CLINICAL SCIENCE
Comparison of Human Tear Film Osmolarity Measured by
Electrical Impedance and Freezing Point
Depression Techniques
Alan Tomlinson, PhD, DSc, Louise C. McCann, MC Optom, and Edward I. Pearce, PhD
Purpose: Tear hyperosmolarity is diagnostic of dry eye disease
(DED), yet difficulty in measurement has limited its utility; develop-
ment of new instruments could facilitate its clinical application. This
study compares the new OcuSense TearLab osmometer (OcuSense,
Inc, San Diego, CA), based on electrical impedance lab-on-a-chip of the tear film and inflammation in the ocular surface
nanoliter technology, with the freezing point depression Clifton
Osmometer (Clifton Technical Physics, Hartford, NY).
Methods: Thirty-six subjects were recruited: 15 DED (9 women,
6 men age: 41 6 16 years) and 21 controls (12 women, 9 men age:
35 6 12 years); criteria for DED were noninvasive tear breakup time
,10 seconds, Schirmer I test ,5 mm, and positive symptoms.
Samples were collected from the inferior tear meniscus for testing
with both osmometers.
Results: Osmolarity values measured with OcuSense TearLab were
308 6 6 and 321 6 16 mOsm/L for controls and dry eye, respectively,
and those measured with Clifton were 310 6 7 and 323 6 14 mOsm/L
for controls and dry eye, respectively; these values were significantly
different. Significant correlation was found between OcuSense and
Clifton measurements (r = 0.904; P = 0.006). BlandAltman analysis
revealed agreement between techniques; the majority of points fell
within the 95% confidence limits, and actual values differed by less
than 1%. A cutoff value of .316 mOsm/L, derived from the
distribution of osmolarity values, was used to diagnose DED with an
effectiveness of 73% sensitivity, 90% specificity, and 85% positive
predictive value for the OcuSense and 73% sensitivity, 71% specificity,
and 65% positive predictive value for the Clifton in the study samples.
Conclusions: Tear film osmolarity measured with the OcuSense
TearLab system correlates well with the Clifton Osmometer. The
new instrument has the potential to provide clinicians with a readily
available clinically applicable measure, which could become the gold
standard in DED.
Key Words: tear film, dry eye, osmolarity
(Cornea 2010;29:10361041)
Received for publication July 31, 2009; revision received October 8, 2009;
accepted November 1, 2009.
From the Department of Vision Sciences, Glasgow Caledonian University,
United Kingdom.
Funding was received from OcuSense, Inc.
Reprints: Alan Tomlinson, Glasgow Caledonian University, 30 Cowcaddens
Road, Glasgow, G4 0BA, United Kingdom (e-mail: a.tomlinson@gcal.ac.uk).
Copyright 2010 by Lippincott Williams & Wilkins
1036 | www.corneajrnl.com
D ry eye disease (DED), as recently defined by the Dry Eye
Workshop,1 is a multifactorial disease of the tears and
ocular surface that results in symptoms of discomfort, visual
disturbance and tear film instability, with potential damage to
the ocular surface. It is accompanied by increased osmolarity
functional unit.1 Tear osmolarity is a function of the rate of
tear secretion and elimination from the eye.2 As tear secretion
decreases in dry eye, osmolarity increases because the volume
of isotonic tears is inadequate to overcome the loss of fluid,
mainly by evaporation.2
Attempts have been made to provide a reliable, highly
sensitive, specific, and clinically applicable test for the
measurement of DED. However, because of the multifactorial
etiology of this disease, diagnosis is difficult. Clinically, the
most common tests used in the assessment of DED are
Schirmer,36 tear breakup time,1,711 and fluorescein staining.12
Such measurements are quick and easy to perform, but their
invasiveness and lack of repeatability (in the case of Schirmer)
lead to the need for a more effective measure of dry eye.
To address this requirement, investigators have studied
numerous tear physiology measures in the detection of DED;
parameters such as evaporation,1316 tear production,1720 and
osmolarity2,21,22 have been employed. However, the need for
high levels of expertise, expense, and length of time required
render these tests impractical in a clinical setting.
Tear hyperosmolarity has been shown to be diagnostic of
DED1,2,11,2124 and the most effective single measure.22
Hyperosmolarity has been shown to be a primary cause of
ocular surface damage and inflammation. Early studies of
rabbits found osmolarity to be a function of evaporation and
tear production.2,25 However, the difficulty in measuring
osmolarity has led to its limited utility in a clinical context.
