibography Systems

Slit-lamp attached
type Mobile type Topography attached type Fundus camera attached type
Light source Wavelength 890 nm Wavelength 940 nm Wavelength 840 nm Infrared illumination
Other functions All functions with a slit lamp Diffuser Topography Fundus camera
Blue filter Tear meniscus
Tear dynamics
Pupillometer
LIPCOF
NIKBUT
Bulbar redness
Fluorescence imaging
Product name SL-D701 BG-4M/ Meibom Pen Keratograph 5M Eye Top Topographer, Sirius Scheimpflug
DC4 BG-5 Camera, and Cobra Fundus Camera
Company (City, TOPCON, (Tokyo, Japan Focus Corporation OCULUS Optikgeräte GmbH CSO (Florence, Italy), bon Optic
Country) Japan) (Tokyo, Japan) (Wetzlar, Germany) Vertriebs GmbH (Lübeck, Germany)
LIPCOF, lid parallel conjunctival folds; NIKBUT, noninvasive keratograph breakup time.

of the upper and lower eyelids within 1 minute.12 A slit-lamp
microscope equipped with a charge-coupled device camera
and infrared-pass filter visualized the meibomian gland as
a bright area (Fig. 1).12 This observation system clearly
revealed dropout, shortening, dilation, or distortion of
meibomian glands related to ocular surface diseases.12–19
Currently, 4 types of noninvasive meibography systems
are commercially available (Table 1): slit-lamp–equipped
type (BG-4M/DC4 BG-5 attached to a slit-lamp microscope;
TOPCON, Tokyo, Japan),12 mobile type (Meibom Pen; Japan
Focus Corporation, Tokyo, Japan),20 topography-equipped
type (Keratograph 5M; OCULUS Optikgeräte GmbH, Wet-
zlar, Germany),21 and fundus camera-equipped type (Eye Top
Topographer, Sirius Scheimpflug Camera, and Cobra Fundus
Camera; CSO, Florence, Italy, and bon Optic Vertriebs
GmbH, Lübeck, Germany).
We previously developed the meiboscore, a semiquali-
tative index obtained by noninvasive meibography.12 The
meiboscore is defined as follows: partial or complete loss of
meibomian glands is scored for each eyelid from grade 0 (no
loss) to grade 3 (lost area constituting more than two-thirds of
the total gland area). The meiboscore of each eyelid is then
summed, giving a total meiboscore for the bilateral upper and
lower eyelids ranging from 0 to 612 (Fig. 2). We found that
a diagnostic cutoff value could be defined based on a com-
parative study of normal and MGD subjects, revealing the
sensitivity and specificity of the meiboscore for the diagnosis
of MGD.14 Other groups have reported several types of
evaluation scales for the morphology of the meibomian
gland.11,22 The subjective intrarater and interrater agreements
of the scales were also evaluated.22 These qualitative evalua-
tions of the meibomian gland were applied to diagnosis and
evaluation of treatment for MGD. However, objective
approaches to meibomian gland evaluation are much more
appropriate for slight changes in the morphology of meibo-
mian glands.23–26

FIGURE 2. Grading of partial or

complete loss of meibomian glands
from grade 0 to grade 3 as the mei-
boscore. Reprinted with permission
from Elsevier from Arita et al12.
Copyright Elsevier, Philadelphia, PA.
All permission requests for this image
should be made to the copyright
holder.

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Cornea  Supplement to Volume 36, Number 11, November 2017 Tear Film Lipid Layer Morphology

TABLE 2. Previous Reports Related to Morphological Changes Evaluated by Noninvasive Meibography