The osmolarity of a sample can be determined in
a number of ways, both in situ and by sampling, using methods
that measure the colligative properties of the tears. These
properties, such as freezing point depression and vapor
pressure, depend on the number of dissolved particles in
a solution but are not dependent on the identity of the particles.
The freezing point depression nanoliter osmometer is at
present the most commonly applied principle in osmolarity
measurement. In this method, the temperature of the freezing
point is directly proportional to the total number of dissolved
particles in the solution. Therefore, the osmolarity can be
calculated from the depression in the freezing point. The most
frequently applied freezing point depression techniques in tear
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Cornea  Volume 29, Number 9, September 2010
research use nanoliter samples, most commonly with a Clifton
nanoliter osmometer (Clifton Technical Physics of Hartford,
NY).26 Although used in the diagnosis of DED, this method
requires significant expertise, takes considerable time, and
is open to potential errors because of evaporation of test
samples.27 Other techniques using the freezing point depres-
sion technique such as the Advanced Tear Osmometer
(Advanced Instruments, Inc, Norwood, MA) and the Otago
Osmometer (Otago Osmometers, Ltd, Dunedin, New Zealand)
are also available.
Vapor pressure techniques have also been employed in
the measurement of osmolarity.28 These work on the principle
that the vapor pressure of a solution is lower than that of
the pure solvent at the same temperature and pressure; the
decrease in vapor pressure, like depression of freezing point,
is proportional to the number of dissolved particles in the
solution. Thus, the osmolarity of a solute can be calculated
from its vapor pressure. Original vapor pressure osmometers
engaged a precision thermocouple hygrometer to measure dew
point depression and required large sample volumes.28 This
necessitated the collection of reflex tears, which in turn could
lower the osmolarity values obtained.29 More recently, vapor
pressure osmometers, such as the Wescor (Wescor, Inc, Logan,
UT) have been used. However, although easier to operate and
more streamlined than freezing point depression osmometers,
they are still not suitable for the quick easy application
required in clinical practice.
There is a need for a new instrument to facilitate clinical
application and the adoption of osmolarity as a primary
diagnostic test in DED. Recently the OcuSense TearLab
system (OcuSense, Inc, San Diego, CA) has been developed.
This new osmometer is based on electrical impedance and
lab-on-a-chip technology, which allows the calculation of
osmolarity. This technique allows osmolarity testing with
a very small volume (less than 20 nL), is a quick and accurate
measurement of osmolarity of the tear film in a clinical setting,
and reduces the evaporation of the fluid. However, although
the device measures charged particles, corrections or
assumptions are made with regards the contribution made
by noncharged particles in the tear sample. The OcuSense
TearLab system is in the final stages of approval as a medical
device by Food and Drug Administration.
This study sets out to compare the new OcuSense
TearLab osmometer (OTO) with the Clifton Osmometer to
determine the comparability of results between the instruments
and the diagnostic efficacy of each test for dry eye.
MATERIALS AND METHODS
Study Design
This study adopted a single visit for comparative
measurements with the 2 instruments. It was conducted
according to the principles contained in the Declaration of
Helsinki. Ethical approval was obtained from the Glasgow
Caledonian University Ethics Committee. Written informed
consent was obtained from all subjects after explanation of the
procedures and study requirements.
q 2010 Lippincott Williams & Wilkins
Comparison of Human Tear Film Osmolarity
Subject Recruitment
Thirty-six volunteers were recruited for this study,
15 with mild to moderate dry eye (9 women, 6 men; mean age:
41.7 6 16.9 years) and 21 controls (12 women, 9 men; mean
age: 35.0 6 12.8 years). Inclusion criteria for DED were
noninvasive tear breakup time (NITBUT) ,10 seconds using
the HirCal grid10 and 2 or more positive symptoms using
McMonnies30 questionnaire. Schirmer I test was carried out on
all participants to determine contribution of aqueous tear
deficiency to the dry eye condition (10 of the dry eye patients
were aqueous deficient with a Schirmer I score of #8 mm in 5
minutes). The controls were asymptomatic and had a Schirmer
score of $15 mm in 5 minutes and a tear breakup time of .10
seconds. Tear samples were collected from the inferior-
temporal conjunctival sac of the right eye of each subject for
both the TearLab (OcuSense, Inc, San Diego, CA) and Clifton
(Clifton Technical Physics, Hartford, NY) osmometers. The
order of test measurements was as follows:
 Symptom questionnaire
 Osmolarity (samples by each instrument was randomized
to avoid bias)
 NITBUT
 Schirmer test
All measurements were on the right eyes only.
Symptoms
Although many diagnostic tests are unreliable, the
response of patients to questioning about dry eye symptoms
has been found to be repeatable.7,3133 The most common
questionnaire used clinically is the McMonnies30 dry eye ques-
tionnaire. If 2 or more subjective responses are positively
reported, this is indicative of dry eye.30
Schirmer I Test
The Schirmer I test is the most widely used test for
investigating tear production in patients with dry eye. A
Schirmer Test Strip (SNO Strip; Clement Clarke International,
Ltd, Harlow, Essex, United Kingdom) was placed in the lower
outer fornix of the unanesthetized eye, and the patient was
advised to close his/her eyes. After 5 minutes, the strip was
removed from the eye and the length of wetting from the notch
was measured (in millimeters).34 A cutoff of 15 mm in 5
minutes for the normal eye was initially suggested by
Schirmer, with further work indicating values less than 5
mm in 5 minutes are pathological. We used a cutoff of #8 mm
to differentiate dry eye from normal.
NITBUT
The HirCal grid consists of a white on black grid pattern
fitted to a Bausch and Lomb keratometer.10 The subject, seated
at the instrument, was instructed to blink normally and then
refrain from blinking. The grid image is reflected from the
surface of the tears, and the first point of disruption of the grid
lines after the complete blink was noted; 3 measurements were
taken, and the average calculated.10
Clifton Osmometer
Osmolarity was measured with the freezing point depres-
sion technique using a Clifton nanoliter osmometer (Clifton
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Tomlinson et al Cornea  Volume 29, Number 9, September 2010

Technical Physics, Hartford, NY). A micro capillary glass tube RESULTS

(Bilbate, Ltd, Northants, United Kingdom) was drawn over
a flame to produce a fine tip. By capillary action, a sample of Statistical Analyses
tears was taken from the marginal tear strip while the patient All of the data were tested for normality using a
was gazing supranasally. This was to avoid reflex tearing.35 The ShapiroWilk test, and found to be normally distributed (SPSS
sample was then injected into a vessel containing heavy oil to Version 11 (SPSS, Inc); a 2-sampled t test was then applied to
avoid evaporation. Samples of nanopure water and 290 standard the data.
solution (Clinitrol 290, Advanced Instruments, Inc) were also
injected (used for calibration during each analysis to control the Osmolarity
variation in environmental conditions). A small sample of each Significant differences were found in this study between
fluid was in turn drawn from the vessels into a capillary tube the mean test values of osmolarity for controls [308 6
attached to a syringe by plastic tubing, supported by a clamp. 6.2 mOsm/L (TearLab); 310 6 7.2 mOsm/L (Clifton)] (P ,
Up to 8 samples were loaded and measured per run. Samples 0.001) and subjects with dry eye [321 6 16.5 mOsm/L
were then loaded into the sample plate and frozen and then (TearLab); 323 6 14.7 mOsm/L (Clifton)] (P , 0.001)
thawed, with the process being viewed through a stereomicro- (Fig. 1). Subjects with dry eye had higher values indicating
scope. The point at which the last crystal of each sample melted increased tear osmolarity. The osmolarity with the Clifton
was noted as the freezing point of the sample. This was repeated instrument was generally higher than with the TearLab system,
3 times and an average taken. The osmolarities of the tear although this difference is not significant, either statistically
samples were then calculated. or clinically (r = 0.904; P = 0.006) with the actual values
differing by less than 1% (approximately 2 mOsm/L).