Number of Subjects Findings Reference
Aging 236 eyes of 236 healthy subjects (age: 4–98 yrs) Morphology of meibomian glands changed with Arita et al12
age (Fig. 2)
37 eyes of 37 healthy adult subjects (age: 19–75 yrs) Number of gland dropouts was correlated with Ban et al25
age
78 eyes of 79 healthy children including infants (age: Morphologies of meibomian glands were similar Shirakawa et al27
1–12 yrs) and 25 eyes of 25 healthy young adults in young adults
(age: 24–39 yrs)
370 eyes of 185 subjects (age: 25–66 yrs) Meibomian gland loss increased with age Yeotikar et al28
Contact lenses 121 eyes of 121 contact lens wearers vs. 137 eyes of Morphological changes in contact lens wearers Arita et al13
137 noncontact lens wearers were significantly worse than those in (Fig. 3)
noncontact lens wearers
70 eyes of contact lens wearers vs. 70 controls A best-fitting multivariate regression model Pucker et al29
revealed that the lost area of meibomian
glands was higher in contact lens wearers
(odds ratio, 2.45)
100 eyes of 100 contact lens wearers with different Changes in meibomian gland morphology and Alghamdi et al30
durations of contact lens wear divided into 5 function were associated with contact lens
groups vs. 20 eyes of 20 controls wear
60 eyes of 60 contact lens wearers vs. 21 eyes of 21 Long-term contact lens wear was associated with Tang et al31
controls meibomian gland loss
Allergy 55 eyes of 55 patients with allergic conjunctivitis vs. Meibomian gland duct distortion was Arita et al18
47 eyes of 47 controls significantly higher in patients with allergic (Fig. 4)
conjunctivitis
58 of the 58 subjects undergoing orthokeratology 57 of the 58 subjects developed papillary Na et al32
hypertrophy and meibomian gland duct
distortion
MGD 53 eyes of 53 patients with MGD vs. 60 eyes of 60 ROC curves were generated and AUC values Arita et al14
controls were calculated to differentiate eyes with (Fig. 5)
MGD from healthy eyes. Diagnosis with any 2
of ocular symptom score, lid margin
abnormality score, and the meiboscore had
sensitivity of 84.9% and specificity of 96.7%
26 eyes of 26 patients with MGD Meibomian gland loss and the meibum grade Eom et al33
showed a significant positive correlation
Chalazion Case report Area of the chalazion showed partial or complete Srinivasan et al34
loss of meibomian glands
Five individuals with chalazion and 3 patients with Area of the chalazion showed low reflectivity Nemoto et al35
sebaceous carcinoma with small lesions of higher reflectivity
corresponding to lipid granules
Glaucoma 31 eyes in 31 glaucoma patients vs. untreated Long-term application of glaucoma eye drops Arita et al16
contralateral eyes affected the morphology and function of
meibomian glands
55 eyes of 39 patients with glaucoma who underwent Blebs could give rise to meibomian gland loss, Sagara et al36
trabeculectomy particularly when the blebs were avascular
Phlyctenular keratitis 16 eyes of 13 patients with phlyctenular keratitis vs. The meiboscore was significantly higher in Suzuki et al37
17 eyes of 17 healthy controls patients with phlyctenular keratitis
Case report Morphology of meibomian glands was detected Koh et al38
in a patient with marginal staphylococcal
keratitis
Rosacea 36 eyes of 18 patients with ocular rosacea vs. 38 eyes The meiboscore was significantly higher in Palamar et al39
of 19 healthy individuals patients with ocular rosacea
82 eyes of 41 skin rosacea patients vs. 88 eyes of 44 Reduced meibomian gland loss and density were Machalinska
healthy controls significantly detected in patients with rosacea et al40
GVHD 172 eyes of 86 patients with ocular GVHD vs. 60 Meibomian gland loss was significantly Engel et al41
eyes of 30 healthy controls increased in patients with GVHD
Granular corneal dystrophy type 11 eyes of 11 patients with granular corneal The meiboscore was significantly higher in Sakimoto42
2 dystrophy type 2 vs. 11 eyes of 11 controls patients with granular corneal dystrophy type
2
Radiotherapy 13 eyes of 8 patients vs. 41 eyes of 21 healthy The meiboscore was significantly higher in Ito et al17,43
controls patients who had undergone radiotherapy
AUC, area under the curve; GVHD, graft-versus-host disease; ROC, receiver–operating characteristic.