OcuSense TearLab Nanoliter Osmometer A significant correlation between osmolarity measure-
The use of electrical impedance to measure the electrical ments with the TearLab and Clifton systems was found (r =
conductivity of a fluid has been well documented.3640 Fluids 0.904; P = 0.006). A scatter graph was plotted, and a Pearson
can be characterized by their ionic content.41 Any change in correlation was determined. This is shown in Figure 2.
composition and concentration of the ions within a fluid can BlandAltman analysis assessed the level of agreement
change the electrical conductivity, an indirect function of between the results with the OTO and Clifton osmometers
osmolarity.39,42 Previously Fouke et al40 had used thin film (Fig. 3). This analysis showed a high level of agreement with
microelectronic technology to produce a flexible sensor, which only a minimal number of points falling out with the 95%
was placed directly on to the ocular surface to calculate the confidence limits.
electrical conductivity of the fluids present. A similar technique Cutoff values (316 mOsm/L for TearLab; 317.2 mOsm/L
was adopted by Ogasawara et al42 who placed a sensor directly for Clifton) for diagnosis were derived from the intercept of
onto the temporal conjunctival cu-de-sac. Tear fluid conduc- the distribution curves of osmolarity values for dry eyes and
tivity was monitored on a display, and the sodium chloride controls. The effectiveness of the individual measurement
concentration of the tears calculated from a calibration curve techniques in the differential diagnosis of the dry eye from
and converted to the equivalent electrolyte concentration.42 One the normal was evaluated. These cutoff values yielded
obvious benefit of this technique is the in situ measurement of
osmolarity, which reduces the chance of evaporation of the tear
fluid on removal from the eye. However, as the sensor is placed
on the ocular surface, reflex tear lacrimation may ensue thus
altering the osmolarity of the tear sample.
Recent work has been done on a novel osmolarity mea-
suring system, the OTO.26 This osmometer employs a proprie-
tary impedance spectroscopy technique, a similar technique as
used in blood glucose monitors where it is used to characterize
tissues based on the knowledge of their electrical properties
in the frequency spectrum. Studies have shown that such
measures of dielectric properties can indicate the pathological
status of tissues.43
The OTO employs a single-use disposable test card
mounted to a collection pen, to obtain a small sample of
tear fluid by passive capillary action from the inferior-temporal
tear meniscus. The pen monitors the collection process and
provides an audible and visual signal when the sample of
tear has been collected. The measurement of the electrical
impedance is carried out within the pen. The pen is then
docked into the reader, which calculates and displays the
osmolarity result. This technology has recently received 510k
approval by the Food and Drug Administration for marketing
in the United States as an aid in the diagnosis of DED. FIGURE 1. Mean osmolarity values for Clifton and OTOs.

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Cornea  Volume 29, Number 9, September 2010
FIGURE 2. Scatter plot showing a significant correlation
between osmolarity measurements with the OcuSense TearLab
and Clifton systems (r = 0.904; P = 0.006). Black line shows 45-
degree line. The dashed line shows the regression line.
a sensitivity of 73%, a specificity of 90%, and a positive
predictive value of 85% for the TearLab system and for the
Clifton values of 73% sensitivity, 71% specificity, and 65%
positive predictive value, respectively.
DISCUSSION
Osmolarity is measured with an instrument that employs
colligative properties such as freezing point depression and is
a powerful tool in the differential diagnosis of dry eye.22
Previous work with the Clifton nanoliter osmometer (Clifton
Technical Physics of Hartford, NY) shows that it can be used
to differentiate dry eye from the normal with 90% accuracy.22
It requires only microliter samples of tear fluid and thus is
FIGURE 3. BlandAltman analysis showing mean value plotted
against the difference between osmolarity values for Clifton
and TearLab osmometers. Dashed lines show 95% confidence
limits.
q 2010 Lippincott Williams & Wilkins
Comparison of Human Tear Film Osmolarity
unlikely to require any stimulation of reflex tearing and is
therefore suitable for basal measurements of tear film. How-
ever, its expense, need for significant expertise, and consider-
able time required to perform this technique have hindered its
adoption as a suitable clinical technique.
Electrical conductivity of tear samples has been shown
to be beneficial in determining tear osmolarity; previous
techniques measured osmolarity directly on the eye surface.
This decreased the potential for evaporative loss from the tear
samples, allowed measures of tear film osmolarity in real
time, and was relatively unobtrusive.42 However, electrical
conductivity is not a colligative property and measures only
charged particles and is dependent on the number of such
particles. This is unlike the freezing point depression and
vapor pressure techniques. Also with previous electrical con-
ductivity techniques, measurement directly on the eye may
precipitate reflex tearing and thus alter the osmolarity of the
sample. In addition, the required sample size, although small,
was actually dependent on the area of the electrode sensor.42
Some of these problems with electrical conductivity as
a measurement of osmolarity have been addressed by recent
developments in this area. These include the design of the
TearLab system using electrical impedance and lab-on-
a-chip technology.26,44 This technique measures osmolarity
immediately after sample acquisition and in real time,
unlike freezing point and other techniques such as vapor
pressure. This is obviously beneficial because it reduces
the evaporation of the tear samplean inherent problem with
the other lab-based techniques. Furthermore, this technique
requires a very small tear sample (;0.2 mL), unlike the
previous electrical conductivity technique, and eliminates the
problem of reflex tearing because the micro scale electrode
does not come into contact with the ocular surface.26,44
The osmotic pressure of a solution is a colligative
property depending solely on the number of dissolved particles
in a solution and not on their size or weight. The electrical
conductivity is dependent on the number of particles and their
charge; it could be argued that the conductivity technique for
measuring osmolarity is limited by its inability to recognize all
particles. The freezing point depression method is the only one
that measures concentration based solely on the number
of dissolved particles in a solution, and it can be considered as
the superior technique. Although both techniques seem to be
measuring different properties of the tear sample, they have
been found to be highly correlated in this study, indicating
that electrical conductivity of the TearLab system may be
considered as a valid alternative to freezing point depression
with the Clifton.
The association between Clifton and TearLab is illu-
strated in a scatter plot fitted with a regression line (Fig. 2).
It can be seen that there is a linear relationship between the
data obtained with these 2 tests, with the Clifton generally
reading slightly higher than the TearLab system. However, the
difference was small (less than 2 mOsm/L or 1%) and not
significant (P . 0.001).
In the literature, the cutoff for osmolarity in dry eye has
been set between 293 and 320 mOsm/L.21,22,35,45,46 Our
findings of a cutoff of 316 mOsm/L for TearLab, 317.2
mOsm/L for Clifton from the intercept of the distribution
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Tomlinson et al
curves for dry eye and normals agree with recent studies22
where values of 316 mOsm/L gave a sensitivity of 59% and
a specificity of 94%.47
In the present study, 2 groups of patients, those with
and without DED, were evaluated for tear osmolarity with
2 osmometers. The results for osmolarity in DED and normals
are similar to those reported recently in a meta-analysis22
(averages of 302 6 9.7 mOsm/L for normal and 326 6 22.1
mOsm/L for dry eye). The means in the present study for
normals were higher at 308 6 6.2 mOsm/L with the TearLab
and 310 6 7.2 mOsm/L with the Clifton and slightly lower for
subjects with dry eye with means of 321 6 16.5 mOsm/L with
the TearLab and 323 6 14.7 mOsm/L with the Clifton. The
difference in values is most likely because of smaller and
different sample sizes in the present study.
On the basis of the present study, the osmolarity values
found with the TearLab system seem to correlate well with the
Clifton (P = 0.006) (Fig. 3). This suggests TearLab is a suitable
alternative technique for the diagnosis of DED, giving
a sensitivity of 73%, a specificity of 90%, and a positive
predictive value of 85%. This does not reach the level of
effectiveness in diagnosis of some other reports26 in which
TearLab had a sensitivity of 94% and a specificity of 84%. This
is probably because of differences in the participants in the
studies with a different (and greater) spectrum of severity in
the previous study.26 In that study, the mean value of
osmolarity for normals was lower (306 mOsm/L compared
with 308 mOsm/L in the present study) and the subjects with
dry eye had a higher mean compared with the present study
(334 mOsm/L compared with 321 mOsm/L). However, it
could be argued that the present study is still a rigorous
assessment of the diagnostic techniques because of the
composition of the participants. The patients with dry eye
in the present study were generally in the mild to moderate
region of the diagnostic spectrum. If a technique is sensitive to
such patients, its effectiveness is validated because it is this
group who are often difficult to diagnose.
CONCLUSIONS
The present study demonstrates that tear film osmolarity
measured with the OcuSense TearLab system correlates well
with the Clifton osmometer. The new instrument has the
potential to provide clinicians with a readily available
clinically applicable measure, which could become the gold
standard in DED. It is also effective as a single test for the
discrimination of those with dry eye from those without the
condition.
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