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Arita et al
Noninvasive meibography allowed us to evaluate
various morphological changes in meibomian glands related
to ocular surface diseases (Table 2). In normal populations,
morphological changes of the meibomian glands increased
with age.12,25,27,28 Contact lens wear was associated with
decreased numbers of functional meibomian glands (Fig.
3).13,29–31 Allergic conjunctivitis induced duct distortion of
meibomian glands (Fig. 4).18,32 In patients with MGD (see
Fig. 5 for representative images), the meiboscore was useful
for diagnosing MGD.14 Moreover, the meiboscore was
correlated with the function of meibomian glands.33 Accord-
ing to some case reports, the area of a chalazion showed
meibomian gland loss.34,35 Patients who used antiglaucoma-
tous eye drops had a significantly higher meiboscore than
control patients.15,16,36 The meiboscore was significantly
higher in patients with phlyctenular keratitis,37,38 rosacea,39,40
graft-versus-host disease,41 and granular corneal dystrophy
type 2,42 and in patients who underwent radiotherapy.43
FIGURE 3. Representative images of meibomian glands in the
upper and lower eyelids of subjects who had been wearing
disposable contact lenses for 14 years. Duct distortion of the
meibomian glands is apparent in the upper eyelid and short-
ening is detected across the whole lower eyelid.
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Cornea  Supplement to Volume 36, Number 11, November 2017
FIGURE 4. Representative images of meibomian glands in the
upper eyelid obtained from a patient with allergic conjuncti-
vitis by noninvasive meibography. Duct distortion is prom-
inent in the upper eyelid.
FUNCTIONAL EVALUATION OF THE
MEIBOMIAN GLAND BY
TEAR INTERFEROMETRY
The oily layer, which is located at the superficial
surface of the tear film, prevents evaporation of the tear
fluid. The distributed oily layer provides an interferometric
fringe of the tear film.44 Tear interferometry can not only
visualize the interferometric pattern but also measure the
thickness of the oily layer of the tear film based on the
interferometric pattern. Currently, Tearscope, Tearscope
Plus (Keeler, Windsor, United Kingdom),45,46 DR-1/DR-
1a (Kowa, Aichi, Japan),47,48 and LipiView (TearScience,
Morrisville, NC)49 are commercially available. The reliabil-
ity of interferometric evaluation was investigated, revealing
that MGD was detectable with sensitivity of 65.8%,
specificity of 63.4%, and lipid layer thickness (LLT) of 75
nm as a cutoff value based on LipiView observation.49
However, these values for the diagnosis of dry eye were not
consistent.49 The number of meibum-secreting meibomian
glands was significantly related to the LLT, based on
observation of 110 patients with dry eye, indicating that
a thinner LLT may induce MGD.49 It was reported that the
LLT measured by LipiView was negatively correlated with
the remaining meibomian gland area evaluated by meibog-
raphy, with LLT being significantly larger in control patients
than in patients with MGD (P = 0.028) in a detailed
quantitative analysis.33 An algorithm to determine LLT
based on interferometric fringes obtained by the DR-1
system was also developed.50 These series obtained with
the DR-1 system revealed that the lipid layer condition of
the tear film was related to the entire tear film condition and
the pattern of blinking.50 Tear interferometry is currently
established as a daily clinical examination to visualize the
lipid layer condition of the tear film.
Based on 138 tear interferometric patterns in normal
subjects, we found that the interferometric patterns could be
classified as follows: pearl-like appearance (monotonous gray
interferometric fringe), Jupiter-like appearance (multicolored
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Cornea  Supplement to Volume 36, Number 11, November 2017 Tear Film Lipid Layer Morphology

FIGURE 5. Representative images

obtained from a patient with MGD.
A, Slit-lamp microscopy revealed
plugging of meibomian glands, vas-
cularity of the lid margin, and col-
larettes around cilia. B, Fluorescein
staining detected superficial punc-
tate keratopathy in the lower part of
the cornea. The tear meniscus was
high. C, D, Noninvasive meibography
showed morphological changes of
meibomian glands including drop-
out, shortening, and distortion in the
upper eyelid (C) and total dropouts in
the lower eyelid (D).

interferometric fringe), and crystal-like appearance (grayish
amorphous interferometric fringe) (Fig. 6).51 We further found
that the combination of the interferometric fringe pattern and
noninvasive breakup time could indicate the dry eye subtypes.51
COMPENSATION THEORY FOR TEAR
FILM HOMEOSTASIS
The tear film, lacrimal glands, corneoconjunctival
epithelium, and meibomian glands coordinately maintain
the homeostasis of the ocular surface. The maintained ocular
surface is critical for visual function. Neural connections,52
systemic hormones,53 antiinflammatory factors,54 immuno-
regulation,54,55 osmolarity,56 tear proteins,57 microbes,58 and
blinking58 all affect homeostasis of the ocular surface.
The balance of the tear film components is important
for stability of the tear film, and thus a tear film compensatory
mechanism regulates the changes in the components of the
tear film.2,47,51,59–62 We previously reported that tear fluid
volume in patients with MGD was positively correlated with
the meiboscore revealing damage to the meibomian glands,62
indicating that increased tear fluid may compensate for
decreased function of the lipid layer.62 Furthermore, we
demonstrated that the LLT was increased in subjects with
decreased lacrimation, indicating that the increased lipid layer
compensated for the decreased function of the aqueous
layer51 (Fig. 7). This compensatory system is changeable,

FIGURE 6. Representative interferometric fringe patterns obtained from a normal subject (A), a patient with aqueous-deficient dry
eye (B), and a patient with MGD (C). The patterns are classified as pearl-like appearance (monotonous gray interferometric fringe),
Jupiter-like appearance (multicolored interferometric fringe), and crystal-like appearance (grayish amorphous interferometric fringe),
respectively. Reprinted from Arita et al51 with permission from the Association for Research in Vision and Ophthalmology. Adap-
tations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both
from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

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Arita et al Cornea  Supplement to Volume 36, Number 11, November 2017
FIGURE 7. Relation between LLT of the tear film and
Schirmer test value. In patients with non-Sjögren syndrome
aqueous-deficient dry eye (non-SS-ADDE), tear secretion was
low, but LLT tended to be increased. In patients with MGD,
the lipid layer was thinned, but tear secretion tended to be
increased. These results indicate the operation of an inter-
active compensatory system to maintain homeostasis of the
tear film. Modified from Arita et al51 with permission from the
Association for Research in Vision and Ophthalmology.
Adaptations are themselves works protected by copyright. So
in order to publish this adaptation, authorization must be
obtained both from the owner of the copyright in the orig-
inal work and from the owner of copyright in the translation
or adaptation.
similar to the tear film conditions, and thus the aqueous layer
or lipid layer may be secreted as a reaction to changes in the
tear film conditions. Our observations did not evaluate the
mucin condition directly. It can be speculated that adaptation
of mucin production may require a longer frame.
Our quantitative evaluation of LLT and tear film
kinetics by LipiView demonstrated the importance of the
tear film compensatory system for maintenance of the tear
film balance, and its failure may result in the abnormalities of
the tear film observed in patients with dry eye.51 Our results
indicated that interferometric fringe patterns and tear film
stability related to the balance between the aqueous layer and
the lipid layer further indicated the subtypes of dry eye
diseases.51
The mechanism for the reaction of the tear film kinetics
to changes in the tear film has not been well investigated. The
LLT and aqueous volume were both low in patients with
combined aqueous-deficient dry eye and MGD. The com-
pensatory system was not functionally active in these patients.
Further investigations are required to reveal the detailed
mechanism of the tear film compensatory system.
CONCLUSIONS
Morphological evaluation by noninvasive meibography
provides much clinical information for the diagnosis of
evaporative dry eye. Furthermore, evaluation of the lipid
layer of the tear film by interferometry enables monitoring of
the function of meibomian glands. Thus, combined evaluation
of the morphology and the function of meibomian glands can
provide important insights into dry eye pathophysiology.
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